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big_patent_10_percent

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description stringlengths 1.17k 417k	abstract stringlengths 76 3.43k
in the figures , the same reference signs denote elements that are the same or functionally the same . fig1 a , b are schematic representations for the explanation of a first embodiment of the production process according to the disclosure for a microneedle arrangement , to be precise fig1 a is a plan view of an etching grid and fig1 b is a cross - sectional view of the etching grid and of the microneedle arrangement resulting from it along the line a - a ′ from fig1 a . in the case of the first embodiment , reference sign 10 ′ denotes an etching mask , which like the etching mask 10 according to fig8 a , b comprises a regular orthogonal grid of horizontal grid bars 100 ′ and vertical grid bars 110 ′. the grid crossing regions are denoted by reference sign 10 ′ a and the grid openings are denoted by reference sign 10 ′ b . by contrast with the etching mask 10 described above , the etching mask 10 ′ has at the grid crossing regions 10 ′ a square reinforcing regions 115 ′, which have a greater cross section than the grid bars 100 ′, 110 ′ and which extend beyond the grid bars 100 ′, 110 ′ into the grid openings 10 ′ b . if the anisotropic / isotropic etching process already described in connection with fig8 is applied to a silicon substrate 1 which is covered by the etching mask 10 ′ of oxide , the form of microneedles represented in fig1 b is obtained , comprising thicker , more stable microneedles 200 ′ than the microneedles 200 in fig8 b . in particular , the supporting region 1 a according to fig8 b has almost completely disappeared in the case of the microneedle arrangement 20 ′ according to fig1 b . fig2 a , b are schematic representations for the explanation of a second embodiment of the production process according to the disclosure for a microneedle arrangement , to be precise fig2 a is a plan view of an etching grid and fig2 b is a cross - sectional view of the etching grid and of the microneedle arrangement resulting from it along the line a - a ′ from fig2 a . in the case of the second embodiment according to fig2 , reference sign 10 ″ denotes an etching mask of oxide , which likewise has horizontal grid bars 100 ″ and vertical grid bars 110 ″, which are arranged in an orthogonal form . in the case of the etching mask 10 ″, the grid crossing regions are denoted by 10 ″ a and the grid openings are denoted by 10 ″ b . as a difference from the first embodiment described above , in the case of the second embodiment the square reinforcing regions 115 ″ a and 115 ″ b at the grid crossing regions 10 ″ a vary with regard to their surface area . for instance , in the case of the present example , the first reinforcing regions 115 ″ a have a larger surface area than the second reinforcing regions 115 ″ b . if the anisotropic / isotropic etching process described above is applied in the case of such an etching mask 10 ″, higher , thicker microneedles 200 ″ a and narrower , lower microneedles 200 ″ b are created , as represented in fig2 b . the higher , thicker microneedles 200 ″ a form under the larger reinforcing regions 115 ″ a , and the narrower , lower microneedles 200 ″ b form under the smaller reinforcing regions 115 ″ b . after the anisotropic etching process , the narrower and thicker microneedles still have in fact the same height , but during the isotropic etching process the narrower microneedles are etched more quickly and lose height in comparison with the thicker microneedles , so that the microneedle arrangement 20 ″ shown in fig2 b is obtained . a typical size for the thicker , higher microneedles 200 ″ a is a height h 1 = 180 μm , a typical order of size for the narrower , lower microneedles 200 ″ b is a height h 2 = 120 μm . tests have shown that extremely efficient piercing characteristics can be achieved if the difference in height between the microneedles 200 ″ a and 200 ″ b is in the range of 20 - 50 %. fig3 a , b are schematic representations for the explanation of a third embodiment of the production process according to the disclosure for a microneedle arrangement , to be precise fig3 a is a plan view of an etching grid and fig3 b is a cross - sectional view of the etching grid and of the microneedle arrangement resulting from it along the line a - a ′ from fig3 a . in the case of the third embodiment , the etching mask 10 ′″ likewise has horizontal grid bars 100 ′″ and vertical grid bars 110 ′, which are arranged in the orthogonal grid form already described . in the case of the etching mask 10 ′″, at the grid crossing regions 10 ′″ a first reinforcing regions 115 ′″ a with a larger area or second reinforcing regions 115 ′″ b with a smaller area are provided and at certain grid crossing regions 10 ′″ a no reinforcing regions at all are provided . the latter grid crossing regions lie in the inner region ib of the etching mask 10 ′″ or of the resulting microneedle arrangement 20 ′″ with the grid openings 10 ′ b . as represented in fig3 b , three different types of microneedle 200 ′″ a , 200 ′ b and 200 ′ c can be produced in the microneedle arrangement 20 ′″ by means of the etching mask 10 ′″ in the etching process already described above . the first microneedles 200 ′″ a are thicker needles with a greater height h 1 of typically 180 μm , the second microneedles 200 ′″ b are narrower , lower microneedles with a height h 2 of typically 120 μm , and the third microneedles 200 ′″ c are very narrow , very low microneedles with a height h 3 of typically 90 μm . as shown in fig3 a , b , the three microneedles 200 ′″ c are not arranged in the outer region ab of the microneedle arrangement 200 ′″, but in the inner region ib thereof . in other words , they are shielded from the outer region ab by the first microneedles 200 ′″ a , so that , for example in the case of porous microneedles of silicon , the risk of breakage due to canting can be reduced or avoided . fig4 a , b are schematic representations for the explanation of a fourth embodiment of the production process according to the disclosure for a microneedle arrangement , to be precise fig4 a is a plan view of an etching grid and fig4 b is a cross - sectional view of the etching grid and of the microneedle arrangement resulting from it along the line a - a ′ from fig4 a . in the case of the fourth embodiment , the etching mask 11 ′″ likewise has horizontal grid bars 100 ′″ and vertical grid bars 110 ′, which are arranged in the orthogonal grid form already described . in the case of the etching mask 11 ′″, at the grid crossing regions 10 ′ a first reinforcing regions 115 ′″ a with a larger area or second reinforcing regions 115 ′ b with a smaller area are provided and at certain grid crossing regions 10 ′″ a no reinforcing regions at all are provided . the latter grid crossing regions lie in the outer region ab ′ of the etching mask 11 ′ or of the resulting microneedle arrangement 21 ′″ with the grid openings 10 ′ b . as represented in fig4 b , three different types of microneedle 200 ′″ a , 200 ′ b and 200 ′ c can be produced in the microneedle arrangement 21 ′″ by means of the etching mask 11 ′″ in the etching process already described above . the first microneedles 200 ′″ a are thicker needles with a greater height h 1 of typically 180 μm , the second microneedles 200 ′″ b are narrower , lower microneedles with a height h 2 of typically 120 μm , and the third microneedles 200 ′″ c are very narrow , very low microneedles with a height h 3 of typically 90 μm . as shown in fig4 a , b , the height of the microneedles 200 ′ a , 200 ′″ b , 200 ′″ c increases in stages from the outer region ab ′ to the inner region ib ′. fig5 a , b are schematic representations for the explanation of a fifth embodiment of the production process according to the disclosure for a microneedle arrangement , to be precise fig5 a is a plan view of an etching grid and fig5 b is a cross - sectional view of the etching grid and of the microneedle arrangement resulting from it along the line a - a ′ from fig5 a . in the case of the fifth embodiment , the etching mask 12 ′ likewise has horizontal grid bars 100 ′″ and vertical grid bars 110 ′, which are arranged in the orthogonal grid form already described . in the case of the etching mask 12 ′″, at the grid crossing regions 10 ′ a first reinforcing regions 115 ′″ a with a larger area or second reinforcing regions 115 ′ b with a smaller area are provided and at certain grid crossing regions 10 ′″ a no reinforcing regions at all are provided . the latter grid crossing regions lie in the inner region ib ″ of the etching mask 12 ′ or of the resulting microneedle arrangement 22 ″ with the grid openings 10 ′ b . as represented in fig5 b , three different types of microneedle 200 ′″ a , 200 ′ b and 200 ′ c can be produced in the microneedle arrangement 20 ′″ by means of the etching mask 12 ′″ in the etching process already described above . the first microneedles 200 ′″ a are thicker needles with a greater height h 1 of typically 180 nm , the second microneedles 200 ′″ b are narrower , lower microneedles with a height h 2 of typically 120 nm , and the third microneedles 200 ′″ c are very narrow , very low microneedles with a height h 3 of typically 90 nm . as shown in fig5 a , b , the height of the microneedles 200 ′ a , 200 ′″ b , 200 ′″ c decreases in stages from the outer region ab ″ to the inner region ib ″. fig6 is a plan view of an etching grid for the explanation of a sixth embodiment of the production process according to the disclosure for a microneedle arrangement . in the case of the sixth embodiment , the etching mask 13 ′″ likewise has horizontal grid bars 100 ′″ and vertical grid bars 110 ′, which are arranged in the orthogonal grid form already described . in the case of the etching mask 13 ′″, at the grid crossing regions 10 ′ a first reinforcing regions 115 ′″ a are provided and at certain grid crossing regions 10 ′ a no reinforcing regions at all are provided . the first reinforcing regions 115 ′″ a are arranged in such a way that the etching mask assumes an “ x ” pattern . this “ x ” pattern is transferred during the etching to the corresponding microneedle arrangement , which then can be used for example in conjunction with a tattooing fluid for the tattooing of a human or animal body . fig7 is a plan view of an etching grid for the explanation of a seventh embodiment of the production process according to the disclosure for a microneedle arrangement . in the case of the seventh embodiment , the etching mask 14 ′″ likewise has horizontal grid bars 100 ′ and vertical grid bars 110 ′″, which are arranged in the orthogonal grid form already described . in the case of the etching mask 13 ′″, at the grid crossing regions 10 ′ a first reinforcing regions 115 ′″ a are provided and at certain grid crossing regions 10 ′ a no reinforcing regions at all are provided . the first reinforcing regions 115 ′″ a are arranged in such a way that the etching mask assumes a “ ” pattern . this “ ” pattern is transferred during the etching to the corresponding microneedle arrangement , which then can likewise be used for example for tattooing . although the present disclosure has been described above on the basis of preferred exemplary embodiments , it is not restricted to these but can be modified in various ways . although in the case of the embodiments described above certain materials have been described , for example silicon as the substrate and oxide for the etching mask , the present disclosure is not restricted to these but can be applied to any materials that have corresponding etching characteristics or a corresponding etching selectivity . the grid form of the etching mask is also not restricted to the orthogonal , square form shown but can in principle be applied to any forms of grid . the reinforcing regions at the grid crossing regions do not have to be square but may assume any geometry , for example also a round geometry or a rhomboidal geometry , etc . furthermore , the present disclosure is not restricted to porous microneedles of silicon but can in principle be applied to any microneedles that can be produced in an etching process using an etching mask .	a production process for a microneedle arrangement and a corresponding microneedle arrangement as well as a use for it is disclosed . the process has the following steps : forming an etching mask in grid form , with grid bars with corresponding grid crossing regions and grid openings in between on a substrate ; carrying out an etching process to form the microneedle arrangement on the substrate using the etching mask and removing the etching mask . the etching mask in grid form has at least some of the grid crossing regions flat reinforcing regions , which extend beyond the grid bars .
as shown in fig1 - 8 , the present invention comprises a first arresting member 10 and a second arresting member 40 , which are disposed in the interior of a tubular body of a pull rod frame of the luggage . the first arresting member 10 comprises a housing seat 11 , a spring 12 , an action member 13 , a locating body 14 , and a locating cover 15 . the housing seat 11 is provided in an upper end 111 with an inner diametrical hole 112 , and in the interior with a receiving slot 113 in communication with the inner diametrical hole 112 . the housing seat 11 is further provided at a bottom end with an opening 114 . the housing seat 11 has an open longitudinal side and a closed longitudinal side 115 opposite to the open longitudinal side , as shown in fig2 . the closed longitudinal side 115 is provided with two retaining holes 116 and an insertion hole 117 located between the two retaining holes 116 . the spring 12 is disposed in the top portion of the receiving slot 113 of the housing seat 11 . the action member 13 is formed of a rod body 131 and a box body 135 greater in diameter than the rod body 131 . the rod body 131 is provided with an inverted hook 132 , a retaining slot 133 , and a through hole 134 . the box body 135 is dimensioned to fit into the receiving slot 113 of the housing seat 11 and is smaller in height than the receiving slot 113 . the box body 135 is provided with two inclined holes 136 opposite in location to each other , and two open sides 137 opposite in location to each other . the action member 13 is joined with the housing seat 11 such that the rod body 131 is fitted into the spring 12 located at the top of the receiving slot 113 , such that the inverted hook 132 and the retaining slot 133 of the rod body 131 are jut out of the upper end 111 of the housing seat 11 via the inner diametrical hole 112 of the upper end 111 of the housing seat 11 , and such that the upper edge of the box body 135 of the action member 13 comes in contact with the bottom end of the spring 12 . the locating body 14 is provided at one end with two protrusions 141 and is disposed in the box body 135 of the action member 13 such that the two protrusions 141 of the locating body 14 are inserted into the two inclined holes 136 of the box body 135 of the action member 13 . the locating cover 15 is of an l - shaped construction and is formed of an upright portion 151 and a horizontal portion 156 . the upright portion 151 is provided with one retaining piece 152 , an insertion piece 153 separated from the retaining piece 152 by a space 154 . the upright portion 151 is further provided with a through hole 155 in alignment with the space 154 . the locating cover 15 is joined with the housing seat 11 such that the retaining piece 152 of the upright portion 151 of the locating cover 15 is retained in one of the two retaining holes 116 of the housing seat 11 , and that the insertion piece 153 of the upright portion 151 of the locating cover 15 is inserted into the insertion hole 117 of the housing seat 11 , and further that the horizontal portion 156 of the locating cover 15 is retained in other one ( lower one ) of the two retaining holes 116 of the housing seat 11 , and further that the horizontal portion 156 of the locating cover 15 seals off the opening 114 of the bottom end of the housing seat 11 , and further that the locating body 14 is confined in the space 154 which is located between the retaining piece 152 and the insertion piece 153 of the upright portion 151 of the locating cover 15 . as the action member 13 is forced by the spring force of the spring 12 to move downward , the locating body 14 is guided by the inclined holes 136 of the box body 135 of the action member 13 to extend out of the locating cover 15 via the through hole 155 of the upright portion 151 of the locating cover 15 . the second arresting member 40 of the present invention comprises a housing 41 , a control member 45 , a first locating body 48 , a second locating body 49 , and a locating plate 52 . the housing 41 has an open top 411 , a chamber 412 in communication with the open top 411 , a closed bottom 414 , a closed side 413 , and an open side 415 opposite to the closed side 413 . the chamber 412 is provided with a horizontal block 417 , a partition 416 located under the horizontal block 417 , a lower cell 418 located between the partition 416 and the closed bottom 414 , and an upper cell 419 located between the partition 416 and the horizontal block 417 . the horizontal block 417 is provided with an upper through hole 420 and a lower through hole 421 , which are extended along the longitudinal direction of the horizontal block 417 . the horizontal block 417 is provided at one end of the bottom thereof with a horizontal insertion piece 422 extending toward the open side 415 of the housing 41 . the bottom edge of the open side 415 of the housing 41 is provided with an inverted hook 423 extending horizontally therefrom . the closed side 413 of the housing 41 is provided with a through hole 424 in communication with the upper cell 419 . the control member 45 has a hollow interior , two openings 451 and 452 opposite to each other , and two face plates 453 opposite to each other . the first face plate 453 is provided with a first guide slot 454 , whereas the second face plate 453 is provided with a second guide slot 455 . the diagonal side of the guide slots 454 and 455 form an upper guide edge 456 and a lower guide edge 457 parallel to the upper guide edge 456 . the control member 45 is provided in the underside of the bottom with a projection 458 extending therefrom . the projection 458 is provided with an upright spring 46 fitted thereover . the control member 45 is disposed in the chamber 412 of the housing 41 such that the upright spring 46 is located in the lower cell 418 of the chamber 412 of the housing 41 , and that the control member 45 is urged by the spring 46 , thereby causing the top of the control member 45 to extend out of the open top 411 of the housing 41 . as a result , the control member 45 is capable of moving up and down . the guide slots 454 and 455 of the control member 45 are located in the upper cell 419 of the housing 41 . the first locating body 48 and the second locating body 49 are respectively provided at one end thereof with a block body 481 , 491 . the second locating body 49 is disposed in the upper cell 419 of the housing 41 such that the block body 491 of the second locating body 49 is juts out of the housing 41 via the through hole 423 of the closed side 413 of the housing 41 . the block body 491 of the second locating body 49 is provided with one inclined plane 493 in contact with the upper guide edge 456 of the control member 45 . in the meantime , the block body 491 of the second locating body 49 urges one end of a horizontal spring 50 . the block body 481 of the first locating body 48 is disposed in the upper cell 419 of the housing 41 such that the block body 481 of the first locating body 48 comes in contact with other end of the horizontal spring 50 , and that an inclined plane 482 of the block body 481 of the first locating body 48 is in contact with the lower guide edge 457 of the control member 45 . the locating plate 52 is provided with an upper insertion hole 521 opposite to the horizontal insertion piece 422 of the housing 41 , a middle through hole 522 opposite to the first locating body 48 , and a lower retaining hole 523 opposite to the inverted hook 423 of the housing 41 . the locating plate 52 is provided in the top with an inverted hook 524 . the open side 415 of the housing 41 is sealed off by the locating plate 52 such that the inverted hook 524 of the locating plate 52 juts out of the housing 41 via the lower through hole 421 of the horizontal block 417 of the housing 41 , and that the horizontal insertion piece 422 of the housing 41 is inserted into the upper insertion hole 521 of the locating plate 52 , and further that the locating body end 483 of the first locating body 48 is inserted into the middle through hole 522 of the locating plate 52 , and still further that the inverted hook 423 of the housing 41 is inserted into the lower retaining hole 523 of the locating plate 52 . the locating body end 483 of the first locating body 48 is extended out via the middle through hole 522 of the locating plate 52 . as shown in fig2 , 4 , and 9 , the first arresting member 10 of the present invention is used in conjunction with a two - segmented pull rod frame 1 . the upper end 111 of the housing seat 11 is inserted into the bottom end of the upper tube 101 . a steel cable 103 is controlled by a handle switch and is provided at the bottom end with an enlarged body 104 , which is retained in the retaining slot 133 of the rod body 131 of the action member 13 . the first arresting member 10 is located at the bottom end of the upper tube 101 by a bolt 105 which is fastened through the horizontal hole 118 of the upper end 111 and the through hole 134 of the rod body 131 of the action member 13 . the first arresting member 10 is extended into the lower tube 106 . the lower tube 106 is provided with a plurality of locating holes 107 , 108 for controlling the handle switch so as to enable the steel cable 103 to be pulled upward , thereby actuating the action member 13 to move up to compress the spring 12 . in the meantime , the protrusions 141 of the locating body 14 are guided by the inclined holes 136 of the action member 13 to enable the locating body 14 to enter the housing seat 11 . as a result , the pull rod frame 1 can be adjusted up and down . as shown in fig3 , 6 , 7 , 8 , 10 , 11 , and 12 , the first arresting member 10 and the second arresting member 40 of the present invention are employed in conjunction with a three - segmented pull rod frame 2 . the top 411 of the second arresting member 40 is put through the bottom end of the middle tube 201 . the second arresting member 40 is located at the bottom end of the middle tube 201 by a bolt 202 which is fastened through the upper through hole 420 of the horizontal block 417 of the second arresting member 40 . the second arresting member 40 is extended into the lower tube 204 . in the meantime , the first arresting member 10 is located at the bottom end of the upper tube 205 and is extended into the top end of the middle tube 201 . the middle tube 201 and the lower tube 204 are provided with a plurality of locating holes 206 , 207 , 208 , 209 for controlling the handle switch to enable the steel cable 103 to be pulled upward , thereby causing the locating body 14 of the first arresting member 10 to move horizontally into the interior of the housing seat 11 . as a result , the pull rod frame 2 can be adjusted up and down . when the upper tube 205 is slid into the middle tube 201 , the bottom end of the first arresting member 10 comes in contact with the top end of the control member 45 of the second arresting member 40 , thereby enabling the second locating body 49 to move away from the locating hole 208 of the lower tube 204 . as a result , the middle tube 201 and the upper tube 205 are slid into the lower tube 204 . the first locating body 48 is engaged with the locating hole 209 of the lower end of the lower tube 204 . as shown in fig1 , the first arresting member 10 and the second arresting member 40 of the present invention are used in conjunction with a four - segmented pull rod frame 3 such that the first arresting member 10 is joined with the lower end of the uppermost 301 , and that the second arresting member 40 is joined with the two middle tubes 302 and 303 . the present invention is versatile in design in that the first arresting member 10 and the second arresting member 40 of the present invention are adapted to a two - segmented , three - segmented , or four - segmented pull rod frame . in light of the locating body 14 , the first locating body 48 , and the second locating body 49 of the present invention being guided by the inclined holes 136 and the guide edges 456 and 457 , the present invention works with precision . in addition , the second arresting member 40 of the present invention is relatively simple in construction and is therefore cost - effective .	an expandable pull rod frame of the luggage includes a first arresting member and a second arresting member , which are adapted to a two - segmented , three - segmented , or four - segmented pull rod frame . the arresting members are provided with the locating bodies , the guide edges , and the inclined holes for guiding the locating bodies , thereby resulting in a precision adjustment in length of the expandable pull rod .
as a general comment on the nomenclature used in connection with the rate of release of active ingredient from the tablets of the present invention , there is lack of uniformity between medical applications on the one hand and agricultural and / or industrial applications on the other hand . accordingly , the rate of release has been arbitrarily classified for the purpose of the present disclosure and claims into the following rough categories : instant ( a few seconds to a few minutes ), immediate ( 30 minutes ), short ( 90 % released in 4 hours ), intermediate ( 85 - 90 % released in 1 - 2 days ), and extended sustained ( 90 % released in 4 days ). commercially available polyvinyl alcohols which have the physical and chemical characteristics required for this invention are the elvanol ® polyvinyl alcohol homopolymers , which are manufactured and sold by e . i . du pont de nemours and company . these crystalline polymers have viscosities of 10 - 70 mpa . sec ; number average molecular weight mn of 25 , 000 - 100 , 000 ; polydispersity of 1 . 4 to 2 . 6 ; surface area of 0 . 6 - 6 . 0 ; percent hydrolysis of 99 . 0 - 99 . 8 ; and a particle size distribution such that less than 5 % is retained on a 20 mesh ( 0 . 833 mm ) screen , less than 50 % is retained on an 80 mesh ( 0 . 175 mm ) screen , more than 70 % is retained on a 200 mesh ( 0 . 074 mm ) screen , and more than 90 % is retained on a 400 mesh ( 0 . 038 mm ) screen . in a photomicrograph , the polymers have the appearance of spheroidal clusters of spheroidal particles . the particles are capable of flowing spontaneously through an orifice of 10 mm diameter and are compressible as pure material to a tablet having a hardness greater than 30scu with a compression pressure of 12 . 3 × 10 6 kg / m 2 . a preferred elvanol ® pva is elvanol ® hv , which is referred to below as crystalline pva - homopolymer . this polymer has a viscosity of 55 - 65 mpa . sec . crystalline vinyl alcohol / methyl acrylate copolymers for use in this invention can be prepared in a continuous polymerizer at 70 - 103 kpa from vinyl acetate monomer ( va ) and methyl acrylate ( ma ) mixtures . the va / ma mixture is purged with nitrogen to remove any residual air , and is mixed with methanol , recycled solvents and vazo ® 64 2 , 2 &# 39 ;- azobis ( isobutyronitrile ), the initiator for the reaction . this mixture is continuously fed to a stirred polymerizer kettle maintained under reflux . a solution containing vinyl acetate / methyl acrylate copolymer , methanol , methyl acetate and va / ma is removed continuously and polymerization is inhibited by addition of hydrazine monoacetate . then , the solution is fed to the top of a stripper column . methanol vapors at atmospheric pressure enter the bottom of the column and strip the va / ma from the polymer . the va / ma and methanol vapors are removed from the top of the column and a solution containing vinyl acetate / methyl acrylate copolymer , methanol and methyl acetate is removed from the bottom . the copolymer / methanol / methyl acetate solution is pulse - fed to a stirred alcoholysis kettle maintained at a constant temperature of 60 - 65 ° c . as the vinyl acetate copolymer is converted to vinyl alcohol copolymer , methyl acetate is produced . the vinyl alcohol copolymer is insoluble in the methanol / methyl acetate and the polymer precipitates . the slurry overflows to a holding tank and is neutralized to ph 5 - 7 by addition of acetic acid . the neutralized slurry is then heated to a temperature of 110 °- 140 ° c . and held for 5 - 20 minutes at this temperature . this heat treatment improves the cold water slurrying characteristics of the copolymer , and causes crystallization in at least the surface portion of the pva particles . the slurry is centrifuged and the cake is dried in a steam tube rotary dryer . solvents and monomer are recovered and recycled . the solution / slurry alcoholysis step described above is key to obtaining granular pva having greater than 98 % hydrolysis and the other physical characteristics required for use in this invention . in other commercial pva manufacturing processes the polyvinyl acetate ( pvac ) solution is run out onto a belt and the belt is run through an alkaline methanol solution to convert the polymer to pva . this alcoholysis method results in relatively low percent hydrolysis and produces non - spheroidal pva particles with poor flow and compression characteristics . the use of pulse feed alcoholysis to produce granular pva is disclosed in tanner u . s . pat . no . 3 , 296 , 236 , issued jan . 3 , 1967 . heat treatment to improve water slurrying properties is disclosed in bristol u . s . pat . no . 3 , 654 , 247 , issued apr . 4 , 1972 , and bristol u . s . pat . no . 3 , 497 , 487 , issued feb . 24 , 1970 . stripping va monomer is disclosed in lankton et al . u . s . pat . no . 3 , 259 , 555 , issued july 5 , 1966 . use of hydrazine to inhibit vinyl polymerization is disclosed in bristol et al . u . s . pat . no . 3 , 583 , 963 , issued june 8 , 1971 . the complete disclosures of these patents are incorporated herein by reference . a pva copolymer containing 9 % methyl acrylate has been prepared by the above - described procedure . this product is referred to herein as crystalline pva / ma 9 % copolymer . crystalline vinyl alcohol / methyl methacrylate copolymers for use in this invention can be made by the same procedure , substituting methyl methacrylate for methyl acrylate . the methyl acrylate and methyl methacrylate are present in the vinyl alcohol copolymers as lactones . for the pva copolymers , the percentage refers to the grams of comonomer ( ma or mma ) per 100 grams of polymer , assuming the original molecular weight of the comonomer . substantially amorphous pva homopolymer and copolymers with methyl acrylate and methyl methacrylate can be prepared by the above - described procedure , except eliminating the heat treatment step . however , for making the amorphous polymers used in the examples a modified procedure was used . the modified polymerization procedure uses sodium nitrite instead of hydrazine monoacetate to stop the polymerization and uses citric acid to inhibit ester exchange reactions . stripping of the polymerizer kettle bottoms is accomplished in a vacuum oven overnight at 75 ° c . to remove the va monomer , methanol and methyl acetate . the polymerizer kettle is operated continuously at 83 kpa . as the pvac solution is removed from the kettle , polymerization is inhibited by addition of sodium nitrite , then the polymer solution is stripped as described above . the modified alcoholysis procedure is batch , rather than semi - continuous ( pulse - fed ) as in the previously - described procedure . the alcoholysis begins by dissolving the polymer obtained as just described in methanol . a solution containing 50 g of polymer , 300 ml of methanol , and 75 ml of methyl acetate is poured into a high - speed , explosion - proof blender . seventy - five ml of 10 % ( in methanol ) sodium methylate is slowly added to the mixture as it is blended . temperature is not controlled in the alcoholysis kettle ; the unit starts out at ambient temperature and temperature rises due to reaction and mixing . after a gel phase has formed and been broken , the mixture is blended for 10 more minutes . the mixture is then neutralized to ph 5 - 7 with acetic acid . the cake is then filtered , washed with methanol , filtered again , screened through a 20 mesh ( 0 . 833 mm ) screen , and dried in a vacuum oven at 70 ° c . the polymer is not heat - treated . pva homopolymer made by this modified procedure is referred to herein as amorphous pva homopolymer . a pva copolymer containing 6 % methyl acrylate made by this modified procedure is referred to herein as amorphous pva / ma 6 % copolymer . the methyl acrylate is present in the final product as a lactone . fig1 is a wide angle x - ray diffraction scan for crystalline pva / ma 9 % copolymer and amorphous pva / ma 6 % copolymer . a polymer is considered amorphous if an x - ray diffraction scan of the polymer is characterized by the lack of distinct peaks in the angular region of the scan dominated by chain - chain interactions . these crystalline peaks are the equatorial reflections ( miller indices hko for a polymer where the polymer - chain axis is coincident with the c - axis of the unit cell ). more specifically , the lack of distinct peaks in the region between 13 degrees and 35 degrees 2 - theta can be tested by the lack of any distinct minima in this region other than the low - and high - angle limits of the broad amorphous peak . a distinct minimum is characterized by having a slope of the first derivative of zero where the curvature or the second derivative is positive or concave upwards . a scan for this test can be obtained on any well - aligned reflection powder diffractometer employing a nickel filter or monochromating crystal and pulse - height analysis set to pass symmetrically 90 % of the characteristic copper radiation . referring to fig1 it will be observed that amorphous pva / ma 6 % copolymer produced no distinct peak in the angular region dominated by chain - chain interactions , i . e ., the region of 15 - 35 degrees 2 - theta , other than the region 19 degrees 2 - theta which corresponds to the amorphous peak . a shoulder in the 23 - degree 2 - theta region suggests some chain - chain interaction , but the polymer is considered to be substantially amorphous . crystalline pva / ma 9 % copolymer , on the other hand produced , a distinct peak at 23 degrees 2 - theta , indicating that it is at least partially crystalline . it is believed that the particles of crystalline pva / ma 9 % copolymer have a crystalline surface and amorphous core . x - ray diffraction scans for crystalline pva homopolymer and amorphous pva homopolymer are similar to those for the crystalline and amorphous copolymers , respectively . a crystalline granular polymer can be converted to a substantially amorphous granular polymer by dissolving in a methanol / acetone mixture and reprecipitating by addition of methanol without heat treatment . similarly , a substantially amorphous polymer can be converted to a crystalline polymer by slurrying in methanol and heat treating under conditions similar to the heat treatment described above . it is possible , though not preferred , to use conventional binders , such as those mentioned in the background of the invention section , in combination with the vinyl alcohol polymers described above . for example , the vinyl alcohol polymer could constitute 30 - 100 % of total binder and 0 - 70 % could be one or more of the conventional binders or a non - granular vinyl alcohol polymer . for preparation of tablets binder and active ingredient substance are mixed in conventional manner , using conventional equipment . the mixture can be wet granulated in the conventional way , but dry granulation is preferred and direct compression is most preferred . the active ingredient can be any active ingredient or mixture of active ingredients capable of being administered or employed in tablet form . we have formulated oxycodone , nalbuphine , phenylpropanolamine , and theophylline as pva tablets . examples of other active ingredients which can be used are those drugs and drug classes listed in schor et al . u . s . pat . no . 4 , 389 , 393 , issued june 21 , 1983 , the disclosure of which is incorporated herein by reference . the ratio of active ingredient to binder will generally be in the range of 3 : 1 to 1 : 10 , preferably 2 : 1 to 1 : 5 , most preferably 1 : 1 to 1 : 3 . in addition to binder and active ingredient , other commonly used tablet fillers and excipients can be used in conventional amounts . inclusion of magnesium stearate as a lubricant in an amount of up to about 1 % of the total ingredients is preferred . other excipients which can be used include other lubricants , flavoring agents , disintegrants , and coloring agents . any conventional tableting machine can be used , and tablets can be made in any conventional size and shape , e . g ., discoid , oblong , or triangular . compression pressures up to the maximum provided by the machine can be used , e . g ., 1 . 6 × 10 8 kg / m 2 or more , but a pressure in the range of about 2 - 5 × 10 6 kg / m 2 will usually be sufficient and preferred for economy . in examples 1 - 4 , below , the drug release characteristics were measured in vitro . dissolution was performed using a procedure described in the u . s . pharmacopeia xxi , page 1243 ( 1985 ). this procedure involves use of a 1 liter glass vessel immersed in water at 30 ° c . or 37 ° c . and an appropriate dissolution medium ( 0 . 1 n hcl , ph 7 . 4 phosphate buffer , buffered saline or water ). this vessel is stirred at a constant rate ( 25 , 50 or 100 rpm ) for the duration of the dissolution procedure to determine the amount of drug released . in examples 1 to 4 , 900 ml of distilled water was used set at 37 ° c . with a stirring speed of 50 rpm . the dissolution profile for examples 1 to 4 are shown in fig3 . in example 5 , drug release was measured in vitro by the same procedure , where the dissolution medium contained 1000 ml of 0 . 1 n hcl and was stirred at 50 rpm . the dissolution profile is shown in fig4 . 2 . compress on manesty f - 3 single punch tablet press at 2 . 7 × 10 6 kg / m 2 pressure with 3 / 8 inch ( 9 . 53 mm ) diameter standard concave tooling to form tablets with average hardness of 12scu . same formula and procedure as example 1 except substitution of non - heat treated amorphous pva homopolymer . average hardness of resulting tablets 12 scu . ( 85 % release in 24 hours ) ______________________________________ingredient mg / tablet______________________________________theophylline 200crystalline pva homopolymer 100amorphous pva / ma 6 % copolymer 100magnesium stearate 5 405______________________________________ 3 . compress on manesty f - 3 tablet press at 2 . 7 × 10 6 kg / m 2 pressure with 9 . 53 mm diameter standard concave tooling to make tablets with a hardness of 12scu . ( 90 % release in 96 hours ) ______________________________________ingredient mg / tablet______________________________________theophylline 200amorphous pva / ma 6 % copolymer 200magnesium stearate 5 405______________________________________ same method of compounding as example 3 . average hardness of resulting tablets 12 scu . ( in vitro -- 100 % release in 24 hours ) ______________________________________ingredient mg / tablet______________________________________amorphous pva / ma 6 % copolymer 237phenylpropanolamine ( ppa ) 60magnesium stearate 3 300______________________________________ 2 . tablet on manesty f - 3 single punch tableting machine with 3 / 8 inch ( 9 . 53 cm ) diameter standard concave tooling compression pressure of 4 . 8 × 10 6 kg / m 2 to form compacts at the target weight of 300 mg , tablet hardness = 12 scu . three dogs were administered , in a cross - over fashion , phenylpropanolamine . hcl i . v . ( 3 mg / kg ), orally ( 30 mg in a gelatin capsule ) and in the above pva / ma copolymer tablet composition containing 60 mg of phenylpropanolamine . hcl . plasma samples were collected as a function of time and frozen until analysis of drug concentration . analysis of phenylpropanolamine in plasma was performed by high pressure liquid chromatography ( hplc ). phenylethylamine , as internal standard , and 3 . 5 % aqueous sodium carbonate were added to 0 . 5 ml plasma samples . two extractions into ethyl acetate and back extraction into 0 . 2 ml of 5 % aqueous acetic acid were performed . the acetic acid solution was injected onto the hplc . the mobile phase consisted of a mixture of 11 % ( v / v ) acetonitrile and 0 . 2 % ( v / v ) 1n . hcl in 0 . 004m aqueous sodium heptane sulfonate . a 25 cm cn column and u . v . detection at = 210 nm were employed . phenylpropanolamine / phenylethylamine peak area ratios were used in construction of calibration curves . the area under each plasma phenylpropanolamine concentration vs . time curve ( auc ) ( fig2 ) was calculated using the trapezoidal method . bioavailability ( f ) was estimated by : ## equ1 ## f represents the percentage of the administered dose absorbed into plasma . sustained plasma concentrations of the drug were observed for 12 hours ( fig2 ), i . e ., a relatively constant plasma concentration is achieved . the oral bioavailability of phenylpropanolamine . hcl when administered in the amorphous pva / ma 6 % copolymer formulation was 78 + 4 % ( mean + sd in 3 dogs ) and that of phenylpropanolamine . hcl when administered in a gelatin capsule was 98 + 8 %. tablets containing 50 % of potassium monopersulfate ( commercial oxidizing agent available from the du pont company under the trademark oxone ®) and 50 % of an amorphous pva / ma 9 % copolymer were prepared according to the technique described in example 1 . the rate of release of the active ingredient is shown in fig5 which is a plot of percent release versus time in hours . it can be seen that 90 % of the active ingredient was released in 4 hours , where a plateau was reached . these can be characterized as short release tablets . when comparing these results with those of example 4 , wherein a fairly similar pva / ma copolymer was used in the same proportion as the tableting material , one notes a considerable difference in the respective rates of release . this may be due to the difference in the properties of the respective active ingredients . while both theophylline and potassium persulfate have similar water solubilities , the persulfate is an energetic oxidizing agent and tends to release gas on contact with water and with organic copolymer . a commercial herbicide material ( metasulfuron methyl , available from the du pont company ) was compounded according to the technique of example 1 as follows : when added to a low electrolyte strength nitrogen fertilizer ( 28 % n , 0 % k , 0 % p ), the active ingredient was completely released in 3 minutes ; when added to high electrolyte strength nitrogen fertilizer ( 32 % n , 0 % k , 0 % p ), it was completely released in 7 minutes . these were instant release tablets , suitable for use in fertilizer spray solutions . hexazinone herbicide was compounded according to the technique of example 1 as follows : the rate of release of the active ingredient in water was 30 seconds ; thus the release was instant . these tablets are suitable for use in aerial broadcasting , where it is not necessary to dust the plants but it is sufficient to deliver the systemic herbicide to the roots , as it dissolves in the moisture of the soil . in a test in which no poison was used , disintegration of tablets in water occurred in 30 min . the pellets were palatable to slugs . by contrast , standard prior art molluscicide tablets are formulated with sugar . under the same accelerated laboratory conditions , such sugar - formulated tablets disintegrate in 20 minutes . under field conditions , tablets of the present invention are only slowly rained away , while the prior art tablets are rained away considerably faster . it is estimated that the tablets of the present invention ( when formulated with active ingredient , such as , for example metaldehyde ) will have sufficiently long sustained activity to last for a full season , while the prior art tablets normally must be applied twice during the same period . all the above examples show the advantages of using the polymers of the present invention as tableting materials . however , the actual rates of release of the active ingredient present in such tablets will depend to some extent not only on the polymer itself but also on the nature of the active ingredient , including its water solubility and activity or chemical reactivity .	method of making tablets for active ingredient delivery by compressing a mixture of active ingredient and granular , high viscosity , fully hydrolyzed polyvinyl alcohol or copolymer of vinyl alcohol with methyl acrylate or methyl methacrylate . by use of a crystalline , heat treated polymer , a tablet providing quick active ingredient release is obtained . by using an amorphous , non - heat treated polymer a tablet providing prolonged active ingredient release is obtained . by using blends of crystalline and amorphous polymers , tablets having a range of active ingredient release characteristics can be obtained . the granular , high viscosity , fully hydrolyzed polymers provide flowability , compressibility and processing versatility advantages over conventional tablet binders .
in the following description , numerous details are set forth for purpose of explanation . however , one of ordinary skill in the art will realize that the invention may be practiced without the use of these specific details . in other instances , well - known structures and devices are shown in a simple diagram form in order not to obscure the description of the invention with unnecessary detail . fig1 illustrates one embodiment of the invention . this figure presents a trimmer 100 coupled to a carriage assembly 105 . the trimmer 100 may be an off the shelf conventional trimmer that includes a handle 110 coupled to a trimmer head assembly 115 . the trimmer head assembly 115 includes a motor placed inside a trimmer housing 120 , a flange formed on the lower portion of the trimmer housing 120 , and a trimmer rotary head located outside the trimmer housing 120 and coupled to the motor inside the trimmer housing 120 . the rotary head includes features for coupling a wire or a blade . the motor spins the trimmer rotary head and thereby the wire or blade that is coupled to the motor and rotated at a speed selected by the user for trimming . alternatively , other types of trimmers that use electric or gas motor are also contemplated . the carriage assembly 105 includes a carriage housing , several wheels 125 coupled to the carriage housing , and a coupler . the carriage housing 200 as shown in fig2 is a rigid shell made from a thin plastic or metal . the carriage housing 200 is circular in shape and includes several protruding shapes such as rectangles 210 . each protrusion 210 blends with the circular carriage 200 and is located on the outer portion of the shell . the protrusion includes features for coupling a wheel as will be described later in more detail . the coupler forms the coupling between the trimmer and the carriage assembly . once coupled , the carriage assembly and the trimmer form a lawnmower . the lawnmower can be maneuvered by a user pushing the trimmer handle and allowing the wheels of the carriage assembly to roll across a lawn . fig3 shows one embodiment of the carriage assembly and the trimmer . this figure presents an exploded view of a carriage 300 , several wheels 310 , and a trimmer 320 . in this embodiment , the rigid shell of the carriage housing 300 includes a small opening 330 on one side and a large opening on the opposite side . the smaller opening 330 allows the trimmer rotary head 340 to pass therethrough and be exposed from larger opening on the opposite side . this allows the wire or blade coupled to the trimmer rotary head 340 direct access to the grass through the larger opening in the carriage housing 310 . various types of couplers can be used for coupling the trimmer to the carriage assembly . these couplers allow easy coupling without a need for any tools . this type of coupling prevents the user from spending any extra time , cost , effort or energy that is typically involved with tool usage . these couplers also allow a user to easily detach the trimmer from the carriage without using any tools . thus a user desiring to trim edges , weeds , shrubs can simply detach the trimmer from the carriage housing by a simple detach operation using the coupler and use the trimmer for trimming . similarly , the trimmer can be attached to the carriage assembly for mowing the lawn by a simple operational step performed by the user on the coupler . fig4 – 6 show these coupling embodiments . fig4 depicts a coupler that uses a snap feature 400 to couple the trimmer 410 to the carriage 420 . this method of coupling requires a user to align the trimmer rotary head 430 with the small opening in the carriage 420 . once aligned , the trimmer rotary head 430 is inserted through the small opening allowing a portion of the trimmer flange 440 to push the snap feature aside to clear its way for a complete insertion of the rotary head 430 . as mentioned earlier , the flange 440 is formed within the trimmer &# 39 ; s housing . the flange includes a lower rim 450 and an upper rim 460 and may be one of two types . the first type includes a lower rim 450 that is wider in diameter than the upper rim 460 . in this case , after inserting the rotary head 430 through the small opening , the user aligns the wider lower rim 450 toggling the trimmer back and forth until the wider upper rim 460 is captured by the snap feature 400 in the carriage housing . the second type of flange 440 includes a lower rim that is narrower in diameter than the upper rim . in this case , once the user aligns and inserts the rotary head 430 into the small opening , the lower rims that is wider in diameter than the rotary head 430 pushes the snap feature 400 aside . once the lower rim of the flange 440 clears the snap feature 400 , the snap 400 retracts to its original position and captures the flange by landing in the area between the narrower lower rim and the wider upper rim thereby fastening the trimmer 410 to the carriage assembly 420 . furthermore , the wider upper rim which has a surface area that is wider than the small opening comes in contact with the surface of the carriage housing and prevents the rotary head from further insertion into the small opening . fig5 depicts a coupling embodiment similar to a screw - faster assembly . in this embodiment , the carriage 500 and the trimmer 520 both include mating threads 530 and 540 for fastening the trimmer 520 to the carriage 500 . in practice , a user can simply align the trimmer rotary head 550 with the smaller opening in the carriage 500 and insert the trimmer rotary head 550 into the small opening by turning the trimmer 520 in a clockwise direction for fastening . to unfasten or detach the trimmer 520 from the carriage 500 , the trimmer 520 is rotated in an anti - clockwise direction . alternatively , the mating may also be configured to rotate anti - clockwise for fastening and clockwise for unfastening . the trimmer 520 maybe rotated along the threads 540 in the carriage 500 until the trimmer flange 560 comes to rest on the surface 570 of the carriage shell thereby fastening to the carriage . at this point , the trimmer 520 is coupled to the carriage assembly and a wire or blade 580 attached to the trimmer rotary head 550 is used for cutting the lawn . fig6 depicts an axle assembly used for coupling the trimmer to the carriage assembly . in this embodiment , the carriage assembly 600 includes a carriage 605 , several wheels 610 coupled to the carriage 605 , a sleeve 615 , a standoff 620 , and a standoff capturing snap 625 . the axle assembly 630 includes an axle 635 , a blade 640 coupled to one end of the axle 635 , and an axle head 645 coupled to the other end of the axle 635 . the axle 635 is snuggly fitted within the sleeve 615 of the carriage assembly 600 allowing vertical and rotational motion of the axle assembly 630 . standoffs 620 with various heights are used to provide a sitting platform for the trimmer 650 . either a single standoff or multiple standoffs stacked one on top of each other can be used . each standoff 620 includes a capturing feature 655 on one side and a groove 660 on the other side . a standoff snap capturing snap 625 located on the carriage captures the capturing feature 655 on the standoff to securely couple the standoff 620 to the carriage . the grooves 660 on the other side serve as a sitting platform for the trimmer housing thereby locking independent horizontal movement of the trimmer 650 . once the trimmer 650 is locked , a horizontal force exerted by the user on the trimmer &# 39 ; s handle moves trimmer and carriage assembly together as one unit in the direction of the force allowing the user to maneuver the lawnmower across the lawn for cutting grass . the axle head 645 is coupled to the trimmer rotary head 657 and receives power through the motor coupled to the trimmer rotary head 657 for spinning . once the trimmer motor is powered “ on ”, the trimmer rotary head 657 coupled to the motor starts rotating . since the axle head 645 is coupled to the rotary head 657 , rotation of the rotary head 657 also causes the entire axle assemble 660 to rotate . this rotation allows the rotating blade 640 at the end of the axle 635 to rotate and cut the grass as the entire carriage assembly is being maneuvered across a lawn . the embodiments of fig5 and 6 also allow a user to adjust the distance between the blade and the grass . the blade is lowered to position a and made closer to the ground to allow for a deeper cut or raised a desired distance to position b from the ground allowing a surface cut . in the embodiment of fig5 , as discussed earlier , the trimmer rotary head is coupled to the carriage assembly by mating the threads on the trimmer with threads on the carriage and rotating the trimmer in a clockwise direction for fixating it to the carriage assembly . in this embodiment , the trimmer the flange acts as a stop feature preventing the trimmer from being inserted further into the carriage opening . a 100 % rotation of the trimmer allows the flange to come in contact with the surface of the carriage shell . since a blade may be coupled to the trimmer rotary head , with each rotation in the direction of fastening the trimmer to the carriage assembly , the trimmer rotary head and the blade coupled to the trimmer rotary head is also lowered thus allowing for a deeper cut . if the user desires to perform a surface cut or a cut of a determinant height then a standoff with a desired height may be placed between the flange and the surface of the carriage shell . the standoff allows the flange to come to a stop before touching the surface of the carriage shell and raises the height of the blade coupled to the trimmer rotary head for regulating the height of the cut grass . although the user may determine the height of the standoff , at least a 30 % rotational engagement between the trimmer threads and the carriage threads is preferred for locking the trimmer to the carriage . in the embodiment of fig6 , as discussed earlier , the trimmer rotary head sits on the grooves of the standoff and is coupled to the axle head of the axle assembly . in this embodiment , the height of the standoff can be varied to lower or raise the blade height from the grass . for example , a standoff that has a smaller height provides a sitting platform for the trimmer that is closer to the carriage and lowers the blade closer to the ground to allow for a deeper grass cut . alternatively , a taller standoff raises the sitting table for the trimmer thereby raising the axle assembly and the blade coupled to the trimmer to allow for a surface cut . fig7 a – 7f illustrate one embodiment of the invention . in progression , these figures present the coupling of a trimmer to a carriage assembly to form a lawnmower . fig7 a depicts an exploded view 700 of this lawnmower . the carriage assembly 703 includes a carriage 706 and several wheels 709 . the carriage 706 is a rigid shell that is circular in shape and includes several protruding shapes such as rectangles . each protrusion blends with the circular carriage and includes features for coupling a wheel 709 . the carriage 706 also includes a cut out 711 for receiving the trimmer 715 for coupling . the trimmer 715 includes a housing 720 coupled to a handle 723 . the handle 723 provides a gripping area for a user for maneuvering the trimmer . a motor is housed inside the housing 720 and is coupled to a rotary head 725 . the motor may be battery or electrically powered . a power cord 727 coupled to the trimmer 715 carries power to the motor for its operation . once powered , the motor rotates the rotary head 725 that is located outside the housing 720 at a user desired speed . the trimmer 715 also includes a flange 730 and a guard 733 . the guard 733 is detachably coupled to the housing 720 and provides a user safety against wire or blade contact while the trimmer is in operation . the guard 733 has features that allow it to be removed from the housing if desired by the user . the flange is formed within the trimmer &# 39 ; s housing and may be circular or of any other shape . as shown in fig7 b , a flange 730 having a circular configuration includes a lower rim 735 that is narrower in diameter than the upper rim 737 of the flange . the area between the lower and upper rim provides a landing area . this landing area is used for coupling the trimmer to the carriage . the upper rim 737 has a surface area that is wider than the small opening comes in contact with the surface of the carriage housing 706 and prevents the rotary head 725 from further insertion into the small opening . the coupling between the trimmer 715 and the carriage assembly 703 is further illustrated in fig7 c and 7d . the cut out portion 711 of the carriage 706 allows the insertion of the trimmer 715 and the trimmer guard 733 in a horizontal direction for coupling . first , the trimmer guard 733 is rotated counter clockwise as shown in fig7 c . the rotation allows the trimmer 715 to be inserted in the cut out portion 711 removing the trimmer guard 733 out of the path of insertion as shown in fig7 d . once the trimmer has been fully inserted , a trimmer housing snap 740 that is coupled to the trimmer housing 720 and trimmer guard snaps 745 coupled to the guard 733 capture the holes 750 in the carriage by retracting during the insertion and snapping into the carriage holes 750 once aligned with the carriage holes 750 at the position of full insertion as shown in fig7 e . as shown in fig7 f , the snaps couple the trimmer 715 and the carriage assembly 706 such that they can be operated as one unit . referring back to fig7 b , the figure illustrates a detail cross section view of the coupling between the trimmer 715 and the carriage assembly 703 . as shown here , the lower rim 735 of the flange 730 is inserted through the small opening in the carriage housing 706 . the insertion places the thin shell of the carriage housing between the lower rim 735 and the upper rim 737 . in addition the insertion allows the housing snap 740 coupled to the trimmer housing to fully inserted into the carriage holes 750 and lock the carriage to the trimmer . in this fully coupled position , the upper rim 737 prevents the trimmer 715 from any downward movement , the housing snap 740 prevents and horizontal movement between the trimmer 715 and the carriage assembly 703 , and the carriage housing 706 trapped between the lower and upper rim obstructs the lower rim 735 from any upward movement thereby completely locking the trimmer 715 to the carriage assembly 703 in all directions . the coupled trimmer along with its guard encapsulates the wire or the blade inside the trimmer such that any debris or cut grass does not fly around . a user may also couple a cut grass collection bag and couple it to the trimmer for grass being collected as it is being cut . fig8 illustrates one embodiment of the invention . this figure presents a carriage 800 having several protruding rectangles 810 . each protruding rectangle 810 includes a groove 820 . the groove 820 provides a guided path for a wheel 830 and includes several twists and turns . each wheel 830 includes a wheel shaft 840 that passes thought the center of the wheel 830 . the wheel shaft 840 is captured within the groove 820 such that each wheel 830 can be maneuvered independently within the guided path of the groove from one position to another . the groove 820 also includes a spring detent 850 for locking wheel position . once the wheel shaft 840 it inserted in a position such as position 1 , the wheel shaft 840 is constrained by the detent 850 and restricted from sliding within the guided path . in addition to the detent 850 , the downward weight force of the carriage forces the wheel shaft 840 upwards towards the end of the groove 820 in position 1 preventing it from sliding . in order to move the wheel 830 from position 1 to position 2 , first a user applies a force on the wheel to move the wheel out of the detent constraint . the move forces the detent aside and allows the wheel shaft 840 to be guided along the groove path . a user can then maneuver the wheel shaft 840 along the groove guided path to a second position where the wheel shaft can be locked by the detent 850 . this movement from one vertical position to another allows the user to adjust the height of the carriage 800 and the blade coupled to the carriage 800 . the blade height adjustment determines the amount of contact a blade will have with the grass and determines the height of cut for the grass . in another embodiment , the carriage 800 includes several holes placed at various horizontal and vertical locations along the carriage 800 . a wheel can be coupled to the carriage by inserting the wheel shaft through any of these holes . a user desiring to adjust the height of the carriage can simply detach the wheel from the carriage 800 and insert the wheel shaft 840 in another hole located at a different vertical location . in addition , the individual movement of each wheel 830 allows the carriage 800 to be balanced even across uneven terrains . by placing one wheel 830 at position 1 and the other at position 2 a user can change the angle of the blade and the carriage and provide a parallel surface between the blade and the grass for a uniformly cut grass on an uneven terrain . various combinations of angles may also be achieved by adjusting each wheel independently either to keep the blade parallel or at a desired angle for cutting the grass . this wheel assisted lift prevents the blade in the carriage from coming in contact with the ground surface either during operation of the lawnmower or when the lawnmower is in a standing position . blade contact with the ground surface during operation causes the blade to dig into the ground surface and ruin the lawn by extracting the roots of the grass . also , if blade contact prevails over time when lawnmower is in a non - operational standing position , this contact can cause either rusting of the blade due to water deposits on ground or blade dullness due to ground contact . in addition , a wheel assisted lift of the carriage prevents a user from exerting energy to lift and push the carriage or accidentally bringing the blade in contact with the ground surface during operation . also , wheel assisted lift ensures that an even amount of grass is cut as the lawnmower is pushed across the grass which in the case of a user assisted lift would require exact precision in maintaining the exact height from the ground to obtain an even cut .	some embodiments of the invention provide a multipurpose gardening tool having an attachable circular carriage for converting an edge trimmer to a lawnmower for cutting and trimming grass and bushes . the circular carriage has an opening configured for receiving the edge trimmer . the multipurpose gardening tool also includes a coupler . the coupler allows a user to fixedly couple the edge trimmer to the carriage housing without use of any tools . the multipurpose gardening tool further includes wheels for maneuvering the lawnmower . a height adjuster couples these wheels to the carriage . the coupling allows the wheels to be manually and independently controlled for lifting the carriage off the surface of the ground and adjusting the height of the carriage .
fig1 is a simplified top view of the composite orthotic insole and sensor layer , illustrating the layout of the sensors in the sensor layer . a schematic top view of a smart orthotic insert 20 is shown . the orthotic insert 20 includes a number of layers . displayed is a sensor layer 22 and a surface layer 24 which the sensor layer is placed on top of . the surface layer 24 would go around the exterior of the orthotic insert 20 and is the surface upon which users contact with their feet . the sensor layer 22 is generally in the shape of a wearer &# 39 ; s foot , and is made up of a plurality of electronic pressure or force sensors 26 wired together in a network . the sensor 26 themselves may merely be conductive contacts that make up a portion of a pressure sensor or switch . the surface layer 30 serves to completely seal and protect the sensor layer ( among other layers ), and may be made from a material such as pdms , or other suitable plastics or gel materials which are flexible , durable and waterproof . each of the active sensors 26 is shown as having a hexagonal shape ( although it should be understood that other shapes of sensors are also possible , such as circular ). the general layout of the sensors 26 in relation to a wearer &# 39 ; s foot shape is shown in fig1 . the number of sensors 26 and their placement / coverage around the shape of the foot is such that all important areas of the foot will be measured , regardless of the wearer &# 39 ; s foot shape specifics , as well as regardless of the wearer &# 39 ; s gait mechanic changes during the orthotic lifetime . an embodiment of the technique introduced here is described herein in the form of a sensor layer 22 of an orthotic insert 10 . however , it should be understood that the sensor layer could instead be used in combination with a regular insole or insert , or by itself as an insert for footwear . fig2 is a cross - sectional view of an embodiment of an orthotic insole having a number of layers . the sensor layer 22 interacts with a number of layers , including a pressure - sensitive resistor layer (“ psr layer ”) 28 . the psr 28 may comprise a layer of velostat as manufactured by the 3 m company . other materials are suitable so long as the material used has a variable electrical resistance which is controlled by the amount of pressure applied to the material . the electrical resistance is reduced when pressure is applied . between the sensor layer 22 and the pressure - sensitive resistor layer 28 is an air gap layer 30 . the air gap layer 30 is established through the structure of the surface layer 24 which keeps the psr layer 28 and the sensor layer 22 split apart . after the orthotic insert 20 is constructed , the air pressure of the air gap layer 30 maintains the integrity of the air gap layer 30 . below the sensor layer 22 are electronic components . the electronic components include a microcontroller 32 , and a wireless communicator 34 . optionally a multiplexer 36 is connected to the microcontroller 32 . the sensors 26 are connected to either the microcontroller 32 or the multiplexer 36 . there is also a differential contact 38 that runs between the microcontroller 32 and the psr layer 28 that completes the circuit . the circuit is powered by a battery 40 . the battery 40 may be rechargeable or replaceable . the general functionality of the layers is as follows . the differential contact 38 carries the voltage difference from the battery 40 to the psr layer 28 . the psr layer 28 changes its resistance when bent , compressed or is otherwise deformed by external forces ( in this case , foot impact ). the air gap layer 30 is placed below the psr layer 28 to provide cushioning and support for the psr layer 28 , and therefore regulate how much pressure is required to alter the shape of the psr layer 28 . in other words , the air gap layer 30 regulates how much force or pressure is required to create the resistance difference in the circuit . where the psr layer 28 contacts the sensor layer 22 ( the particular sensors 26 ) a circuit is completed . the changing resistance is measured in the microcontroller 32 , and converted into digital data points for software interpretation . the recorded voltage enables calculation of the magnitude of pressure applied to the sensor as well as the timing for the applied pressure . based on the number of sensors 26 , the orthotic insert 20 makes use of the multiplexer 36 . where the microcontroller 32 is configured to accept all of the inputs on the of the sensors 26 directly , no multiplexer 36 is required . where the number of sensors 26 is greater than the number of sensor inputs on the microcontroller 32 , a multiplexer 36 enables additional sensor input to the microcontroller 32 . in at least one embodiment , the sensor coverage will be such that a minimum of nine sensors 26 providing pressure data points at all times . in at least one embodiment , the complete pressure sensors are composed of a velostat ™ layer , an air gap layer , sensor layer and electronic components . sensors 26 can be sized as desired , possibly in the 5 mm to 40 mm range . the sensors are semi - custom , in that the sensors 26 are based on a standard set of layers , and customized in terms of shape and size to fit the design of the sensor sheet . an example of a suitable off - the - shelf complete pressure sensor that utilizes a usable pressure - sensor configuration is the teksan ™ flexiforce ™ a201 . the sensor sheet can be used in contact with a human foot and placed above an orthotic insert ( which itself is preferably one that has been customized to a shape or profile to provide the wearer with specific biomechanical improvements ). the sensor layer can provide gait and stride force / pressure feedback to validate these improvements , and predict future orthotic refinements . the gathered data could be used for performance analysis , performance improvement recommendation , health tracking , injury prevention , and various other biomechanical applications . fig3 is a schematic diagram illustrating the wiring for the sensors 26 in the sensor layer 22 and illustrating the multiplexer 36 function . the schematic diagram illustrates the wiring 42 of nine separate sensors 26 and the multiplexer 36 function . to enable 9 + channels of data logging , one or more multiplexer switches 36 is used . the sensors are wired through one or more multiplexer switch 36 , which can be analog 32 - channel switches , for example . from the multiplexer switch 36 , the wiring 42 runs to a microcontroller 32 , which is limited to 8 inputs . it may be preferable that a particular sensor sheet be made up of sensors 26 that are standardized and the same size , since this makes the sensor sheet more readily customizable and facilitates comparisons ( and provides for uniformity ) of the various sensor signals from the same foot or from different wearers ; however , sensors 26 of differing sizes could be used . the multiplexer 36 will switch between the sensors 26 rapidly , i . e ., fast enough to ensure that any measurable pressure changes can be detected and recorded . the multiplexer 36 switches one of multiple inputs to the common output , determined by a unique binary address lines ( samples are marked on each sensor 26 ). for 9 - 16 sensors , a 16 - channel analog multiplexer can be used , switching one of 16 inputs to one , determined by four - bit binary address lines ( in this case , a 32 - channel analog multiplexer could also be used ). for 17 - 32 sensors , a 32 - channel analogy multiplexer can be used , switching one of 32 inputs to one , determined by five - bit binary address lines . alternatively , where appropriate , two or more multiplexers 36 can be used in combination . the signal from the sensors is passed to a microcontroller 32 , which can include a microcontroller and associated electronic equipment ( including battery unit and communication hardware ). the above - described approach involving relatively large numbers of sensors is practical in combination with the use of electronics that consume small amounts of power ( such as low - power sensors ) and that require low - power for communication through the wireless communicator 34 . bluetooth 4 . 0 standard technology , compatible with ibeacon ™, for example , can be used to conserve battery life . other forms of wireless communicators 34 are also suitable such as wifi or cellular ( gsm , cdma , gprs , etc . . . ) so long as the wireless communicator 34 is compact . fig4 is a top view of a sensor sheet 44 , along with an enlarged fragmentary view of a section thereof , illustrating the wiring 42 of the sensors 26 . the sensor sheet 44 itself can be designed to allow trimming and customizing for each unique footprint . the sensors 26 a and peripheral sensors 26 b are placed and wired in such a way that the electrical wires 42 are directed generally towards the center of the basic foot shape . this enables adding or subtracting to the sensor sheet 44 design without disrupting the wiring 42 of the sensor 26 . this also provides the advantage of being able to trim / customize each sheet to a specific foot shape , by cutting through some of the peripheral sensors 26 b , without significantly affecting the functionality of the sensor layer 26 as a whole . in fig4 , the trim line 46 for the sensor layer 22 for a particular foot - size indicates that certain peripheral sensors 26 b will be compromised by the trimming and would not function ; other active sensors 26 a ; however would continue to be able to record pressure data . the production process can start with a set of standard sensor sheets 44 . in some embodiments these sensor sheets 44 are categorized for one or more shoe sizes . in some embodiments , the sensor sheets 44 are suitably large to be used for all shoe sizes . the customization of the orthotic inserts 20 begins with the sizing of the sensor sheet 44 . where customized foot sized data is received by the manufacturer , a very particular foot shape may be cut into the sensor sheet 44 matching foot of the intended user as accurately as possible . this is technique is highly customizable , in part , as a result of the repeating , pattern of the sensors 26 on the sensor sheet 44 , and that the wiring 42 for each of the sensors 26 is routed towards the center of the sensor sheet 44 . routing the wiring 42 to the center of the sensor sheet 44 enables large variation in the foot size cut 46 into the sensor sheet 44 while still enabling the wiring 42 to function for all remaining sensors 26 . this is illustrated in fig5 a and 5b , which show two differently sized sensor sheets 44 a and 44 b , and illustrate how each could be trimmed to be formed into a sensor layer for two different - sized feet ( in this case , sensor sheet 44 a for a relatively larger foot , and sensor sheet 44 b for a relatively smaller foot ). it also may be preferable that the sensor sheet 44 be made relatively thin — in practice , a thickness of less than about 2 . 6 mm may be considered optimal . the optimal sized sheet is chosen , then trimmed / customized along the trim lines 46 a and 46 b respectively for the individual foot shape . each standard sheet size could be produced in bulk using a packaging machine , or produced using additive manufacturing with a modified 3d printer . it also may be preferred to determine sensor spacing based on foot size . for example , relatively smaller foot sizes may require less spacing between sensors than larger sizes . in cases where a standardized sensor sheet 44 is used , there is a positive correlation between a number of sensors 26 to the foot size trim lines 46 . further , in those embodiments there is a static density of sensors 26 despite variance to the foot size trim lines 46 . fig6 is a side view of an embodiment of an orthotic insole including a number of electronic components . in addition to a set of pressure sensors 26 , additional instruments 48 can be inserted in the orthotic insert 20 to provide data . the additional instruments 48 may include , for example : a geolocation sensor ( such as a gps ), a thermometer , an accelerometer , an ultrasonic sensor , a heartbeat sensor and / or a gyroscope . more than one of the additional instruments 48 may be placed within the orthotic insert 20 . the additional instruments feed collected data to the microcontroller 32 which in turn feeds data to the wireless communicator 34 for transmission . the additional instruments 48 provide additional data that help shape the machine understood story of the travel a foot , a pair of feet , or even a whole body take . in some embodiments , the additional instruments 48 are socketed into an insole without the pressure sensors . rather than use a layered pressure sensor , the additional instruments 48 are inserted into sockets in the surface layer 24 . between the sockets wiring connects the microcontroller 32 and the wireless communicator 34 and the battery 40 . fig7 is a block diagram of a system including an external user device and an application server . the orthotic insert 20 uses the internal wireless communicator 34 to transmit data and signals 49 collected and processed by the microcontroller 32 to an external device 50 . the external device 50 , may be a number of devices including but not limited to a smart phone , a tablet , a laptop or desktop computer , a virtual reality interface , a augmented reality interface , and a suitable control module known in the art . processed data and signals 49 are either used directly by the external device 50 , or forwarded to an applications server 52 . the external device 50 may be connected to the application server 52 through wireless , network , or wired connections . in some embodiments , the processed data and signals 49 are used to construct analytical models of the wearer &# 39 ; s gait , physical stresses , and body health . another possible application for the disclosed system is for entertainment purposes . for example , the foot pressure on the wearer may be tracked through the layer of sensors and used as inputs to a connected user - interactive processing device ( such as a video game system or a virtual reality hardware device ). the wearer can provide instructions to or otherwise control the processing device , at least in part , via the foot pressure communicated ( e . g . the wearer may represent / simulate actions such as jumping , walking , hopping , balancing , etc .). fig8 is a cross - sectional view of an embodiment of an orthotic insole 20 having a support pillar 54 in an air gap layer 30 . in order to increase the resistance of the air layer 30 beyond air pressure , one or more collapsible support pillars 54 or substrate may be affixed within the air gap layer 30 increasing the amount of pressure required upon the psr layer 38 in order to make contact with the sensor layer 22 . fig9 is a flowchart of a method for customization of an orthotic insole . in step 902 , a insole manufacturing station receives foot size parameters . the scope of insole manufacturing station is general . included examples of a insole manufacturing station are a corporate entity with the purpose of manufacturing insoles , a 3d printer , a single machine that assembles insoles , or a group of machines that assemble insoles . the foot size parameters pertain to the size of a customer &# 39 ; s foot as measured by an external method . in step 904 , the insole manufacturing station determines the correct sensor sheet 44 to use for the particular customer &# 39 ; s foot size parameter . in step 906 , the insole manufacturing station cuts the sensor sheet to the foot size parameter . in doing so , extraneous sensors 26 b and wiring 42 for those sensors are stripped away leaving only the sensors 26 a which will remain in the sensor layer 22 . in step 908 , the remainder of the sensor matrix is completed : the psr layer 28 and the air gap layer 30 are formed . the electronic components ( microcontroller 32 , multiplexer 36 , and wireless communicator 34 ) are connected to the wiring 42 and the differential contact 38 is connected to the psr layer 28 . in step 910 , any additional instruments 48 are added as suitable . in step 912 , the layers , including the surface layer 24 are fixed into positon and a completed custom orthotic insert 20 is ready to ship to the customer . fig1 is a flowchart of a method of receipt and transmission of signals from an orthotic insert . in step 1002 , the orthotic insert 20 receives a footfall , the footfall imparting pressure upon the insert 20 . in step 1004 , the imparted pressure increasing the conductivity of the psr layer 28 of the insole 20 . in step 1006 , the imparted pressure further causes the air gap layer 30 to at least partially collapse . the collapse of the air gap layer 30 causes the psr layer 28 to contact one or more sensors 26 on a sensors layer 22 of the insert 20 . in step 1008 , the orthotic insert 20 completes one or more circuits between the one or more sensors 26 and the psr layer 28 . in step 1010 , each completed circuit delivers a signal to a microcontroller 32 , each signal including a unique identifier associated with each of the one or more sensors that complete the one or more circuits . in inserts 20 with a multiplexer 36 the unique identifier is determined by a binary code corresponding to the input on the multiplexer 36 . in inserts 20 without a multiplexer , the unique identifier is indicated by the input used on the microcontroller 32 . in step 1012 , the microcontroller 32 processes the received signals . in step 1014 , the microcontroller 32 delivers the processed signals to the wireless communicator 34 for transmission . in step 1016 , the signals are analyzed with a measured voltage to determine the magnitude of the pressure supplied by the footfall across each sensor 26 receiving pressure . step 1016 may be performed either by the microcontroller 32 prior to step 1014 , or after step 1014 by an external device 50 or an application server 52 . depending on how the transmitted data is to be used by the external device 50 or application server 52 , the method proceeds to step 1018 or 1020 . in step 1018 , the external device 50 or application server 52 uses the transmitted signals to develop analytical models of footfalls . in step 1020 , the transmitted signals provide user input to an entertainment apparatus such as a game system or virtual / augmented reality apparatus . the embodiments described herein are not , and are not intended to be , limiting in any sense . one of ordinary skill in the art will recognize that the disclosed technique ( s ) may be practiced with various modifications and alterations , such as structural and logical modifications . although particular features of the disclosed technique ( s ) may be described with reference to one or more particular embodiments and / or drawings , it should be understood that such features are not limited to usage in the one or more particular embodiments or drawings with reference to which they are described , unless expressly specified otherwise .	the disclosed technique relates to an insert for footwear and to a composite orthotic insole comprising said insert , wherein the insert is embedded with a plurality of force sensors , and may be used to provide feedback on important information regarding the wearer &# 39 ; s gait biomechanics . the layer of sensors may be used to assist in monitoring the wearer &# 39 ; s health via foot pressure tracking . the insole can use a relative large number of sensors , which together provide broad coverage of the human foot impact area .
one embodiment 100 of this breading machine is shown in the perspective view of fig1 as well as the side view of fig2 and the top view of fig3 . breading machine 100 includes molded base shell 2 , domed transparent cover 1 with doors , such as sliding doors 3 and 4 , egg mixture tray 5 , and bread crumb tray 6 . base shell 2 and domed cover 1 , which fits over it , can be molded of the same transparent resin such as acrylic or polycarbonate . while cover 1 shows a dome with flat sliding doors 3 and 4 , it is known that access to the interior may be of other configurations , such as by one or more flat or hinged doors . in addition , the dome itself could be bifurcated in two split parts , such as semi - spherical cover portions 203 and 204 , shown in the embodiment of fig5 and 6 . while semi - spherical parts 203 and 204 may be fixedly attached to a base shell , such as base shell 202 or other base shells , they can also be removably attached by other fasteners to a base shell . further with respect to fig1 and 3 , mechanism armature 7 , preferably tubular , extends vertically upward and is rigidly attached to the center of the base 2 . trays 5 and 6 are attached to armature 7 . a main operating armature 8 fits coaxially within the armature 7 and extends beyond doors 3 and 4 , which have semicircular holes at their contact center to accommodate such penetration . a rigid food carrier grate 11 is pivotally attached to the main operating armature 8 such that it is able to be rotated or “ flipped ”. knob 9 is used to rotate carrier grate 11 laterally , to align it with either the egg tray 5 or the crumb tray 6 . knob 9 may additionally be used to control the dipping process . grate 11 has an openable , preferably removable and flexible , grate cover section 12 which is of similar size to grate 11 , and which attaches to grate 11 via fasteners , such as , for example integral spring clips ( not shown ) to hold food items to be breaded of varying thicknesses . a small knob 10 atop tube 25 , which is coaxially within the main operating armature 8 , is used for the grate flipping operation . the operation involves the steps of first filling tray 5 with egg mixture and tray 6 with a bread or flour crumb mixture . then , the flexible carrier grate cover 12 is opened from a rigid lower section of grate 11 , to permit the food to be breaded to be placed upon the carrier grate 11 , and then is locked in place by re - attaching the flexible grate 12 over it . the knob 9 is rotated in a direction 17 to place grate 11 squarely over tray 5 . then knob 9 is pressed downward in the direction 16 to dip the grate 11 into the egg mixture . both trays 5 and 6 preferably have slots with self - sealing flexible lip seals ( not shown ) at the center of their proximal vertical sides to permit the grate pivot shaft to travel down beyond the edge of the trays , without spilling contents therefrom . upon release of the knob 9 , grate 11 rises by a force , such as a spring force from spring 28 within vertical armature 7 , and the knob 10 attached to tube 25 is pressed or pulled up in direction 18 a short distance , until grate 11 is flipped 180 degrees . at this time knob 9 is pressed downward again to dunk the opposite side in the egg mixture . upon release , the knob 9 is rotated either clockwise or counterclockwise until grate 11 is now over crumb tray 6 . then the dunking and flipping motions as in the egg tray situation are repeated to coat both sides with crumbs . thereafter the door 3 is slid open in the direction 15 to retrieve the breaded food items . access to egg tray 5 is achieved by sliding door 4 open in a direction 14 . the mechanism to achieve these operating steps is revealed in the side cross - section of fig4 . the up and down movement of the main operating armature 8 within base armature 7 is mediated by return spring 28 within base armature 7 , which impinges upon and supports the sealed bottom of main operating armature 8 . tube 18 ( within main operating armature 8 ) preferably has a cutout 29 , with gear rack 27 on one side . this engages pinion gear 26 , which is rigidly attached to the support shaft of grate 11 . then as knob 10 is moved up or down relative to knob 9 , it is understood that gear 26 will rotate , thereby causing grate 11 to flip over . in fig5 a working perspective drawing illustrates the present invention according to an alternative embodiment of the current invention . base shell 202 provides an enclosure for the operating mechanisms and prevents baking goods from splattering . a dome formed by domed cover portion 203 and domed cover portion 204 may be of a transparent material as described herein , enclosing the operating mechanisms as to prevent splattering and the possible spread of salmonella and other food related diseases . domed cover portions 203 and 204 may slide closed , meeting at the centerline of the invention , such that the semi - spherical cutaways 201 allow for the protrusion of the tube 208 . the fastening mechanism may comprise hinges or other fasteners , which allow for the removal of the domed cover portions 203 and 204 from base shell 202 for the purpose of conventionally washing . the domed cover portions 203 and 204 may be attached fixedly or removably to base shell 202 . alternatively , the domed cover may be continuous , such shown as domed cover 2 in fig1 - 3 , and thus be removable from base shell 2 by simply sliding upward in conjunction with a locking means . other transparent geometric forms can be used to cover trays 205 and 206 . [ 0057 ] fig6 illustrates a detailed perspective drawing of the alternate embodiment of the current invention . similar to the preferred embodiment of fig1 fig2 and fig3 the alternate embodiment includes a molded base shell 202 , domed transparent cover 201 with domed cover portions 203 and 204 functioning as doors , providing access to egg mixture tray 205 and bread crumb tray 206 . base shell 202 , preferably round in geometry , and domed cover 201 , which fits over it , can be molded of the same transparent resin such as acrylic or polycarbonate . lower base armature 207 , preferably tubular , is rigidly attached to the center of the base shell 202 . trays 205 and 206 may be part of base shell 202 , or may be attached to armature 207 by a removable means , such as a tongue and groove combination or simply by corresponding slots or keyholes . a spring 228 is placed in communication with the inside perimeter of the armature 207 . a main operating mid armature tube 208 fits coaxially within the lower base armature 207 , and extends beyond dome cover portion doors 203 and 204 , which have semicircular cutaways at their contact center to accommodate such penetration . the main operating mid armature tube 208 is free to rotate axially and free to move upwards and downwards upon applied pressure , and against the effective pressure of the spring 228 being in a state of compression . a slit 240 extends horizontally from the side of the tube 208 to a point past the center point of the mid armature tube 208 . the slit 240 is tapered , forming a lock - in section for receipt of a horizontally - extending axle 244 supporting open walled food grate 212 . two stops 271 may extend horizontally and opposing from two points on the armature tube 208 below slit 240 . the stops 271 act to prevent free rotation . rigid food carrier support 212 may be removably attached to mid armature tube 208 by insertion of the axle 244 into the slit 240 of mid armature 208 such that the food carrier support 212 is locked in place as to prevent lateral movement , but free to rotate , thus being in rotational communication with mid armature tube 208 . [ 0061 ] fig6 also shows food carrier 212 and food carrier support axle 244 as in fig5 . the axle 244 comprises shaft 270 and a pinion 246 rigidly attached to the shaft 270 . the pinion 246 of axle 244 is also in communication with rack 272 of tube 225 , to permit rotation of food grate 212 . knob 209 is used to rotate food carrier 211 horizontally with respect to the mid armature tube 208 , to align it with either the egg tray 205 or the crumb tray 206 . food carrier 212 has a removable flexible grate cover section 266 which is of similar size and attaches to food carrier 212 via fasteners 268 , such as , for example integral spring clips ( not shown ) to hold food items to be breaded of varying thickness &# 39 ;. a small knob 210 atop upper armature tube 225 , which is coaxially within mid armature tube 208 , is used for the food carrier 212 flipping operation . the operation involves the steps of first filling egg tray 205 with egg mixture and crumb tray 206 with a bread or flour crumb particulate mixture . then the flexible grate cover section 266 is detached from a rigid section of grate 212 to permit the food to be breaded to be placed upon the food carrier 212 and then is locked in place by re - attaching the grate section 266 over grate 212 . the knob 209 is rotated in a horizontal direction 217 , to place food carrier 211 squarely over food tray 205 . then knob 209 is pressed downward , in the direction 218 , to dip the food carrier 211 into the egg mixture . the grate 212 may be rotated in the vertical plane by means of pinion 246 engaging rack 272 of upper armature 225 . upper armature tube 225 ( within mid armature tube 208 ) has a cutout , with gear rack 272 on one side . this engages pinion gear 246 , which is rigidly attached to the axle 244 of food support carrier 212 . then as knob 210 is moved up or down relative to knob 209 , it is understood that pinion 246 will rotate , thereby causing food carrier 212 to flip over . both trays 205 and 206 may optionally have slots with self - sealing flexible lip seals ( not shown ) at the center of their proximal vertical sides to permit the grate pivot shaft 244 to travel down beyond the edge of the trays 205 and 206 , without spilling contents . upon release of the knob 209 , food carrier 211 rises by a force , such as a spring force of spring 228 . then the small knob 210 is pressed or pulled up in directions 218 a short distance until food carrier 211 is flipped over 180 degrees . subsequently , knob 209 is pressed again to dunk the opposite side in the egg mixture . upon release , knob 209 is rotated either clockwise or counterclockwise until food carrier 212 is now moved horizontally over crumb tray 206 . then , the dunking and flipping motions as in the egg tray situation are repeated to coat both sides with crumbs . thereafter , the semi - spherical door 203 is slid open to retrieve the breaded food items . access to egg tray 205 is achieved by sliding door 204 open . [ 0068 ] fig7 shows an alternate embodiment for the operation of food carrier 300 , wherein rigid food carrier grate 313 is pivotally attached to the armature 308 such that it is able to be rotated or “ flipped ”. carrier 300 has a pair of removable flexible grate sections 317 . armature 308 preferably has a cutout 340 , for entry of pinion 346 of food carrier 300 therein , to engage a gear rack ( not shown ) within armature 308 . slit 340 extends horizontally from the side of the tube 308 to a point past the center point of the tube 308 . the slit 340 is tapered , forming a lock - in section for receipt of an axle 344 supporting food grate 212 . two stops 310 may extend horizontally and opposing from two points on the armature tube 308 below slit 340 . the stops 310 act to prevent free rotation . rigid food carrier support 313 may be removably attached to armature tube 308 by insertion of the axle 344 into the slit 340 such that the food carrier support 313 is locked in place as to prevent lateral movement , but free to rotate , thus in rotational communication with tube 308 . [ 0070 ] fig7 also shows axle 344 comprising a pinion 346 , rigidly attached to shaft 345 . the pinion 346 of axle 344 is also in communication with a rack , such as rack 272 of fig6 to permit rotation of food grate 313 . food is placed within carrier grate 313 . axle 344 is connected to supports 318 of grates 313 , which are opposite outer supports 319 , connected by side walls 314 to supports 318 . the side walls 314 and 315 of the food carrier 313 also have a first set of vertical slits 316 which align with the second set of vertical slits 317 of the food carrier support 313 . a pin 320 is inserted through both sets of slits , thereby movably connecting food carrier 313 to supports 318 and 319 . in this fashion , the food carrier is capable of sliding vertically relative to the supports 318 , 319 under the force of gravity . in so , the food carrier is biased to submerge into either the fluid tray or the particulate tray as opposed to remaining in a fixed position ( relative to the supports ) inhibiting the ability for the tray 300 to undergo a dipping process resulting in an effective coating of food matter . this pin and slit mechanism may also be incorporated into the food carrier embodiment of fig1 or fig5 without the loss of design characteristics previously mentioned or the addition of characteristics not mentioned . for example the supports 314 , 315 as shown in fig7 may easily be reconstructed to fit the perimeter of the semi - circular food carrier 212 of fig6 . the axle 244 would then be in rigid connection with the supports in place of the food carrier 212 directly . the food carrier 212 would alternatively be in movable communication with the support system of the pin and slit mechanism mentioned herein . in the foregoing description , certain terms and visual depictions are used to illustrate the preferred embodiment . however , no unnecessary limitations are to be construed by the terms used or illustrations depicted , beyond what is shown in the prior art , since the terms and illustrations are exemplary only , and are not meant to limit the scope of the present invention . it is further known that other modifications may be made to the present invention , without departing the scope of the invention , as noted in the appended claims .	a food breading machine includes a lowerable cage carrier grate of two grids between which the cutlet resides . the cage supports a meat , fish or vegetable cutlet thereon , which descends into a first basin having a bath of raw egg fluid . the egg saturated product is then lifted and horizontally rotated in a plane to an adjacent basin having bread crumbs . the device can have a manually rotatable knob at the top to control flipping , or it can be automated . a protective transparent domed hood is also included . the parts are disassembled so that they can be washed .
referring now to the drawings , and with special reference to fig1 , a medical device constructed in accordance with the teachings of the disclosure is generally referred to by reference number 3 . the medical device 3 is adapted to be inserted into tissue and to be located using a magnetic resonance imaging ( mri ) device 27 . in fig1 , the medical device 3 is represented as having a generally tubular shape such as that of a catheter or stent . however , the teachings of the disclosure can be used in conjunction with other types of medical devices , including , but not limited to guidewires , sheath introducers and biopsy needles . the medical device as shown is for illustrative purposes only . nevertheless , those embodiments in which the medical device is a catheter will generally include a lumen 30 , through which a liquid 5 may flow . as shown in fig1 , the medical device 3 may include a housing 6 , a first temperature modulator 9 , a hydrophilic layer 12 , and a material 15 that possesses a curie point . in some embodiments , the medical device 3 may also include radiopaque material 21 , which allows the medical device 3 to be visible using techniques utilizing x - rays . all medical devices and methods of using medical devices in this disclosure are understood to be capable of including embodiments comprising radiopaque material 21 in any number of different patterns and arrangements . while the device 3 in fig1 is shown with the first temperature 9 modulator and a second modulator 10 , the medical device 3 may include at least a first temperature modulator 9 or a greater number of temperature modulators as well . in certain embodiments , the first temperature modulator 9 will be capable of causing an increase or decrease in the temperature of all or part of the medical device 3 . in some embodiments , a first temperature modulator 9 will be able to increase the temperature of all or part of the medical device 3 , and the second temperature modulator 10 will be able to decrease the temperature of all or part of the medical device 3 . in fig1 , the temperature modulator is shown affecting the temperature of a temperature zone 18 , but that is for illustrative purposes only . temperature modulators , e . g . reference numbers 9 and 10 in fig1 , can take on different types , shapes and placements , and those shown in fig1 are only representative and illustrative . in fact , the lumen 30 and accompanying fluid 5 , may also serve as a temperature modulator . as explained below , temperature modulators can include , but are not limited to , peltier elements , heating bands and systems employing gas expansion . such gas expansion systems use a gas flowing through a first lumen , which is then expanded and returns through a second , wider lumen . in general , a temperature modulator is understood to be a component capable of creating a temperature differential with its environment . in fig1 , the hydrophilic layer 12 is shown covering only a portion of an outer surface 25 of the housing 6 , but the hydrophilic layer 12 may cover different parts of the surface 24 , all of the surface 24 , or be absent altogether . the hydrophilic layer also need not be located on the surface 24 of the housing 6 . the hydrophilic layer comprises hydrophilic material , and may contain other elements including , but not limited to , water , paramagnetic material , superparamagnetic material , and material 15 that possesses a curie point . hydrophilic material may also be found elsewhere in the medical device in other embodiments . in some embodiments , the hydrophilic layer 12 comprises a hydrogel . unless stated to the contrary , a hydrophilic layer 12 is generally understood to include embodiments where the hydrophilic layer comprises a hydrogel . while the hydrophilic layer 12 , when located on the surface 24 , may be located anywhere on the surface 24 , in some embodiments the hydrophilic layer 12 will be found on the outer surface 25 . in some embodiments , the hydrophilic layer 12 will be found on an inner surface 26 . certain embodiments may also lack a hydrophilic layer 12 . generally , the thicker the hydrophilic layer 12 , the greater the number of protons that will be affected during magnetic resonance imaging , and the more signal distortion in the average voxel signal . in some embodiments , the affected protons may be within the housing 6 of the medical device 3 . one making use of the medical device 3 , and other embodiments taught by this disclosure , will appreciate that the thinner the hydrophilic layer 12 , the greater the temperature difference has to be to have an effect on the average voxel temperature . while there is no real limit to the thickness of the hydrophilic layer 12 , one will appreciate that the thickness of the hydrophilic layer 12 may be limited by the size of the body cavity into which the medical device 3 will be placed as well as the size of the medical device 3 . in some embodiments , the hydrophilic layer is 0 . 1 mm thick . in some embodiments , the hydrophilic layer is from 0 to 5 mm thick . in some embodiments , the hydrophilic layer is from 0 to 1 mm thick . in some embodiments the hydrophilic layer is from 0 . 05 to 0 . 5 mm thick . one will also appreciate that the hydrophilic layer 12 may expand or contract depending on its environment , thus affecting the thickness of the hydrophilic layer 12 . while the hydrophilic layer 12 has been discussed in relation to medical device 3 , in general this same description of the hydrophilic layer 12 is applicable to the other embodiments of this disclosure as well . in fig1 , the medical device 3 is shown as containing material 15 possessing a curie point . the material 15 may possess a curie point either above or below body temperature . body temperature is understood to be 37 . degree . c . on average for humans . what body temperature is in a given embodiment will depend on , but is not limited to , such factors as where in the body the medical device is positioned , disease states , the kind ( species ) of subject into which the medical device is placed , and the type of temperature modulators employed in the medical device . in some embodiments , a first material 15 with a curie point above body temperature , and a second material 16 with a curie point below body temperature , or vice versa , may be used , or both may be above body temperature , or both below . in a given embodiment there may be any given number of materials , e . g . 15 , 16 , that possess a curie point and each one is capable of possessing a unique curie point . curie point in this disclosure is considered to be that temperature below which a material becomes ferromagnetic , and above which ceases to be come ferromagnetic , though it is also understood that the ferromagnetic transition may in actuality take place over a temperature range , rather than at a discrete temperature , and as such curie points in the disclosure may be taken as midpoints or averages . the material with a curie point , e . g . 15 and 16 , may be distributed in any configuration and in either part or all of the medical device 3 including , but not limited to , the housing 6 and the hydrophilic layer 12 . in fig1 , the first material 15 with a curie point is located in temperature zone 18 and hydrophilic layer 12 , but this is for illustrative purposes only , as the material 15 may be located in any of a number of different areas of the medical device 3 . the material 15 with a curie point may be located in any number of a different patterns in the medical device 3 . depending on the particular embodiment , there may be multiple patterns and positions of the material 15 , and a particular region may have material 15 with the same or varying curie point . moreover , the material 15 in one region may have the same or different curie point as that in a different region . the curie point material 15 may have a curie point of any temperature , which an individual would desire . some embodiments will possess a material 15 with a curie point that falls in the range of 25 and 50 degrees celsius . some embodiments will possess a material 15 with a curie point that falls in the range of 32 and 42 degrees celsius . some embodiments will possess a material 15 with a curie point that falls in the range of five degrees higher and five degrees lower than body temperature . some embodiments will have a material 15 that possesses a curie point that comprises at least one element selected from the group consisting of cobalt , palladium , nickel , silicon , chromium , iron , manganese and copper , so as to achieve a desired curie point . oxides and other chemical variants of these metals are also understood to be within the scope of the disclosure . fig2 outlines a general method according to the disclosure for detecting a medical device 3 that has been inserted into a subject . the medical device , e . g . 3 , which is the focus of the method , may comprise a housing 6 , and a temperature modulator 9 , the temperature modulator 9 being operatively associated with the housing 6 . a first step , as indicated by reference number 57 , may be to insert the medical device 3 into a subject ( not shown ). next , as indicated by reference number 60 , a temperature of the medical device 3 is modulated so that the temperature of at least part of the medical device 3 is altered so as to modify the detectability of the medical device 3 via magnetic resonance imaging . after that , as indicated by reference number 63 , the medical device 3 is visualized using magnetic resonance imaging . this method may be applied to the medical device 3 , illustrated in fig1 , however , it may also be applied to other medical devices as well . this method is discussed in reference to medical device 3 for illustrative purposes only . many other embodiments of the method represented in fig2 also exist , some of which are discussed below . in some embodiments , the modulating step 60 alters a temperature of the hydrophilic layer 12 , operatively associated with the housing 6 . in some embodiments , the modulating step 60 decreases the temperature of the hydrophilic layer 12 . in some embodiments , the modulating step 60 decreases the temperature of the hydrophilic layer 12 at least one degree celsius . in some embodiments , the modulating step 60 increases the temperature of the hydrophilic layer 12 . in some embodiments , the modulating step 60 increases the temperature of the hydrophilic layer 12 at least one degree celsius . in some embodiments , the modulating step 60 further utilizes the material 15 with a curie point . as indicated above , the material 15 may have a curie point that is below body temperature . in some embodiments , the modulating step 60 results in the material 15 becoming ferromagnetic . in other embodiments , the modulating step 60 further comprises an additional modulation step 66 following the visualization step 63 , comprising raising the temperature of the medical device above the curie point so that the material is again not ferromagnetic . the raising of the temperature may be performed actively or passively or may include both active and passive temperature change . the modulating step 60 may further utilize a material 15 having a curie point that is above body temperature , and in some embodiments , the modulating step 60 may result in the material no longer being ferromagnetic . the modulating step 60 may further comprise an additional modulation step 69 following the visualization step 63 , wherein the temperature of the medical device 3 is lowered below the curie point so that the material 15 becomes ferromagnetic again . the lowering of the temperature may be performed actively or passively or may include both active and passive temperature change . in some embodiments , the method will include an additional step 72 following additional modulation step 66 or 69 , wherein the method is repeated beginning with the modulating step 60 . for the method depicted in fig2 , and for all methods according to the teachings of this disclosure , it is contemplated that one may perform additional steps between the described steps , perform additional steps prior to the described steps , as well as perform additional steps after the described steps . one may also alter the order of the described steps and still fall within the teachings of the disclosure . additionally , one may repeat individual or series of steps . furthermore , while a given method may refer to a particular medical device , e . g . 3 , that is for illustrative purposes only , as performing the method in conjunction with other medical devices is also contemplated . the description of how materials , e . g . 15 , 16 , with a curie point may be used in conjunction with a medical device 3 , as well as the qualitative nature of those materials , also apply to the methods described in relation to fig2 , those methods described below , and all other methods taught by this disclosure . fig3 outlines another general method according to the disclosure for detecting a medical device 3 that has been inserted into a subject . first , as indicated by reference number 105 , the medical device 3 is inserted into tissue ( of a subject ), wherein the medical device 3 may comprise a housing 6 and at least one lumen 30 , the lumen being operatively associated with the housing and able to accept a fluid 5 . next , as indicated by reference number 108 , fluid is run through one or more of the lumens , e . g . 30 , so as to affect the visibility of the medical device 3 using mri . after that , as indicated by reference number 111 , the medical device 3 is visualized using magnetic resonance imaging . in some embodiments of the method represented in fig3 , the running fluid step 108 , further comprises modulating the temperature of the fluid 5 so as to cause an increase or decrease of a temperature of at least part of the medical device 3 . in some embodiments , the fluid 5 is run through the lumen 30 so as to lower the temperature of at least part of the medical device 3 below the curie point of a material 15 in the medical device 3 so that the material 15 becomes ferromagnetic . in some embodiments , the fluid 5 is run through the lumen 30 so as to raise the temperature of at least part of the medical device above the curie point of a material 15 in the medical device 3 so that the material 15 is no longer ferromagnetic . fig4 shows another medical device 147 according to this disclosure . the medical device 147 is adapted to be inserted into tissue and to be located using a magnetic resonance imaging device . the medical device 147 may comprise a housing 150 , bands , e . g ., 153 and 154 , composed of a conductive material being operatively associated with the housing 150 , arranged along a longitudinal axis 174 of the medical device 147 , and a conductive material 156 for connecting the bands , e . g . 153 , 154 , to each other and to a current source 189 . the conductive material 156 composing the bands 153 , 154 , may have a higher resistivity than the conductive material 156 connecting the bands 153 , 154 , to each other and to a current source 189 . in some embodiments , the medical device 147 , the conductive material 156 connecting the bands 153 , 154 to each other and to a current source , comprises non - ferromagnetic metal , including , but limited to silver , copper and gold , wires not more than 7 cm in length 171 and a marker 177 positioned so as to form / complete an electrical loop ( circuit ). in some embodiments , the medical device 147 , the conductive material composing the bands 153 , 154 , and the conductive material 156 connecting the bands 153 , 154 to each other and to a current source both comprise a conductive polymer . all types of conductive polymers are contemplated . such conductive polymers include , but are not limited to , poly - p - phenylenevinylene , and polyanilines such as panipol . rtm ., and conjugated polymers such as poly - pyrrole ( ppy ), poly - aniline , poly - thiophene ( pth ) and paraphenylene vinylene ( ppv ). further improvements can be obtained with doping of metallic elements within the polymer matrix . in some embodiments , the medical device 147 , shown in fig4 , includes bands 153 , 154 of a width 180 sufficient to cover about two voxels in a magnetic resonance image with minimal voxel size taken to be approximately 0 . 64 mm . sup . 3 , i . e . a cube with sides of approximately 0 . 4 mm . a voxel refers to a volume element in mri . magnetic resonance images comprise picture elements called pixels . the intensity of a pixel is proportional to the nuclear magnetic resonance ( nmr ) signal intensity of a voxel &# 39 ; s content of an imaged object . the width 180 is defined as the distance between one edge 162 of the band 154 , and another edge 183 of the band 154 , with the understanding that the width 180 of the band 154 may vary . in some embodiments the width 180 can be from 0 . 8 mm to 10 mm . in some embodiments the width 180 can be from 1 mm to 10 mm . in some embodiments the width 180 can be from 0 . 8 mm to 3 mm . in some embodiments the width 180 can be from 0 . 8 mm to 4 mm . in some embodiments the width 180 can be from 3 mm to 10 mm . bands 180 of 3 or 4 mm or even 10 mm in width 180 provide for a larger thermal mass and minimize image noise . in some embodiments , the medical device 147 shown in fig4 includes bands 153 , 154 spaced apart at a distance 171 between 3 millimeters and 15 millimeters , but narrower and wider distances 171 are also contemplated . the distance 171 is defined as the length between the edge 159 of one band 153 and the edge 162 of the adjacent band 154 , with the understanding that the distance 171 may vary . in various embodiments , it is understood that the medical device 147 shown in fig4 , may include a hydrophilic layer 168 on at least a portion of a surface of the medical device 147 . hydrophilic layer 168 shown in fig4 is analogous to hydrophilic layer 12 of medical device 3 shown in fig1 . moreover , medical device 147 can possess all the variations and elements described above for medical device 3 . for example , the medical device may include a material 15 with a curie point , analogous to the material , e . g . 15 , 16 , show in fig1 for medical device 3 . for illustrative purposes only , the material 15 that possesses a curie point is shown within and around the heating bands , e . g . 153 , 154 , and within the hydrophilic layer 168 . fig5 a , 5 b , 5 c , 5 d , and 5 e show a medical device 216 , according to the disclosure , which is adapted to be inserted into tissue and to be located using a magnetic resonance imaging device , and may include a lumen 222 , through which a fluid 5 may flow through . the medical device includes a housing 219 , which surrounds a lumen 222 . as visible in fig5 b , 5 c , and 5 d , the housing 219 includes three layers : a first layer 234 surrounding the lumen 222 , a second layer 237 surrounding the first layer 234 , a third layer 240 surrounding the second layer 237 . a fourth layer 243 surrounds the third layer 240 , but is not part of the housing . the medical device 216 also includes at least one heating region , e . g ., 225 , 226 and 227 , along a longitudinal axis 252 of the medical device 216 . fig5 d shows that the medical device 216 also includes a means 255 for completing a electrical circuit between the first layer 234 and the third layer 240 on the distal end 261 of the medical device 216 . as shown in fig5 e , a first conductive ring 246 is positioned over the first layer 234 and a second conductive ring 249 placed over the third layer 240 at the proximal end 258 of the medical device 216 so as to allow connection to a current source 189 . the first layer 234 and third layer 240 comprise a conductive polymer . the second layer 237 comprises a conductive polymer with a resistivity higher than the conductive polymer of the first layer 234 and third layer 240 in each heating region , e . g . 225 , 226 and 227 . the second layer 237 comprises an isolating ( insulating ) material in the non - heating regions , e . g . 231 , 232 and 233 . isolating / insulating materials that may be used include , but are not limited to , non - conducting polymers . some embodiments employ polymers such as pebax 72d , nylon 12 , pellethane , ptfe , hdpe , which provide the stiffness and other mechanical properties required of a standard catheter . the medical device 216 shown in fig5 a - e further comprises a fourth layer 243 surrounding the third layer 240 , wherein the fourth layer 243 , a hydrophilic layer , comprises a hydrophilic material such as a hydrogel . although depicted as covering the entire third layer 240 , it is to be understood that the fourth layer 243 may cover all or part of the surface 264 of the housing 219 . in other embodiments , the hydrophilic layer 243 may be located elsewhere in the medical device 216 . the fourth layer 243 comprising hydrophilic material shown in fig5 a - e is analogous to hydrophilic layer 12 of medical device 3 shown in fig1 . moreover , medical device 216 can possess all the variations and elements described above for medical device 3 . fig6 represents a method according to the disclosure for imaging a medical device , e . g . 147 as described above , within a subject . examples of such a medical device are shown in fig4 , 5 a - 5 e . the method represented in fig6 comprises the following steps . first , the medical device , e . g . 147 , is inserted into a subject , as indicated by step 327 . next , in a step 330 , electric current is passed through the medical device , e . g . 147 , so as to heat at least part of the medical device , e . g . 147 , above body temperature to see a sufficient effect ( contrast ) using a mri device . after that , in step 333 , the current traversing through the medical device , e . g . 147 , is ceased . then , in step 336 , the medical device , e . g . 147 , is visualized using mri . in some embodiments , the method represented in fig6 , comprises an additional step 339 of returning to the step 330 and repeating the method from that step . in such embodiments the resulting cycle can be repeated as many times as is necessary to produce the desired image quality . in some embodiments , the passing current step 330 further comprises heating a hydrophilic layer , e . g . 168 , of the medical device , e . g . 147 . in some such embodiments , the hydrophilic layer , e . g . 168 , may be heated to at least 41 . degree . c . ferromagnetic materials are materials , which , upon exposure to an alternating magnetic field , vibrate at the frequency of the applied field . due to such vibration , material , or material upon which the ferromagnetic material is embedded or attached , is heated due to the hysterisis losses associated with the vibration . moreover , the ferromagnetic materials are not only heated , but are heated only to a constant temperature known as the curie temperature ( point ) of the material , whereupon the vibrations cease and the material begins to cool . accordingly , if such a ferromagnetic material is provided on , or embedded within , a medical device , and the device is then subjected to an alternating magnetic field , such as that generated by the magnetic resonance imaging device , the medical device will elevate in temperature . this elevation in temperature will then be visible via the magnetic resonance imaging equipment . the imaging can be enhanced by incorporating the ferromagnetic material within a hydrophilic layer such as a hydrogel , which is then adhered or otherwise attached to the housing of a medical device . the radio frequency pulse sequence of the mri device can be alternated , i . e . switched on and off to alter the visibility of the device . during the radiofrequency field “ on ” status there is no image . therefore , it would be proposed that a pulse sequence would be used which alternately turns the radio frequency coil on and off to heat the device followed by an “ off ” period to gather the magnetic resonance signals . while such a pulse sequence is generally employed in mri , this disclosure teaches the unique practice of designing the pulse sequence to have a prolonged “ on ” period so as to heat the material with a curie point sufficiently . fig7 represents a method according to the disclosure for visualizing a medical device in a subject . the method involves a medical device , similar to 147 , but lacking the direct current source 189 and connecting elements 156 , marker 177 along with any other necessary modifications . the medical device comprises a housing 150 , bands , e . g . 153 , 154 composed of a conductive material being operatively associated with the housing 150 , arranged along a longitudinal axis 174 of the medical device 147 , and a material 15 that possesses a curie point above body temperature , the material 15 being operatively associated with the housing 150 . the method may include a first step 372 of inserting the medical device , e . g . 147 , into a subject . next , in a step 375 , a radiofrequency pulse is emitted so as to heat at least part of the medical device 147 above body temperature to see a sufficient effect ( contrast ) on a mr image . after that , in a step 378 , the radiofrequency pulse is ceased . then , in a step 381 , the medical device 147 is visualized using mri . in some embodiments , the method represented in fig7 , further comprises an additional step 384 of repeating the method at the emitting step 375 . in some embodiments of the method shown in fig7 , the sending step 375 further comprises a hydrophilic layer 168 , such as a hydrogel , on all or part the surface 165 of the housing 150 in such embodiments , the inserting step 372 utilizes a housing 150 , which is composed of a polymer , and the material 15 , that possesses a curie point , is 0 % to 5 % by weight of the medical device 147 , with modifications as discussed above , in those areas of the medical device 147 possessing the material 193 . the hydrophilic layer may also include a material 15 with a curie point . fig8 depicts a medical device 414 which is adapted to be inserted into tissue and to be located using a magnetic resonance imaging device 27 . the medical device 414 comprises a housing 417 , a surface of the housing 420 , at least one peltier element 423 , 424 , each peltier element being operatively associated with the housing 417 . a means 426 of connecting the peltier elements 423 , 424 to each other and a power source 189 , and a hydrophilic layer 438 operatively associated with the housing 417 are also provided . in some embodiments , the medical device 414 is constructed such that each peltier element 423 , 424 includes a hot region , 432 , 433 , and a cold region 429 , 430 , whereby the peltier elements 423 , 424 , are arranged along a longitudinal axis 435 of the medical device 414 . in such embodiments , the hot regions 432 , 433 of two adjacent peltier elements 423 , 424 , face each other , or the cold regions 429 , 430 of two adjacent peltier elements 423 , 424 , face each other . in other words , the cold region 429 of one peltier element 423 does not face the hot region 433 of an adjacent peltier element 424 . in some embodiments , the hydrophilic layer 438 , covers the cold regions , e . g . 429 and 430 . in some embodiments , the hydrophilic layer 438 , covers the hot regions ; for example , in such an embodiment , the orientation of both of the peltier elements 423 and 424 along the axis 435 are flipped 180 . degree . so that hot regions 432 and 433 face each other . in some embodiments , the means 426 of connecting peltier elements 423 , 424 to each other and to a power source 189 comprises a conductive polymer . in some embodiments , each peltier element 423 , 424 comprises alternating n - type semiconductor segments 444 and p - type semiconductor segments 447 arrayed around a perimeter 450 of the medical device 414 , as shown in fig8 . in some embodiments , the medical device 414 further comprises a material 15 that possesses a curie point below body temperature . in some embodiments the medical device 414 comprises a material 15 that possesses a curie point above body temperature . the material 15 that possesses a curie point , if present , may be present in all possible positions , arrangements and configurations in the medical device 414 , as described for medical device 3 in fig1 . fig9 a depicts a medical device 415 , which is a variation of that shown in fig8 . device 415 is adapted to be inserted into tissue and to be located using a magnetic resonance imaging device 27 . the medical device 415 comprises a housing 417 surrounding a lumen 480 . three layers are depicted in fig9 b as contained within the housing 417 of the medical device 415 . a first layer 483 surrounds the lumen 480 . a second layer 453 surrounds the first layer 483 . a third layer 486 surrounds the second layer 453 . at least one passive peltier element 423 , 424 is arranged along a longitudinal axis 435 of the medical device 415 . the first layer 483 comprises a conductive polymer . the second layer 453 comprises an isolating / insulating material . the third layer 486 comprises at least one peltier element , e . g . 423 , 424 , and at least one stripe 491 of conducting polymer connecting the peltier elements 423 , 424 and to an external source of electricity 189 . the stripe 491 and first layer 483 , shown in fig9 a and 9b , correspond to the means 426 shown in fig8 . the hot regions 432 , 433 , of two adjacent peltier elements 423 , 424 face each other , or the cold regions 429 , 439 of two adjacent peltier elements 423 , 424 face each other . each peltier element 423 , 424 comprises alternating n - type semiconductor segments 444 and p - type semiconductor segments 447 arrayed around the perimeter 450 , and contained within the third layer 486 of the medical device 415 as shown in fig9 b . as the medical device in 415 is a variation of medical device 414 , it may similarly include a hydrophilic layer 438 and a material 15 that possesses a curie point . fig1 a and 10b depict a medical device 416 , which is another variation on that embodiment shown in fig9 a and 9b . in the medical device 416 shown in fig1 a and b , the first layer 483 is absent , and the third layer 486 contains at least two stripes : a first stripe 465 and a second stripe 468 of conductive polymer . the first stripe 465 and second stripe 468 serve as the means 426 shown in fig8 . each peltier element 423 , 424 comprises at least three n - type semiconductor segments 444 and at least three p - type semiconductor segments 447 . the first stripe 465 of conductive polymer is connected to n - type semiconductor segments 444 and p - type semiconductor segments 447 in each peltier element 423 , 424 , wherein the number of n - type semiconductor segments 444 connected to the first stripe 465 is twice the number of p - type semiconductor segments 447 connected to the first stripe 465 . the second stripe of conductive polymer 468 is connected to n - type semiconductor segments 444 and p - type semiconductor segments 447 in each peltier element 423 , 424 , wherein the number of p - type semiconductor segments 447 connected to the second stripe 468 is twice the number of n - type semiconductor segments 444 connected to the second stripe 468 . the first stripe 465 carries current in one direction along a longitudinal axis 435 of the medical device 414 , and the second stripe 468 carries current in a direction opposite to the direction of the first stripe 465 . as the medical device in 416 is a variation of medical device 414 , it may similarly include a hydrophilic layer 438 and a material 15 that possesses a curie point . fig1 depicts a method for visualizing a medical device such as that depicted in fig8 . this method can be used in conjunction with medical devices 414 , 415 and 416 shown in fig8 , 9 a , 9 b , 10 a and 10 b , and other suitable medical devices as well . the method involves a medical device , e . g . 414 , which comprises a housing 417 , at least one peltier element 423 , each peltier element being operatively associated with the housing 417 , and a means 426 of connecting the peltier elements 423 to each other and a power source 189 . the method involves a first step 549 of inserting the medical device 414 into a subject . next , in a step 552 , electric current is passed through the medical device 414 in a direction so as to cool at least a portion of the medical device 414 relative to body temperature in order to see a sufficient effect ( contrast ) on a mri . after that , in a step 555 , the current traversing through the medical device 414 is ceased . then , in a step 558 , the medical device 414 is visualized using mri . alternatively , the method depicted in fig1 may further comprise an additional step 561 , following the visualization step 558 , of returning to the step 552 and repeating the cycle . in addition , the passing an electric current step 552 may further comprise cooling a hydrophilic layer 438 of the medical device 414 . the method may further include cooling a material 15 operatively associated with the housing 417 that possesses a curie point below body temperature so that the material becomes ferromagnetic . the direction of the current applied in the passing the current step 552 can also be reversed so as to heat rather than cool at least a portion of the medical device 414 relative to body temperature in order to see a sufficient effect ( contrast ) on a magnetic resonance ( mr ) image . in such embodiments , the passing an electric current step 552 further may comprise heating the material 15 operatively associated with the medical device 414 that possesses a curie point above body temperature so that the material 15 is no longer ferromagnetic . those medical device and method aspects and embodiments of the disclosure described above can utilize any kind of electro - active temperature modulator element , not just peltier elements . modifications can be made to the particular aspects and embodiments depending on the particular electro - active temperature modulator elements employed . fig1 depicts a method of manufacturing a medical device , according to the present disclosure . the method may comprise the following steps . first , as indicated by reference number 594 , two stripes of conducting polymer are extruded along a longitudinal axis of the medical device each of the stripes covering a metal wire that also runs along the longitudinal axis of the medical device . next , as indicated by reference number 597 , the wire is removed in those sections where a band ( heating element ) is desired to be located . fig1 depicts an alternative method according to the disclosure for manufacturing a medical device , e . g . 416 shown in fig1 a . the method may comprise the following the steps . first , as indicated by reference number 630 , extruding at least two stripes of conducting polymer along a longitudinal axis of the medical device . next , as indicated by reference number 633 , the conductive polymer is removed in those sections where an electro - active temperature modulator element , such as a peltier element , is to be inserted . after that , as indicated by reference number 636 , electro - active temperature modulator elements are inserted in those areas where the conductive polymer has been removed . all of the devices and methods taught by this exposure are capable of being used with human beings . specifically , a medical device , e . g . 3 , 147 , 216 , 414 , 415 , and 416 , is capable of being inserted into tissue wherein that tissue is that of a human subject , and the methods herein described involve inserting a medical device into tissue wherein that tissue is that of a human subject . the tissue may be part of either a living or a deceased subject . while the devices and methods of this disclosure are can be used in human beings , they are also capable of being used in and with tissue of non - human subjects , including but not limited to mammals other than humans . from the forgoing , one of ordinary skill in the art will appreciate that the disclosure teaches medical devices adapted to be inserted into tissue and to be located using a magnetic resonance imaging device , methods for visualizing such medical devices , as well as methods of manufacturing such medical devices . the devices and methods of this disclosure provide powerful new tools that will help advance the field of medicine .	this disclosure employs temperature , magnetism and curie point transition to construct and use catheters and other medical devices that can be visualized using magnetic resonance imaging . accordingly , this disclosure includes , but is not limited to , medical devices , means of constructing medical devices , and methods of imaging medical devices using magnetic resonance and other technologies .
hereinafter , the dish washer with dryer of the present invention will be explained according to fig1 to fig8 . a washing and drying plastic compartment 2 is located in a machine made of metal frame 1 of the dish washer with dryer ( s ). the drying compartment 2 is composed of an upper case 4 formed with the upper wall , both side walls and back wall 3 in one molded body and having an open - type lower portion , and a lower case 7 formed with the bottom wall 5 , both side walls , front wall and back wall 6 in one molded body by jointing one to the other . a door 8 and panel 9 are located in the front face of the machine frame 1 and drying compartment 2 . the upper case 4 and lower case 7 , wherein the back wall 6 is formed with the water compartment 10 as one body , integral unit with adhesive and other fastening means . in the washing and drying compartment 2 formed in such a manner , a nozzle 12 executes the washing by spraying water by means of a pump 11 and a heater 13 which raises the temperature of the washing water ( rinsing water ) and generates hot air by heating the air in the compartment during the drying process . also , they are located so that dishes can be placed and removed easily . the upper case 4 comprises a vertical duct 14 in the lower and central portion of back wall 3 . a leading inlet 15 having an upward cut shape is located as one integral unit at the lower end part of the back wall 3 ( along the jointing ) corresponding to the duct 14 . the upper case 4 is also formed with a leading outlet 16 in one upper end of back wall 3 together with a rib 17 in the back face of the back wall 3 so that a u - shaped pathway is formed on the back face near the center thereof while surrounding the outlet 16 . moreover , bosses 18 and reinforcing ribs 19 are formed in the proper portions as one body . a fan casing 22 composed of a driving motor 20 and double faced fan 21 is fixed in the upper central part of the back wall 3 of the upper case 4 . and , a suction opening 23 is jointed with the end of a u - shaped pathway formed by the rib 17 and a delivery hole 24 which is joined to the aforesaid duct 14 at its upper side . that is , the circulating air pathway runs from the drying compartment 2 through leading outlet 16 , u - shaped pathway 25 , suction opening 23 , double faced fan 21 , delivery opening 24 , duct 14 , and leading inlet 15 and returns to drying compartment 2 . in the leading outlet 16 , the body frame 26 has an l - shaped section installed which can be easily dismantled to deflect the drying air in the upward direction . a drain hole 27 is also formed together with a guard rib 28 surrounding the hole 27 from upper side in an umbrella - shape and deflecting the drying air and is formed as one integral unit at the lowest portion of the u - shaped pathway . the backside of the circulating air pathway 25 is closed by a partition board 29 except the back faces of the duct 14 and double faced fan 21 . the partition board 29 can be composed of metal , plastic or other materials , and is fixed on the boss 18 . the back face of the machine frame 1 is covered with a back cover 30 made of metal . the back cover 30 is formed with a recessed part 31 attached on the outside of the partition board 29 and the lowest portion of the u - shaped pathway , and is formed together with suction holes 32 having many holes facing the double faced fan 21 . also , an exhaust hole 35 is formed on the part corresponding to the lowest portion of the u - shaped pathway of the swelled stepped portion 34 which is formed on the back side of bottom plate 33 of the machine frame 1 . namely , the cooling air pathway 36 therefore has the routing from the suction opening 32 through the double faced fan 21 to the exhaust opening 35 which is formed by partitioning between the partition board 29 and back cover 30 with a recessed part 31 . drainage from the washing and drying compartment 2 is carried out by reversing the pump 11 . the drain hose 37 is assembled on the reinforcing rib 19 and is bent to form an upside down u - shape . the drainage hole of the hose 37 is installed in an l - shaped elbow 38 . on the other hand , a supporting plate 39 is horizontally extended toward the notched portion of the swelled stepped portion 34 from the lower case 7 as one integral unit . and , the supporting plate 39 is installed so that the stepped portion 34 which covers the notched portion and the plate is fixed if necessary . the supporting plate 39 is also positioned below the stepped portion 34 and is set around the elbow 38 so that the elbow can be rotated . however , the parts are engaged by cogs for each of the other eight ( 8 ) points around the inserted portion so that the parts are not easily rotated but can be moved step by step during rotation . the elbow 38 made of a relatively soft plastic is formed by blow molding process including the aforesaid cogged section and stopping flange to connect the drain hose 40 of the end below the stepped portion 34 [ refer to fig8 ( a ) and ( b )]. next , each cycle ( process ) of washing and drying will be explained . after the door 8 is opened and dishes and other tableware are put in the washing and drying compartment 2 , when the starting key is turned , water is supplied from the water supply source until the water surface reaches the cleaning water level . cleaning water is then sprayed from the nozzle 12 by the pump 11 while the water is circulating . the cleaning water is then heated by the heater 13 till it becomes warm . during washing , the cleaning water is made fresh several times , however , the cleaner or detergent is supplied only on the first cycle . after the second cycle , each washing operation is combined with rinsing . when the last washing cycle is completed and water fully drained , the heater 13 and double faced fan 21 ( motor 20 ) are activated . the compartment air is heated by the heater 13 and the air is circulated between the circulating wind pathway 25 and drying compartment 2 by the double faced fan 21 . moreover , the outside air is also passed into the cooling air pathway 36 by the double faced fan 21 . since the drying air is drawn from the suction side of the double faced fan 21 , flow velocity of the air is slow . after the air goes out from the leading outlet 16 in the upward direction , the air flows downward and upward again . then , the air is drawn into the fan 21 and reaches the duct 14 leading to the inlet 15 . on the other side , since the outside air is drawn from the suction opening 32 just near the double faced fan 21 , flow velocity of the air is quick . so , the air lowers the temperature of that portion of the u - shaped pathway . accordingly , since the drying air which goes out to the circulating air pathway 25 has a slow flow velocity , there is a large cooling capacity and large area of heat exchange . the air is effectively dehumidified and heated again in the drying compartment 2 ready for drying . condensation is generated in the u - shaped pathway of the circulating air pathway 25 . the water flows down along the partition board 29 to the drain hole 27 in the lowest portion and then , the water is discharged from the drying compartment 2 . as shown in fig7 the water can be discharged through the drain hole 27 on the rib 17 in the lowest portion of u - shaped pathway . here , in addition to being close to the guard rib 28 by about 2 mm distance from the rib 17 in the lowest portion of u - shaped pathway , the protruded face is also close , about 2 mm distance from the partition board 29 . accordingly , the circulated drying air does not flow into the drain hole 27 decreasing the dehumidification efficiency caused by leakage of the drying air . the back wall 3 of the upper case 4 made of plastic receives the warm water spray during the washing process and passes the drying air during the drying process . accordingly , the back wall 3 can easily generate noise plus being expanded or shrunken by the heat . however , for the dish washer with dryer according to the embodiment of the present invention , since the rib 17 , reinforcing rib 19 and duct 14 standing away from the back wall 3 to form the u - shaped pathway are composed as one integral unit , in addition to increasing the strength , the noise can be suppressed . furthermore , since the pathway of the air is not composed of different kinds of materials , ease of assembly will be improved . according to the dish washer with dryer ( s ) as mentioned above , since the heat of the air used for drying is exchanged with outside air during the circulation of drying air between the drying room and air circulation pathway , the drying air will become dehumidified and the drying efficiency can be increased markedly . also , reduction of the environmental conditions of the kitchen or cooking room caused by drainage due to air of high humidity can be prevented . therefore , a dish washer with dryer possessing high drying performance and a high degree installation flexibility is created . furthermore , according to the dish washer with dryer ( s ), the washing and drying compartment made of plastic is reinforced by the ribs which constitute the circulating pathway . in addition , to achieve the damping action against impingement of the cleaning water , leakage of the air and water can be prevented by suppressing the expansion caused by heat . also , leakage of air from the drain hole can be inhibited by applying the guard rib . therefore , a dish washer with dryer possessing high drying efficiency and yet emitting a minimum of noise during washing can be created . next , another embodiment of the present invention will be explained according to fig9 to 11 . a washing and drying compartment 102 composed of upper and lower cases is located in the machine ( metal fabrication ) frame 101 . a nozzle which does the washing work while cleaning water is circulated by a pump and a heater to increase the temperature of the cleaning water ( rinsing water ) and heats the interior air of the compartment for dish drying are located in the drying compartment 102 . a door and panel is provided in the front face portion of the machine frame 101 and drying compartment 102 . here , a leading outlet 104 , leading inlet 105 and drain hole 106 for condensation is opened on the room wall 103 of the upper case of the aforesaid drying compartment 102 ( for example , back wall or side wall ). a heat exchanger unit 107 is composed of a u - shaped pathway 109 partitioned by a plastic made rib 108 hanging in the box , fan casing 111 connected with a suction opening 110 at the terminal end of the u - shaped pathway in the horizontal axis , a motor 112 and double faced fan 113 fixed on the casing 111 , the u - shaped pathway 109 and casing 111 in a closed form and a partition board 114 which exposes the outer face of the double faced fan 113 . a inlet tube 115 protrudes from the starting end of the box bottom face of the u - shaped pathway 109 as one integral unit and a drain tube 116 also protrudes on the lowest portion of the box bottom face of the u - shaped pathway 109 as one integral unit . the oblong delivery opening of the fan casing 111 is a delivery opening 117 extending in the same direction as that of the aforesaid tubes 115 and 116 , and is located on the lower portion of the fan . the fan casing 111 is fixed on a partition board 114 and the partition board 114 is fixed on a boss protruded from the u - shaped pathway 109 . the partition board 114 is a plate made of metal or plastic having high heat exchange performance characteristics . an upward deflector 118 is located inside the box of the leading exit tube 115 . also , an umbrella - shaped guard rib 119 is provided inside the box drain tube 116 as one integral unit in order to prevent the air leakage . then , the relative positioning between the leading outlet 114 and the leading exit tube 115 , between the leading inlet 105 and the delivery tube 117 , and between the drain hole 106 and drain tube 116 are arranged so as to correspond to each other . the tubes are respectively inserted into the corresponding holes ( including outlet and inlet ) by applying the heat exchanger 107 unit from the back side of the washing and drying compartment 102 and the unit 107 is fixed by adequate means at three supporting points . in such a manner , the drying compartment 102 is connected to the circulating air pathway which consists of the u - shaped pathway 109 and fan casing 111 . accordingly , during drying , the drying air is circulated inside the inner face of the double faced fan 113 between the drying room 102 and the circulating air pathway by driving the double faced fan 113 . the outside air flows along the outer face of the partition board 114 outside the outer face of the fan . thereby , heat exchange is carried out through the partition board 114 and the drying air is also dehumidified , so , the drying efficiency is increased . the condensation on the inner face of the partition board 114 flows down from the drain tube 116 through the drain hole 106 and is discharged from the drying compartment 102 . the heat exchanger 107 unit is covered with a back cover 120 of the machine frame 101 . in order to improve the flow of the outside air , the cooling air pathway 123 is created in the space between the back cover 120 and partition board 114 by the suction hole 121 with many holes and recessed part . according to the dish washer with dryer ( 100s ) as described in the above , since the drying air is dehumidified and reused , the drying efficiency can be improved . moreover , since function of heat exchanger ( dehumidification ) is formed in a unit which is demountable , the ease of assembly can also be improved .	a dish washer with dryer comprising a washing and drying compartment defined in a main body wherein tableware to be cleaned and dried are loaded , a washing pump for spraying cleaning water into the compartment , a heater and fan for feeding drying air into the compartment after the spraying of the cleaning water , the dish washer with dryer comprising : a leading inlet and outlet for the drying air located on a compartment wall of the washing and drying room ; suction and exhaust holes for outside air located on an outer body wall of the main body wall ; a circulating air pathway for connecting the leading inlet with the leading outlet and a cooling air pathway for connecting the suction hole with the exhaust hole between the room wall and the outer body wall ; a double faced fan which forms a part of a partition board by which both pathways are partitioned .
as illustrated in fig1 and 2 , a representative embodiment of an edible particulate feeder 100 generally comprises a particulate handling portion 102 , a drive portion 104 , a mounting portion 106 and a quick - change portion 107 . edible particulate feeder 100 can comprise appropriate materials of construction for use in high volume production and processing of edible food products including routine sanitization and cleaning . representative materials for use in edible particulate feeder 100 can comprise stainless steel , aluminum and suitable plastics . with reference to fig1 , 2 , 3 , 4 and 5 , particulate handling portion 102 can comprise a drum housing 108 , a receiving drum 110 and a dispensing drum 112 . drum housing 108 is generally defined by a front mounting plate 114 , a side mounting plate 116 , a rear mounting plate 118 , a feed bin 120 , a portioning wall 122 and a transfer block 124 . front mounting plate 114 , portioning wall 122 and transfer block 124 generally define a receiving drum mount area 126 . feed bin 120 is generally defined by a bin loading end 128 and a bin dispensing end 130 . feed bin 120 can comprise a bin agitation assembly 132 . portioning wall 122 comprises an inner portioning surface 134 defining a generally arcuate profile adapted to closely conform to and interface with the receiving drum 110 . transfer block 124 can comprise a receiving surface 136 and a dispensing surface 138 having a plurality of transfer bores 140 defined therebetween . referring to fig3 , receiving drum 110 can comprise a receiving drum body 142 defined by a receiving drum diameter 144 , a receiving drum width 146 and a receiving drum perimeter surface 148 . receiving drum perimeter surface 148 comprises a plurality of spaced apart receiving apertures 150 arranged so as to define a plurality of receiving aperture rows 152 . each receiving aperture 150 can define a generally cylindrical receiving area for receiving desired quantities of edible particulates based on the volume of the receiving area . each receiving aperture row 152 can comprise any number of receiving apertures 150 , for example three receiving apertures 150 per receiving aperture row 152 as shown in fig3 . the number of receiving apertures 150 per receiving aperture row 152 , as well as the number of receiving aperture rows 152 , can vary based upon manufacturing characteristics of the edible products being produced such as , for example , production volume and product size . in addition , the size and shape of receiving apertures 150 can be varied . as illustrated in fig3 , dispensing drum 112 can comprise a dispensing drum body 154 defined by a dispensing drum diameter 156 , a dispensing drum width 158 and a dispensing drum perimeter surface 160 . dispensing drum perimeter surface 160 comprises a plurality of spaced apart dispensing apertures 162 arranged so as to define a plurality of dispensing aperture rows 164 . each dispensing aperture 162 can define a generally cylindrical dispensing for dispensing desired quantities of edible particulates based on the volume of the dispensing area . each dispensing aperture 162 has a dispensing area volume that is equal to or greater than the volume of the receiving area of each receiving aperture 150 . each dispensing aperture row 164 can comprise any number of dispensing apertures 130 . generally , the size and spacing of the dispensing apertures 162 within each dispensing aperture row 164 will correspond to the size and spacing of the receiving apertures 150 within each receiving aperture row 152 . as shown in fig4 , the transfer block 124 is mounted between the receiving drum 110 and the dispensing drum 112 with the receiving surface 136 proximate the receiving drum 110 and the dispensing surface 138 proximate the dispensing drum 112 . transfer bores 140 preferably resemble in size and appearance the receiving apertures 150 and dispensing apertures 162 . in a preferred embodiment , the number of transfer bores 140 , receiving apertures 150 and dispensing apertures 162 are equal . as such , transfer bores 140 generally serve to operably interconnect one receiving aperture 150 with a corresponding dispensing aperture 162 when the receiving drum 110 is rotatably positioned with one receiving aperture row 152 proximate the receiving surface 136 and one dispensing aperture row 164 proximate the dispensing surface 138 . referring to fig1 , 2 , 6 and 7 , drive portion 104 can comprise a shaft housing 166 having a first housing portion 168 , a second housing portion 170 and a drive mounting wall 172 . when combined with rear mounting plate 118 , the first housing portion 168 , second housing portion 170 and drive mounting wall 172 define an enclosed drive shaft area 174 for preventing personnel exposure to rotating drive shafts including a receiver drum drive shaft 176 , a dispensing drum drive shaft 178 and an agitation drive shaft 180 . attached to a rear exposed surface of the drive mounting wall 172 is a receiving drum drive motor assembly 182 and a dispensing drum drive motor assembly 184 . attached to side mounting plate 116 is an agitation drive motor assembly 186 . as illustrated in fig1 , 2 and 8 , mounting portion 106 can comprise a mounting platform 188 operably attaching to and supporting the particulate handling portion 102 . mounting platform 188 can attach to a rotating support bracket 190 having an upper horizontal support member 192 , a lower horizontal support member 194 and a brace member 196 . rotating support bracket 190 can further comprise upper and lower mounting pins 198 for rotatably mounting the edible particulate feeder 100 with respect to other process machinery such as , for example , extruders , conveyors and the like . quick - change portion 107 can comprise a receiving drum mounting assembly 200 and a dispensing drum assembly 202 . receiving drum mounting assembly 200 and dispensing drum assembly 202 can be similar with respect to components , materials of construction and operation but can differ based upon size and strength requirements necessary for proper operation and function with the corresponding receiving drum 110 and dispensing drum 112 . generally , the receiving drum mounting assembly 200 and dispensing drum assembly 202 each comprise a shaft collar 204 , a bearing assembly 206 , an alignment plate 208 and a mounting shaft 210 . as will be understood by a person of skill in the art , the edible particulate feeder 100 and its related components and sub - components can be assembled using suitable fabrication techniques . in order to prevent unnecessary confusion and obfuscation with respect to the current invention , individual fasteners used in the construction of the edible particulate feeder 100 have not been individually identified within the specification . in addition to the use of fasteners , other appropriate joining and / or fastening techniques , such as for example , welding , can be used to construct the edible particulate feeder 100 . in use , the edible particulate feeder 100 can supply edible particulates to a variety of food processing machinery for manufacturing ready - to - eat or ready - to - cook edible products . edible particulate feeder 100 provides repeatable , portioned amounts of edible particulates for placement on an exterior surface or within an edible product . generally , a bulk amount of edible particulates is fed into the bin loading end 128 of feed bin 120 . depending upon processing variables such as , for example , production volume and processing sophistication , the edible particulates can be manually loaded or continually , automatically loaded using suitable bulk feeding equipment such as , for example , a vibratory feeder . a wide variety of edible particulates , in either a whole or bit amount , can be portioned and supplied with the edible particulate feeder including items such as , for example , candy particulates , nut particulates , fruit particulates and vegetable particulates . due to the unique quick - change aspects of the edible particulate feeder 100 , which is discussed in detail below , the use of edible particulate feeder 100 can be especially beneficial in portioning and dispensing edible particulates which by their nature are susceptible to melting , smearing and / or deformation including items such as , for example , chocolate , peanut butter , butterscotch and / or similarly flavored chips and / or chunks . within feed bin 120 , the bin agitation assembly 132 driven by agitation drive motor assembly 186 , prevents the edible particulates from agglomerating such that the edible particulates are readily gravity fed to the bin dispensing end 130 . at the same time , receiving drum drive motor assembly 182 causes receiving drum 110 and more specifically , receiving drum perimeter surface 144 to rotate past the bin dispensing end 130 . as the receiving drum perimeter surface 144 rotates , the receiving aperture rows 152 are sequentially directed past the bin dispensing end 130 such that each receiving aperture 150 is exposed to and consequentially filled with the edible particulates . as the receiving drum 110 continues its rotation , filled receiving apertures 150 encounter the portioning wall 122 wherein excess edible particulates are essentially swept from the receiving apertures 150 and retained within the feed bin 120 due to the close conformity of the inner portioning surface 134 with the receiving drum perimeter surface 144 . these excess edible particulates remain within the bulk feeder 120 for loading into receiving apertures 150 within a subsequent receiving aperture row 152 . as receiving drum 110 continues its rotation , a filled receiving aperture row 150 , comprising a plurality of equivalently filled receiving apertures 150 , traverses the portioning wall 122 , and more specifically the inert portion surface 134 such that the edible particulates are physically retained within the receiving apertures 150 . as the receiving drum 100 continues its rotation , the filled receiving aperture row 150 encounters the receiving surface 136 of transfer block 124 . at the receiving surface 136 , each filled receiving aperture 150 is placed into aligned relation with a corresponding transfer bore 140 , wherein the edible particulates are subsequently gravity released from the filled receiving apertures 150 and enter the transfer bore 140 . as the edible particulates fall from each receiving aperture 150 into the corresponding transfer bore 140 , the edible particulates are directed from the receiving surface 136 to the dispensing surface 138 . at the dispensing surface 138 , the transfer bores 140 interface with the dispensing drum 112 . the dispensing drum 112 is generally rotated by the dispensing drum drive motor assembly 184 such that the dispensing drum 112 rotates in an opposed direction to the receiving drum 110 . the dispensing drum perimeter surface 160 is rotated along the transfer block 124 such that each dispensing aperture row 164 is directed proximate the dispensing surface 138 wherein each dispensing aperture 162 is placed into aligned relation with the corresponding transfer bore 140 . once a dispensing aperture 162 is aligned with its corresponding transfer bore 140 , the edible particulates fall from the transfer bore 140 into the dispensing aperture 162 . dispensing apertures 162 generally have a volume that is greater than or equal to the receiving apertures 150 such that the dispensing aperture 162 accepts the entire volume of edible particulates within each transfer bore 140 . as the dispensing drum 112 continues to turn , the now filled dispensing apertures 162 are directed to a downwardly facing disposition where the portioned amounts of edible particulates can be transferred to another processing system or placed onto a food product . during operation of the edible particulate feeder 100 , it can become necessary at various times to terminate the dispensing of the edible particulates and adjust process variables or to clean / sanitize the edible particulate feeder 100 . for instance , it can become necessary to vary the amount of edible particulates being dispensed with edible particulate feeder 100 based on product size or type . alternatively , it may be necessary to clean and / or sanitize the edible particulate feeder 100 if the type of edible particulate changes or following production runs or designated time periods . in order to reduce process downtime , edible particulate feeder 100 provides for rapid adjustment of particulate dispensing and cleaning / sanitization by providing for quick and easy removal and replacement of receiving drum 110 and dispensing drum 112 . receiving drum 110 is externally accessible for change - out utilizing the receiving drum mounting assembly 200 while the dispensing drum 112 is similarly accessible with the dispensing drum mounting assembly 202 . for example , both the receiving drum 110 and dispensing drum 112 can be quickly and easily replaced by removing the appropriate shaft collar 204 from the corresponding drive shaft , either receiver drum drive shaft 176 or dispensing drum drive shaft 178 . once the shaft collar 204 has been removed from the appropriate drive shaft , the alignment plate 208 including the bearing assembly 206 can be pulled from the drive shaft such that the alignment plate 208 can be rotated about the mounting shaft 210 such that either the receiving drum 110 or the dispensing drum 112 is exposed for removal . in some instances , a portable davit assembly or similar lifting apparatus can be used to slidably withdraw the exposed drum , either receiving drum 110 or dispensing drum 112 . for purposes of adjusting process variables including changing production rates and the amount of particulates dispensed , receiving drum 110 can be replaced with a second receiving drum that is substantially the same as receiving drum 100 with respect to exterior dimensions and construction with the exception of possible changes to the configuration of the receiving aperture rows 152 and the individual receiving apertures 150 . for instance , more or less edible particulates can be dispensed by selectively increasing or decreasing the volume of the receiving apertures 150 . in some instances , the number of receiving aperture rows 152 on the receiving drum perimeter surface can be selectively increased or decreased to accommodate increased or decreased production of the food product . depending upon the types of changes made to receiving drum 110 , it may become necessary to similarly replace the transfer block 124 and dispensing drum 112 , especially in the instance when changes are made to the size and / or spacing of the receiving apertures 150 . when such changes are made , a second transfer block and second dispensing drum having transfer bores 140 and dispensing apertures 162 corresponding to the receiving apertures 150 on the second receiving drum , can be reinstalled to the edible particulate feeder 100 . in the case of cleaning and / or sanitization of the edible particulate feeder 100 , removal of the receiving drum 110 , dispensing drum 112 and transfer block 124 can provide for easier access to surfaces in frequent contact with the edible particulates . in addition , receiving drum 110 , dispensing drum 112 and transfer block 124 can each be replaced with a similarly configured drum or block , such that the edible particulate feeder 100 can be quickly brought on line with “ clean ” components while the receiving drum 110 , dispensing drum 112 and transfer block 124 are cleaned and / or sanitized as individual components . this can provide for decreased downtime and increased production as compared to feeding units requiring cleaning and / or sanitization in an assembled or semi - assembled state . to facilitate operation of the edible particulate feeder 100 , it will be understood that suitable control and monitoring instrumentation can be utilized to ensure proper coordination of the receiving drum 110 and dispensing drum 112 . for instance , operation and rotation of the receiving drum 110 and dispensing drum 112 can be conducted using a suitable control instrument such as , for example , a microprocessor based control system or a plc ( programmable logic controller ) based system . in addition , positioning of the drum and more particularly , the aperture rows can be verified using optical , mechanical , proximity and / or other representative sensors and transmitters providing positioning information to the control system . in addition to varying process conditions by replacing the receiving drum 110 , dispensing drum 112 and transfer block 124 , the various drive systems including the receiving drum drive motor assembly 182 and the dispensing drum drive motor assembly 184 can include variable speed motors wherein rotation speeds for the receiving drum 110 and dispensing drum 112 can be selectively varied . in addition to controlling operation of the edible particulate feeder 100 , the control instrument can interface with other processing equipment including , for example , a particulate feeding system for filling the feed bin 120 with edible particulates and any processing equipment subsequent to the edible particulate feeder 100 for preparing the food product such as for example , conveying and / or packaging equipment . although various embodiments of the invention have been disclosed here for purposes of illustration , it should be understood that a variety of changes , modifications and substitutions may be incorporated without departing from either the spirit or scope of the invention .	methods and apparatus for accurately and repeatably depositing edible particulates on edible products . a dual - drum rotary feed system accurately meters an amount of edible particle for each edible product with a first rotary drum while a second rotary drum deposits the edible particulates onto or within the edible product . the dual - drum rotary feeder can comprise replaceable drums wherein drums can be quickly removed and replaced for cleaning , sanitization and to adjust processing conditions such as , for example , changes in production rates and / or product size .
referring to fig1 - 5 , there is shown the therapeutic shoe of this invention generally designated as numeral 10 . as depicted in fig1 - 4 , shoe 10 is shown as the insert with the over - structure comprising the conventional top , lacing and undersole not being shown for purposes of clarity ; it being understood that such over - structural elements will conform to the specific type of shoe desired . referring specifically to fig1 shoe 10 , comprises a top or foot - bearing portion 11 , a sole or ground bearing portion 12 , a lateral portion 13 , a medial portion 14 , a heel portion 15 , and a raised toe portion 16 for reasons hereinafter more fully explained . shoe 10 or more accurately ground bearing portion 12 is also formed with a groove or metatarsal split 17 to be more fully discussed hereinafter . all of said portions are the specific sub - structures forming same are enclosed in a high elastomeric sheathing 18 , which stretches at and with the compression and extension experienced at the aforesaid respective shoe portions . the bottom portion 18a of 18 may serve as the sole member . shoe 10 is sized in relation to the foot intented for its use , but is proportional to the specific size of the foot , and is also specifically designed to the approximate weight of user . as shown in fig1 and 5 , the user &# 39 ; s foot 20 is disposed within the confines of the lateral , medial and heel portions . the user &# 39 ; s toe 21 resides rearwardly of the raised top portion 16 as at interior curved portion 22 , and the user &# 39 ; s heel 23 resides forwardly of the raised portion 24 of heel portion 15 . referring to fig2 - 4 , the internal structure of shoe 10 is shown and comprises a scarfed or tapered top rubber member 25 and a bottom scarfed or tapered rubber member 26 which form a wedge - shaped internal configuration 27 which configuration extends from the toe as at 29 to , on the medial side , just beyond the metatarsal region as at 28 , and on the lateral side to the end of the heel reclined as at 30 . a plurality of transverse , angled ribs 31 formed of rubber are adhesively secured between members 25 and 26 so as to form a plurality of prism - shaped , air - tight chambers 32 . chambers 32 vary in size , and progressively increase in size from toe to heel . the ribs 31 may also increase in size , i . e . thickness , from toe to heel . each chamber is filled with a fluid , customarily a gas such as air under pressure , and the pressure within each chamber generally increases from toe to heel ; the thicker ribs being better suited to retain the greater air pressure . this concommitantly the heel region chambers , as are on the lateral side , are less compressible than the toe region chambers . in the aforesaid manner of construction , the weight of the foot will cause the fore - metatarsal portion to more compressibly yield than the aft - metatarsal portion , thus supporting the foot as well as cushioning same . in the medial region there is a fluid ( e . g . air )- filled , fluid - tight bag 35 , formed of thick rubber walls 36 . the walls 36 have a limited degree of elasticity so that the high pressure air in the bag 35 will not generally compress with the weight of the foot . of course the wall 36 strength is determined by the pressure inside the bag 35 and the weight the user exerts on this portion . bag 35 is adjacent to and adhesively sealed with ribs 31 so as to form an integral structure therewith as at 37 . the prism - shaped chambers are designed to be more compressible than the bag 35 chamber , so that the weight of the foot in the toe , metatarsal heads , and lateral portions proportionately compresses those portions but does not likewise compress the medial bag portion , whereby the effect is to provide a firm arch - support in the medial region while cushioning the foot , particularly so in the front regions . the toe region 16 is also of a specialized construction insofar as a thick - walled , fluid - filled , air - tight bag 39 , protects and cushions the forward parts of the toes . bag 39 is sealed to and made integral with member 25 , as at 40 and 41 . in another aspect the present invention comprises a metatarsal split integrally formed with and as a part of the shoe construction . specifically , bottom or sole member 26 is formed with transverse vee - groove 17 wherein the bottom of groove 17 is parallel to and disposed below the metatarsal line 44 . sheath 18 overlies this groove 17 . in walking , jogging or running the metatarsal groove 17 provides flexibility , and the shoe is thus a combined therapeutic supportive , cushioning and flexible construction . referring to fig5 there is shown a schematic outline of the shoe as at 42 with the foot bone structure 43 placed thereon . a line 44 indicates the metatarsal split , and is parallel with the bottom of groove 17 ( fig1 - 3 ). circumscribed region 46 defines the aft toe cushion regions , while circumscribed region 54 defines the compressible toe , metatarsal lead , and lateral positions , and region 45 defines the relatively non - compressible medial region . without wishing to be bound by any theory or mechanism it is believed that the more compressible lateral region in contradistinction to the medial region , and the raised heel portion , permit the correct parts of the foot namely the lateral aspect , metatarsal heads and digits to bear the weight in a cushioning manner , while the medial portion forms a supportive arch with the compression or depression of the aforesaid correct positions . it is also within the contemplation of this invention to provide a specific contour to the foot bearing surface so to provide a mechanical advantage to certain regions such as the anterior compartment of the leg and also posterior muscle group and intrinsic muscle group by allowing the toes to grasp and exercise the leg muscles comfortably . it is also within the scope of this invention to provide a dynamic system constituting fluid - filled chambers contained within the sole that redistributes weight automatically upon weight bearing pressure to the portions of the foot best adapted for bearing weight . the parts of the foot structured to bear the body weight are the lateral aspect , the fourth and fifth metatarsal shafts , bases and cuboid , and the first , second , third , fourth and fifth metatarsal heads distal to the surgical necks . in motion , as the weight on different parts of the foot shifts , an automatic cushion of the fluid forms under the excessive weight - bearing segment thereby redistributing the weight . therefore this dynamic system allows the foot to assume its correct neutral position where weight is on the lateral aspect and metatarsal heads and through the hallux yet it is sufficiently flexible to allow for individual deviations . it is also within the scope of this invention to include a broader heel base for a firmer , steadier support of the body weight . it may also be described to have a toe box portion forward of and adjacent to the toe portions to eliminate rubbing by the toes against the top shoe portion which causes corns and toenail loss . one preferred embodiment of the present invention is for the uniform distribution throughout the sole of variably compressible air - tight , air - filled chambers located between the inside of the shoe and the sole . the air - filled chambers are more compressible laterally than medially so that greater weight bearing will be on the lateral aspect . another preferred embodiment of the present invention is a therapeutic shoe having a sole member with a foot bearing portion and an oppositely disposed ground bearing portion which has a transversely disposed groove located below the metatarsal line of the foot . without wishing to be bound by any theory or mechanism it is believed that this transverse groove thus disposed will allow for easier dorsiflexion and relieve stress in the muscles of the anterior compartment of the leg . the laces , if any , should also begin , in the top shoe portion , aft the metatarsal split so as not to inhibit dorsiflexion . to achieve the aforementioned preferred embodiments , the chambers may be of any size or shape as long as the lateral aspect of the shoe is more compressible than the medial aspect . therefore , chambers located laterally may contain more compressible contents or be smaller than chambers located medially . it is also to be understood that chambers may contain any compressible contents such as air , sand , gas to attain the desired result . it is also understood that the invention may be made of any suitable material such as rubber , rubberized fabric , plastic , styrene - butadiene block polymers , butyl rubber or any equivalent material . the present invention may also be covered with any desirable material such as canvas , vinyl , leather or cotton . the afore - described distal toe region is an optional aspect of the present construction , and it is within the contemplation of this invention that the shoe 10 not be formed with element 39 , but may instead terminate at element 29 . the metatarsal phlangeal split 17 , is in a preferred aspect directly below line 44 . however , split 17 may more accurately contour the true metatarsal parabola and be slightly arched in this respect . raised heel portion 15 is found to relieve stress on the anterior and lateral muscular compartments of the leg thereby alleviating fatigue , and relieves stress on the posterior muscles as well . it is to be borne in mind that the air bag 35 while shown as a simple bag construction may nevertheless be constructed as compartments , with sufficient fluid pressure to exert a force against the medial portion of the foot with compression in the lateral portion . other materials and construction in addition to fluid - filled bags are also within the contemplation of this invention . the air - tight chambers can be filled by an desirable means such as pumping contents into the chambers , filling the chambers under pressure or suctioning the contents into the chambers . rubber cement may then be used to seal the chambers . the shoe of the present invention is useful in athletic footwear such as in sneakers , jogging shoes , soccer shoes , rugby shoes , tennis shoes , basketball shoes , football shoes , ski boots , climbing boots and the like ; as well as in normal walking footwear . a particularly preferred use with the present invention is in jogging shoes . as various other modifications may be made to the present invention as will be known to those skilled in the art , the present invention is not to be construed as being limited to the specific details as heretofore shown and discussed but shall be construed by the appended claims .	a therapeutic shoe is disclosed wherein a sole member contains a plurality of differently sized air - tight compartments of differing compressibility so that the weight of the foot in the metatarsal and lateral regions compresses so as to form a supportive arch in the medial position . this therapeutic shoe provides supportive therapeutic aspects combined with cushioning aspects for comfort to the user . suitable applications include the broad range of athletic uses including jogging shoes , and walking shoes as well .
the current arrangements for attaching biosensors to a living being have several shortcomings associated with them . one issue is that the sensor bandages are uncomfortable for the user . the adhesive material used to secure the sensor bandage to the body can be irritating to the skin . another issue is that the sensor bandage may fall off of the body . the adhesive material tends to breakdown quickly from exposure to sweat and moisture . the adhesive material also loses effectiveness as the skin exfoliates skin cells . thus , the bandage typically needs to be changed after a few days . a further issue is that the bandages cannot be cleaned , and after a short period of time may become dirty . again , the bandage typically needs to be changed after a few days . a still further issue is that the bandage sensor requires the conscious effort to attach the sensor to the body of the user . the living being may be a human , a domesticated animal ( e . g . a dog , cat , horse , cow , etc . ), or an undomesticated animal ( e . g . a tiger , elephant , cougar , etc .). embodiments of the invention provide a button that comprises a self - contained biosensor , where the button is located on an article of clothing . the sensor button solves the issues described above . the button sensor is not uncomfortable to wear and does not use an adhesive to attach itself to the body . the button sensor is hermetically sealed , and thus is not affected by moisture or sweat . also , because it is hermetically sealed , the button sensor may be washed along with the garment to which it is attached . the button sensor does not require separate conscious effort by the user . the user would merely put on the garment or article of clothing , e . g ., a shirt or pants , and then the button is operative . a garment may have one or more buttons according to embodiments of the invention . examples of a garment include a shirt , a pair of pants , a hat , a mask , underwear , a brassier , a hospital gown , a vest , a belt , jewelry ( such as a bracelet , a necklace , a wristwatch , a ring ), glasses , a hand bag , a wallet , a jacket , a sweat band , socks , shoes , and boots . the button sensor may serve a function for the garment to which it is attached . for example , the button may be used to hold portions of the garment together . such a button may be used to fixedly hold the portions together , so that a wearer cannot unbutton the portions , e . g . the button on the top of a hat . the button may be used to removably hold the portions together , so that a wearer can unbutton the portions , e . g . the button on the front of a dress shirt . the button may also connect two garments together , by being fixedly attached to a first garment , and allowing a second garment to be buttoned to the first garment . similarly , the button may connect more than two garments together . to secure the portions , the button may connect with a connector located on the other portion , e . g . a snap button engages with a snap connector . as another way to secure portions , the button may slip through a hole located on the other portion . the button also may serve as ornamentation on the garment , e . g . the button is an accent to the look of the garment , and does not have a functional aspect . the button may have both a functional aspect and an ornamental aspect . a button sensor may be used to monitor different biometrics of the body of the wearer of the garment . for example , a button sensor may be used to monitor temperature , oxygen content , blood component content , blood sugar content , heart rate , breathing rate , apnea , brain activity , altitude , cramps , bleeding , asthma attacks , anxiety attacks , loss of consciousness , high force impacts , a sudden fall , perspiration , moisture , velocity , movement , distance , location ( with a gps component ), etc . to measure these different metrics , the button sensor may incorporate one or more sensors . for example , a thermostat to measure temperature , an accelerometer to measure motion , a audio sensor to detect noise , a light sensor to detect light ( or wavelength ( s ) of light ), an electromagnetic wave detector , a radio wave detector . a button sensor has a transmitter to wirelessly send the data from the sensor to a remote receiver . a button sensor may act as a relay for a sensor that is located within a body . thus , such a button may receive data from an internal sensor , and then broadcast the data to a receiver . the antenna for the transmitter may be located within the button , and / or be a part of the button ( e . g ., the holes or the shell ). the antenna may also include passive elements that are exterior to the button . for example , the active elements may be located within the button , and the passive elements may comprise the wire that sews the button to the garment . in one embodiment , the antenna is woven into a garment with conductive thread and connected to the button sensor with conductive thread . note that the button sensor may receive information as well . for example , the button may receive operational instructions , e . g ., a command to take measurements , a command to send data , software updates , store data , analyze data , reset , deactivate , power down , and combinations thereof , etc . the receiver includes a memory to record the data . the receiver may also include a processor and associated software to process the received data into information usable by a technician , nurse , doctor , or other medical practitioner . the receiver may be a handheld unit , such as a personal data unit , a cell phone , or other handheld computing unit . the receiver may also be a portable unit , such as a monitor . the portable unit may include physical connections for power and or data . the receiver may also comprise a fixed data collection point that is permanently mounted in the garment wearer &# 39 ; s location . such a receiver may be located in a hospital , retirement home , or other facility that provides medical care . in one embodiment , the receiver is in a vehicle , for example to operate with roadside assistance systems . in another embodiment , the receiver is coupled to public transportation , for example to operate with emergency warning systems . in yet another embodiment , the receiver is a cellular phone , operating with emergency 911 systems . a sensing garment , or the garment having a button sensor , may comprise a single button sensor , or may comprise multiple button sensors . each button sensor may sense a single metric or may sense multiple metrics . a sensing garment may have multiple button sensors , with some of the button sensors providing measurements of one metric and other buttons sensors providing measurements of one or more other metrics . other sensing garments may have one or more buttons that measure a single metric and one or more buttons that measure multiple metrics . the sensing garment may have multiple buttons sensing the same metric , with the data from the buttons being correlated to determine information of the metric . for example , one embodiment may have multiple button sensors to measure body temperature . the sensors may be located at different parts of the body . the receiver would then receive the data from the sensors , and knowing the position of the sensors , determine the temperature of the core of the body of the wearer . the sensing garment may have multiple buttons sensing the same metric , with the data providing differential information to determine the metric . for example , an embodiment may have multiple button sensors to measure movement . the sensors may be located at different parts of the body , with one sensor located near the sternum , and another sensor located near the clavicle . as the wearer breathes , the sensor near the sternum would move , while the sensor near the clavicle would remain relatively stationary . the data from the sensor buttons could then be used by the receiver to determine a rate of breathing of the wearer . in another embodiment , sensing garments on multiple living beings interact . in this embodiment , a sensor network collects social behavior data , such as social interactive patterns , and can facilitate detecting hostile , violent and / or dangerous events . in one example , the sensor network enables studying of interpersonal stimulus / response or unconscious interpersonal communication . the button may use one or more technologies to transmit the information to the receiver . for example , the button may use a bluetooth transmitter , an infrared transmitter , a wireless lan - type transmitter , a short range cellular - type transmitter , a radio frequency ( rf ) transmitter , a gigahertz range transmitter , etc . the button sensor is fixedly attached to its associated garment . it may be attached by having thread or wire sewn through holes in the button sensor to the garment . it may also be attached by using a rivet that connects the button to the garment . in either event , the button sensor remains with the garment , and is hermetically sealed such that when the garment is washed and / or dried , the electronic aspects of the button sensor are not harmed . the button sensor is a material capable of withstanding water , exposure to corrosive materials such as laundry soap , bleach or other oxidizing agents , and the vibration and heat of a dryer . suitable materials are known to exist , for example plastics or epoxies . the button sensor is not coupled to an external power source , and thus the button sensor would have to store power sufficient for extended operations , to generate its own power , or both . garments used in institutional settings , e . g . hospitals , may use sensor buttons that only have power storage . such garments may be have the power supply recharged on a periodic basis . for example , many institutions change gowns on a daily basis ( if not sooner ). the power storage is able to power the button for a few days before a recharge is necessary . furthermore , the operation of the buttons may be cascaded . for example , a gown may have two sensor buttons sensing the same metric , with only one button operating at a time . thus , the second button would begin operations when the first button has exhausted its power supply . the first button may send a signal that is received by the second button to begin operations , or the receiver may send a signal to the second button to begin operations , after the receiver has stopped receiving data from the first button . the button sensor may use one or more different types of power generation to provide itself power for its operations . for example , one type of power generation is solar power . the button sensor may include one or more solar panels that receive light and generate power from the light . the button sensor may also have an ambient rf or direct rf generator that uses radio frequency ( rf ) energy to generate power . another type of power generation is piezoelectric power generation . the button sensor includes a piezoelectric device to generate power from vibration . for example , as the button sensor is bounced around in a washer and / or a dryer , the button generates power . another type of power generation uses a thermocouple . the button sensor includes a thermocouple to generate power from a heat differential to which the button is exposed . the side of the button that is closer to the body is warmer than the side of the button facing away from the body . this temperature differential may be used to generate power . another type of power generation uses a kinetic generator . the button sensor includes such a generator so that as the button is moved , it generates power . other types of power generation include a chemical reaction . in one embodiment , the power generator is attached to the garment ( for example , a flexible solar panel on the back of a shirt ) and coupled to the button sensor with conductive thread . in another embodiment , short range magnetic conduction , and / or wireless power is used for connectivity . a sensing garment may have multiple buttons , with different ones of the buttons using different power generation methods . for example , one button may be using solar power to generate power , another button may be using a kinetic generation , and a further button may be using a thermocouple . thus , at any given time , at least one of the buttons will be generating power . note that the location of the button on the garment may be used to select the type of power generation . for example , a long sleeve shirt may use kinetic generation for a button located on the sleeves , solar generation for a button located on the collar or upper chest , thermocouple for a button located on the lower chest , and infrared solar power for a button located at the bottom of the shirt ( which may be tucked into pants ). note that the metric to be sensed may select the type of power generation . for example , if the button is to measure movement , then the power button may use a kinematic generator . thus , the button would generate power to measure the movement , and if there is no movement , there is no data needed to be taken , and thus no power is required or provided . fig1 depicts a perspective view of a button sensor 100 , according to embodiments of the invention . in this arrangement , the button 100 would be secured to an article of clothing or garment via the holes 102 . thread , wire , pins , rivets , etc . would pass through the holes and connect the button to the garment . the button 100 includes a sealed container 101 that includes a wireless sensor ( not shown ) that would sense data for a metric from a living being wearing the garment . the wireless sensor is formed into a shape that allows the holes 102 to pass through the button 100 without interfering with the operation of the wireless sensor . the button 100 can be formed using many different production processes . for example , the button 100 can be formed by using an injection molding process . the wireless sensor is placed into an injection mold . material is then injected into the mold to encapsulate the wireless sensor and form the button 100 . the holes 102 may then be drilled into the button or may be formed as part of the injection molding process . the button 100 can also be formed by using a package . the button is secured in a package . a lid is then welded , e . g . via ultrasonic welding , onto the package . the holes 102 already exist in the package and the lid . either process results in a hermetically sealed button 100 that comprises the wireless sensor . note that other processes may be used to form the button 100 , as long as the button 100 is hermetically sealed and able to perform the functions described herein . fig2 a - 2c respectively depict a perspective view , a side elevation view , and a bottom elevation view of another button sensor 200 , according to embodiments of the invention . in this arrangement , the button 200 would be secured to an article of clothing or garment via an attachment assembly including a post 203 and a base 202 . the button 200 has an upper portion 201 that is a sealed container and includes a wireless sensor ( not shown ) that would sense data for a metric from the living being wearing the garment . the button 200 is attached to a garment by passing the post 203 through the garment . the base 202 is then secured to the post by riveting the base 202 to the post 203 . the base 202 may also be secured to the post 203 by an adhesive , welding ( e . g . ultrasonic welding ), screwing the base 202 to the post 203 , friction , etc . in this embodiment , the post 203 and the base 202 may perform functions beyond attaching the button 200 to the garment . the post 203 and the base 202 may comprise power storage and / or power generation aspects of the button 200 . for example , the base 202 and / or the post 203 may include a battery , capacitor , or other power storage unit . furthermore , the base 202 may serve as a heat sink for a thermocouple power generator . the base 202 is adjacent to or in contact with the body of the wearer of the garment , and thus is exposed to body heat . the upper portion is located away from the body , and is exposed to ambient temperature . the upper portion may then use the temperature differential to generate electricity . the post 203 would conduct the body heat from the base 202 to the upper portion 201 . as another example , the base 202 may comprise an infrared solar panel to generate electricity from body heat . the post 203 and the base 202 may also be part of the antenna of the button . for example , the base 202 may have a passive element energized by an active element located within the upper portion 201 . the base 202 may also have an active element of the antenna that is connected to a signal source located within the upper portion 201 through the post 203 . the base 202 may also include a sensor 204 that is used to measure a metric of the wearer of the garment . the base 202 is adjacent to or in contact with the body of the wearer of the garment , and thus the sensor 204 would be able to more accurately measure the desired metric . the button 200 may be formed by using either the injection molding process or the packaging process described above with respect to the button 100 . note that other processes may be used to form the button 200 , as long as the button 200 is hermetically sealed and able to perform the functions described herein . fig3 depicts a block diagram showing an exemplary arrangement of a wireless sensor circuit 300 embedded into a button sensor 100 or 200 , according to embodiments of the invention . the circuit 300 uses a controller 304 to manage operations of the circuit 300 . the controller 304 executes software that is stored in a memory 303 in performing its various functions . the circuit 300 includes at least one sensor 305 that measures a body metric . the circuit may include multiple sensors , each of which measures a different metric . the controller 304 may direct the sensor as to when and how long to take measurements . alternatively , the sensor may be set to continuously take measurements . the data from the measurements is stored in the memory 303 . the circuit 300 uses a transceiver 302 to send the measured data to a receiver . the controller 304 may direct the transceiver 302 as to when to send data . alternatively , the transceiver may be set to continuously send data . the transceiver 302 is coupled to an antenna 301 to send the data . the transceiver , via the antenna 301 , may also receive data from an external source . the received data may be operating commands , e . g . turn on / off , send data , etc , or may be other information , e . g . software updates , etc . the circuit 300 is self - powered and includes at least a power storage device 306 or power generator 307 . the power storage device 306 may be a battery , a capacitor , or other power storage unit . in some situations , the power storage device may be able to be recharged on a periodic basis . for example , if the button is located on a garment that is used in an institutional setting , e . g . a hospital or retirement home , and the care of the garment is handled by the institution , then the power storage device may be recharged on a periodic basis . alternatively , the circuit 300 includes a power generator 307 that generates power for use by the circuit 300 . excess power is stored in the power storage device 306 . the controller 304 may direct the power generator 307 as to when to operate . alternatively , the power generator 307 may be set to continuously operate , so long as capable . note that the button may include a power generator or a power storage device , or both . fig4 a depicts a cross - section of an exemplary structure 400 of the wireless circuit 300 of fig3 embedded in the button sensor 100 of fig1 . the structure 400 in this arrangement is a through silicon stacked ( tss ) integrated circuit . the various layers communicate with each other and be powered by vertical through silicon vias ( tsvs ). note that this arrangement is by way of example only , as other types of circuits may be used . the circuit 400 includes a package substrate 404 , upon which other circuit components are stacked . the various components function as described in the preceding paragraphs . the circuit includes a controller 402 , and a memory 403 . the structure 400 also includes a power storage 406 and power generator 407 . as an example , the structure 400 uses a solar panel as the power generator 407 . thus , a lid 409 includes a window 408 to allow light ( either visible and / or infrared light ) to reach the solar panel . the structure 400 also includes antenna 401 and transceiver 412 . the sensor 405 of the circuit 400 is located on the side of the button that is adjacent to the body of the wearer . as an example , the sensor 405 receives the electromagnetic impulses that a heart generates in beating . thus , the sensor 405 measures heart rate . in this example , the structure 400 is located in a package 410 , and surrounded by material 411 , such as a plastic or epoxy , to protect the circuit from damage . the connection between the lid 409 and the package 410 is hermetically sealed . the package may be formed by injection molding or insert molding . fig4 b depicts a cross - section of an exemplary circuit 450 of the wireless circuit 300 of fig3 embedded in the button sensor 200 of fig2 a - 2c . the circuit 450 in this arrangement is a through silicon stacked integrated circuit . the various layers would communicate with each other and be powered by vertical through silicon vias . note that this arrangement is by way of example only , as other types of circuits may be used . the circuit 450 includes a substrate 454 , upon which other circuit components are stacked . the various components function as described in the preceding paragraphs . the circuit includes a controller 452 , and a memory 453 . the circuit 450 also includes a power storage 456 and a power generator 457 . as an example , the circuit 450 uses a thermocouple as the power generator 457 . thus , heat from the body of the wearer is transmitted from the base 458 to the power generator 457 . to facilitate heat transfer , the post 460 includes heat conductive material 462 , e . g . a metal . similarly , the base 458 also includes a heat conductive material 464 . the metal may be coated with a material to prevent corrosion . the circuit 450 also includes an antenna 451 and a transceiver 465 . the sensor 455 of the circuit 400 is located at the base of the post 460 . this location places the sensor either directly in contact with the wearer or adjacent to the wearer . as an example , the sensor 455 detects the temperature of the wearer . in this example , the circuit is formed in a button that has been injection molded . the button may include an outer layer 459 of a decorative material . the injection molding surrounds the circuit 450 with a material 461 , such as plastic or epoxy . the package may be formed by injection molding or insert molding . a retaining clip 463 is also shown . the retaining clip 463 holds a garment between the retaining clip 463 and the base 458 to prevent the garment from riding up the post 460 . fig5 is a schematic diagram of an exemplary arrangement of a wireless communication system 500 that includes at least one button sensor 501 - 1 , 501 - n , of fig1 and / or fig2 a - 2c . for purposes of illustration , fig5 depicts multiple buttons 501 - 1 to 501 - n communicating with receivers 502 and 504 . the receiver 502 may be a hand - held receiver , such as cell phone or personal data assistant , while the receiver 504 may be fixed or portable , e . g . a base monitor , a meter reader , or laptop computer . note that this is by way of example only , as there may only be one button , and there may be more / fewer receivers . the buttons 501 - 1 - 501 - n may communicate with either receiver 502 , 504 . each of the receivers may send data to or receive data from the buttons . the receivers 502 , 504 may communicate with each , other either directly , or by using a cell system 503 , or a cell system that is coupled to a land line system 505 . although specific circuitry has been set forth , it will be appreciated by those skilled in the art that not all of the disclosed circuitry is required to practice the invention . for example , the controller and memory could be integrated into a single chip . similarly , the power storage and power generator could be implemented as a single chip . other combinations of separately shown ( or combined ) circuits are also contemplated . moreover , certain well known circuits have not been described , to maintain focus on the invention . note that any of the functions described herein may be implemented in hardware , software , and / or firmware , and / or any combination thereof . when implemented in software , the elements of the present invention are essentially the code segments to perform the necessary tasks . the program or code segments can be stored in a processor readable medium . the “ processor readable medium ” may include any medium that can store or transfer information . examples of the processor readable medium include an electronic circuit , a semiconductor memory device , a rom , a flash memory , an erasable rom ( erom ), a floppy diskette , a compact disk cd - rom , an optical disk , a hard disk , a fiber optic medium , etc . the code segments may be downloaded via computer networks such as the internet , intranet , etc . although the present invention and its advantages have been described in detail , it should be understood that various changes , substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims . moreover , the scope of the present application is not intended to be limited to the particular embodiments of the process , machine , manufacture , composition of matter , means , methods and steps described in the specification . as one of ordinary skill in the art will readily appreciate from the disclosure of the present invention , processes , machines , manufacture , compositions of matter , means , methods , or steps , presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention . accordingly , the appended claims are intended to include within their scope such processes , machines , manufacture , compositions of matter , means , methods , or steps .	a hermetically sealed electronic closure device , or button , includes a self - renewing power source , a sensor for measuring a metric , a memory storing information , a data processing circuit for controlling operations of the device , and a transceiver for sending and receiving information . the device is a standard part of a clothing item that is inconspicuous to a wearer of the clothing item .
the bifurcated peritoneal catheter provides a second internal catheter tube , i . e ., within the peritoneal cavity of the patient , to provide a secondary or backup path for the introduction of dialysate fluid and the withdrawal of contaminated fluid during peritoneal dialysis . this greatly reduces the need for surgery to remove a single internal tube and to install a new tube in the patient , as there is a much greater likelihood that one of the two internal tubes will remain open . as both internal tubes perform the same function , fluid flow through the two internal tubes and the primary tube is always in the same direction at any given time , i . e ., into the peritoneal cavity or out from the peritoneal cavity . a number of different embodiments are disclosed herein . fig1 of the drawings illustrates a top plan view of a first embodiment of the bifurcated peritoneal catheter , designated as bifurcated peritoneal catheter ( or catheter ) 100 . the catheter 100 includes a thin , elongate primary tube 102 having a closed wall 104 with an open proximal end 106 and an opposite open distal end 108 . some portion of the length of the primary tube 102 to the proximal end 106 thereof extends externally from the patient to appropriate fluid delivery and collection points external to the patient during the dialysis procedure . the distal end portion 108 of the primary tube 102 is surgically implanted within the patient . first and second internal tubes , respectively 110 a and 110 b , are adapted for surgical placement within the peritoneal cavity of the patient . each of these two internal tubes 110 a , 110 b comprise a long , thin element having a wall , respectively 112 a and 112 b , with an open proximal end , respectively 114 a and 114 b , and opposite open distal end , respectively 116 a and 116 b . the proximal ends 114 a , 114 b of the two internal tubes 110 a , 110 b are joined to and communicate with the distal end 108 of the primary tube 102 and with one another and foil a small acute angle 118 between the two proximal ends 114 a , 114 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . this greatly improves the fluid flow through the bifurcated catheter 100 by reducing fluid turbulence at the juncture of the tubes . it will be seen that this structure results in unidirectional flow of any fluid flowing within the catheter 100 at any given time , as fluid cannot flow in one direction through one of the internal tubes and in an opposite direction in the other of the internal tubes due to their common connection to and communication with the distal end 108 of the primary tube 102 . the walls 112 a , 112 b of the two internal tubes 110 a , 110 b have closed portions 120 a , 120 b extending for some lengths from points adjacent their proximal ends 114 a , 114 b , but have porous portions 122 a , 122 b extending for some lengths from points adjacent their distal ends 116 a , 116 b to the closed wall portions 120 a , 120 b thereof . in the catheter 100 example of fig1 , a single annular subcutaneous cuff 124 is located concentrically about the distal end 108 of the primary tube 102 , adjacent its juncture with the proximal ends 114 a and 114 b of the two internal tubes 110 a and 110 b . this subcutaneous cuff 124 serves as a seal between the skin and body of the patient and the primary tube 102 . an additional cuff may be provided , as shown and described further below for other embodiments . it will also be noted in the catheter 100 example of fig1 that the first internal tube 110 a is substantially straight , while the second internal tube 110 b is curved away from the first internal tube 110 a . this configuration is exemplary and any practicable number of different straight , curved , and / or coiled internal tubes can be formed , with various examples illustrated in subsequent drawing figs . and described below . fig2 of the drawings illustrates a second embodiment bifurcated peritoneal catheter 200 . the catheter 200 is configured similarly to the catheter 100 of fig1 , i . e ., having a thin , elongate primary tube 202 with a closed wall 204 , open proximal end 206 , and opposite open distal end 208 . it will be seen that the length of the primary tube 202 is somewhat shorter than the length of the primary tube 102 of the catheter 100 of fig1 . the primary tube lengths of any of the bifurcated peritoneal catheters described herein , as well as their two internal catheters , can be formed or adjusted as desired . first and second internal tubes , respectively 210 a and 210 b , are also adapted for surgical placement within the peritoneal cavity of the patient . these two internal tubes 210 a , 210 b each comprise a long , thin element having a wall , respectively 212 a and 212 b , with an open proximal end , respectively 214 a and 214 b , and opposite open distal end , respectively 216 a and 216 b . the proximal ends 214 a , 214 b of the two internal tubes 210 a , 210 b are joined to and communicate with the distal end 208 of the primary tube 202 and with one another and form a small acute angle 218 between the two proximal ends 214 a , 214 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 212 a , 212 b of the two internal tubes 210 a , 210 b have closed portions 220 a , 220 b extending for some lengths from points adjacent their proximal ends 214 a , 214 b , but have porous portions 222 a , 222 b extending for some lengths from points adjacent their distal ends 216 a , 216 b to the closed wall portions 220 a , 220 b thereof . a single annular subcutaneous cuff 224 is located concentrically about the distal end 208 of the primary tube 202 , adjacent its juncture with the proximal ends 214 a and 214 b of the two internal tubes 210 a and 210 b . it will be noted in the catheter 200 example of fig2 that both of the internal tubes 210 a and 210 b are curved away from one another . this , and the shorter length of the primary tube 202 , is the primary distinction between the bifurcated peritoneal catheter embodiment 100 of fig1 and the embodiment 200 of fig2 . fig3 of the drawings illustrates a third embodiment 300 of the bifurcated peritoneal catheter . the catheter 300 is configured similarly to the catheter 100 of fig1 , i . e ., having a thin , elongate primary tube 302 with a closed wall 304 , open proximal end 306 , and opposite open distal end 308 . first and second internal tubes , respectively 310 a and 310 b , extend from the distal end 308 of the primary tube 302 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 312 a and 312 b , an open proximal end , respectively 314 a and 314 b , and opposite open distal end , respectively 316 a and 316 b . the proximal ends 314 a , 314 b of the two internal tubes 310 a , 310 b are joined to and communicate with the distal end 308 of the primary tube 302 and with one another and form a small acute angle 318 between the two proximal ends 314 a , 314 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 312 a , 312 b of the two internal tubes 310 a , 310 b have closed portions 320 a , 320 b extending for some lengths from points adjacent their proximal ends 314 a , 314 b , but have porous portions 322 a , 322 b extending for some lengths from points adjacent their distal ends 316 a , 316 b to the closed wall portions 320 a , 320 b thereof . the first internal tube 310 a is straight and the second internal tube 310 b is curved , as in the bifurcated peritoneal catheter embodiment 100 of fig1 . the above - described structure of the third embodiment catheter 300 is essentially the same as that of the first embodiment catheter 100 of fig1 . however , it will be seen that the bifurcated peritoneal catheter 300 of fig3 includes two annular cuffs thereon . a first annular cuff 324 comprising a subcutaneous cuff is located about the medial portion 326 of the primary tube 302 , with a second or deep cuff 328 disposed about the distal end 308 of the primary tube 302 adjacent its juncture with the proximal ends 314 a and 314 b of the two internal tubes 310 a and 310 b . the second or deep cuff 328 provides a secure passage for the distal end 308 of the primary tube 302 through the abdominal wall of the patient . fig4 of the drawings illustrates a fourth embodiment 400 of the bifurcated peritoneal catheter . the catheter 400 is configured similarly to the catheter 300 of fig3 , i . e ., having a thin , elongate primary tube 402 with a closed wall 404 , open proximal end 406 , and opposite open distal end 408 . first and second internal tubes , respectively 410 a and 410 b , extend from the distal end 408 of the primary tube 402 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 412 a and 412 b , an open proximal end , respectively 414 a and 414 b , and opposite open distal end , respectively 416 a and 416 b . the proximal ends 414 a , 414 b of the two internal tubes 410 a , 410 b are joined to and communicate with the distal end 408 of the primary tube 402 and with one another and form a small acute angle 418 between the two proximal ends 414 a , 414 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 412 a , 412 b of the two internal tubes 410 a , 410 b have closed portions 420 a , 420 b extending for some lengths from points adjacent their proximal ends 414 a , 414 b , but have porous portions 422 a , 422 b extending for some lengths from points adjacent their distal ends 416 a , 416 b to the closed wall portions 420 a , 420 b thereof . the bifurcated peritoneal catheter embodiment 400 of fig4 differs from the embodiment 300 of fig3 in that both of the two internal tubes 410 a , 410 b have slight curvatures and are curved away from each other , as in the catheter embodiment 200 of fig2 . the above - described structure of the fourth embodiment catheter 400 is essentially the same as that of the first embodiment catheter 200 of fig2 . however , it will be seen that the bifurcated peritoneal catheter 400 of fig4 includes two annular cuffs thereon . a first annular cuff 424 comprising a subcutaneous cuff is located about the medial portion 426 of the primary tube 402 , with a second or deep cuff 428 disposed about the distal end 408 of the primary tube 402 adjacent its juncture with the proximal ends 414 a and 414 b of the two internal tubes 410 a and 410 b . fig5 of the drawings illustrates a fifth embodiment 500 of the bifurcated peritoneal catheter . the components of the catheter 500 are somewhat analogous to those of the catheter 400 of fig4 , i . e ., having a thin , elongate primary tube 502 with a closed wall 504 , open proximal end 506 , and opposite open distal end 508 . first and second internal tubes , respectively 510 a and 510 b , extend from the distal end 508 of the primary tube 502 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 512 a and 512 b , an open proximal end , respectively 514 a and 514 b , and opposite open distal end , respectively 516 a and 516 b . the proximal ends 514 a , 514 b of the two internal tubes 510 a , 510 b are joined to and communicate with the distal end 508 of the primary tube 502 and with one another and form a small acute angle 518 between the two proximal ends 514 a , 514 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 512 a , 512 b of the two internal tubes 510 a , 510 b have closed portions 520 a , 520 b extending for some lengths from points adjacent their proximal ends 514 a , 514 b , but have porous portions 522 a , 522 b extending for some lengths from points adjacent their distal ends 516 a , 516 b to the closed wall portions 520 a , 520 b thereof . the bifurcated peritoneal catheter 500 of fig5 includes two annular cuffs thereon , as in the catheter embodiments 300 of fig3 and 400 of fig4 . a first annular cuff 524 comprising a subcutaneous cuff is located about the medial portion 526 of the primary tube 502 , with a second or deep cuff 528 disposed about the distal end 508 of the primary tube 502 adjacent its juncture with the proximal ends 514 a and 514 b of the two internal tubes 510 a and 510 b . the bifurcated peritoneal catheter embodiment 500 of fig5 differs from the embodiment 400 of fig4 in two different ways related to the orientation of the primary tube 502 and the two internal tubes 510 a and 510 b . first , it will be seen that the primary tube 502 includes an acute bend or curvature 530 between the two cuffs 524 and 528 . ( this is known as a “ swan neck ” curve in the field of the invention .) this assists in positioning the external portion of the primary tube 502 relative to the patient . second , it will be seen that both of the porous wall portions 522 a and 522 b of the two internal tubes 510 a , 510 b are coiled , with the coiled portions subtending approximately 570 degrees , more or less . this provides a greater length of internal tube in a relatively small area , in order to more efficiently distribute dialysate fluid and draw contaminated fluid from the peritoneal cavity of the patient . in the example of fig5 , the first coiled portion 522 a is coiled in a first direction , e . g ., counterclockwise in the plan view of fig5 , with the second coiled portion 522 b being coiled opposite the direction of the first coiled portion 522 a , i . e ., clockwise for the second coiled portion . fig6 of the drawings illustrates a sixth embodiment 600 of the bifurcated peritoneal catheter . the components of the catheter 600 are somewhat analogous to those of the catheter 500 of fig5 , i . e ., having a thin , elongate primary tube 602 with a closed wall 604 , open proximal end 606 , and opposite open distal end 608 . first and second internal tubes , respectively 610 a and 610 b , extend from the distal end 608 of the primary tube 602 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 612 a and 612 b , an open proximal end , respectively 614 a and 614 b , and opposite open distal end , respectively 616 a and 616 b . the proximal ends 614 a , 614 b of the two internal tubes 610 a , 610 b are joined to and communicate with the distal end 608 of the primary tube 602 and with one another and form a small acute angle 618 between the two proximal ends 614 a , 614 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 612 a , 612 b of the two internal tubes 610 a , 610 b have closed portions 620 a , 620 b extending for some lengths from points adjacent their proximal ends 614 a , 614 b , but have porous portions 622 a , 622 b extending for some lengths from points adjacent their distal ends 616 a , 616 b to the closed wall portions 620 a , 620 b thereof . the bifurcated peritoneal catheter 600 of fig6 includes two annular cuffs thereon , as in the catheter embodiments 300 , 400 , and 500 , respectively of fig3 , and fig5 . a first annular cuff 624 comprising a subcutaneous cuff is located about the medial portion 626 of the primary tube 602 , with a second or deep cuff 628 disposed about the distal end 608 of the primary tube 602 adjacent its juncture with the proximal ends 614 a and 614 b of the two internal tubes 610 a and 610 b . the bifurcated peritoneal catheter embodiment 600 of fig6 differs from the embodiment 500 of fig5 due to the configurations of the internal tubes 610 a and 610 b . it will be seen that the first internal tube 610 a is straight , while the porous wall portion 612 b of the second internal tube 610 b is coiled , with the coiled portion subtending approximately 570 degrees , more or less . in the example of fig6 , the coiled portion 622 b of the second internal tube 610 b is coiled in a first direction , e . g ., counterclockwise in the plan view of fig6 , resulting in its coil being toward the straight length of the first internal tube 610 a . fig7 of the drawings illustrates a sixth embodiment 700 of the bifurcated peritoneal catheter . the components of the catheter 700 are essentially similar to those of the catheter 600 of fig6 , i . e ., having a thin , elongate primary tube 702 with a closed wall 704 , open proximal end 706 , and opposite open distal end 708 . first and second internal tubes , respectively 710 a and 710 b , extend from the distal end 708 of the primary tube 702 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 712 a and 712 b , an open proximal end , respectively 714 a and 714 b , and opposite open distal end , respectively 716 a and 716 b . the proximal ends 714 a , 714 b of the two internal tubes 710 a , 710 b are joined to and communicate with the distal end 708 of the primary tube 702 and with one another and form a small acute angle 718 between the two proximal ends 714 a , 714 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 712 a , 712 b of the two internal tubes 710 a , 710 b have closed portions 720 a , 720 b extending for some lengths from points adjacent their proximal ends 714 a , 714 b , but have porous portions 722 a , 722 b extending for some lengths from points adjacent their distal ends 716 a , 716 b to the closed wall portions 720 a , 720 b thereof . the bifurcated peritoneal catheter 700 of fig7 includes two annular cuffs thereon , as in the catheter embodiments 300 through 600 , respectively of fig3 through 6 . a first annular cuff 724 comprising a subcutaneous cuff is located about the medial portion 726 of the primary tube 702 , with a second or deep cuff 728 disposed about the distal end 708 of the primary tube 702 adjacent its juncture with the proximal ends 714 a and 714 b of the two internal tubes 710 a and 710 b . the bifurcated peritoneal catheter embodiment 700 of fig7 differs from the embodiment 600 of fig6 due to the curvature or coil of the second internal tube 610 b . in the example of fig7 , the coiled portion 722 b of the second internal tube 710 b is coiled in a second direction , e . g ., clockwise in the plan view of fig7 , resulting in its coil being away the straight length of the first internal tube 710 a . fig8 of the drawings illustrates an eighth embodiment 800 of the bifurcated peritoneal catheter . the components of the catheter 800 are quite similar to those of the catheter 500 of fig5 , i . e ., having a thin , elongate primary tube 802 with a closed wall 804 , open proximal end 806 , and opposite open distal end 808 . first and second internal tubes , respectively 810 a and 810 b , extend from the distal end 808 of the primary tube 802 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 812 a and 812 b , an open proximal end , respectively 814 a and 814 b , and opposite open distal end , respectively 816 a and 816 b . the proximal ends 814 a , 814 b of the two internal tubes 810 a , 810 b are joined to and communicate with the distal end 808 of the primary tube 802 and with one another and form a small acute angle 818 between the two proximal ends 814 a , 814 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 812 a , 812 b of the two internal tubes 810 a , 810 b have closed portions 820 a , 820 b extending for some lengths from points adjacent their proximal ends 814 a , 814 b , but have porous portions 822 a , 822 b extending for some lengths from points adjacent their distal ends 816 a , 816 b to the closed wall portions 820 a , 820 b thereof . the bifurcated peritoneal catheter 800 of fig8 includes two annular cuffs thereon , as in the catheter embodiments 300 through 700 respectively of fig3 through 7 . a first annular cuff 824 comprising a subcutaneous cuff is located about the medial portion 826 of the primary tube 802 , with a second or deep cuff 828 disposed about the distal end 808 of the primary tube 802 adjacent its juncture with the proximal ends 814 a and 814 b of the two internal tubes 810 a and 810 b . the bifurcated peritoneal catheter embodiment 800 of fig8 differs from the embodiment 500 of fig5 due to the orientation of the coiled porous portion 822 a of the first internal tube 810 a . in fig8 , the coiled porous portion 822 a of the first internal tube 810 a is coiled in the same orientation or direction as the coiled porous portion 822 b of the second internal tube 810 b , i . e ., both are coiled in a first or clockwise orientation as viewed from the orientation shown in fig8 . fig9 of the drawings illustrates a ninth embodiment 900 of the bifurcated peritoneal catheter . the components of the catheter 900 are somewhat analogous to those of the catheter 500 of fig5 , but rather than the internal tubes of the catheter being coiled as in the catheter embodiment 500 of fig5 , the internal tubes of the catheter embodiment 900 of fig9 are straight . the catheter 900 has a thin , elongate primary tube 902 with a closed wall 904 , open proximal end 906 , and opposite open distal end 908 . first and second internal tubes , respectively 910 a and 910 b , extend from the distal end 908 of the primary tube 902 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 912 a and 912 b , an open proximal end , respectively 914 a and 914 b , and opposite open distal end , respectively 916 a and 916 b . the proximal ends 914 a , 914 b of the two internal tubes 910 a , 910 b are joined to and communicate with the distal end 908 of the primary tube 902 and with one another and form a small acute angle 918 between the two proximal ends 914 a , 914 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 912 a , 912 b of the two internal tubes 910 a , 910 b have closed portions 920 a , 920 b extending for some lengths from points adjacent their proximal ends 914 a , 914 b , but have porous portions 922 a , 922 b extending for some lengths from points adjacent their distal ends 916 a , 916 b to the closed wall portions 920 a , 920 b thereof . the bifurcated peritoneal catheter 900 of fig9 includes two annular cuffs thereon , as in the catheter embodiments 300 through 800 respectively of fig3 through 8 . a first annular cuff 924 comprising a subcutaneous cuff is located about the medial portion 926 of the primary tube 902 , with a second or deep cuff 928 disposed about the distal end 908 of the primary tube 902 adjacent its juncture with the proximal ends 914 a and 914 b of the two internal tubes 910 a and 910 b . the bifurcated peritoneal catheter embodiment 900 of fig9 differs from the embodiment 800 of fig8 in that the two internal tubes 810 a and 810 b are both straight , and diverge from their juncture with the distal end 808 of the primary tube 802 by a constant small included angle , as described further above . otherwise , the bifurcated peritoneal catheter 900 of fig9 is substantially the same as the bifurcated peritoneal catheter of fig8 . fig1 of the drawings illustrates a tenth embodiment 1000 of the bifurcated peritoneal catheter . the catheter 1000 is essentially a combination of the catheter 400 of fig4 with its straight primary tube and the catheter 600 of fig6 with its coiled perforated portion of the second internal tube . the catheter 1000 has a thin , elongate primary tube 1002 with a closed wall 1004 , open proximal end 1006 , and opposite open distal end 1008 . first and second internal tubes , respectively 1010 a and 1010 b , extend from the distal end 1008 of the primary tube 1002 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 1012 a and 1012 b , an open proximal end , respectively 1014 a and 1014 b , and opposite open distal end , respectively 1016 a and 1016 b . the proximal ends 1014 a , 1014 b of the two internal tubes 1010 a , 1010 b are joined to and communicate with the distal end 1008 of the primary tube 1002 and with one another and form a small acute angle 1018 between the two proximal ends 1014 a , 1014 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 1012 a , 1012 b of the two internal tubes 1010 a , 1010 b have closed portions 1020 a , 1020 b extending for some lengths from points adjacent their proximal ends 1014 a , 1014 b , but have porous portions 1022 a , 1022 b extending for some lengths from points adjacent their distal ends 1016 a , 1016 b to the closed wall portions 1020 a , 1020 b thereof . the bifurcated peritoneal catheter embodiment 1000 of fig1 differs from the embodiment 400 of fig4 in that the first internal tube 1010 a is straight , while the porous portion 1022 b of the second internal tube 1010 b is coiled toward the first internal tube 1010 a . this configuration of the internal tubes is similar to that of the sixth embodiment catheter 600 of fig6 . however , the catheter 1000 of fig1 is similar to the embodiments 300 of fig3 and 400 of fig4 in that the primary tube 1002 is straight , rather than having an acute bend or curve therein . it will also be seen that the bifurcated peritoneal catheter 1000 of fig4 includes two annular cuffs thereon , as in the embodiments 300 and 400 respectively of fig3 and 4 . a first annular cuff 1024 comprising a subcutaneous cuff is located about the medial portion 1026 of the primary tube 1002 , with a second or deep cuff 1028 disposed about the distal end 1008 of the primary tube 1002 adjacent its juncture with the proximal ends 1014 a and 1014 b of the two internal tubes 1010 a and 1010 b . fig1 of the drawings illustrates an eleventh embodiment 1100 of the bifurcated peritoneal catheter . the catheter 1100 is essentially a combination of the catheter 400 of fig4 with its straight primary tube and the catheter 800 of fig8 with its two coiled perforated portions of its two internal tubes . the catheter 1100 has a thin , elongate primary tube 1102 with a closed wall 1104 , open proximal end 1106 , and opposite open distal end 1108 . first and second internal tubes , respectively 1110 a and 1110 b , extend from the distal end 1108 of the primary tube 1102 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 1112 a and 1112 b , an open proximal end , respectively 1114 a and 1114 b , and opposite open distal end , respectively 1116 a and 1116 b . the proximal ends 1114 a , 1114 b of the two internal tubes 1110 a , 1110 b are joined to and communicate with the distal end 1108 of the primary tube 1102 and with one another and form a small acute angle 1118 between the two proximal ends 1114 a , 1114 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 1112 a , 1112 b of the two internal tubes 1110 a , 1110 b have closed portions 1120 a , 1120 b extending for some lengths from points adjacent their proximal ends 1114 a , 1114 b , but have porous portions 1122 a , 1122 b extending for some lengths from points adjacent their distal ends 1116 a , 1116 b to the closed wall portions 1120 a , 1120 b thereof . a first annular cuff 1124 comprising a subcutaneous cuff is located about the medial portion 1126 of the primary tube 1102 , with a second or deep cuff 1128 disposed about the distal end 1108 of the primary tube 1102 adjacent its juncture with the proximal ends 1114 a and 1114 b of the two internal tubes 1110 a and 1110 b . the bifurcated peritoneal catheter embodiment 1100 of fig1 differs from the embodiment 800 of fig8 in that the primary tube 1102 is straight , rather than having an acute bend or curve therein . the two perforated portions 1122 a and 1122 b of the internal tubes 1110 a and 1110 b are both coiled in the same direction , i . e ., clockwise . this is the same orientation as the coils of the perforated portions 822 a , 822 b of the catheter embodiment 800 of fig8 , but the orientation may appear different in the embodiment 1100 of fig1 due to the straight primary tube 1102 . fig1 of the drawings illustrates a twelfth embodiment 1200 of the bifurcated peritoneal catheter . the catheter 1200 most closely resembles the catheter 1000 of fig1 , excepting the relative placement of the straight and curved internal tubes . the catheter 1200 has a thin , elongate primary tube 1202 with a closed wall 1204 , open proximal end 1206 , and opposite open distal end 1208 . first and second internal tubes , respectively 1210 a and 1210 b , extend from the distal end 1208 of the primary tube 1202 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 1212 a and 1212 b , an open proximal end , respectively 1214 a and 1214 b , and opposite open distal end , respectively 1216 a and 1216 b . the proximal ends 1214 a , 1214 b of the two internal tubes 1210 a , 1210 b are joined to and communicate with the distal end 1208 of the primary tube 1202 and with one another and form a small acute angle 1218 between the two proximal ends 1214 a , 1214 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 1212 a , 1212 b of the two internal tubes 1210 a , 1210 b have closed portions 1220 a , 1220 b extending for some lengths from points adjacent their proximal ends 1214 a , 1214 b , but have porous portions 1222 a , 1222 b extending for some lengths from points adjacent their distal ends 1216 a , 1216 b to the closed wall portions 1220 a , 1220 b thereof . a first annular cuff 1224 comprising a subcutaneous cuff is located about the medial portion 1226 of the primary tube 1202 , with a second or deep cuff 1228 disposed about the distal end 1208 of the primary tube 1202 adjacent its juncture with the proximal ends 1214 a and 1214 b of the two internal tubes 1210 a and 1210 b . the bifurcated peritoneal catheter embodiment 1200 of fig1 differs from the embodiment 1000 of fig1 in that the porous portion 1222 a of the first internal tube 1210 a is coiled , while the second internal tube 1210 b is straight . the orientation of the porous coiled portions 1022 b of the embodiment of fig1 and 1222 a of the embodiment of fig1 is the same , i . e ., clockwise in both cases . it will be seen that this orients the coil of the second internal tube 1010 b of the embodiment of fig1 toward the opposite first internal tube 1010 a , while the coil of the first internal tube 1210 a of the embodiment of fig1 is oriented away from the opposite second internal tube 1210 b . fig1 of the drawings illustrates a thirteenth embodiment 1300 of the bifurcated peritoneal catheter . the catheter 1300 is similar to the catheter 1100 of fig1 , excepting the orientation of the porous coiled portion of the second internal tube . the catheter 1300 has a thin , elongate primary tube 1302 with a closed wall 1304 , open proximal end 1306 , and opposite open distal end 1308 . first and second internal tubes , respectively 1310 a and 1310 b , extend from the distal end 1308 of the primary tube 1302 , with the first and second internal tubes each comprising a long , thin element having a wall , respectively 1312 a and 1312 b , an open proximal end , respectively 1314 a and 1314 b , and opposite open distal end , respectively 1316 a and 1316 b . the proximal ends 1314 a , 1314 b of the two internal tubes 1310 a , 1310 b are joined to and communicate with the distal end 1308 of the primary tube 1302 and with one another and form a small acute angle 1318 between the two proximal ends 1314 a , 1314 b , e . g ., on the order of twenty to thirty degrees included angle therebetween . the walls 1312 a , 1312 b of the two internal tubes 1310 a , 1310 b have closed portions 1320 a , 1320 b extending for some lengths from points adjacent their proximal ends 1314 a , 1314 b , but have porous portions 1322 a , 1322 b extending for some lengths from points adjacent their distal ends 1316 a , 1316 b to the closed wall portions 1320 a , 1320 b thereof . a first annular cuff 1324 comprising a subcutaneous cuff is located about the medial portion 1326 of the primary tube 1302 , with a second or deep cuff 1328 disposed about the distal end 1308 of the primary tube 1302 adjacent its juncture with the proximal ends 1314 a and 1314 b of the two internal tubes 1310 a and 1310 b . the bifurcated peritoneal catheter embodiment 1300 of fig1 differs from the embodiment 1100 of fig1 in that the porous coiled portion 1322 b of the second internal tube 1310 b is coiled in the opposite direction from the corresponding portion 1322 a of the first internal tube 1310 a , i . e ., counterclockwise , with the coiled porous portion 1322 a of the first internal tube being coiled clockwise . in other words , the first and second internal tubes 1310 a , 1310 b are coiled away from one another . it will be seen that further permutations and combinations of the bidirectional peritoneal catheter can be provided in addition to those illustrated in the drawing figs . and described above . such permutations and combinations can include one or two cuffs , straight or curved primary tubes , various combinations of straight and curved or coiled internal tubes , etc ., as desired . it is to be understood that the present invention is not limited to the embodiments described above , but encompasses any and all embodiments within the scope of the following claims .	the bifurcated peritoneal catheter serves as a peritoneal dialysis device for patients with kidney failure . the catheter includes a primary tube with two porous internal tubes extending therefrom at a small acute angle to one another . the two internal tubes provide a solution to the potential problem of blockage in a single catheter tube , greatly reducing the potential need for surgery to remove and replace such a single catheter tube . the bifurcated peritoneal catheter includes a subcutaneous cuff , and can include a second deep cuff in the abdominal wall . either or both of the internal tubes can be straight , curved or coiled , with the curvatures and coils oriented in the same direction , toward one another , or away from one another .
the medical imaging system shown in fig1 comprises ( 1 ) a c - arm ( vascular gantry ) carrying ( 2 ) a radiation source at one end ( for example x - rays ) and ( 3 ) a sensor at the other end . conventionally , the c - arm can be swiveled around the axis of a table 4 designed to carry the patient being imaged and can be moved around said table 4 in various movements l , p , c , designated by the double arrows in the figure , in such a way as to adjust the positioning of said arm in relation to the part of the patient undergoing imaging . note that , movement l corresponds to the c - arm &# 39 ; s horizontal movement ( swinging movement around the axis going by source 2 and sensor 3 ); movement c corresponds to the c - arm moving around its own axis , on its own plane ; movement p corresponds to the c - arm &# 39 ; s movement around the table &# 39 ; s main axis . for the various movements , the centered positions as represented in fig1 are designated by o . source 2 , for example , is an x - ray source . it radiates conically and the radiation is picked up by sensor 3 after going through the patient undergoing the imaging . sensor 3 is of the matrix type and for this purpose possesses a 3 a detector matrix . the signals sent from the detectors of the 3 a matrix are then digitalized , and a processing unit 5 receives , processes , and where applicable , memorizes the resulting 2 - d digital images . before and after processing , the resulting 2 - d digital images may also be memorized independently of processing unit 5 , and for this purpose any type of media may be used : cd - rom , usb drive , central server etc . conventionally , it is possible for example to carry out prior acquisition of a set of 2 - d images of the organ to be examined , by having the c - arm orbit around the patient . the resulting set of 2 - d images is then processed in order to generate a 3 - d image of the organ that is to be imaged . the procedures for isolating a given organ and determining a 3 - d image from a set of 2 - d images are well known . the 3 - d image is then displayed from a given angle , with the 3 - d image points corresponding to the x and y coordinates in the plane perpendicular to the angle from which view z was shot , being projected in accordance with their depth along that direction . the 3 - d image can , for example , be displayed in superimposition over a 2 - d image , for example a fluoroscopic image acquired in real - time in the course of an operation . an example of this type of processing is described in the scientific article “ model of a vascular c - arm for 3 - d augmented fluoroscopy in interventional radiology ”, sebastien gorges et al , which was presented at the international miccai 2005 conference in palm springs , usa . the goal of the calibration is to determine the mechanical parameters of table 4 from a set of x - ray images of a phantom target placed on the table , with the images having been shot using different table positions . the mechanical model of table 4 is made up of parameters that model the movements of table 4 and its distortions . in the rest of the description , a simple model of table 4 is considered , comprising transfer movements only . v { right arrow over ( _ )} la =[ x la , y la , z la ] t v { right arrow over ( _ )} lo =[ x lo , y lo , z lo ] t v { right arrow over ( _ )} h =[ x h , y h , z h ] t \| ( equation 1 ) are the vectors that represent the three directions of the table 4 in the process of being determined . naturally , the simplified model described here is intended only as at non - limiting example . x { right arrow over ( _ )} la =[ x la , y la , z la ] t v { right arrow over ( _ )} lo =[ x lo , y lo , z lo ] t v { right arrow over ( _ )} h =[ x h , y h , z h ] t \| ( equation 2 ) d_la , d_h are measurements of the table 4 &# 39 ; s movements ( for example , in 1 / 10 mm ) generated from external sensors making it possible to measure the movements of table 4 with relationship to a reference position . for a given orientation of the vascular gantry and a focal length , the definition consists of + max , − max , and ‘ centered ’, on the following table 4 positions : 1 . centered : is the position of table 4 when the helix is iso - centered 2 . − max : maximum transfer movement that may be applied while maintaining the image of the helix in the x - ray image 3 . + max : symmetrical transfer movement . in addition , in the rest of the text , m = k * e designates the image projection matrix of an object positioned on table 4 in a given relative position of table 4 and the vascular gantry , where k is the matrix of the intrinsic parameters that take into account the internal geometry of the vascular gantry , and where e is the matrix of the extrinsic parameters that describe table 4 &# 39 ; s and the gantry &# 39 ; s relative positioning . a description of the projection matrix parameters can be found in the article “ multiple view geometry in computer vision ”, richard hartley and andrew zisserman , cambridge press university , june 2000 . the matrix k of the intrinsic parameters correspond to the projection parameters of source 2 from sensor 3 . the matrix e of the extrinsic parameters depends on the position of c - gantry in relation to the table . in order to determine the parameters of table 4 &# 39 ; s mechanical model for various positions of table 4 , we acquire a certain number of images from a phantom helix that is positioned on table 4 . for example , sets of three or five x - ray images are acquired for the various positions of the c - arm and the following movements : position of the c - arm such that l = p = c = 0 with the table being moved according to v_la , position of the c - arm such that l = 0 ( with the plane of the c - arm being perpendicular to the table &# 39 ; s axis ) and p = c = o , the table being moved according to v_lo , position of the c - arm such that l = 0 ( with the plane of the c - arm being perpendicular to the table &# 39 ; s axis ) and p = c = o , with the table being moved according to v_h position of the c - arm such that l = 0 ( with the plane of the c - arm being perpendicular to the table &# 39 ; s axis ), p = o , c = 90 ( with the c - arm swiveling on its own axis ), and the table being moved according to v_h , position of the c - arm such that l = o ( with the plane of the c - arm being perpendicular to the table &# 39 ; s axis ), p = o , c = 90 ( with the c - arm swiveling on its own axis ), and the table being moved according to v_lat . once the various image sets have been acquired , calibration is carried out in the following manner : in this description the goal is to determine the transfer vectors for table 4 representing the three degrees of play , namely : for each set of images , we detect for the image processing the 2d positioning of the calibration target points in the x - ray images that were obtained . following this , a method is used in order to determine the m_i projection matrix as well as the k_i and e_i matrices of the intrinsic parameters and extrinsic parameters corresponding to each of the images i of the set of positions , with m_i = k_ie_i . the calculation carried out for this purpose is for example determined by unit 5 . such a method is described for example in vision par ordinateur ( using the computer as a vision tool ) by radu horaud and olivier monga , chapter 5 ; “ an optimal solution for mobile camera calibration ”, by puget and skorda , eccv 1990 ; and “ geometrical calibration for 3 d x - ray imaging ”, by rougé , picard , trousset et ponchut , spie 1993 - 161 - 169 . for each set of images corresponding to a single movement of the table ( i . e . image sets named v_la , v_lo , and v_h set ) we will determine in linear fashion the table &# 39 ; s transfer movement vectors . for this purpose , for each image set , we carry out the following processing : we determine table 4 &# 39 ; s single ( simple ) movements by combining the extrinsic parameters e_ref taken from a reference position and the intrinsic parameters e_i of any position , determined in step 1 . movement d of table 4 between the two positions can now be given by : where r is equal to the identity if the table 4 is not rotated . since we also know the length of the movement effectively measured by the system &# 39 ; s sensors between position i and the reference position ref , we infer that table 4 &# 39 ; s movement v \| corresponds to the image set being processed . where d is the movement of table 4 measured by the system sensors . on the basis of several successive determinations and on the basis of several reference points selected in the image set being processed , we calculate a mean value for this movement vector in order to improve the precision of this estimation , we optimize , in non - linear fashion , a criterion c that verifies acquired x - ray images in all positions : where q_ij is the i th target point detected in image j , m_j is the projection matrix constructed from data from the model of table 4 as well as table 4 &# 39 ; s position sensors , and xi is the i th 3d calibration target point . in our example , the table 4 model is made up solely of transfer vectors , in such a way that mj is given by : with dla , dlo and dh , the length of the transfer generated by the transfer sensors in relationship to the reference position respectively for the lateral , longitudinal and height axes . v { right arrow over ( _ )} la =[ x la , y la , z la ] t v { right arrow over ( _ )} lo =[ x lo , y lo , z lo ] t v { right arrow over ( _ )} h =[ x h , y h , z h ] t \| ( equation 10 ) when the transfer movement vectors ( v { right arrow over ( _ )} la v { right arrow over ( _ )} lo v { right arrow over ( _ )} h )\| have been established , we possess precise knowledge of the table &# 39 ; s basic movement axes ( in the present case , its transfer movement directions ). this information is taken into account by unit 5 when it calculates table 4 &# 39 ; s true position . unit 5 calculates the true position by combining the vectors from the basic movements with the controlled movement for table 4 . the transfer vectors thus determined are used in applications in order to calculate the new projection matrix mj taking into account the table &# 39 ; s movement . the table vectors and the position sensor values ( in accordance with the above equation referenced eq 1 ) are combined in order to determine the new matrix . the new matrix can then be used in augmented fluoroscopy applications to help in guiding tools .	a method of calibrating a mechanical model of behaviour and movement of an interventional radiology table by moving the table over at least one degree of freedom , acquiring at least one set of images corresponding to different positions of the table and c - arm , obtaining at least one set of images of a test object from different positions , using the images of the test object to determine parameters of the mechanical model of table behaviour and movement , and combining these parameters with data given by table movement sensors so as to deduce the true relative positions of the table with respect to the medical imaging system .
example embodiments will now be described more fully with reference to the accompanying drawings . example embodiments are provided so that this disclosure will be thorough , and will fully convey the scope to those who are skilled in the art . numerous specific details are set forth such as examples of specific components , devices , and methods , to provide a thorough understanding of embodiments of the present disclosure . it will be apparent to those skilled in the art that specific details need not be employed , that example embodiments may be embodied in many different forms and that neither should be construed to limit the scope of the disclosure . the terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting . as used herein , the singular forms “ a ”, “ an ” and “ the ” may be intended to include the plural forms as well , unless the context clearly indicates otherwise . the terms “ comprises ,” “ comprising ,” “ including ,” and “ having ,” are inclusive and therefore specify the presence of stated features , integers , steps , operations , elements , and / or components , but do not preclude the presence or addition of one or more other features , integers , steps , operations , elements , components , and / or groups thereof . the method steps , processes , and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated , unless specifically identified as an order of performance . it is also to be understood that additional or alternative steps may be employed . when an element or layer is referred to as being “ on ”, “ engaged to ”, “ connected to ” or “ coupled to ” another element or layer , it may be directly on , engaged , connected or coupled to the other element or layer , or intervening elements or layers may be present . in contrast , when an element is referred to as being “ directly on ,” “ directly engaged to ”, “ directly connected to ” or “ directly coupled to ” another element or layer , there may be no intervening elements or layers present . other words used to describe the relationship between elements should be interpreted in a like fashion ( e . g ., “ between ” versus “ directly between ,” “ adjacent ” versus “ directly adjacent ,” etc .). as used herein , the term “ and / or ” includes any and all combinations of one or more of the associated listed items . although the terms first , second , third , etc . may be used herein to describe various elements , components , regions , layers and / or sections , these elements , components , regions , layers and / or sections should not be limited by these terms . these terms may be only used to distinguish one element , component , region , layer or section from another region , layer or section . terms such as “ first ,” “ second ,” and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context . thus , a first element , component , region , layer or section discussed below could be termed a second element , component , region , layer or section without departing from the teachings of the example embodiments . spatially relative terms , such as “ inner ,” “ outer ,” “ beneath ”, “ below ”, “ lower ”, “ above ”, “ upper ” and the like , may be used herein for ease of description to describe one element or feature &# 39 ; s relationship to another element ( s ) or feature ( s ) as illustrated in the figures . spatially relative terms may be intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures . for example , if the device in the figures is turned over , elements described as “ below ” or “ beneath ” other elements or features would then be oriented “ above ” the other elements or features . thus , the example term “ below ” can encompass both an orientation of above and below . the device may be otherwise oriented ( rotated 90 degrees or at other orientations ) and the spatially relative descriptors used herein interpreted accordingly . according to the principles of the present teachings , a device for endoscopic treatment of upper gastrointestinal bleeding ( generally referred to as endocutter 10 ) is provided having advantageous construction and method of use . the endocutter 10 of the present teachings can employ mechanical power to break blood clots and other stomach contents down into pieces that are small enough to pass through the conventional endoscope vacuum channel . the endocutter 10 , which can be in the form of a releasable attachment , is designed to prevent damage to the stomach mucosa by the spinning blade while still preserving the functions of an endoscope , and is used in conjunction with a method that efficiently removes clots and improves the overall effectiveness of the procedure . referring now to the figures , endocutter 10 is an endoscope accessory that is designed to be compatible with any single or dual channel endoscope 100 . the device 10 is used in conjunction with the existing suction power of endoscope 100 and is operable to chop or otherwise cut blood clots and other stomach content into smaller pieces before such pieces enter the narrow instrument channel of the conventional endoscope . generally , endocutter 10 comprises a motor 12 having a pair of electrical input contacts 14 , 16 , an internal drive system for converting electrical power received through the pair of electrical input contacts 14 , 16 to rotational drive power via an output shaft 18 . motor 12 rotatably supports a spinning cutting blade 20 operably coupled to output shaft 18 of motor 12 for rotation therewith . cutting blade 20 can comprise , in some embodiments , one or more sharpened edge ( or beveled ) regions 22 to aid in cutting . however , it should be appreciated that non - sharpened edges can also be used . still further , in some embodiments , cutting blade 20 can be shaped to promote a desired circulating flow of material , such as by way of a pitched or otherwise inclined cutting blade or propeller . according to the present teachings , cutting blade 20 is encased within a clear polycarbonate casing 24 . in some embodiments , casing 24 is a cylindrical member being made of polycarbonate , such as a transparent biocompatible plastic material , having a proximal end 26 and a distal end 28 . it should be appreciated that casing 24 can have alternative shapes , including a venturi shape , a converging or diverging cone shape , or any other shape conducive for use within a gastrointestinal system and in conjunction with material flow . in some embodiments , cutting blade 20 is generally surrounded and recessed within casing 24 in order to protect the stomach and upper gi tract lining from contact with cutting blade 20 . in this way , cutting blade 20 is inwardly spaced from distal end 28 of casing 24 a sufficient distance to prevent or at least minimize the occurrence of stomach lining intruding within an inner volume of casing 24 and contacting cutting blade 20 . in some embodiments , motor 12 is sized sufficiently small to be placed within casing 24 , while preserving vision through the objective lens and use of the instrument channel for the flow of material . in some embodiments , proximal end 26 of casing 24 can be attached or otherwise fastened to a distal end 102 of endoscope 100 . in some embodiments , this can be achieved using a rubber attachment member generally surrounding endocutter 10 and endoscope 100 . the rubber attachment member can be sized to exert a reliable and simple connection between endocutter 10 and endoscope 100 . in this way , power lines ( not shown ) that are electrically coupled to electrical input contacts 14 , 16 can extend through an internal channel of conventional endoscope 100 to provide electrical energy to motor 12 . the power lines can be coupled to a power source , such as a dc power source . a switch ( not shown ) can be used to actuate motor 12 . endocutter 10 thus permits the physician to quickly locate the bleeding site without the need for repeated endoscope reinsertions or extended patient stay . in some embodiments , by way of non - limiting example , endocutter 10 can be 30 mm long with an outer diameter of 14 . 6 mm ( similar in diameter to dual - channel endoscopes ). the hydrophobic - coated polycarbonate casing 24 can be 25 mm long , 1 mm thick , and transparent to maximize the field of vision . a motor holder 50 can extend from an inner wall 52 of casing 24 to support motor 12 and can define an inner diameter of 5 . 5 mm and a curvature angle from 45 degrees to 360 degrees ( or any curvature in between ) to receive and secure the motor 12 . motor holder 50 can extend the length of motor 12 , such as for example about 16 mm . motor holder 50 can comprise a stem 54 connecting motor holder 50 to inner wall 52 of casing 24 . generally , in some embodiments , motor 12 is 6 mm in diameter , 22 . 9 mm in length , and the tip of the motor shaft is placed 1 mm from distal end 28 of casing 24 . the cutting blade 20 is connected to the output shaft 18 using a blade connector placed over the shaft . the cutting blade 20 can , in some embodiments , be 10 mm in length , 1 mm in width , and 0 . 1 mm in thickness and can be passed over the spindle of the blade connector and glued using industrial stainless steel adhesive . the terminals of the motor can be enclosed in a wire cap to ensure robust fastening of wires . a rubber attachment can be fixed over the other end of the casing and secures the endocutter 10 at the distal end 102 of the endoscope 100 . it should be appreciated that the motor placement and blade size are specifically designed to maximize cutting ability while still maintaining use of the endoscope &# 39 ; s resources ( i . e . the objective lens and instrument channels ). the device is also compatible with current therapeutic measures that are required during upper gi bleeding , so the physician does not have to retract and reinsert the endoscope for active - bleed treatment . it should also be appreciated that case size and motor size are specifically designed to permit unobstructed flow of cut blood clots and other stomach content passed the motor , within the internal volume of the casing , and subsequently into the vacuum lines of the endoscope . it has been found that in some embodiments , 80 % or less obstruction can suffice ; however , in some embodiments , 50 % or less obstruction provides improved performance . such measurements can be obtained by defining a cross - sectional area along a plane orthogonal to a longitudinal axis of the motor and / or casing and comparing the same to an internal cross - sectional area of the casing along the same plane . the foregoing description of the embodiments has been provided for purposes of illustration and description . it is not intended to be exhaustive or to limit the invention . individual elements or features of a particular embodiment are generally not limited to that particular embodiment , but , where applicable , are interchangeable and can be used in a selected embodiment , even if not specifically shown or described . the same may also be varied in many ways . such variations are not to be regarded as a departure from the invention , and all such modifications are intended to be included within the scope of the invention .	a medical device designed for gastrointestinal endoscopists who require a more effective means of removing blood clots from the upper gi tract during episodes of upper gi bleeding . it is an endoscope attachment that breaks down blood clots , allowing them to be removed through the existing endoscope suction channel . current methods are time - consuming , ineffective , and often life - threatening . this device offers an efficient alternative that makes the procedure quicker , safer , easier , and more cost - effective . the product offers simple solution to a life - threatening problem .
in describing preferred embodiments of the present invention illustrated in the drawings , specific terminology is employed for the sake of clarity . however , the invention is not intended to be limited to the specific terminology so selected , and it is to be understood that each specific element includes all technical equivalents that operate in a similar manner to accomplish a similar purpose . with reference to fig1 to 3 , 7 and 8 , the cage trap of the present invention is generally designated by reference numeral 10 . trap 10 includes a box - like cage having an elongated base 12 and opposed sidewalls 14 and 16 preferably formed and folded from a single piece of wire mesh . the sidewalls emanate from the longitudinal edges 18 and 20 of the base 12 in an upward direction . the walls 14 and 16 define planes that are essentially parallel to each other . as seen particularly in fig1 and 3 , in the preferred form of the invention , the base 12 and side walls 14 , 16 include wire elements 13 , 15 welded at their crossing points to form generally rectangular apertures 17 , with the side walls bent up at right angles from the base . the rectangular apertures are approximately 1 ″ square . the rear wall structure 36 of the trap is also made from a sheet of wire mesh in a generally rectangular configuration to form rear wall 22 , having a bottom edge 24 and a top edge 26 , and two sidewalls 28 and 30 . the two side walls 28 and 30 emanate perpendicular to and away from the rear wall . as shown in fig1 , the lower half of walls 22 , 28 and 30 of the wire mesh contains openings 25 that are approximately ½ ″ by 1 ″. the top half of the same walls of the wire mesh contains openings 27 which are approximately 1 ″ square . the rear wall structure 36 is positioned so that the bottom edge 24 mates with the rear edge 21 of base 12 . in like manner , the rear sidewalls 28 and 30 overlap the base sidewalls 14 and 16 . the rear wall structure 36 is attached to the base wall structure through the use of a series of circular wire rings that are strategically crimped in place as shown , for example , by crimped rings 32 in fig2 . for ease of review , the crimped rings are only shown in fig2 with the realization that they are present in all of the views of the wire mesh . further , the arrangement of the crimped rings 32 in fig2 is by way of example . any arrangements of the rings that hold the wire mesh together are contemplated . the basic cage structure is completed through the mounting of an elongated cover or roof 40 which may preferably be stamped from sheet metal . as shown in fig1 , 2 and 14 , the rectangular roof generally consists of a piece of sheet metal formed to provide a front edge 42 , side edges 44 and 46 , and rear edge 48 . the sheet metal is bent at the rear edge 48 to provide a downwardly extending rectangular shaped flange 50 that is integral with the full length of the transverse edge 48 . the sheet metal is also bent upwardly at the side edges 44 and 46 to provide upwardly extending flanges 54 and 56 and then bent downwardly to form longitudinally extending flanges 64 and 66 that span the full lengths of the longitudinal side edges 44 and 46 , respectively . with reference to fig1 , 15 and 25 , the flange pairs 54 - 64 and 56 - 66 define elongated channels 53 and 55 that fit over and receive the top edges of walls 14 and 16 , respectively . defined along the surface of flange 54 of the cover 40 are a series of stamped tabs 62 ( fig1 , 24 and 25 ). similar tabs 62 are defined along the surface of flange 56 of the roof . with reference to fig1 , 2 and 14 , the roof 40 is positioned and secured to the previously assembled wire mesh structure in the following manner . the elongated cover 40 is positioned so that the longitudinally extending channels 53 and 55 receive the top portions of the side walls 14 and 16 and the rear wall 22 . as shown in fig1 and 25 , using side wall 14 as an example , the top portion of the side wall is positioned within the channel 53 defined by flanges 54 and 64 . the bendable tabs 62 are then pressed inwardly ( fig2 and 25 ) in the direction of flange 64 and in this way , the bent tabs capture the upper portion of the side wall 14 so that it cannot be separated from the roof structure . similar action takes place with regard to the bendable tabs 62 of flanges 56 and 66 in order to secure the top portion of side wall 16 to the cover . the rear depending flange 50 extends over the top portion of the rear wall 22 to provide a cover therefor . a shown in fig1 and 15 , a wire re - enforcing frame 111 is secured about the opening 81 of the cage to the wire mesh of the cage by suitably spaced bent fasteners 113 . the top 115 of the wire frame 111 spans across the top of each flange 54 and 64 to provide a support for the actuating cable 34 . when fully assembled , the various elements constituting the cage define a vacant interior 70 for receiving an animal that is to be trapped . in order to hold an animal within the enclosure , a trap door mechanism must be provided . such a mechanism is illustrated in fig1 , 2 , 10 , 16 , and 18 . the trap door mechanism , generally designated by reference numeral 80 , includes an elongated door 58 preferably made of sheet metal . with reference to fig1 , the upper portion of the door 58 contains a yoke 60 that is generally u - shaped with straight leg portions 86 and 88 extending outwardly beyond the side edges 71 and 72 of the door panel . the lower portion 74 of the yoke is secured to the door panel through the use of bent tabs 75 and 76 formed in the door . the straight leg portions of the yoke are secured to the side edges of the door panel through the use of bent tabs 77 and 78 also formed in the door . with reference to fig1 and 2 , the cylindrically - shaped ends 86 and 88 of the yoke 60 are received in mounting holes 102 and 104 defined in the flange portions 56 and 66 . the holes 102 and 104 are positioned aft of the front opening 81 of the cage about one - third of the length of the longitudinal axis of the cage . a door lock plate 106 is positioned horizontally and secured by fasteners 107 along the lower edge 108 of the door panel . alternatively , the lock plate 106 could be an integral component of the door 58 if stamped or otherwise formed in the door . a rectangular - shaped locking wire yoke 110 has a lower portion 112 which wedges up against the corner created by the upper edge 114 of the door lock plate and the outer surface 68 of the door when the door is in the closed position . see fig8 . the ends 116 and 118 of the yoke are rotatably positioned in mounting holes 122 and 124 , respectively , provided in the flanges 56 and 66 . the mounting holes 122 and 124 are located forward of the mounting holes 102 and 104 provided for the door and aft of the front end 81 of the trap . a torsion wire spring 126 is provided to bias the yoke in a downward direction toward the door . see fig1 . the bottom portion 128 of the door lock plate contains a transversely extending hole 130 ( fig2 a ) which receives one end 132 of the actuating cable 34 . the cable 34 passes beneath the bottom of the yoke 110 and over the surface 68 of the door panel in an upward direction to pass over the top 115 of the wire frame 111 and over the cover 40 . the cable is held in place on bottom portion 128 by crimp 96 . with reference to fig1 - 5 , a rear latch assembly , generally designated by reference numeral 150 , is mounted on top of the roof 40 along the trap longitudinal axis a . the rear latch assembly 150 includes a pair of spaced mounting holes 152 and 154 defined on wing portions 156 and 158 emanating from a housing 160 . the assembly is fastened to the rear portion of the roof with suitable fasteners such as screws or the like ( not shown ) passing through the mounting holes . mounted about a third of the distance aft of the front 81 of the trap also along the longitudinal axis a is a front actuating assembly , generally designated by reference numeral 170 . this assembly contains a housing 172 from which emanates mounting wings 174 and 176 that contain holes 177 and 178 for receiving mounting screws or the like ( not shown ). as best seen in fig3 , the top portions of both the front actuating assembly 170 and the rear latch assembly 150 include cylindrical bores 145 and 146 , respectively , which are arranged spaced from and generally parallel to the longitudinal axis a of the roof . these bores are shaped to receive an elongated cylindrically shaped rod 138 . an elongated hand grip 134 contains a bore 136 through its longitudinal axis . this bore is sized so that grip 134 may be slidably mounted on the rod 138 . as shown in fig5 and 10 - 12 , the rear portion 118 of the hand grip 134 contains a recess 116 and a vertically oriented support member 90 that glides along the roof surface as the grip slides along the rod 138 . the front end of the grip 134 contains a forwardly extending handle cable pocket 100 . as shown in fig1 and 11a , the pocket 100 consists of a longitudinally extending bore 98 that receives the other end of the cable 34 . this end of the cable is held in place also through a wire crimp 96 . the forwardmost portion of the handle cable pocket 100 contains a transverse cross piece 94 which , as will be explained later , engages with the front actuating assembly to provide a safety lock to prevent the hand grip 134 from sliding rearwardly , thereby insuring that the door of the trap stays closed during transport . the recess 116 defined in the rearward end 118 of the handle 134 is defined in part by an indented ledge 92 that is shaped to mate with a rear latch 157 in a manner to be described hereinafter . with reference to fig1 - 12 , and 19 , the front actuating assembly , generally designated by reference numeral 170 , consists of basically four parts , a front housing 172 , a front paddle mechanism 171 that is movably mounted within the housing , and a torsion wire spring 173 that is secured to the front paddle to bias the paddle in the downward direction relative to the front actuating assembly 170 . as best seen in fig1 , the front paddle mechanism 171 consists of a cylindrical shaft 175 which terminates in a paddle handle 167 that can be moved by the thumb or fingers of the user in order to rotate the front paddle 171 . about half way along the cylindrical axis of shaft 175 , an engaging foot 179 is defined . the engaging foot contains an extended downwardly projecting toe 148 which , in use , engages with the cross bar 94 of the hand grip 134 in order to hold the handle in place after the trap has been tripped and the door panel is closed . with reference to fig1 a , it can be seen that the spring 173 biases the engaging foot 179 into the area 100 defined behind the cross bar 94 in the hand grip 134 . fig1 shows how the front actuating assembly 170 may be assembled . as oriented in fig1 , the cylindrical housing 172 is supported on a pair of downwardly - extending walls 41 and 43 that mate respectively with mounting wings 174 and 176 . each of the walls contains a cutout 166 that is sized to allow passage of the engaging foot 179 from outside the actuating assembly 170 into a space 45 defined between the walls 41 and 43 . the top 47 of each cutout defines half of a round hole to receive the smaller cylindrical portions of shaft 49 . a u - shaped wedge 51 is inserted from underneath the housing 172 so that each leg 57 and 59 fills the spaces 166 . the top 61 of each leg is shaped to complete the round hole for rotatably receiving the portions 49 of shaft 175 . with reference to fig5 , 12 , 17 and 20 - 23 , the rear latch assembly 150 consists of essentially five pieces . the first piece is a rear housing 151 . at the aft end of the rear housing there is a vertically extending bore 153 which is sized to receive a cylindrically shaped spring tensioner 155 . defined within the interior of the rear housing 151 is an opening to receive a rear latch 157 . a rear housing insert 159 holds the latch 157 in place so that it may rotate about a transverse axis b . the rear end of the rear latch 157 contains a bore 161 for receiving one end of a compression spring 163 . the other end of the compression spring in received within a cylindrical indentation 165 formed in the bottom of the spring tensioner . the forward end of the rear latch 157 contains a latching mechanism 121 . this latching mechanism includes a downwardly projecting hook 123 having an opening 125 for receiving and holding the top section 141 of a rectangular - shaped yoke wire member 143 that has its free ends 135 and 137 secured to pedal 19 near the top edge by bent tabs 82 and 84 , respectively . the pedal 19 serves as the trip mechanism in accordance with the present invention . the bottom end of pedal 19 is rotatably secured to the bottom of the cage by bent crimps 79 which are evenly spaced along the bottom edge and bent around one of the wires of the wire mesh . the front end of the rear latch also includes a ledge 127 for receiving and holding the latch portion 92 at the rear 118 of the hand grip 134 . in order to set the trap 10 , it is first placed on the ground or supporting surface . the front paddle 171 of the front actuating assembly 170 is then rotated in a clockwise direction by the user manipulating paddle handle 167 , thus rotating the engaging foot 179 out of the cross bar opening 100 of the hand grip 134 . this allows the user to move the handle along the longitudinal axis of the rod 138 in a rearward direction toward the rear latch assembly 150 with one hand , while the handle grip is also supported by the glide member 90 . it is again noted that the actuating cable 34 passes underneath the lower portion 112 of the locking wire yoke 110 , as shown in fig8 , 10 and 13 . this arrangement of components assures that the locking wire yoke 110 automatically disengages from the lock plate 106 as the hand grip 134 is moved away from its forward position adjacent the front actuating assembly 170 . accordingly , a trapped animal can be released by a person located at the rear of the trap by disengaging the hand grip 134 from the front actuating assembly 170 and moving the hand grip 134 rearwardly on rail 138 . once the hand grip 130 is released from the front assembly 170 , the grip 134 can be moved rearwardly until the recess 116 of the grip engages the upward portion of the latch 127 so that the latch holds the handle in its rearwardmost position . rearward movement of the handle 134 results in the cable 34 moving in a rearward direction to rotate the door 58 about ends 86 and 88 in an upward direction and set the door in a loaded position . having accomplished this action with one hand , the trap is now set awaiting the entrance of an animal to activate the trap . with reference to fig1 and 5 , in order to entice the animal into the trap , a suitable bait is inserted into the interior of the trap aft of the pedal 19 . when the animal enters the trap and steps on the pedal 19 , the pedal is rotated in a downward direction which causes the top section 141 of the yoke or trigger rod 143 to pull the latch 121 in a downward direction thereby releasing the recess 116 of handle 134 from engagement with the latch ledge 127 . when this happens , the weight of the door 58 causes the door to rotate in a downward direction to rapidly close the interior space 70 and trap the animal within the cage 10 . as used herein , the term “ trigger rod ” is intended to have its broadest meaning and can include cable or other trigger mechanisms to release handle 134 from latch ledge 127 when pedal 19 is rotated to its downward position . in addition , those skilled in the art can appreciate that the trigger rod 143 could be a single rod and could be formed with latch mechanism 121 as one piece , such as by molding ; and the pedal 19 could also be integral with the rod 143 . other trip mechanisms with which the animal interacts , as by pulling , could be substituted for pedal 19 and be formed as part of the trigger rod . downward rotation of the door 58 also moves the handle grip 134 to its forwardmost position with cross - piece 94 moving past engaging foot 179 , to lock the hand grip 134 into the front actuating assembly . at the same time , as best seen in fig8 and 18 , the downwardly biased yoke 112 through the urging of torsion spring 126 presses up against the top surface 68 of door 58 and is lodged in the corner created by the upper edge 114 of the door lock plate 128 and the top surface 68 of the door when the door is in the closed position . under these conditions , if the animal tries to open the door , the bottom of the yoke will press against the door latch plate preventing the animal from rotating the door in an upward direction . when the user desires to release a trapped animal , the user follows a procedure similar to setting the trap . the engaging foot 179 of the front actuating assembly 170 is disengaged from the handle cable pocket 100 at the front end of the hand grip 134 by the user manipulating the paddle handle 167 . the grip 134 is then free to slide rearward on rail 138 by the user &# 39 ; s hand to open the door 58 by the pulling action of cable 34 . initial rearward movement of the grip 134 tensions the actuating cable 34 which causes the locking yoke 110 to be lifted in an upward direction disengaging from the top edge 114 of the door lock plate 106 by the urging of the end 132 of the actuating cable 34 . sliding the grip 134 to its most rearward position engages the grip to the latch mechanism 150 which resets the trap . another feature of the present invention is an adjustable pedal sensitivity feature . this is accomplished , as shown in fig2 , by providing an upwardly extending ledge 101 near the bottom circumferential ledge 103 of the spring tensioner 155 . when the spring tensioner 155 is rotated within the vertically extending bore 153 , the compressive force on the spring 163 may be changed by the displacement of the spring tensioner 155 in a downward direction against one end of the spring 163 based on the clearance provided within the assembly through the use of a series of indentations 105 a - 105 e positioned radially about the bottom 109 of the bore 153 within the rear housing 151 . in this way , the tension required on the pedal to activate the trap can be adjusted so that if a small animal enters the trap , the weight of the animal will not trip the trap . it is to be understood that the present invention is not limited to the illustrated embodiments described herein . modifications and variations of the above described embodiments of the present invention are possible as appreciated by those skilled in the art in light of the above teachings . for example , as shown in fig2 , the moving hand grip 134 and rail 138 system could be eliminated . the cable 34 could terminate in a simple hook 23 at the latch end . the hook structure would include glide member 90 to support the hook to facilitate tripping the trap . this embodiment would not be as user friendly and would require a separate carrying handle but does work for functionality . in addition , the pedal 19 and trigger rod 143 could be replaced with a combination bait holder / rod that would activate the latching mechanism when it was pulled or moved a certain distance .	a cage - type animal trap made of wire mesh having a roof and a front end provided with an animal access opening . a door movably mounted at the front end operates in an opened position to reveal the access opening and in a closed position to block the access opening . a hand grip mounted on a rail positioned on the roof moves bi - directionally between a first position near the front end of the trap and a second position near the rear end of the trap . an actuating cable has one end secured to the bottom of the door and another end secured to the hand grip so that when the hand grip is moved by the user from a first position with the door closed to a second position with the door opened the trap can be set by a latch mechanism which releasably holds the hand grip in its second position . a pedal is movably mounted inside the trap with a trigger rod secured to the pedal and to the latch mechanism so that when an animal enters the trap , the weight of the animal moves the pedal from a first position to a second position for causing the trigger rod to move the latch thereby releasing the hand grip resulting in the handgrip moving from its second position to its first position and the door moving from the opened position to the closed position thus trapping the animal inside the trap . a paddle mechanism maintains the hand grip in its first position , and a door lock at the bottom of the door prevents the door from being opened by a trapped animal . finally , the latch mechanism is adjustable to allow the user to adjust the weight sensitivity of the pedal so that only an animal of predetermined weight can move the pedal to trip the trap .
the embodiments of the apparatus and / or methods are disclosed . in the following description , for purposes of explanation , numerous specific details are set forth in order to provide a thorough understanding of the embodiments of the disclosure . it is apparent , however , to one skilled in the art that the present disclosure may be practiced without these specific details or with an equivalent arrangement . the embodiments of the present disclosure are able to apply in all kinds of drip bottle . please refer to fig1 and fig2 . fig1 is a structure view of a warning device for an infusion apparatus which is installed at between a drip stand and a drip bottle . fig2 is a block diagram of a warning device for an infusion apparatus . in fig1 , a warning device for an infusion apparatus 1 is installed at between a drip stand 2 and a drip bottle 3 , in which the warning device 1 monitors a dosage value within the drip bottle 3 . in fig2 , the warning device 1 includes an alarm module 10 , a setting interface 12 , a measurement module 14 , a control module 16 and a power supply module 18 , in which the control module 16 electrically connects to the alarm module 10 , the setting interface 12 , the measurement module 14 and the power supply module 18 respectively . then , the alarm module 10 includes a visual alarm unit 100 and an audible alarm unit 102 , in which the visual alarm unit 100 is a light emission element such as a led or a lamp to make the light warning , and the audible alarm unit 102 is a sound device such as a buzzer to make the audible warning . in addition , the alarm module 10 has a primary warning mode and an emergency warning mode . when the alarm module 10 is in the primary warning mode , the alarm module 10 will executes the visual alarm unit 100 and the audible alarm unit 102 every minute in a time interval , so that the alarm module 10 has one time warning every minute in the time interval . when the alarm module 10 is in the emergency warning mode , the alarm module 10 will starts the visual alarm unit 100 and the audible alarm unit 102 sustained in the time interval , so that the alarm module 10 has warns continuously in the time interval to attain a more strongly warning for the user . the setting interface 12 is an operation platform for operating the warning device 1 which includes an adjustment modify unit 120 and a display unit 122 . the user can set a total dosage value by using the adjustment modify unit 120 according to the dosage how much the user want to inject , and the total dosage value can be showed on the display unit 122 for the user . the display unit 122 may be a display panel , and the adjustment modify unit 120 may has an increase key button and a decrease key button for adjusting the total dosage value . the measurement module may be an electronic scale , and further includes or connects to a hanging tool to hang the drip bottle 3 ( as shown in the fig1 ). generally , the electronic scale includes a weight sensor therein and the electronic scale will apply a voltage to the weight sensor . when an analytic object applying a weight on the weight sensor , weight sensor is deformed which is caused by the gravity so as to the resistance of the weight sensor is to be changed and the voltage is also to be change . when there is a change in the weight of the analytic object , the voltage is also to be changed . in other words , when the drip bottle 3 includes the drug therein on the hanging tool , the measurement module 14 will generate an origin voltage according to the weight of the drip bottle 3 which includes the drug therein . the measurement module 14 continuously monitors the voltage changed by changing the weight of the drip bottle 3 includes drug therein . with the dosage slowly drips into the patient &# 39 ; s vein , the weight of the drip bottle 3 includes the dosage will be reduced . thus , the measurement module 14 detects the voltage value which different from the original voltage value so as to a current voltage value is to be generated . it should be illustrated that in one infusion procedure , the initial voltage is defined as a constant value as the start of the infusion . because there are many detection processes during the infusion process depended on the measuring frequency to generate a plurality of current voltage values . the control module 16 electrically connects to the alarm module 10 , the setting interface 12 and the measurement module 14 respectively . the control module 16 loads the total dosage value from the setting interface 12 , and receives the original voltage value and the current voltage value from the measurement module 14 and according to the total dosage value , the original voltage value and the current voltage value that measured in accordance with measurement rules to execute the control module 10 for warning alert actions refer to fig3 , which is a flow chart of a measurement rule . according to the warning device for an infusion apparatus 1 of the present invention , the measurement rule includes the step s 50 denotes an original voltage that is received from a measurement module . the step s 51 denotes an original weight that is calculated corresponding to the original voltage , and the original weight is the original weight of the drip bottle with the dosage therein . the step s 52 denotes a ratio of the voltage and weight is calculated according to the original voltage and the original weight , and the ratio of the voltage and weight is a ratio value of the original voltage and the original weight . the step s 53 denotes a total dosage value that is loaded from the setting interface . the step s 54 denotes a current voltage is received from the measurement module and a voltage difference is calculated by comparing the current voltage and the original voltage . the step s 55 denotes a weight difference is calculated by the voltage difference and the ratio of the voltage and weight , in which the ratio of the voltage difference and the weight difference are equal to the ratio value of the original voltage and the original weight , and the weight difference is the decrease of the drip bottle 3 when the starting of the infusion of the drip bottle 3 , and the decrease of the drip bottle 3 is the amount of the infusion dosage . the step s 56 denotes a residual dosage is obtained from the total dosage value subtracted the weight difference and when the residual dosage is lower than a first warning value , the alarm module is executed to a primary warning mode in the step s 57 . when the residual dosage is lower than a second warning value , the alarm module is executed to an emergency warning mode in the step s 58 , and the first warning value is larger than the second warning value . for example , if the weight of 1 milliliter ( ml ) of the drug is 1 gram ( g ), the total weight of 200 ml dosage and drip bottle 3 with the dosage therein is 500 g and before the infusion treatment beginning , the measurement module 14 can detects an original voltage of the drip bottle 3 with the dosage therein which is denoted as the original voltage . the original voltage is transmitted to the control module 16 to calculate the original weight of the drip bottle 3 with the dosage therein is 500 g , which is the sum of the weight of the dosage and the drip bottle 3 . then , the ratio of the voltage and weight of the drip bottle 3 with the dosage therein is to be calculated in step s 52 , if the dosage of the infusion is 200 ml , the user can set the total dosage value is 200 ml through the setting interface 12 and the control module 16 can load the total dosage value is 200 ml from the setting interface 12 . then , in a measurement frequency , when the infusion dosage is dipped out off the drip bottle 3 is 10 ml , the measurement module 14 will measure the voltage according to the reduction of 10 ml of the drip bottle 3 containing the dosage therein , and the voltage is the current voltage . at this time , the control module 16 compares the current voltage value with the original voltage in accordance with the step s 54 to calculate the voltage difference and the weight difference is 10 g in accordance with the step s 55 . that is to say , the infusion of dosage is 10 ml . thus , the residual dosage is 190 ml in the drip bottle 3 according to the step s 56 , and the residual dosage ( 190 ml ) is larger than the first warning value such that the control module 16 did not execute the alarm module 10 to alarm . how ever , with more and more of the dosage is dripped out off the drip bottle 3 , the residual dosage within the drip bottle 3 is also fewer and fewer . when the residual dosage is lower than the first warning value , the control module 16 will executes the alarm module 10 to be the primary warning mode according to the step s 57 to alarm the dosage is to be exhausted and to be replaced or supplement for the user . if the dosage is still dripped out off the drip bottle 3 and the user does not replace a new drip bottle 3 or supplement more dosage into the drip bottle 3 , to let the residual dosage is lower than the second warning value such as 5 ml , the control module 16 transforms the alarm module 10 to an emergency warning mode from the primary warning mode to remind the dosage within the drip bottle 3 is to be run out for the user , whereby , by two - stages warning mechanism not only reduces the work loading and burden for the staff and improves the medical service quality of medical facilities can be improved by adding the alarm frequency . furthermore , the user may add the additional drug into the drip bottle 3 during the infusion process . at this time , the user can adjust the dosage within the drip bottle 3 by the adjustment modify unit 120 of the setting interface 12 after additional drug is added into the drip bottle 3 . the added dosage is added to the total dosage value within the drip bottle 3 . for example , if the additional drug is 50 ml , the total dosage value within the drip bottle 3 is adjusted to 250 ml according to above measurement rule . that is to say , the original dosage is 200 ml that is to be changed as the 250 ml , in this way , the additional dosage of the drug will not affect the original timing for warning , to achieve higher compatibility and higher maneuverability . according to the above embodiments , the warning device 1 containing infusion apparatus further includes a power supply module 18 . the power supply module 18 is the power supply for the warning device 1 , and electrically connects to the control module 16 . the control module 16 compares the surplus power supply value and a power warning value , when the surplus power supply value is lower than the power warning value , the control module 16 will instruct the alarm module 10 to alarm a lower battery message . certainly , the surplus power supply value can also display on the display unit 122 of the setting interface 12 . thus , the surplus power supply value of the power supply module can show for the user clearly and convenience for charging . otherwise , the above alarm message can also show on the display unit 122 of the setting interface 12 , and the residual dosage is calculated according to the step s 56 within the drip bottle 3 can also be displayed on the display unit 122 of the setting interface 12 to show the residual dosage more clearly for the user . accordingly , the warning device can set the desired infusion dosage through the setting interface , the weight of the drip bottle is measured continuously by the measurement module , the residual dosage within the drip bottle is calculated according to the measurement rule of the control module and the control module executes the alarming when the residual dosage within the drip bottle is lower than the emergency warning value such that the work loading and burden for the staff and the quality of medical care of the medical facility can be improved . while the invention has been described in connection with a number of embodiments and implementations , the invention is not so limited but covers various obvious modifications and equivalent arrangements , which fall within the purview of the appended claims . although features of the invention are expressed in certain combination among the claims , it is contemplated that these features can be arranged in any combination and order .	a warning device for an infusion apparatus is installed at between a drip stand and a drip bottle , and the warning device includes an alarm module , a setting interface , a measurement module and a control module . the alarm module used to warn , the setting interface provides a total pharmaceutical dosage value , the measurement module measures the weight of the drip bottle with dosage to generate an original voltage value , and the control module connects with the alarm module , the setting interface and the measurement module respectively to read the total pharmaceutical dosage value and the original voltage value and to alarm by the alarm module . therefore , the warning device solves the compatibility problem and able to apply in all kind of drip bottles such that the work loading and burden for the staff and the quality of medical care of the medical facility can be improved .
a more detailed description of example embodiments of the invention will now be given . the virtosomes are prepared from any non - dividing cells or tissues either in its newly synthesised form in the cytosol or after its spontaneous release from cells . the following example will demonstrate the retention of biological activity by the virtosomes isolated from either the cell environment ( e . g . culture medium ) or the cytosol . freshly isolated mouse spleen lymphocytes are cultured at a concentration of 5 × 10 6 cells for 16 h overnight at 37 . 5 ° c . in 100 ml of rp mi 1640 medium ( 88 ml ) containing cpsr - 2 ( 10 ml ), 10 % gentamycin ( 0 . 8 ml ) and 200 mm glutamine ( 1 . 2 ml ) as a settling - in period . the cells are then separated by gentle centrifugation followed by re - suspension and re - incubation . the medium containing the virtosomes is made by seeding lymphocytes at a concentration of 3 × 10 6 ml − 1 in 100 ml of rpmi medium 1640 ( 88 ml ) + 10 % cprs - 2 ( 10 ml ), 10 % gentamycin ( 0 . 8 ml ) and 200 mm glutamine ( 1 . 2 ml ) at 37 . 5 ° c . and removing them after 8 h by centrifugation at 500 g for 10 min . the supernatant is further centrifuged at 1 . 2 × 10 5 g for 1 h in a preparation centrifuge . the preparation of the virtosomes from the cytosol of either any cell type e . g . lymphocytes ( 26 ) or any tissue e . g . liver ( 26 ) is made by gently breaking the cells / tissues open in a serum - free medium using a tenbrock glass homogeniser ( 10 up - and - down gentle passes ) with a teflon pestle . the resultant homogenate is centrifuged at 500 g for 10 min . the supernatant is further centrifuged at 1 . 2 × 10 5 g for 1 h in an ultracentrifuge ( 26 ). only the virtosomes of the cytosolic particles are not pelleted after ultracentrifugation . isolation of the virtosomes after ultracentrifugation from either supernatant is achieved by agarose gel chromatography . agarose gel columns ( 48 cm long × 2 . 5 cm diameter ) with an exclusion limit of 1 . 5 × 10 6 daltons are equilibriated with phosphate buffered saline ( ph 7 . 4 ). two ml of the ultra - centrifuged medium are loaded onto the column and eluted by gravity flow with the same buffer ( 30 ml h − 1 flow rate ). of the 50 fractions collected , fractions 32 - 42 contain the eluted virtosomes from either source . the void volume is determined with blue dextran and serum albumin is used to determine the molecular weight elution pattern . the virtosomes may also be prepared by filtration of the supernatant from ultra - centrifugation through a millipore bacterial filter of pore size 0 . 2 μm . alternatively , the virtosomes may be separated by density gradient centrifugation using e . g . sucrose ( 7 ) or caesium chloride gradients ( 1 ). the purified virtosomes are tested for the retention of biological activity after purification . thus , either the cytosolic or the culture medium derived virtosomes purified from either non - stimulated mouse lymphocytes or mouse liver are tested against a culture of mouse tumour cell line j774 . as a control , the virtosomes from cells of tumour cell lines j774 and p497 are similarly prepared and tested against the tumour cell line j773 cells . the sterilized solutions are added to the cell cultures so forming 20 % of the final cell incubation medium . the results indicate that neither the j774 nor the p497 virtosomes have an effect upon the j774 cells . however , the virtosomes isolated from the non - stimulated lymphocyte result in a reduction of j774 dna synthesis and hence cell replication , by almost 70 % whilst the liver cytosolic virtosomes yield an inhibition of approximately 60 % ( 26 ). however , j774 and the p497 virtosomes have little effect ( 10 - 15 %) on normal dividing 3t3 fibroblasts . in addition , the tumour cell line sw480 co - cultured with virtosomes from non - dividing hepatocytes for 24 h showed a reduction of cell replication of more than 80 %. a similar experiment with ht1080 , a fibrosarcoma cell line , showed a reduction of about 90 % after 24 h treatment . without further treatment , the remaining cells were able to divide and so escape the effects of the virtosomes . moreover , when virtosomes were introduced into a 4 - day culture of ht1080 cells where the cell numbers had reached to between 100 , 000 to 150 , 000 , the addition of hepatic virtosomes reduced the cells number by three to seven times depending upon the concentration of the virtosomes added . human non - stimulated lymphocyte virtosomes also block cell division in stimulated lymphocytes ( 27 ). the virtosomes so produced from non - dividing cell populations ( either from cultures or tissues ) are injected intravenously into the tumour - bearing rats . this can involve virtosomes that have been prepared from the tumour bearer &# 39 ; s own cells / tissues . thus , transfer of the application of virtosomal inhibition of tumour cell replication in vitro to an in vivo model was achieved after confirming that virtosomal preparations from non - dividing hepatocytes had no effect upon the rat strain bdix employed . daily intravenous injection was made for 10 consecutive days of non - dividing hepatocyte virtosomes into bdix male rats that had been previously inoculated with dhd / k12 - prob cells in order to induce the formation of a tumour similar to colon adenocarcinoma . the presence of the virtosomes limited tumour development for the following 14 days , the tumours being either partially or completely reduced in size . as has been mentioned for the in vitro tumour cell cultures , the tumours reduced in size will require additional virtosomal treatment to reduce them further . the examples and embodiments given in the present application are , of course , only for illustrative purposes and should not be considered in a limiting fashion . other variants using equivalent means are of course possible as well without imparting from the spirit a scope of the present invention . in particular , other applications may be envisaged in he frame of the present invention and different embodiments may also be combined . 1 . stroun , m . & amp ; anker , p . ( 1972 ) nucleic acids spontaneously released by living frog auricles . biochem j 128 : 100 - 101 . 2 . stroun , m . & amp ; anker , p . ( 1972 ) in vitro synthesis of dna spontaneously released by bacteria or frog auricles . biochimie 54 : 1443 - 1452 . 3 . anker , p . stroun , m . & amp ; maurice , p . ( 1975 ) spontaneous release of dna by human blood lymphocytes as shown in an in vitro system . cancer res 354 : 2375 - 2382 . 4 . anker , p . & amp ; stroun , m . ( 1977a ) the release of newly synthesized dna from frog auricles . arch sci genève 30 : 230 - 241 . 5 . stroun , m . anker , p ., gahan , p . b . & amp ; henri , j . ( 1977b ) spontaneous release of newly synthesized dna from frog auricles . arch sci geneva 30 : 229 - 241 . 6 . stroun , m ., anker , p ., beljanski , m ., henri , j ., lederrey , c ., ojha , 0 . & amp ; maurice , p . ( 1978 ) presence of rna in the nucleoprotein complex spontaneously released by human lymphocytes and frog auricles in culture . cancer res 38 : 3546 - 3554 . 7 . adams , d . h . & amp ; gahan , p . b . ( 1982 ) stimulated and non - stimulated rat spleen cells release different dna complexes . differentiation 22 : 47 - 52 . 8 . adams , d . h . & amp ; gahan , p . b . ( 1983 ) the dna extruded by rat spleen cells in culture . int j biochem 15 : 547 - 552 . 9 . stroun , m ., gahan , p . b . & amp ; sarid , s . ( 1969 ) agrobacterium tumefaciens rna in non - tumorous cells . biochem biophys res commun 37 : 652 - 657 . 10 . stroun , m . ( 1971 ) on the nature of the polymerase responsible for the transcription of released bacterial dna in plants . biochem biophys res commun 44 : 571 - 578 . 11 . stroun , m ., anker , p . gahan , p ., rossier , a . & amp ; greppin h . ( 1971 ) agrobacterium tumefaciens ribonucleic acid synthesis in tomato cells and crown gall induction . j bacteriol 106 : 634 - 639 . 12 . anker , p . & amp ; stroun , m . ( 1972 ) bacterial ribonucleic acid in the frog brain after bacterial peritoneal infection . science 178 : 621 - 623 . 13 . anker , p ., stroun , m . & amp ; maurice , p . ( 1976 ) spontaneous extracellular synthesis of dna released by human blood lymphocytes . cancer res 36 : 2831 - 2839 . 14 . anker , p . & amp ; stroun , m . ( 1977 ) spontaneous extracellular synthesis of dna released by frog auricles . arch sci genève 30 : 263 - 278 . 15 . gahan , p . b . & amp ; stroun , m . ( 2010 ) the virtosome , a novel cytosolic informative entity and intercellular messenger . cell biochem funct 28 : 1 - 10 . 16 . cohen , z ., bacharach , e . & amp ; lavi , s . ( 2006 ) major mouse satellite dna is prone to eccdna formation via dna ligase iv - dependent pathway . oncogene 25 : 4515 - 4524 . 17 . adams , d . h . & amp ; macintosh , a . a . g . ( 1985 ) studies on the cytosolic dna of chick embryo fibroblasts and its uptake by recipient cultured cells . int j biochem 17 : 1041 - 1051 . 18 . speese , s . d ., ashley , j ., johki , v ., et al . nuclear envelope budding enables large ribonucleoprotein particle export during synaptic wnt signaling . ( 2012 ) cell 149 : 832 - 846 . 19 . mcintosh , a . a . g . & amp ; adams , d . h . ( 1985 ) further studies of the extrusion of cytosol macromolecules by cultured chick embryo fibroblasts cells . internat j biochem 17 : 147 - 153 . 20 . challen , c . & amp ; adams , d . h . ( 1987 ) the assembly of the dna complex present in chick embryo cell cytosol . internat j biochem 19 : 235 - 243 . 20 . 21 . viola - magni , m . p . ( 2011 ) the biochemical composition of virtosomes . j nucleic acids invest 2 ( suppl 1 ): 10 . 22 . challen , c . & amp ; adams , d . h . ( 1986 ) further studies on the size and composition of chick embryo fibroblast cytosolic dna complex . int j biochem 18 : 423 - 429 . 23 . anker , p ., jachertz , s ., maurice , p . a . & amp ; stroun , m . ( 1984 ) nude mice injected with dna released by antigen by antigen stimulated human t lymphocytes produce specific antibodies expressing human characteristics . cell biochem function 1 : 33 - 37 . 24 . anker , p ., jachertz , d ., stroun , 0 ., brogger , r ., lederrey , c ., henri , j . & amp ; maurice , p . ( 1989 ) the role of extracellular dna in the transfer of information from t to b human lymphocytes in the course of an immune response . j immunogenet 6 : 475 - 481 . 25 . anker , p ., lyautey j ., lefort , f ., lederrey , c . & amp ; stroun , m ( 1994 ) transformation of 3t3 cells and sw 480 cells displaying k - ras mutation . c . r . acad . sci . 10 : 869 - 74 . 26 . adams , d . h ., diaz , n . & amp ; gahan , p . b . ( 1997 ) in vitro stimulation tumour cell media of [ 3h ] thymidine incorporation by mouse spleen lymphocytes . cell biochem function 15 : 119 - 124 . 27 . viola - magni , m . p ., sesay , a ., cataldi , s ., gahan , p . b . & amp ; stroun , m . ( 2011 ) biological activity of virtosomes released by stimulated and non - stimulated lymphocytes . j . nucleic acids invest 2 : suppl . 1 p37 . 28 . trombone , a . p . f ., silva , c . l ., lima , k . m ., oliver , c ., jamur , m . c ., prescott , a . r . & amp ; coelho - castelo , a . a . m . ( 2007 ) endocytosis of dna - hsp65 alters the ph of the late endosome / lysosome and interferes with antigen presentation . plos one2 ( 9 ): e923 . doi : 10 . 1371 / journal . pone . 0000923 . 29 . wolff , j . a ., malone , r . w ., williams , p ., chong , w ., acsadi , g ., jani , a . & amp ; felgner , p . l , ( 1990 ) direct gene transfer into mouse muscle in vivo . science 247 , 1465 - 1468 . 30 . basner - tschakarjan , e ., mirmohammadsadegh , a ., baer , a . & amp ; hengge , u . r . ( 2004 ) uptake and trafficking of dna in keratinocytes : evidence for dna - binding proteins . gene therapy 11 , 765 - 774 . 31 . haegle , h ., allam , r ., pawar , r . d . & amp ; anders , j - h . ( 2009 ) double - stranded rna activates type i interferon secretion in glomerular endothelial cells via retinoic acid - inducible gene ( rig )- 1 . nephrology dialysis transplantation doi : 10 . 1093 / ndt / gfp339 . 32 . zhang , l ., gu , f . x ., chan , j . m ., wang , a . z ., langer , r . s . & amp ; farokhzad , o . c . ( 2008 ). nanoparticles in medicine : therapeutic applications and developments . clinical pharmacology and therapeutics 83 , 761 - 69 . 33 . de jong , w . h . & amp ; borm , p . j . a . ( 2008 ) drug delivery and nanoparticles : applications and hazards . int . j . nanomedicine 3 , 133 - 149 .	the present invention concerns a pharmaceutical composition comprising virtosomes isolated from non - dividing cells or the medium in which the cells are grown , for use in the inhibition of tumour growth and / or prevention of metastases .
the present invention is directed to an apparatus and method for providing passive thermal control capability to a heating device . the configuration and use of the presently preferred embodiments are discussed in detail below . it should be appreciated , however , that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of contexts other than devices for heating food and beverages . accordingly , the specific embodiments discussed are merely illustrative of specific ways to make and use the invention , and do not limit the scope of the invention . in addition , the following terms shall have the associated meaning when used herein : “ container ” means and includes any receptacle in which material may be held or carried , including without limitation a can , carton , bowl , jar or other receptacle ; and “ heater ” means and includes any device in which reactants react to generate heat . as will be apparent to those skilled in the art , many of the heating devices are depicted herein without each and every component required for full functionality , such as , for example , devices shown without a flexible actuating lid or a blister assembly . in each case the depiction is intended to show the functional aspects of the heater for a better understanding of the invention and should not necessarily be construed as including all of the elements of a fully operational device . it should be noted that in the description and drawings , like or substantially similar elements may be labeled with the same reference numerals . however , sometimes these elements may be labeled with differing numbers , such as , for example , in cases where such labeling facilitates a more clear description . additionally , the drawings set forth herein are not necessarily drawn to scale , and in some instances proportions may have been exaggerated to more clearly depict certain features . such labeling and drawing practices do not necessarily implicate an underlying substantive purpose . the present specification is intended to be taken as a whole and interpreted in accordance with the principles of the present invention as taught herein and understood to one of ordinary skill in the art . referring now to fig2 a and 2b , wherein the heater is activated , thereby enabling it to transmit thermal energy through its interior and then externally through the heater wall . if the heat transmitted to the package is steadily transmitted to a surrounding fluid coolant as shown in fig2 a , then the design interior temperature profile of the heater is established . if the coolant is not present as shown in fig2 b , the energy cannot be as readily transmitted and the interior temperature of the heater reaches a much higher level . the interior temperature of the active heater thus effectively provides a means of “ sensing ” the presence or absence of an adjacent heat source which may constitute an untoward hazardous condition . if a sufficient heat sink is not present , and higher than normal temperatures build up inside the heater , methods and systems presented herein will activate a passive thermal control ( ptc ) mechanism to dissipate excess thermal energy and thereby moderate the temperature of the heater and package . knowing the thermal characteristics of the normally present heat sink ( fluid contents of the package ) is useful in defining the cooling requirements of the ptc mechanism for the intended application . for example , an efficient solid state heater that raises the temperature of 240 ml of a beverage by 40 ° c . in two minutes delivers about 40 kj of energy to the liquid at an average power output of approximately 650 watts . the high heat capacity of water ( 4 . 18 j / g -° c .) relative to many other substances translates to a relatively small sensible temperature rise of the fluid contents from this powerful energy flux . if ptc functionality is to be achieved by introducing new components into the heater in a mass efficient way , then the added components must have a higher total specific heat absorption capacity , relative to the normally present heat sink . in addition to its high specific heat capacity , another distinctive property of water is its high latent heat of vaporization ( 2260 j / g ). it can be shown that summing the requisite latent and sensible heat of water , under closed adiabatic conditions , the example 40 kj heater above would only convert less than 16 g of water to steam , resulting in a final temperature of the complete system of only about 100 ° c . in an open system , the steam of this example ( occupying less than 20 liters under ambient conditions ) can escape under its own pressure carrying away its high energy content . this example illustrates how a relatively small mass of material can have a large cooling effect by absorbing heat and being expelled from the system . there are significant practical difficulties associated with directly incorporating and isolating fluid water in a solid - state heater . even a partial pressure of water vapor inside the heater could cause side reactions with the components of the fuel / oxidizer reactant mixture . in fluid form water could leak internally to or outside of the heater . thus , it may be preferable to have no free water in liquid form inside the solid state heater . certain inorganic compounds and salts , in dry solid form contain significant levels of bound water , which they release as vapor on heating above a characteristic threshold decomposition temperature , with large endothermic energy absorption . some examples of these materials are given in table 1 . these materials contain chemically bound rather than absorbed or free water and thus provide a “ dry ” method of introducing materials with higher total specific heat absorption capacity for passive thermal control . selecting a material with a preferred threshold temperature for decomposition can be beneficial in controlling the conditions under which ptc is activated . there are other endothermically decomposing chemical compounds , that is materials that are thermally decomposed to release gases and absorb energy at various activation temperatures and , in certain embodiments might also be used as thermally responsive materials for passive thermal control of a chemical heater . endothermic decomposition is inherent in a broad range of common and low - cost materials . these include : magnesium and aluminum hydroxides , together with various hydrates and carbonates . many of these compounds , when thermally decomposed , give off carbon dioxide and / or water as gaseous byproducts . we have previously described how an endothermically decomposing compounds , when heated to a certain threshold temperature , can rapidly decompose to release a volume of gas , the energy of which does work to effect a mechanical auto - shutdown of a heater device . simply allowing these gases to be discharged from the heater will also produce cooling . as the examples below show , passive thermal control functionality can be achieved by introducing the materials described in table 1 or analogous material components in certain regions of the heater device structure . basing a passive thermal control mechanism operation on a material &# 39 ; s physical property responses to temperature , rather than the actuation of mechanical elements improves system reliability , and can be accomplished simply and with low cost . a thermodynamically defined response coupled to a transmissible energetic fluid is inherently a highly reliable way of delivering a passive response . fig3 shows a diagram of a heater construction of prior art without passive thermal control functionality . in this configuration , the pre - mixed fuel - oxidizer reaction mix 301 is housed in the base of the cylindrical heater cup 302 . the mixture of reactants 301 is ignited near its center by various means known in the art such as , for example , a starting pellet 303 . the energy producing chemical reaction proceeds internally to the heater as a solid flame front . as shown in fig3 , the reaction pathway 304 spreads generally radially outward from the starting pellet 303 , continuing to propagate throughout the interior until the entire mixture of reactants 301 has reacted to generate the full energy content of the heater . fig4 and fig5 show one embodiment of the current invention wherein passive thermal control functionality is incorporated within a modified heater design . in this embodiment , passive thermal control regulation becomes an onboard property of the heater , invocable whether the heater is bare or installed in an empty container . in fig4 and 5 , the basic solid state heater design of fig3 is retained now as the core structure of a device , surrounded by an “ active ” passive thermal control layer 307 packed between the heater cup wall 302 and the outer wall 311 of the heater device . here the term “ active ” refers to the physical ( heating and phase change ) and / or chemical ( thermal decomposition ) responsiveness of the material comprising the active passive thermal control layer 307 . note that the figures do not represent the relative scale of the features shown and in practical implementations the additional surrounding thermal control layer 307 and outer wall 311 are chosen by design to be thin and comprised of materials with good thermal conductivity to minimize their combined thermal resistance to heat flow . the actuating container lid 271 spans and encloses both the fuel matrix 301 and thermally transmissive ptc layer 307 regions , and has a vent 502 to release vapor as needed when ptc is actuated . fig6 is a vertical cross - sectional view of the lower portion of a filled self - heating container with an activated modular heater incorporating passive thermal control installed in its base demonstrating the action of the ptc mechanism during normal operation ( a filled beverage can ). since the can is filled , the fluid acts as a thermal sink carrying heat away from the interface . with a good heat transfer coefficient for flow of thermal energy into the beverage the thermal energy of the heater is transmitted through the ptc layer , minimizing energy accumulation and temperature build up in this region . the bulk of the ptc layer material is kept below the decomposition temperature at which water is driven from the matrix . although there may be some small partial degree of decomposition , overall there is no significant endothermic activity generating gasses or vapors and dissipating heat out of the system . fig7 is a vertical cross - sectional view of the lower portion of an empty self - heating container with an activated modular heater incorporating passive thermal control installed in its base demonstrating the action of the passive thermal control mechanism during out of range conditions ( empty beverage can ). under these conditions the empty can acts as thermal barrier and energy released by the heater accumulates in the ptc layer and the heater core . thermal decomposition of a major portion of the active material of the ptc layer takes place and water vapor ( steam ) is expelled from the heater vents and away from the package . allowing the steam generated to be emitted away from the heater and the heated package thereby removes significant energy from the system and can produce a very large cooling effect for a substantial reduction of the overall temperature of the system compared to the temperatures that would be realized in the absence of passive thermal control . while steam level temperatures may be present in the region of the low volume of emitted steam , this is substantially less hazardous than the extreme temperature excursions that might otherwise occur . fig8 shows a vertical cross section view of one embodiment of a solid state modular heater used for practical demonstration of passive thermal control in the examples that follow . in the following examples 1 through 7 , 11 g of a passive thermal control mix 244 is compacted in the annular space between the 25 mm metal heater cup 245 and an outer metal cup 246 that encloses the heater . in examples 8 and 9 the mass of passive thermal control mix used is 9 g . the formulations of the ptc mix used are given below and in fig9 . in example 10 the passive thermal control mix 244 and inner heater cup 245 are not included , so as to provide a basis for comparison . in each of the following examples 1 through 7 , 21 g of heat - generating fuel / oxidizer formulation 243 is compacted into the inner heater cup 245 . in examples 8 and 9 the mass of passive thermal control mix used is 24 g . in example 10 , 21 g of heat - generating fuel / oxidizer formulation 243 is compacted into the outer heater cup 246 . although other formulations could be used , the heat - generating formulation 243 used in these examples is a mixture containing 15 - 25 % aluminum , with particle size of 2 - 30 microns , 20 - 30 % silicon dioxide , 25 - 45 % alumina , and additives and reaction aids such as potassium chlorate , calcium fluoride , and barium peroxide . an initiating pellet 242 is pressed centrally into the surface of the fuel / oxider mix 243 , and a heater activation mechanism 250 is placed on top of the pellet 242 and covered with insulator 248 and actuator button 249 . a metal lid 241 is crimped onto the outer cup 246 . the heater module thus assembled was installed into the base of beverage can for testing . temperature time profiles for can bottom , middle , and top temperatures were recorded . the flux of steam ( if any ) emitted was noted . each example heater configuration was tested with a beverage can containing 288 ml of water as well as with an empty beverage can . bare heater modules were also tested . fig9 is a tabled listing of experimental parameters used and results obtained for the following numbered example embodiments . calcium hydroxide / potassium alum ( 50 : 50 ) mixture is used for the ptc layer formulation . calcium hydroxide : alumina ( 50 : 50 ) mixture is used for the ptc layer formulation . calcium hydroxide : anhydrous calcium sulfate ( 50 : 50 ) mixture is used for the ptc layer formulation . calcium hydroxide : calcium sulfatex semi - hydrate ( 50 : 50 ) mixture is used for the ptc layer formulation . calcium oxide : potassium alum ( 50 : 50 ) mixture is used for the ptc layer formulation . anhydrous calcium sulfate : potassium alum ( 50 : 50 ) mixture is used for the ptc layer formulation . this example is a modification of example 1 using 34 mm diameter heater cup 245 9 g of calcium hydroxide / potassium alum ( 50 : 50 ) mixture as the ptc layer formulation 244 , and 24 g of fuel / oxidizer mix 243 . this example is a modification of example 1 using 34 mm diameter heater cup 245 9 g of calcium oxide / potassium alum ( 50 : 50 ) mixture as the ptc layer formulation 244 , and 24 g of fuel / oxidizer mix 243 . in this control configuration the inner heater cup 245 and the ptc layer 244 are not present . fig1 is a graph showing the time / temperature response for activated heaters of example 1 ( with passive thermal control ) and example 10 ( without passive thermal control ) in an empty container . the temperature plotted in fig1 is the surface temperature of the metal can at its midpoint . fig1 demonstrates that the surface temperature of the example 10 heater ( no ptc ) increases to a peak temperature of nearly 500 ° f . within 2 minutes , whereas the surface temperature of the example 1 heater incorporating ptc increases at a lower rate and to a more bounded maximum temperature of about 220 ° f . fig1 is a graph showing the time / temperature response for activated heaters of example 1 ( with passive thermal control ) and example 10 ( without passive thermal control ) in a filled container . the temperature plotted in fig1 is the surface temperature of the metal can at its midpoint . both example 1 and example 10 heaters deliver the same endpoint product target temperature of 140 ° f ., although the heating rate is slightly lower for the example 1 heater . comparing the temperature response from fig1 and fig1 of the example 1 heater in the unfilled and filled can conditions shows that the ptc cooling embodiment does not cause undesired cooling in normal operation of filled package heating but is selectively activated in the empty package to produce highly effective cooling . in order to practically achieve passive thermal control according to the principles described , some system development and optimization is needed . by design ptc is incorporated into a device whose normal function is heating and ptc cannot interfere with that functionality . but it must also reliably perform efficient cooling in a safe way when that response is needed . ptc should not unduly burden the heater with mass or complexity . heater design and material selection for the ptc layer are two factors that can be used to achieve appropriate ptc functionality for a heater device . locating the ptc layer between the core heat generating source and adjacent to the outermost wall of the heater sets up a thermal energy balance that enables sensing and actuation ptc mechanism . the rate of heat transfer is dependent upon , and may be adjusted through , physical parameters of the system such as : geometry of component parts , particle size and density of mix , material thermal properties , and heat transfer coefficients . the inner heater cup wall may be formed from a thin foil to provide a chemical barrier with minimal thermal resistance . the active component of the ptc layer is a material with a high chemically bound water content that when heated above some characteristic threshold temperature decomposes releasing molecular water that further heating converts to steam . the energy absorbed by thermal decomposition and the phase change of water vaporization allows for a relatively small mass to absorb a large quantity of energy and lower the system temperature significantly . while many other compounds could be used , some examples of suitable active materials are given in table 1 . each has its own characteristic thermal response . for example aluminum hydroxide contains 1 . 5 waters of hydration per molecule all of which is rapidly released in a single decomposition step , whereas potassium alum contains 12 waters of hydration per molecule which are sequentially released in a multi - step decomposition reaction process . potassium alum also has a band of increasing onset temperatures for thermal decomposition of each additional water molecule and this combination of properties produces a time - release response with a low steady flux of steam . as illustrated in examples 1 through 9 , the ptc formulation may be comprised of a single chemical component or could also be a mixture of several different materials , some which may have ptc character combined with others that are inert in this regard . low cost , environmentally friendly , and consumer safe materials are preferred . some mass of inert material mass may be in the ptc layer to buffer temperature and moderate the rate of thermal decomposition . inert additives can also beneficially increase the thermal conductivity of the ptc layer to enhance its transmission of thermal energy , although the ptc layer may also be designed to provide some lowering of the thermal flux . varying the particle size and density of the packed ptc layer can be used to regulate the timing and volume of heated vapors from the layer . the ptc layer itself must have a selective , tuned , and controlled response . the ptc response characteristics of the various ptc layer compositions of examples 1 through 10 are described in the table of fig9 . columns 2 through 6 of fig9 show how in normal heating mode , the : heating time , maximum temperature of the heated fluid , time and quantity of steam released and useful energy content may vary with composition . generally a shorter heating time with maximum heat transfer efficiency , minimal thermal decomposition and release of steam are preferred . columns 7 through 10 of fig9 show how in an empty can , the temperatures at various points on the surface of the metal container ( bottom , middle , top ) and the volume of steam released may vary with composition . generally lower surface temperatures and moderate steam flux is preferable . columns 11 through 13 of fig9 show how for a bare heater , the temperatures at various points on its surface ( bottom , middle , top ) may vary with composition . in this condition , again lower surface temperatures are preferable . the ptc of the present invention does not substantially detract from or negate the existing beneficial characteristics of the self - heating technology of this invention and prior inventions , so that the heater device construction will remain relatively small , simple , robust , easy to manufacture , and economically low - cost . embodiments of the present invention also provide a controllable output that enables , for example , designing in a defined acceptable maximum temperature realized at the surfaces of the heater or the package in which it may be contained . the heater in various embodiments is designed to allow safe and gentle release of excess pressure when passive thermal control is activated . for example , the crimped seal between the heater cup and lid may be designed to stress relieve slightly to bleed off pressure through the seal . the heater construction may provide for any emitted gas streams to be filtered through a porous insulator so there is no emergent steam or particulates . the complete self - heating package described herein consists of additional components besides the modular solid state heater . one embodiment of a complete package assembly is shown in fig1 . in these examples , the self - heating package is a 3 - piece nominal 12 oz . beverage container . however , embodiments of the invention may alternatively be realized with a 2 - piece beverage container or other package forms . referring to fig1 , the can body 1603 and top end 1602 , consisting of , in at least one embodiment , an easy opening lid for convenience , are conventional can package components . the non - easy - opening ( neo ) end 1605 is specifically designed for mechanical and thermal interfacing of the package and heater . an insulating plastic lip guard 1601 and paper or plastic thermal label 1604 provide thermal safety . once the heater is installed in the neo , there are additional components at the heated end of the can ; these may include an external insulator 1607 which may be a non - woven polymer or fiberglass mat and a plastic base cap 1608 . the external insulator may also incorporate materials such as activated carbon or baking soda to absorb any trace odors emitted by the activated heater . for effective implementation of passive thermal control , these components must be implemented , for example be porous or vented , so as to allow heated gases and vapors to be readily and safely discharged from the package and carrying away thermal energy . while the present device has been disclosed according to the preferred embodiment of the invention , those of ordinary skill in the art will understand that other embodiments have also been enabled . even though the foregoing discussion has focused on particular embodiments , it is understood that other configurations are contemplated . in particular , even though the expressions “ in one embodiment ” or “ in another embodiment ” are used herein , these phrases are meant to generally reference embodiment possibilities and are not intended to limit the invention to those particular embodiment configurations . these terms may reference the same or different embodiments , and unless indicated otherwise , are combinable into aggregate embodiments . the terms “ a ”, “ an ” and “ the ” mean “ one or more ” unless expressly specified otherwise . when a single embodiment is described herein , it will be readily apparent that more than one embodiment may be used in place of a single embodiment . similarly , where more than one embodiment is described herein , it will be readily apparent that a single embodiment may be substituted for that one device . in light of the wide variety of possible heating methods and systems available , the detailed embodiments are intended to be illustrative only and should not be taken as limiting the scope of the invention . rather , what is claimed as the invention is all such modifications as may come within the spirit and scope of the following claims and equivalents thereto . none of the description in this specification should be read as implying that any particular element , step or function is an essential element which must be included in the claim scope . the scope of the patented subject matter is defined only by the allowed claims and their equivalents . unless explicitly recited , other aspects of the present invention as described in this specification do not limit the scope of the claims .	a modular heating system and method is presented that automatically dissipates thermal energy from a heater or heated package if the energy cannot be assimilated without excessive temperature increase . a heater containing reactants that generate heat when combined is placed in thermal contact with a passive thermal control material which is in thermal contact with a container configured to contain a substance to be heated . the passive thermal control material allows the transmission of heat between the heater and the container as long as the temperature of the heat passing through the passive thermal control material does not exceed the activation temperature of the material . if the temperature of the heat passing through the passive thermal control material exceeds the material &# 39 ; s decomposition temperature , the passive thermal control material decomposes and thereby dissipates heat .
the probe 1 according to the present invention has an outer metal pipe 2 , through which a double - lumen plastic flexible tube 3 is led , which protrudes at the distal end of the pipe 2 with a bent , prestressed distal end 3 . 1 . the flexible tube 3 has an outer wall 3 . 2 with a circular cross section and two ducts , which are insulated by a partition 3 . 3 and have a partly circular cross section . a probe head 4 ( fig2 ), which forms a distal end part 1 . 1 of the probe 1 and is preferably connected to the flexible tube 3 in substance , especially by bonding ( e . g ., with silicone adhesive ) in the exemplary embodiment shown in fig4 , is inserted into the distal end 3 . 1 of the flexible tube 3 . the probe head 4 has a partly spherically rounded end face 4 . 1 . the probe head 4 has , furthermore , two electrodes 4 . 3 separated from one another by an insulating web 4 . 2 consisting of plastic in the form of metal bodies . the electrodes 4 . 3 are designed at first as partly cylindrical in their end facing away from the end face 4 . 1 . their distal end is such that the distal end face of the probe head as a whole is partly spherical , especially hemispherical . the electrodes 4 . 3 have , in their surfaces facing each other , transversely extending , partly cylindrical depressions 4 . 4 . the depressions extend at right angles to the insertion direction parallel to one another . they are not flush in the direction in which they extend , but have a finite distance at right angles to this . the depressions 4 . 4 are filled here by cured plastic 4 . 5 connecting in substance a cylindrical expansion 4 . 5 . 1 of the plastic insulating web 4 . 2 and the electrodes 4 . 3 . instead of partly cylindrical depressions extending in the transverse direction and a corresponding cylindrical expansion 4 . 5 . 1 , partly spherical depressions in the electrodes 4 . 3 and a corresponding spherical thickened part of the adhesive 4 . 5 may be provided . further , there are depressions 4 . 2 . 1 in the insulating web 4 . 2 , which are likewise filled by cured adhesive 4 . 5 . in addition to the connection of the electrodes 4 . 3 and the intermediate layer 4 . 2 in substance , a positive - locking connection may also be established by the expansion 4 . 5 . 1 of the cured adhesive 4 . 5 . instead of by bonding , the connection in substance of the electrodes 4 . 3 and the insulating layer 4 . 2 may also be established by injecting or pouring in the insulating layer between the electrodes 4 . 3 . due to this design especially with the depressions 4 . 4 and the expansions 4 . 5 . 1 , any axial displacement of the electrodes 4 . 3 during the bending of the distal end 3 . 1 of the flexible tube 3 is avoided when the curvature of said flexible tube is changed , due , for example , to pushing into and out of another outer pipe ( see below ) or due to pressing against tissue . the electrodes 4 . 3 of the head 4 have proximal plate - like attachments 4 . 6 . the head 4 is connected in substance , especially by bonding , on the one hand , at the distal end - face end of the flexible tube 3 to the outer wall 3 . 2 of said end and , on the other hand , to distal lateral surfaces of the partition 3 . 3 via the attachments 4 . 6 . furthermore , stripped ends of connection wires 5 are fixed on the outer sides of the plates 4 . 6 by connection in substance , for example , by soldering or also by bonding with an electrically conductive adhesive . electric voltage can be applied from the proximal end of the probe 1 via the wires 5 on the partial body acting as electrodes 4 . 3 . the connection wires are designed as round wires over their length and are preferably insulated , for example , by insulating lacquer or else a usual outer plastic flexible tube ( not shown in detail ). in their distal area 5 . 1 , they are flattened in the above - described manner for connection to the electrodes 4 . 3 . at its proximal end area , the metal pipe 2 has a radial incision 2 . 1 , via which the probe 1 can be fixed axially and angularly in a grip . the probe 1 has , furthermore , at first a contact insulation 2 . 7 separating the pipe 3 from a contact socket 2 . 4 in the proximal direction and , adjoining the contact socket 2 . 4 , an insulation piece 2 . 3 separating this from a proximal contract bush 2 . 5 . the contact socket 2 . 4 and the contact bush 2 . 5 are used as terminal contacts . one of the connection wires 5 is connected electrically conductively to the socket 2 . 4 and the connection wire is connected electrically conductively to the bush 2 . 5 , and the latter wire being guided with a stripped end in this bush , which closes off the probe 1 on the proximal end face and is in electrically conductive connection with the bush 2 . 5 . the parts are connected by bonding . all metallic parts , especially electrodes 4 . 3 , pipe 3 , contact socket and contact bush 2 . 4 , 2 . 5 and connection wires 5 preferably consist of special steel . the electrically conductive parts consist of plastic and the double - lumen flexible tube 3 consists , in particular , of an elastomer , such as polyether block amide ( peba ; commercially available , for example , under the trade name pebax ), the insulating web 4 . 2 between the electrodes consists of polyamide ( pa ); the adhesive 4 . 5 connecting the latter is an epoxy resin adhesive ; the insulation piece 2 . 3 consists of polyoxymethylene ( pom ). for use , the probe 1 is inserted into a grip 7 having a metal shaft 6 . the grip 7 comprises two grip parts 7 . 1 , 7 . 2 , which are elastically connected to one another and which are displaceable in relation to one another via a guide pin 7 . 3 . the probe 1 is fixed axially and angularly via the radial incision 2 . 1 . the grip parts 7 . 1 , 7 . 2 are kept at a distance in the inoperative position in relation to one another via an elastic spring - loaded connection part 7 . 4 , i . e ., they are kept at a distance from one another without load , as this is shown in fig7 . the distal end of the probe 1 is moved extensively into the shaft 6 and projects over same only slightly , as this is shown in fig7 . by actuating the grip 7 by moving the grip parts 7 . 1 , 7 . 2 in relation to one another along the guide pin 7 . 3 against the spring action of the connection part 7 . 4 , the probe is moved through the shaft 6 in the distal direction by means of the grip part 7 . 2 , so that the distal tip 3 . 1 of the probe 1 is moved distally out of the shaft 6 and it can assume its prestressed curvature ( fig8 ), while it is held stretched in the withdrawn position according to fig7 ( with the grip not stressed ) by the shaft 6 . towards the proximal end of the probe 1 , the grip part 7 . 2 has a coaxial recess 7 . 5 , into which a connector plug with electric contacts can be inserted for contacting the metal sockets 2 . 4 , 2 . 5 . as was stated , the distal end 3 . 1 of the probe 1 is moved out of the shaft 6 by actuating the grip 7 and can contact tissue . when voltage is applied to the probe 1 via the described electrically conductive parts , which are connected to one another , obliteration of tissue , etc ., can then be performed . while specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention , it will be understood that the invention may be embodied otherwise without departing from such principles .	a device for obliterating tissue with a bipolar probe , which has a distal end part with two electrodes electrically insulated against one another by an insulating web which is electrically insulating . to make such a device with a bipolar probe safer , the electrodes have depressions located opposite each other , which are filled by electrically insulating insulating material .
the synthesis of the sucrose - derived contrast agent 3 is depicted in fig1 . to an argon - degassed solution of azide 1 ( 16 ) ( 1 . 85 g , 2 . 43 mmol ) and octaalkyne 2 ( 18 ) ( 271 mg , 0 . 28 mmol ) in 9 / 1 thf / water ( 50 ml ) were added cuso 4 ( 80 mg , 0 . 5 mmol ) and sodium ascorbate ( 160 mg , 0 . 8 mmol ). the mixture was stirred under argon at room temperature for 24 h . volatiles were evaporated and the residue was diluted with water ( 50 ml ), the solution was washed with a mixture of dithiazone in chloroform ( 20 mg / l , 5 × 100 ml ), and lyophilized to give a residue , which was loaded onto a reversed phase ( c - 18 ) silica gel column . the column was eluted with acetonitrile / water ( 80 / 20 ) to yield the product 3 as a non - hygroscopic cream - colored solid ( 1 . 81 g , 0 . 25 mmol , 89 %). maldi - tof ms was performed as shown in fig2 , and calculated for c 252 h 414 n 64 o 91 gd 8 was 7056 . 366 [ m + h ] + , while we observed at 7056 . 328 , and at 3528 [ m + 2h ] 2 + confirming the presence of 8 gd - dota chelates per sucrose scaffold . initial mill characterization of the gd - dota - sucrose compound was accomplished in phantoms of varying concentrations according to previously described protocol ( 16 ). similarly , these phantoms were studied using progressive saturation experiments ( ps ), with 11 tr values exponentially spaced from 30 s to 60 ms . nonlinear least squares regression was employed to determine the relaxation time - and relaxation rate constants , t 1 and r 1 = 1 / t 1 , respectively . weighted linear regression was used to determine the r 1 value as a function of concentration , and the relationship between r 1 and [ gd - dota - sucrose ca ] was estimated for the average multimer . the weights used in the fit were inversely proportional to the variance in r 1 for each concentration , ( 1 / s 2 r1 , i ) a human colorectal cell line engineered to express luciferase ( hct - 116 / luc ) was used to generate orthotopic crc xenograft tumors . eight female scid / beige mice each received injections into the lining of the rectum , 4 - 5 mm beyond the anal verge , of 1 × 10 6 hct 116 / luc cells in a 10 μl volume ( mixed in a solution of x ul pbs ). mice were allowed to recuperate for two weeks , while being weighed daily , and then monitored for tumor growth by bioluminescence imaging in the iv is 200 ( perkin elmer ) 2 times per week . after approximately 2 weeks , tumor growth also was monitored via t 2 - weighted mri ( spin echo multi slice sequences with te / tr = 72 / 1000 ms , slice thickness of 0 . 785 mm and resolution of 350 × 350 × 100 um over 6 minutes ). upon tumor detection (˜ 3 weeks after injection ), contrast enhanced imaging experiments were initiated . compound 3 was dissolved in 100 mm sodium phosphate buffer , ph 7 . 4 , at a concentration of 2 . 5 mm for gavage administration . gavage was given at 10 μl per gram of body weight . imaging began within 30 minutes of contrast agent administration . for i . v . contrast administration , compound 3 was dissolved in pbs at a concentration of 25 μmol / kg of body weight , and administered in 150 μl volume via tail vein catheter during the imaging session , with image acquisition occurring before , during and after injection . mri was performed at baseline and at 30 minutes and at 5 , 24 and 48 hours following gavage administration . all imaging data were acquired using a 7 - t horizontal magnet ( asr 310 , agilent technologies ) equipped with nested 305 / 120 / hds gradient set . prior to acquisitions , animals were placed in an induction chamber and anesthetized using 2 % isoflurane . the mice were then restrained in a specific holder and inserted into the magnet and 35 - mm quadrature coil ( doty scientific ) with a constant supply of isoflurane and heated air gas in order to maintain a temperature of 37 ± 1 ° c . body temperature and respiratory functions were monitored using the saii system ( small animals instrument inc , stony brook , n . y .) and temperature control of the imaging gradients was achieved by means of a water chiller ( neslab waters ) and maintained at 12 ° c . for all acquisitions . applying a coronal slice orientation , 3 - dimensional t 1 - weighted spin - echo ( se3d ) sequences were acquired with te / tr = 10 . 6 / 31 . 6 ms , field of view = 90 × 45 × 16 mm , matrix = 256 × 128 × 16 and four averages in 4 . 3 min . images were acquired prior to contrast and at 30 min , 5 , 25 and 48 hours post gavage . for the dynamic scans , contrast was administered via tail vein catheter during imaging with two dimensional spin - echo multislice ( sems ) with t 1 - weighting using te / tr = 10 / 233 ms , field of view = 90 × 45 mm , matrix = 256 × 128 and 9 slices with 1 mm thickness . the total scan time equaled 90 min ( 5 min prior to contrast and 85 min post ). for both scans , spatial resolution was hence 351 × 351 × 1000 μm . signal intensity ( si ) in the tumors and kidneys was calculated using manually drawn regions of interest ( rois ) in vnmrj ( agilent technologies , inc .) and normalized to surrounding tissue intensity . each mouse was used as its own control and the percent increase in si was calculated individually and then averaged . statistical analysis was performed using graphpad prism software ( graphpad , san diego , calif ., usa ) and one - way analysis of variance ( anova ) followed by the tukey test for comparison of mean values . a confidence interval of 95 % was chosen and thus statistical significance was pre - determined at p & lt ; 0 . 05 . for elemental analysis studies , four female scid mice weighing between 24 and 26 grams each were administered 200 μl of compound 3 in 0 . 1 m sodium phosphate buffer via oral gavage . this delivers 3 . 52 mg of 3 ( gdsucrose ) into each mouse . mice were then immediately transferred individually to metabolic caging , designed to separately capture urine and feces . after 72 hours , mice were euthanized and colons were removed , lightly rinsed with pbs and collected in individual tubes . urine and feces were collected separately . all samples were lyophilized , and subsequently sent to elemental analysis , inc ., ( lexington , ky .) for detection of gadolinium via instrumental neutron activation analysis ( inaa ). following mm , animals were euthanized and tumor sections fixed , mounted in paraffin , cut into sections , mounted on slides and stained with hematoxylin & amp ; eosin ( h & amp ; e ) for histology examination . the calculated mass for compound 3 ( c 252 h 414 n 64 o 91 gd 8 ) is 7056 . 366 [ m + h ] + . by maldi - tof ms ( fig2 ), the observed mass was 7056 . 328 , and the average number of gd - dota chelates per sucrose was determined to be 8 . during the phantom portion of this study , it was noted that the solubility of this current compound 3 differed substantially from the ca previously presented by martinez et al ( 19 ). specifically , we observed that while 3 dissolved rather easily in water or aqueous buffer , the previous compound was not soluble in water and required 15 % ethanol to achieve suspension . mr relaxivity measurements clearly demonstrated differences in t 1 - shortening and thus contrast enhancement in the various phantoms ( i . e . concentrations ) could readily be observed in shaded t 1 maps ( fig3 a ). the shaded t 1 maps demonstrate the variance in t 1 - times between phantoms of various concentrations . phantom concentrations range as following [ μm ]; a = 2500 ; b = 1250 ; c = 625 ; d = 313 ; e - 156 ; f = 78 ; g = 39 ; h = 20 and w = 0 ( i . e . pure water ). note that a , b and c had to be excluded due to oversaturation effects . due to shortening of spin - spin ( t 2 ) relaxation , three of the highest concentration phantoms were excluded for quantitative analysis of relaxivity . to determine the molar relaxivity ( r 1 ) of this improved agent , 3 , a weighted linear regression model was applied to the phantom data ( fig3 b ). impressively , the fitted value for molar relaxivity ( r 1 ) was 213 ± 1 . 7 mm s − 1 with r 2 = 0 . 983 , which is an 8 - fold increase compared to our previous compound ( 16 ). relaxation experiments were accomplished with multiple tr spin echo experiments on two separate eppendorf tube phantoms prepared with identical concentrations of gd - dota - sucrose ca . error bars denote standard deviations . in vivo , the passage of the ca and potential tumor uptake in crc xenografts were monitored by a series of two - and three - dimensional t 1 - weighted sequences ( see protocol ). herein clearly visualized by maximum intensity projections ( mip ), the agent showed rather fast movement throughout the mouse gi - tract ( fig4 a ). maximum intensity projections ( mip ) generated from t 1 - weighted spin echo sequences ( 3d ) demonstrate the passage of ca throughout the gastrointestinal tract of a representative animal at baseline ( bl ) and 30 minutes at 5 , 25 and 48 hours post gavage . in fact , as early as 30 min following gavage administration , the agent had moved from the stomach to the upper intestinal areas . at the 5 - hour time point it appeared that the agent had partially cleared the animal with notable enhancement remaining in the intestines . by 24 hours , only small amounts of compound could be detected in the intestines and this contrast appeared to be associated with feces . by 48 hours post ca , we could no longer detect any enhancement . more importantly , and although non - targeted at this point , the contrast agent of the present disclosure induced notable signal enhancement in the tumors at 5 hours post - gavage . zoomed in on the tumor solely , 3d spin echo images of pre - contrast fig4 b , and 5 hours post - gavage fig4 c , show the relative contrast enhancement . this enhancement was particularly noticeable in the tumor rim , and revealed a potentially necrotic core . to investigate this darker inner core further , h & amp ; e stained tumor sections were evaluated , and did indeed demonstrate substantial cellular necrosis in the tumor center versus the outer rim ( fig4 d & amp ; 4e ). additionally , enhancement was observed in the bladder at the 5 hour time - point , which was co - incident with tumor enhancement . since we had previously not observed uptake of the original compound in the bladder ( 19 ), and the original study did not include tumors , while not wishing to be bound by theory , we believe that this could be due to systemic uptake through the orthotopic xenograft tumor . quantitatively , tumor signal intensity ( si ) was determined for each animal using manually drawn rois and compared to pre - gavage values . confirming the visual observations , a significant increase of 40 % in tumor si was noted by 5 h post gavage and persisted throughout the 24 - hour time point . see fig4 f which shows percent change in tumor signal intensity compared to baseline values before contrast . by 48 hours post ca administration , the enhancement had dropped to 20 % above baseline values and the ca appeared to largely have cleared the animal . this observation was further confirmed by elemental analysis , which showed that the gadolinium levels in the colon and urine were below the limits of detection , while a notable portion was found in the feces ( see fig5 ). since the elemental analysis study was conducted using animals that did not bear tumors , and gd was not detected in the colon tissue or urine , this observation further supports the idea that the bladder uptake in the mm study was due to systemic uptake via the orthotopic tumor and not uptake through the unaffected gi tract . to evaluate the properties of this agent following intravenous administration and determine kidney clearance rates , mice ( n = 4 ) received contrast ( compound 3 ) by an i . v . tail vein catheter while inside the magnet . as demonstrated in fig6 a which shows t 1 - weighted spin echo multi slice ( sems ) showing baseline ( bl ), and at 2 minutes , 10 minutes , 30 minutes , and 1 hour post iv injection of contrast agent , dramatic signal enhancement within the tumor could be detected immediately following the i . v . injection ( lower arrow 10 ) and the kidneys showed maximum uptake at this point ( upper arrow ). these observations were in agreement with quantitative analysis showing an increase of signal intensity of tumor contrast by 72 % within the first 5 minutes following injection ( fig6 b ). by 15 minutes post ca , the increase in signal intensity reached 93 %, following which , the signal intensity appeared to decrease exponentially . by 90 min , the signal intensity had dropped back to 16 % above baseline values and the imaging session was terminated . kidney clearance of the ca was also quantified and showed an increase in signal intensity of 185 % by 3 min post injection followed by a fast wash - out of the agent ( fig6 c ). neutron activation analysis specifically detected gadolinium in colon tissue , urine and feces collected over the first 72 hours post gavage . detection of gadolinium in urine and colon tissue was under 5 ppm or less in all samples , which is the limit of detection of the analysis . in feces , the samples averaged 126 . 5 ppm . this indicates that most , if not all , of the gd - dota - sucrose probe passed through the gi tract and was excreted in the feces . these non - tumor bearing mice did not have measurable excretion through the urine or uptake in colon tissue , in contrast to what was seen in tumor - bearing mice during imaging sessions . our first generation gd - dota - sucrose contrast agents had superior relaxometric properties compared to gd - dota in its lower limit of detectability and remained in the gi tract throughout the passage . in this study , we improved our first generation gd - dota - sucrose contrast agents by increasing the average number of gd - dota chelates per sucrose to 8 . to improve relaxivity , the chelates were shortened to induce stiffness thus increasing the rotational correlation time . these modifications yielded an 8 - fold increase in spin - lattice - relaxivity which also was observed in vivo ( 212 from 29 ). the new molecule has shorter arms and limits motion and rapidly clears the kidney . in vivo , tumor signal intensity enhanced 40 % ( gavage ) and 93 % ( tail - vein injection ). kidney uptake was maximized by 3 min post i . v . injection and cleared by 10 min ( significantly faster than reported magnevist renal clearance ). rapid kidney uptake could be improved by co - injection with diuretics , etc ., which could enhance circulation time and increase tumor uptake . hence , allowing for detection of smaller or flat lesions with greater sensitivity . tumor bearing mice experienced uptake via gavage , indicated by bladder enhancement non tumor bearing mice for inaa had no measurable gd in urine , indicating no uptake via gavage while not wishing to be bound by theory , it is believed that uptake is by tumor - associated vasculature or other tumor related physiology while enhancement was observed in the bladder in the mm studies with the current compound , but was not observed in the previous study ( 16 ). and since gd was not detected in the colon or urine by elemental analysis in the absence of a tumor . again , while not wishing to be bound by theory , we hypothesize that the tumor uptake allowed systemic clearance and , hence , bladder contrast enhancement . but this would not be observed in normal , unaffected gi tracts that do not bear tumors . however , the tumor contrast enhancement by both the oral and intravenous routes of administration suggests that the current untargeted contrast agent could provide significant benefit when combined with standard mri based virtual colonoscopy . the rapid systemic clearance of the agent through the renal system implies that intravenous administration has potential . additionally , since this novel contrast agent has greater relaxivity than standard contrast , and rapid systemic clearance , also may demonstrate greater utility for contrast - enhanced mri for a wide range of cancers in addition to colorectal cancers . it is also believed that the larger size , mass , of the current gd - sucrose compound ( 3 ) could restrict extravasation in normal tissues , while allowing extravasation in tumors with more leaky vasculature , allowing for improved contrast with surrounding normal tissues . various changes may be made in the above disclosure without departing from the spirit and the scope of the disclosure . as another modification , a gadolinium - dota sucrose - derived agent was synthesized using an argon - degassed solution of azide , octaalkyne in 9 / 1 thf / water , cuso 4 and sodium ascorbate . the compound was improved by increasing the number of gadolinium - dota chelates per sucrose to eight and shortening the chelates to induce stiffness and increase the rotational correlation time , inducing an eight - fold increase in spin - lattice - relaxivity . for in vivo assessment , scid mice were intra - rectally injected with human crc cells . then , the mice received the gadolinium - 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society task force on colorectal cancer , and the american college of radiology . gastroenterology 134 , 1570 - 1595 ( 2008 ); published online epubmay ( 10 . 1053 / j . gastro . 2008 . 02 . 002 ). 11 . b . saar , a . meining , a . beer , m . settles , h . helmberger , e . frimberger , e . j . rummeny , t . misch , prospective study on bright lumen magnetic resonance colonography in comparison with conventional colonoscopy . br j radiol 80 , 235 - 241 ( 2007 ); published online epubapr ( 10 . 1259 / bjr / 83959666 ). 12 . g . pappalardo , e . polettini , f . m . frattaroli , e . casciani , c . d &# 39 ; orta , m . d &# 39 ; amato , g . f . gualdi , magnetic resonance colonography versus conventional colonoscopy for the detection of colonic endoluminal lesions . gastroenterology 119 , 300 - 304 ( 2000 ); published online epubaug ( 13 . d . hartmann , b . bassler , d . schilling , h . e . adamek , r . jakobs , b . pfeifer , a . eickhoff , c . zindel , j . f . riemann , g . layer , colorectal polyps : detection with dark - lumen mr colonography versus conventional colonoscopy . radiology 238 , 143 - 149 ( 2006 ); published online epubjan ( 10 . 1148 / radio1 . 2381041756 ). 14 . w . ajaj , g . pelster , u . treichel , f . m . vogt , j . f . debatin , s . g . ruehm , t . c . lauenstein , dark lumen magnetic resonance colonography : comparison with conventional colonoscopy for the detection of colorectal pathology . gut 52 , 1738 - 1743 ( 2003 ); published online epubdec ( 15 . s . c . goehde , e . descher , a . boekstegers , t . lauenstein , c . kühle , s . g . ruehm , w . ajaj , dark lumen mr colonography based on fecal tagging for detection of colorectal masses : accuracy and patient acceptance . abdom imaging 30 , 576 - 583 ( 2005 ); published online epub2005 september - october ( 10 . 1007 / s00261 - 004 - 0290 - 4 ). 16 . g . v . martinez , s . navath , k . sewda , v . rao , p . foroutan , r . alleti , v . e . moberg , a . m . ahad , d . coppola , m . c . lloyd , r . j . gillies , d . l . morse , e . a . mash , demonstration of a sucrose - derived contrast agent for magnetic resonance imaging of the gi tract . bioorgmed chem lett 23 , 2061 - 2064 ( 2013 ); published online epubapr ( 10 . 1016 / j . bmc1 . 2013 . 02 . 008 ). 17 . p . caravan , protein - targeted gadolinium - based magnetic resonance imaging ( mri ) contrast agents : design and mechanism of action . acc chem res 42 , 851 - 862 ( 2009 ); published online epubjul ( 10 . 1021 / ar800220p [ pii ] 10 . 1021 / ar800220p ). 18 . v . rao , r . alleti , l . xu , n . k . tafreshi , d . l . morse , r . j . gillies , e . a . mash , a sucrose - derived scaffold for multimerization of bioactive peptides . bioorgmed chem 19 , 6474 - 6482 ( 2011 ); published online epubnov ( 10 . 1016 / j . bmc . 2011 . 08 . 053 ). 19 . martinez g v , navath s , sewda k , rao v , foroutan p , alleti r , moberg v e , ahad a m , coppola d , lloyd m c , gillies r j , morse d l , mash e a , “ demonstration of a sucrose - derived contrast agent for magnetic resonance imaging of the gi tract ”, bioorganic & amp ; medicinal chemistry letters 23 ( 2013 ) 2061 - 2064 .	disclosed is ct or mr contrast agent which comprises a base or carrier scaffold formed of a polyhydroxol compound having a linker to which a gd - dota is covalently bonded . also disclosed is a method of screening a patient for colon cancer using a ct or mr contrast , which method comprises administering to a patient undergoing screening a compound as above described .
the present description provides compositions comprising rifabutin , clarithromycin , and clofazimine and methods of using same . the rifabutin , clarithromycin , and clofazimine of the compositions are provided in ratios that yield improved pharmacokinetic properties . the present compositions reduce potentially deleterious elevations of rifabutin serum concentration that resulted from administration of earlier known formulations . in contrast to earlier known formulations , the present compositions further provide the advantage of maintaining patient blood drug levels well below adverse effect ranges , e . g ., below ranges implicating leucopenia or uveitis . moreover , the subject compositions also maintain higher levels of serum concentrations of clarithromycin as compared to earlier formulations , thereby inhibiting resistance development . furthermore , the present compositions allow reaching minimum effective patient clofazimine serum levels faster than with previous formulations . in one embodiment , present compositions comprise rifabutin , clarithromycin , clofazimine , and a pharmaceutically acceptable carrier , wherein the amount of clofazimine is 5 - 18 % w / w relative to the amount of clarithromycin ( such as , 7 - 16 %, 9 - 14 %, 9 - 12 %, 10 - 15 %, or 0 - 11 % w / w ) and 10 - 25 % w / w relative to the amount of rifabutin ( such as , 12 - 25 %, 12 - 23 %, 15 - 25 %, 15 - 23 %, 18 - 25 %, 18 - 23 %, 20 - 25 %, 20 - 23 %, or 21 - 23 %). in further embodiments , the present compositions comprise rifabutin , clarithromycin , and clofazimine in about a 9 : 19 : 2 w / w / w ratio , wherein each of the variables are free to vary ± 2 , 1 , 0 . 5 , or 0 . 25 ( e . g ., 9 ± 0 . 5 : 19 ± 5 : 2 ± 0 . 5 ). for example in some instances , the present compositions comprise 90 mg rifabutin (± 30 , 20 , 10 , 5 , 2 , or 1 mg ), 190 mg clarithromycin (± 60 , 40 , 20 , 10 , 5 , 2 , or 1 mg ), and 20 mg clofazimine (± 10 , 7 , 5 , 2 , or 1 mg ). in another instance , the present compositions comprise 45 mg rifabutin (± 15 , 10 , 7 , 5 , 2 , or 1 mg ), 95 mg clarithromycin (± 30 , 20 , 10 , 5 , 2 , or 1 mg ), and 10 mg clofazimine (± 6 , 5 , 2 , or 1 mg ). in some instances the present compositions further comprise an absorption enhancer that may improve bioavailability of one or more of the active ingredients . the amount of absorption enhancer may between 300 - 700 % w / w relative to the amount of clofazimine including 400 - 600 % or 450 - 550 % or 475 - 525 %. in certain embodiments , the absorption enhancer is polyethylene glycol ( peg ), for example , polyethylene glycol having an average molecular weight of between 200 - 20 , 000 including between 1000 - 15000 or 5000 - 12000 or 7000 - 9000 or 7500 - 8500 , for example peg 8000 ). the present compositions may further include one or more additional excipients , such as microcrystalline cellulose ( mcc ) tabulose ® sc 200 ), mg stearate , sodium lauryl sulfate ( sls ) emal ® 10pwd hd , a polysorbate ( such as , polysorbate 80 ), or a combination thereof , including all of these . in some instances , the present compositions include both polyethylene glycol and a polysorbate , such as polysorbate 80 , wherein the amount of polysorbate is 30 - 120 % w / w relative to the amount of clofazimine ( such as 50 - 100 %, 50 - 85 %, or 60 - 75 %). additional excipients contemplated for use with the present compositions are described further below . the present compositions may further include one or more ionic or non - ionic surfactants . in particular , the present compositions may comprise sodium lauryl sulfate . in one embodiment , the present compositions are provided in a single dosage form , for example a tablet , capsule , caplet or lozenge , etc . additional contemplated dosage forms are described further below . the present compositions are useful for treating a patient suffering from or susceptible to a mycobacterium paratuberculosis ( map ) infection . in some instances , such treatments include the treatment of inflammatory bowel disease ( ibd ), such as crohn &# 39 ; s disease , ulcerative colitis , indeterminate colitis , microscopic colitis and collagenous colitis , in addition to sarcoidosis . in preferred embodiments , the present methods are useful for the treatment of crohn &# 39 ; s disease or colitis . hence , in one embodiment the present methods include a method of treating a patient suffering from or susceptible to a mycobacterium paratuberculosis infection , comprising co - administering to the patient in a single dosage form rifabutin , clarithromycin , and clofazimine in a 8 - 10 : 18 - 20 : 1 - 2 . 5 w / w / w ratio ( for example , a 8 . 5 - 9 . 5 : 18 . 5 - 19 . 5 : 1 . 5 - 2 . 5 w / w / w ratio or a 9 : 19 : 2 ratio , wherein each variable is free to vary ± 0 . 5 or 0 . 25 ). in another embodiment , the present method may include a composition comprising a single dosage form comprising 90 mg rifabutin (± 30 , 20 , 10 , 5 , 2 , or 1 mg ), 190 mg clarithromycin (± 60 , 40 , 20 , 10 , 5 , 2 , or 1 mg ), and 20 mg clofazimine (± 10 , 7 , 5 , 2 , or 1 mg ). in another embodiment , the present method may include a composition comprising 45 mg rifabutin (± 15 , 10 , 7 , 5 , 2 , or 1 mg ), 95 mg clarithromycin (± 30 , 20 , 10 , 5 , 2 , or 1 mg ), and 10 mg clofazimine (± 6 , 5 , 2 , or 1 mg ). in some instances , the rifabutin , clarithromycin , and clofazimine are co - administered once each day for a first period of treatment ( for example , 1 - 3 weeks , including 1 week , 2 weeks or three weeks ) in the following amounts : ( i ) 80 - 100 mg rifabutin ( such as , 85 - 95 mg or 90 mg ± 1 . 5 mg ), ( ii ) 180 - 200 mg clarithromycin ( such as , 185 - 195 mg or 190 mg ± 2 mg ), and ( iii ) 15 - 25 mg clofazimine ( such as 17 - 23 mg or 20 ± 1 mg ). the method may further include the step of linearly increasing the amounts of the rifabutin , clarithromycin , and clofazimine while maintaining a 8 - 10 : 18 - 20 : 1 - 2 . 5 w / w / w ratio ( for example , a 8 . 5 - 9 . 5 : 18 . 5 - 19 . 5 : 1 . 5 - 2 . 5 w / w / w ratio ora 9 : 19 : 2 ratio , wherein each variable is free to vary ± 0 . 5 or 0 . 25 ratio ) for a second period of treatment ( for example , from 4 - 10 weeks ). in an embodiment , the linearly increasing amounts of the rifabutin , clarithromycin , and clofazimine do not exceed maximum amounts of ( i ) 420 - 480 mg rifabutin ( such as , 440 - 460 mg or 450 mg ), 920 - 980 mg clarithromycin ( such as , 940 - 960 mg or 950 mg ), and ( iii ) 80 - 120 mg clofazimine ( such as , 90 - 110 mg or 100 mg ) during the second period of treatment . in certain instances , the linearly increasing amounts of rifabutin , clarithromycin , and clofazimine comprise : a ) ( i ) 160 - 200 mg rifabutin ( such as , 170 - 190 mg or 180 mg ± 2 mg ), ( ii ) 360 - 400 mg clarithromycin ( such as , 370 - 390 mg or 380 mg ± 2 mg ), and ( iii ) 30 - 50 mg clofazimine ( such as , 35 - 45 mg or 40 mg ± 1 mg ) once each day for two weeks ; b ) ( i ) 250 - 290 mg rifabutin ( such as , 260 - 280 mg or 270 mg ± 2 mg ), ( ii ) 550 - 590 mg clarithromycin ( such as , 560 - 580 mg or 570 ± 2 mg ), and ( iii ) 50 - 70 mg clofazimine ( such as , 55 - 65 mg or 60 mg ± 1 . 5 mg ) once each day for two weeks ; c ) ( i ) 340 - 380 mg rifabutin ( such as , 350 - 370 mg or 360 mg ± 2 mg ), ( ii ) 740 - 780 mg clarithromycin ( such as 750 - 770 mg or 760 mg ± 2 mg ), and ( iii ) 60 - 100 mg clofazimine ( such as , 70 - 90 mg or 80 mg ± 1 . 5 mg ) once each day for two weeks ; and d ) ( i ) 420 - 480 mg rifabutin ( such as , 440 - 460 mg or 450 mg ± 2 mg ), ( ii ) 920 - 980 mg clarithromycin ( such as , 940 - 960 mg or 950 mg ± 2 mg ), and ( iii ) 80 - 120 mg clofazimine ( such as , 90 - 110 mg or 100 mg ± 1 . 5 mg ) once each day for a week . in certain embodiments , the method further includes , following step d ) above , the step of simultaneously co - administering ( i ) 420 - 480 mg rifabutin ( such as , 440 - 460 mg or 450 mg ± 2 mg ), ( ii ) 920 - 980 mg clarithromycin ( such as , 940 - 960 mg or 950 mg ± 2 mg ), and ( iii ) 80 - 120 mg clofazimine ( such as , 90 - 110 mg or 100 mg ± 1 . 5 mg ) once each day for a third period of treatment . in some embodiments , the third period of treatment is 1 , 2 , 4 , 6 , 8 , 12 weeks ; 3 , 6 , or 12 months or longer . in one embodiment the third period of treatment continues until the map infection has been treated , for example , to the point of eradication , reduction , or at least to the point of halting the progression of the infection . in some instances , the method further includes , after the map infection has been treated , the step of simultaneously co - administering to the patient ( i ) 210 - 240 mg rifabutin ( such as , 220 - 230 mg or 225 mg ± 2 mg ), ( ii ) 460 - 490 mg clarithromycin ( such as , 470 - 480 mg or 475 mg ± 2 mg ), and ( iii ) 40 - 60 mg clofazimine ( such as , 45 - 55 mg or 50 mg ± 1 mg ) once each day , for example , to inhibit recurrence or prevent recurrence of map infection . in some instances , the patient was previously treated with a combination of rifabutin , clarithromycin , and clofazimine . also contemplated is a method of inhibiting occurrence of a mycobacterium paratuberculosis infection in a patient , comprising simultaneously co - administering to the patient in need thereof ( i ) 210 - 240 mg rifabutin ( such as , 220 - 230 mg or 225 mg ± 2 mg ), ( ii ) 460 - 490 mg clarithromycin ( such as , 470 - 480 mg or 475 mg ± 2 mg ), and ( iii ) 40 - 60 mg clofazimine ( such as , 45 - 55 mg or 50 mg ± 1 mg ) once each day . the present methods further contemplate a method of increasing the reduced metabolism of rifabutin caused by clarithromycin in a patient ; comprising co - administering clofazimine with rifabutin and clarithromycin to the patient , wherein the amount of clofazimine is 5 - 18 % w / w relative to the amount of clarithromycin , for example , 6 - 18 %, 7 - 16 %, 9 - 14 %, 9 - 12 %, 10 - 15 %, or 10 - 11 % w / w . in another embodiment , the present methods further include a method of reducing the increased metabolism of clarithromycin caused by rifabutin in a patient , comprising co - administering clofazimine with rifabutin and clarithromycin to the patient , wherein the amount of clofazimine is 5 - 18 % w / w relative to the amount of clarithromycin , for example , 6 - 18 %, 7 - 16 %, 9 - 14 %, 9 - 12 %, 10 - 15 %, or 10 - 11 % w / w . the present methods further contemplate a method of increasing the reduced metabolism of rifabutin caused by clarithromycin in a patient , comprising co - administering clofazimine with rifabutin and clarithromycin to the patient , wherein the amount of clofazimine is 10 - 25 % w / w relative to the amount of rifabutin , for example , 12 - 25 %, 12 - 23 %, 15 - 25 %, 15 - 23 %, 18 - 25 %, 18 - 23 %, 20 - 25 %, 20 - 23 %, or 21 - 23 % w / w . in another embodiment , the present methods further include a method of reducing the increased metabolism of clarithromycin caused by rifabutin in a patient , comprising co - administering clofazimine with rifabutin and clarithromycin to the patient , wherein the amount of clofazimine is 10 - 25 % w / w relative to the amount of rifabutin , for example , 12 - 25 %, 12 - 23 %, 15 - 25 %, 15 - 23 %, 18 - 25 %, 18 - 23 %, 20 - 25 %, 20 - 23 %, or 21 - 23 % w / w . in certain instances , the increase in rifabutin metabolism in the above methods is assessed by measuring a first c max of rifabutin or 25 - o - desacetyl rifabutin in the patient &# 39 ; s serum following administration of clofazimine and comparing the first c max to a second c max of rifabutin or 25 - o - desacetyl rifabutin . the second c max , of rifabutin or 25 - o - desacetyl rifabutin may correspond to a reference value , for example , an average or mean value obtained from the literature , from one or more other patients with similar physical profiles ( age , health , metabolism , and / or disease profile , etc .) or from the same patient at an earlier time . for instance , in some embodiments , the second c max of rifabutin or 25 - o - desacetyl rifabutin is measured in a second patient &# 39 ; s serum , wherein the second patient has been co - administered rifabutin and clarithromycin without co - administration of clofazimine . in another embodiment , the second c max of rifabutin or 25 - o - desacetyl rifabutin was previously measured in the same patient &# 39 ; s serum , wherein the same patient had been co - administered rifabutin and clarithromycin without co - administration of clofazimine . in one embodiment , the first c max of rifabutin is decreased as compared to the second c max of rifabutin by at least 5 %, 10 %, 20 %, 30 , or 40 %. in another embodiment , the first c max of 25 - o - desacetyl rifabutin is decreased as compared to the second c max of 25 - o - desacetyl rifabutin by at least 5 %, 10 %, 20 %, 30 , or 40 %. in some instances , the increase in rifabutin metabolism in the above methods is assessed by measuring a first auc 0 - 24 of 25 - o - desacetyl rifabutin in the patient &# 39 ; s serum following co - administration of clofazimine and comparing the first auc to a second auc 0 - 24 of 25 - o - desacetyl rifabutin . the second auc 0 - 24 of 25 - o - desacetyl rifabutin may correspond to a reference value , for example , an average or mean value obtained from the literature , from one or more other patients with similar physical profiles ( age , health , metabolism , and / or disease profile , etc .) or from the same patient at an earlier time . for example , in certain instances , the second auc 0 - 24 of 25 - o - desacetyl rifabutin is measured in a second patient &# 39 ; s serum , wherein the second patient has been co - administered rifabutin and clarithromycin without co - administration of clofazimine . in another embodiment , the second auc 0 - 24 of 25 - o - desacetyl rifabutin was previously measured in the same patient &# 39 ; s serum , wherein the same patient had been co - administered rifabutin and clarithromycin without co - administration of clofazimine . in one embodiment , the first auc 0 - 24 is decreased as compared to the second auc 0 - 24 by at least 5 %, 10 %, 20 %, 30 , or 40 %. for the compositions employed in the present methods , in some instances , at least two of the rifabutin , the clarithromycin , and the clofazimine arc co - formulated into a single dosage form . for example , in some instances , each of the rifabutin , the clarithromycin , and the clofazimine are co - formulated into a single dosage form . any of the above - mentioned compositions are contemplated for use with the present methods . for example , in some instances the present methods contemplate use of compositions comprising an absorption enhancer that may improve bioavailability of one or more of the active ingredients . the amount of absorption enhancer may between 300 - 700 % w / w relative to the amount of clofazimine ( such as , 400 - 600 %, 450 - 550 %, or 475 - 525 %). in certain embodiments , the absorption enhancer is polyethylene glycol , for example , polyethylene glycol having an average molecular weight of between 200 - 20 , 000 ( such as , between 1000 - 15000 , 5000 - 12000 , 7000 - 9000 , or 7500 - 8500 , for example peg 8000 ). the present methods further contemplate a method for the treatment of inflammatory bowel disease comprising administering to a patient in need of such treatment effective amounts of rifabutin , clarithromycin , and clofazimine , in ratios , dosages , and / or dosage forms as described herein , and immunizing the patient with an immunizing amount of a mycobacterial extract or product . for example , a patient previously not treated or on current anti - inflammatory therapies may be treated by immunization with a mycobacterial extract or product ( living or dead , or its extracted wall and dna components ) as an immunizing agent to stimulate leucocytes in the immunized patient . such immunizing agents may be extracts or products from known , non - pathogenic mycobacteria such as m . vaccae of m . phlei . as used herein , the expression “ mycobacterial extract or product ” refers to whole - killed mycobacteria or mycobacterial extract , with or without adjuvants . an example of a suitable mycobacterial product or extract is regressin , available from bioniche of london , ontario , canada . the mycobacterial product may be used to recurrently immunize the patient using the product as an immunostimulant . the mycobacterial product can be administered via any of several routes , such as oral , intravenous , intramuscular , or subcutaneous . such immunizations can reduce or even rid the patient of the map infection and have the ability to inhibit or cure the disease or place the patient into a prolonged remission . administration of the mycobacterial product or extract is typically from weekly to monthly , but may be more or less frequent . an appropriate treatment regime may be arrived at readily by a medical practitioner in any particular case , given the teaching herein . the mycobacterial product or extract may be administered before , after , or simultaneous to administration of rifabutin , clarithromycin , and clofazimine . doses of the mycobacterial extract can be given in any frequency ranging from 25 - 500 μg , for example , 50 - 500 μg . in certain embodiments ; adequate immuno - stimulation can be maintained by weekly to monthly , typically weekly or monthly , regimens . in another embodiment , therapy with mycobacterium phlei extract ( e . g ., regressin ) includes a weekly immunization program , increasing the dosage by 20 - 80 μg , for example , 40 - 60 μg or 50 μg , of the extract every week until the patient develops fever , rigors , and nausea . the dose is then dropped by 20 - 80 μg , for example , 40 - 60 μg or 50 μg , to the lower level and the patient continues maintenance immunization on a monthly basis . the treatment can last from 4 - 8 weeks , such as 6 weeks , up to a monthly immunization program of 1 - 2 years or more . in another form of therapy standard anti - inflammatory therapy can be combined with recurrent regressin immunization . dosages of rifabutin , clarithromycin , and clofazimine used in conjunction with mycobacterial extract correspond to those described above . all combinations of the dosages and treatment schedules for rifabutin , clarithromycin , and clofazimine and mycobacterial extract described herein are contemplated . the present methods further contemplate combined use with one or more additional agents , such as anti - tb agents , such as salazopyrin , olsalazine or mesalazine , as well as other less known aminosalicylic acids . the 4 - aminosalicylic acids or 5 - aminosalicylic acids can be combined with rifabutin , clarithromycin , and clofazimine . dosages of these additional agents are generally known . for example the typical dosage range for salazopyrin is in the range of from 500 mg to 4 g per day , and for olsalazine or mesalazine from 0 . 500 mg to 3 g per day . hence , the present methods may further include one or more agents effective against tuberculosis . such additional agents may be administered before , after , or simultaneous to administration of rifabutin , clarithromycin , and clofazimine . furthermore , such agents may be administered as part of the same dosage form ( e . g ., tablet , capsule , caplet , etc .) or in a different dosage form as that including the rifabutin , clarithromycin , and clofazimine . the present compositions may be available in the form of a tablet containing at least one of rifabutin , clarithromycin , and clofazimine in a powdered form . in some instances two or all of rifabutin , clarithromycin , and clofazimine are in a powdered form . alternatively , present compositions may be in the form of a tablet capsule containing at least one of rifabutin , clarithromycin , and clofazimine in a microencapsulated form . in some instances , two or all of rifabutin , clarithromycin , and clofazimine are in a microencapsulated form . as another possibility , present compositions may be in the form of a tablet capsule containing at least one of rifabutin , clarithromycin , and clofazimine in a powdered form , and the remaining agents present in a microencapsulated form . as a further possibility , present compositions may be in the form of a tablet capsule containing one or more of rifabutin , clarithromycin , and clofazimine present in a microgranulated form . in additional possibilities , present compositions may be in the form of a tablet containing one or more of rifabutin , clarithromycin , and clofazimine within a capsule , a capsule containing one or more of rifabutin , clarithromycin , and clofazimine within a tablet , a capsule containing one or more of rifabutin , clarithromycin , and clofazimine within an outer capsule containing the other agents , or any combination of the above . in a further embodiment , the present compositions comprise an inner capsule containing rifabutin , within an outer capsule containing clarithromycin and clofazimine , wherein clarithromycin and clofazimine may be present in powdered , microencapsulated , or microgranulated forms . the present methods may be carried out by administration of one or more tablets / capsules containing rifabutin , clarithromycin , and clofazimine as described above , or through the administration of each of these separately . in preferred embodiments , rifabutin , clarithromycin , and clofazimine are administered simultaneously in one dose . the present compositions may be prepared by means known in the art for the preparation of pharmaceutical compositions including blending , grinding , homogenizing , suspending , dissolving , emulsifying , dispersing , and , where appropriate , mixing of rifabutin , clarithromycin , and clofazimine together with selected excipients , diluents , carriers and adjuvants . for oral administration , the present compositions may be in the form of tablets , lozenges , pills , troches , capsules , elixirs , powders , including lyophilized powders , solutions , granules , suspensions , emulsions , syrups and tinctures . slow - release , or delayed - release , forms may also be prepared , for example in the form of coated particles , multi - layer tablets or microgranules . solid forms for oral administration may contain pharmaceutically acceptable binders , sweeteners , disintegrating agents , diluents , flavorings , coating agents , preservatives , lubricants , and / or time delay agents . suitable binders include gum acacia , gelatin , corn starch , gum tragacanth , sodium alginate , carboxymethylcellulose or polyethylene glycol ( peg ). suitable sweeteners include sucrose , lactose , glucose , aspartame or saccharine . suitable disintegrating agents include corn starch , methylcellulose , polyvinylpyrrolidone , xanthan gum , bentonite , alginic acid or agar . suitable diluents include lactose , sorbitol , mannitol , dextrose , kaolin , cellulose , calcium carbonate , calcium silicate or dicalcium phosphate . suitable flavoring agents include peppermint oil , oil of wintergreen , cherry , orange , or raspberry flavoring . suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters , waxes , fatty alcohols , zein , shellac or gluten . suitable preservatives include sodium benzoate , vitamin e , alpha - tocopherol , ascorbic acid , methyl paraben , propyl paraben or sodium bisulphite . suitable lubricants include magnesium stearate , stearic acid , sodium oleate , sodium chloride or talc . suitable time delay agents include glyceryl monostearate or glyceryl di stearate . liquid forms for oral administration may contain , in addition to the above agents , a liquid carrier . suitable liquid carriers include water , oils , such as olive oil , peanut oil , sesame oil , sunflower oil , safflower oil , arachis oil , coconut oil , liquid paraffin , ethylene glycol , propylene glycol , polyethylene glycol , ethanol , propanol , isopropanol , glycerol , fatty alcohols , triglycerides , or mixtures thereof . suspensions for oral administration may further include dispersing agents and / or suspending agents . suitable suspending agents include sodium carboxymethylcellulose , methylcellulose , hydroxypropylmethyl - cellulose , poly - vinyl - pyrrolidone , sodium alginate or ceryl alcohol . suitable dispersing agents include lecithin , polyoxyethylene esters of fatty acids such as stearic acid , polyoxyethylene sorbitol mono - or di - oleate , - stearate or laurate , polyoxyethylene sorbitan mono - or - dioleate , - stearate or - laurate , and the like . emulsions for oral administration may further include one or more emulsifying agents . suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth . variations , modifications , and other implementations of what is described herein will occur to those of ordinary skill without departing from the spirit and the scope of the present disclosure . accordingly , these are not to be limited only to the preceding illustrative description . for additional illustrative features that may be used with the present compositions and methods , including the embodiments described here , refer to the documents listed herein , which are incorporated by reference in their entirety . all operative combinations between the above described illustrative embodiments and those features described in documents and references cited herein are considered to be potentially patentable embodiments . with aspects of the present compositions and methods now being generally described , these will be more readily understood by reference to the following examples , which are included merely for purposes of illustration of certain features and embodiments of the present compositions and methods invention and are not intended to be limiting . the objectives of this study were to 1 ) determine and compare the rate and extent of absorption and 2 ) to assess the safety and tolerability of 2 test formulations of a combination product of clarithromycin , rifabutin and clofazimine ( herein after “ triple combination ”). this study followed a randomized , open - label , single - dose , 1 - way 2 - arm parallel design in 24 normal , healthy , non - smoking male and female subjects . all subjects completed the study , and their data were used for pharmacokinetic and statistical analyses . subjects were admitted to the clinic the day before dosing , and remained until the 24 . 00 hour post - dose blood draw , at which time they were allowed to leave the clinic and after which they were required to return for subsequent blood draws . following a high fat meal , subjects received 2 triple combination capsules ( dry formulation ) or 2 triple combination capsules ( peg formulation ) on day 1 of the study period . during the study , 19 blood samples were collected from each subject , for pharmacokinetic and statistical analyses . over the course of the entire study , approximately 236 . 5 ml of blood was collected from male subjects and approximately 241 . 5 ml of blood was collected from female subjects . these volumes include all required samples , as described further below . the randomization scheme was computer - generated and subjects were assigned a 15 treatment sequence before period i dosing . this was an open - label study ; however , the bioanalytical group was blinded to the randomization scheme . this scheme was made available for statistical and reporting purposes only after the completion of the bioanalytical portion of the study . water was provided ad libitum until 1 . 0 hour pre - dose and after 1 . 0 hour post - dose . with the exception of the whole milk provided to all subjects during the high fat content meal , the only fluid intake allowed during this time was 240 ml of ambient temperature dosing water . following an overnight fast of at least 10 hours , subjects began a high fat content meal 30 minutes prior to drug administration . subjects consumed this meal in 30 minutes or less ; however , the study drug was administered 30 minutes after the start of the meal . the fda standard high - fat content breakfast consisted of the following : 2 eggs fried in butter , 2 strips of bacon , 2 slices of toast with butter , 4 ounces of hash brown potatoes and 8 fluid ounces (. about . 240 ml ) of whole milk . no food was allowed for at least 4 hours post - dose . at 4 . 5 , 9 . 5 , and 13 . 5 hours post - dose , standardized meals and beverages were provided to the subjects . all meals and beverages were free of alcohol , grapefruit products , xanthines and caffeine and were identical for both study treatments . following an overnight fast of at least 10 hours , and 30 minutes after the start of a high fat content meal , subjects received one of the following treatments at 0 . 00 hour on day 1 of the study period according to a randomization scheme : treatment a : 2 triple combination capsules ( dry formulation ) with 240 ml of ambient temperature water ( treatment dose = 190 mg of clarithromycin , 90 mg of rifabutin and 20 mg of clofazimine ). treatment b : 2 triple combination capsules ( peg formulation ) with 240 ml of ambient temperature water ( treatment dose = 190 mg of clarithromycin , 90 mg of rifabutin and 20 mg of clofazimine ). the medications were administered orally . the drugs were given 1 or more capsules at a time . all capsules were ingested within 1 minute . approximately 236 . 5 ml , of blood was collected from male subjects and 241 . 5 ml of blood was collected from female subjects over the study period , as detailed in : during the study period , 19 blood samples ( 1 . times . 4 ml and 1 . times . 6 ml tube for each sampling time point ) were collected from each subject by direct venipuncture or by vasofix ® intravenous catheter using pre - cooled , labelled blood collection tubes containing potassium ethylenediaminetetraacetic acid ( edta ) as the anticoagulant . blood samples were collected at 0 . 00 ( pre - dose ), 0 . 25 , 0 . 50 , 0 . 75 , 1 . 00 , 1 . 50 , 2 . 00 , 2 . 50 , 3 . 00 , 4 . 00 , 6 . 00 , 8 . 00 , 10 . 00 , 12 . 00 , 16 . 00 , 24 . 00 , 48 . 00 , 60 . 00 , and 96 . 00 hours post - dose . the clock times of all blood draws for plasma concentration analyses were recorded . the 6 ml tubes were used to measure clarithromycin and 14 - hydroxyclarithromycin . the 4 ml tubes were used to measure rifabutin , 25 - o - desacetylrifabutin and clofazimine . the blood samples were stored in an ice bath before centrifugation and were centrifuged as soon as possible under refrigerated conditions ( at 4 ° c .) at 3500 rpm for 7 minutes . the collected plasma from each blood collection tube was aliquotted into pre - cooled labelled polypropylene tubes . a minimum of 1 . 5 ml of plasma was transferred from the 6 ml tubes into the first polypropylene tube , and all remaining plasma , if any , was transferred into a second polypropylene tube . the samples were kept in an ice bath , and flash frozen in an upright position , then stored at − 70 ± 10 ° c . until assayed . in another procedure , the blood samples were stored in an ice bath before centrifugation and were centrifuged as soon as possible under refrigerated conditions ( at 4 ° c .) at 3500 rpm for 7 minutes . the collected plasma from each blood collection tube was aliquotted into pre - cooled labelled polypropylene tubes . a minimum of 0 . 8 ml of plasma was transferred from the 4 ml , tubes into the first polypropylene tube , and all remaining plasma , if any , was transferred into a second polypropylene tube . the samples were kept in an ice bath , and flash frozen in an upright position , then stored at − 70 ± 10 ° c . until assayed . upon completion of the clinical portion of the study , all samples were analysed for clarithromycin and 14 - hydroxyclarithromycin in the plasma samples or for rifabutin , 25 - o - desacetylrifabutin and clofazimine in the plasma samples . the direct measurements of this study were the plasma concentrations of clarithromycin and 4 - hydroxyclarithromycin performed , and rifabutin , 25 - o - desacetylrifabutin , and clofazimine performed . the pharmacokinetic parameters were derived from the plasma clarithromycin , 14 - hydroxyclarithromycin , rifabutin , 25 - o - desacetylrifabutin , and clofazimine concentrations . clarithromycin and 14 - hydroxyclarithromycin — information about these analytes was obtained using routine methods known in the art . rifabutin , 25 - o - desacetylrifabutin , and clofazimine - rifabutin , 25 - o - desacetylrifabutin , clofazimine , and the internal standard , diltiazem , were extracted by solid phase extraction into an organic medium from 0 . 20 ml of human plasma . an aliquot of this extract was injected into a high performance liquid chromatography system and detected using a mass spectrometer . the analytes were separated by reverse phase chromatography . evaluation of the assay was carried out by the construction of an eight ( 8 ) point calibration curve ( excluding zero concentration ) covering the range of 9 . 996 ng / ml to 1279 . 470 ng / ml for rifabutin , 2 . 499 ng / ml to 319 . 917 ng / ml for 25 - o - desacetylrifabutin , and 4 . 997 ng / ml to 639 . 586 ng / l ., for clofazimine in human plasma . the slope and intercept of the calibration curves were determined through weighted linear regression analysis ( i / conc . 2 ). two calibration curves and duplicate qc samples ( at 3 concentration levels ) were analysed along with each batch of the study samples . peak area ratios were used to determine the concentration of the standards , quality control samples , and the unknown study samples from the calibration curves . the following pharmacokinetic parameters for clarithromycin , rifabutin and clofazimine and the metabolites 14 - hydroxyclarithromycin and 25 - o - desacetylrifabutin were calculated by standard non - compartmental methods : auc 0 - t , auc 0 - inf , auc 0 - t / auc 0 - inf , c max , t max , t 1 / 2 , k el , and m / p ratio . using general linear model ( glm ) procedures in statistical analysis system ( sas ), analysis of variance ( anova ) was performed on in - transformed auc 0 - t , auc 0 - inf , auc 0 - t / auc 0 - inf , and c max and on untransformed t 1 / 2 , k el , and m / p ratio at the significance level of 0 . 05 . the intra - subject coefficient of variation ( cv ) was calculated using the mean square error ( mse ) from the anova table . the ratio of geometric means and the 90 % geometric confidence interval ( 90 % c . i .) were calculated based on the difference in the least squares means of the in - transformed auc 0 - t , auc 0 - inf , auc 0 - t / auc 0 - inf , and c max between the dry and peg formulations . t max was analysed using nonparametric methods . the pharmacokinetic parameters for clarithromycin , 14 - hydroxyclarithromycin , rifabutin , 25 - o - desacetylrifabutin , and clofazimine derived for both treatments were : auc 0 - t = area under the concentration - time curve from time zero to time of last measurable concentration , calculated using the linear trapezoidal rule auc 0 - inf = area under the concentration - time curve from time zero to infinity m / p ratio = metabolite / parent ratio for auc 0 - inf —( the conversion to molar units occurs prior to the computation of the ratio ). the arithmetic mean , standard deviation ( sd ) and cv were calculated for plasma clarithromycin , 14 - hydroxyclarithromycin , rifabutin , 25 - o - desacetylrifabutin , and clofazimine concentrations for each sampling time and formulation , and for the pk parameters auc 0 - t , auc 0 - inf , auc 0 - t / auc 0 - inf , c max , t max , t 1 / 2 , k el , and m / p ratio . anovas ( with the following factors : treatment , period , sequence , subject within sequence ) were performed on the in - transformed data for auc 0 - t , auc 0 - inf , auc 0 - t / auc 0 - inf , c max . anovas were also performed on the untransformed data to compare the t 1 / 2 , k el , and m / p ratio . all anovas were performed with the sas glm procedure . t max was analysed using nonparametric methods . the equality of treatment effect in both arms was evaluated using wilcoxon rank - sum tests . for all analyses , effects were considered statistically significant if the p - value associated with was less than or equal to 0 . 050 . based on the anova results and the pair - wise comparisons of the in - transformed auc 0 - t , auc 0 - inf , auc 0 - t / auc 0 - inf , c max data , the intra - subject cv , the relative ratios of the geometric means ( calculated according to the formula : e [ dry - peg ] × 100 %), and the 90 % geometric c . i . were determined . twenty - four subjects participated in this study , and samples from the 24 completing subjects ( 12 per arm ) were assayed for drug concentration . the principal statistical software used was sas ®, version 8 . 2 . all analyses were performed on the platform of the sas ® suite of statistical programs , using coded procedures that have been written and verified by the staff in the pharmacokinetics and statistics department of bcr . twenty - four subjects ( 12 males and 12 females ) with a mean age of 31 years ( range = 18 to 45 years ) were enrolled in and completed the study . the completing subjects &# 39 ; mean height was 170 cm ( range = 149 to 187 cm ) and their mean weight was 71 kg ( range = 48 to 104 kg ). the subjects &# 39 ; mean bmi was 24 . 7 kg / m 2 ( range = 18 . 6 to 29 . 7 kg / m 2 ). the completing subjects consisted of 9 caucasians , 5 asians , 5 blacks and 4 hispanics and 1 mulatto . clarithromycin and 14 - hydroxyclarithromycin — information about these analytes was obtained using routine methods known in the art . rifabutin , 25 - o - desacetylrifabutin , and clofazimine — the plasma samples were analysed for rifabutin , 25 - o - desacetylrifabutin , and clofazimine . accuracy and precision of this method were evaluated both within run ( intra - assay — table 2 ) and between runs ( inter - assay — table 3 ) by the analysis of the lowest limit of quantification ( lloq ) and quality control samples at 3 different concentrations ( qc high , qc med and qc low ) in human plasma prepared in the range of the calibration / standard curve . the accuracy and precision determined , at each concentration level , were reported as percent relative error (% re ) and percent coefficient of variation (% cv ), respectively . long term stability in matrix — long term stability of rifabutin , 25 - o - desacetylrifabutin , and clofazimine in human plasma can be determined by comparing the concentration of freshly prepared ( not frozen ) qc samples ( qc low and qc high ) with aged qc samples of the same concentration . mean clarithromycin , 14 - hydroxyclarithromycin , rifabutin , 25 - o - desacetylrifabutin , and clofazimine plasma concentration - time profiles ( linear and semi - logarithmic plots ) are presented in fig1 , 3 , 4 , and 5 , respectively . the mean pharmacokinetic parameters for clarithromycin , 14 - hydroxyclarithromycin , rifabutin , 25 - o - desacetylrifabutin , and clofazimine are summarized below in tables 4 , 5 , 6 , 7 , and 8 , respectively . the peak and systemic exposures of clarithromycin were ˜ 25 % and ˜ 20 % lower after the single oral dose of triple combination capsules ( dry formulation ) when compared to triple combination capsules ( peg formulation ). also , the statistical results indicated that the 90 % confidence intervals of the geometric mean ratios ( dry / peg ) for auc 0 - t , auc 0 - inf , and c max were 47 . 58 % to 135 . 69 %, 48 . 33 % to 135 . 03 %, and 46 . 57 % to 120 . 88 %, respectively . a single dose of 250 mg of clarithromycin resulted in a c max of 780 ± 250 ng / ml . the results obtained from dry and peg formulations of triple combination capsules were approximately proportional to literature findings . chu et al . ( 1993 ) reported that the rise of clarithromycin peak concentrations occur non - linearly to dose which might explain any slight disproportionality between the literature values and those obtained from triple combination capsules dry and peg formulations . there was however , no significant difference in the rate of exposure ( t max ) of clarithromycin between the 2 formulations , indicating a similar rate of absorption between the dry and peg formulations ( median t max 4 . 00 hours ). similarly , the elimination half - life was also found to be similar between the dry and peg formulations ( p value & gt ; 0 . 05 ). the peak and systemic exposures of the metabolite , 14 - hydroxyclarithromycin were ˜ 12 % and ˜ 7 % lower after the single oral dose of triple combination capsules ( dry formulation ) when compared to triple combination capsules ( peg formulation ). also , the statistical results indicated that the 90 % confidence intervals of the geometric mean ( dry / peg ) for auc 0 - t , auc 0 - inf , and c max were 65 . 11 % to 133 . 20 %, 65 . 43 % to 132 . 57 %, and 61 . 72 % to 125 . 43 %, respectively . similar to the parent compound , there was no significant difference in the rate of exposure ( t max ) of 14 - hydroxyclarithromycin between the 2 formulations , indicating a similar rate of absorption between the dry and peg formulations ( median t max 4 . 00 hours ). similarly , the elimination half - life was also found to be similar between the dry and peg formulations ( p values & gt ; 0 . 05 ). the peak and systemic exposures of rifabutin were ˜ 11 % and ˜ 23 % lower after the single oral dose of triple combination capsules ( dry formulation ) when compared to triple combination capsules ( peg formulation ). also , the statistical results indicated that the 90 % confidence intervals of the geometric mean ratios ( dry / peg ) for auc 0 - t , auc 0 - inf , and c max were 57 . 12 % to 103 . 80 %, 53 . 02 % to 101 . 13 %, and 71 . 44 % to 110 . 23 %, respectively . gatti et al . ( 1998 ) conducted a comparative study of rifabutin absorption and disposition in hiv - infected patients with or without wasting syndrome . they found that the c max ( peak concentration ) was 340 ± 140 ng / ml , in 10 hiv patients without wasting syndrome after a single 300 mg dose of rifabutin administered under fasting conditions . there was however , no significant difference in the rate of exposure ( t max ) of rifabutin between the 2 formulations , indicating a similar rate of absorption between the dry and peg formulations ( median t max 6 . 00 hours ). similarly , the elimination half - life was also found to be similar between the dry and peg formulations ( p values & gt ; 0 . 05 ). the peak and systemic exposures of the metabolite 25 - o - desacetylrifabutin were ˜ 26 % lower after the single oral dose of triple combination capsules ( dry formulation ) when compared to triple combination capsules ( peg formulation ). also , the statistical results indicated that the 90 % confidence intervals of the geometric mean ratios ( dry / peg ) for auc 0 - t and c max were 55 . 19 % and 97 . 71 %, respectively . approximately 65 % of subjects were excluded from the statistical analysis of auc 0 - inf , k el , and t 1 / 2 due to the auc 0 - inf extrapolation being more than 20 %. hence , the pharmacokinetic discussion was not based on the outcome of auc 0 - inf . similar to the parent compound , there was no significant difference in the rate of exposure ( t max ) of 25 - o - desacetylrifabutin between the 2 formulations , indicating a similar rate of absorption between the dry and the peg formulation ( median dry and peg t max 6 . 01 hours and 7 . 04 hours , respectively ). similarly , the elimination half - life was also found to be similar between the dry and peg formulations ( p values & gt ; 0 . 05 ). the peak exposure of clofazimine was ˜ 19 % ( c max ) higher after the single oral dose of triple combination capsules ( dry formulation ) when compared to triple combination capsules ( peg formulation ). however , the total systemic exposure ( auc 0 - t ) was found to be similar between the 2 formulations , with a geometric mean ratio of 102 %. the statistical results indicated that the 90 % confidence intervals of the geometric mean ratios ( dry / peg ) for auc 0 - t and c max were 66 . 12 % to 158 . 52 %, and 83 . 26 % to 169 . 02 %, respectively . approximately 50 % ( treatment a ) and 75 % ( treatment b ) of subjects were excluded from the statistical analysis of auc 0 - inf , k el and t 1 / 2 due to the auc 0 - inf extrapolation being more than 20 %. hence , the pharmacokinetic discussion was not based on the outcome of auc 0 - inf . nix et al . ( 2004 ) reported proportional values after administration of a 200 mg dose . the c max was found to be 227 ng / ml . these values are proportional to the values obtained from administration of triple combination capsules in the current study . there was however , no significant difference in the rate of exposure ( t ) of clofazimine between the 2 formulations , indicating a similar rate of absorption between the dry and peg formulations ( median t . sub . max 8 . 00 hours ). similarly , the elimination half - life was also found to be similar between the dry and peg formulations ( p values & gt ; 0 . 05 ). the relative bioavailability of clarithromycin , rifabutin , clofazimine , and their metabolites were assessed by measuring and comparing the peak and total systemic exposures from the 2 treatments ( using auc 0 - t , auc 0 - inf , and c max ). the dry / peg geometric mean ratios of the total systemic exposures ( aucs ) for clarithromycin , rifabutin and their metabolites were lower by ˜ 7 %- 26 %. similarly , the dry / peg geometric mean ratios of the peak systemic exposures ( c max ) for clarithromycin , rifabutin , and their metabolites were found to be ˜ 11 %- 26 % lower when compared to the peg formulation . however , the total systemic exposures for clofazimine ( auc 0 - t ) were similar between the dry formulation and the peg formulation , the peak exposure of the dry formulation was ˜ 19 % ( c max ) higher than that of the peg formulation . there was no significant difference in the time to peak concentration for any of the analytes from either the dry or the peg formulation treatment group . overall , triple combination ( dry and peg formulations ) were well tolerated as a single - dose of about 190 mg of clarithromycin , about 90 mg of rifabutin , and about 20 mg of clofazimine , and no significant safety issues emerged . clofazimine — c max fed = 227 ng / ml after 200 mg dose ( nix , et al ., 2004 ). triple combination ( dry form ) 38 . 32 ± 20 . 98 ng / ml . triple combination ( peg form ). 29 . 82 ± 11 . 37 ng / ml ( bioavailability study with 20 mg ). 20 mg dose gives c max of 23 ng / ml . rifabutin — c max ( peak concentration ) was 340 ± 140 ng / ml in 10 hiv patients without wasting syndrome after a single 300 - mg dose of rifabutin administered fasting ( comparative study of rifabutin absorption and disposition in hiv - infected patients with or without wasting syndrome . gatti g , di biagio a , de pascalis c , guerra m , bassetti m , bassetti d . int conf aids . 1998 ; 12 : 554 ( abstract no . 32171 )). triple combination ( dry form ) 151 . 41 ± 60 . 47 ng / ml . triple combination ( peg form ) 166 . 39 ± 44 . 37 ng / ml ( bioavailability study with 90 mg ). 90 mg dose gives c max of 102 ng / ml . clarithromycin — 500 mg ( four 125 - mg capsules , abbott laboratories ) every 12 hours for 5 doses . c max 2410 ± 670 mg / l and 660 ± 210 ng / ml for metabolite . single dose of 250 mg resulted in c max of 780 ± 250 ng / ml . triple combination ( dry form ) 450 . 69 ± 251 . 30 , triple combination ( peg form ) 549 . 18 ± 253 . 41 ( bioavailability study with 190 mg ). 190 mg dose gives c max of 593 ng / ml . those skilled in the art will recognize , or be able to ascertain using no more than routine experimentation , numerous equivalents to the compounds , compositions , and methods of use thereof described herein . such equivalents are considered to be within the scope of the present disclosure and are covered by the following embodiments . the contents of all references , patents and published patent applications cited throughout this application , as well as their associated figures are hereby incorporated by reference in their entirety . it will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the invention as shown in the specific embodiments without departing from the scope of the invention as broadly described . the present embodiments are , therefore , to be considered in all respects as illustrative and not restrictive .	oral administration of a solid dosage form of the present invention comprising an effective amount of rifabutin , an effective amount of clarithromycin , an effective amount of clofazimine , and an effective amount of an absorption enhancer , is used to treat a subject suffering from , or susceptible to , mycobacterium avium subspecies paratuberculosis infection . in an embodiment , the solid dosage form is sufficiently designed to result in a reduction in the increased metabolism of clarithromycin caused by rifabutin . in an embodiment , the solid dosage form is sufficiently designed to result in a reduction in the metabolism of rifabutin caused by clarithromycin . in an embodiment , the solid dosage form is sufficiently designed to result in a reduction in risk of a subject developing leucopenia or uveitis as a result of rifabutin .
exenatide is a synthetic version of exendin - 4 , a hormone found in the saliva of the gila monster that displays biological properties similar to human glucagon - like peptide - 1 ( glp - 1 ), a regulator of glucose metabolism and insulin secretion . the incretin hormones , glp - 1 and glucosedependent insulinotropic peptide ( gip ), are produced by the l and k endocrine cells of the intestine following ingestion of food . glp - 1 and gip stimulate insulin secretion from the beta cells of the islets of langerhans in the pancreas . although only glp - 1 causes insulin secretion in the diabetic state , it is ineffective as a clinical treatment for diabetes as it has a very short half - life ( a few minutes ) in vivo . exenatide is a 39 - amino - acid peptide , an insulin secretagogue , with glucoregulatory effects . the medication is injected subcutaneously twice a day using a filled pen device . exenatide bears a 50 % amino acid homology to glp - 1 , is structurally analogous to glp - 1 , and has a longer half - life ( 2 . 4 h ) in vivo . thus , it was tested for its ability to stimulate insulin secretion and lower blood glucose in mammals , and was found to be effective in the diabetic state . in studies on rodents , it has also been shown to increase the number of beta cells in the pancreas . exenatide raises insulin levels quickly ( within about ten minutes of administration ) with the insulin levels subsiding substantially over the next hour or two . exenatide has been approved as an adjunctive therapy for patients with type 2 diabetes failing to achieve glycemic control with oral antidiabetic agents . a dose taken after meals has a much smaller effect on blood sugar than one taken beforehand . the effects on blood sugar diminish after six to eight hours . the medicine is available in two doses : 5 μg and 10 μg . treatment often begins with the 5 μg dosage , which is increased if adverse effects are insignificant . according to the manufacturer , the autoinjector must be stored in a refrigerator between 2 and 8 ° c . before first use , and then at a temperature between 2 and 25 ° c . in hot weather , therefore , it should be continuously refrigerated . it should be emphasized that a potential disadvantage in exenatide clinical applications is the frequent subcutaneous ( sc ) injections required . sc injections can cause pain , side effects and possible infections at the sites of injection that could adversely affect patient compliance . a long - acting release form of exenatide has been developed for use as a once - weekly injection . this sustained - release formulation consists of injectable microspheres of exenatide and poly ( d , l lactic - co - glycolic acid ), a common biodegradable polymer with established use in absorbable sutures and extended - release pharmaceuticals , that allows gradual drug delivery at a controlled rate . thus , exenatide extended release is a useful option for the treatment of type 2 diabetes , particularly in patients where bodyweight loss is an essential aspect of the individual patient &# 39 ; s management . however , it is still an injection and need to be injected once weekly . exenatide and insulin are hydrophilic biomacromolecules which exhibit low oral human bioavailability ( estimated at less than 2 %) following extrapolation from data regenerated in animals , which has been attributed to proteolytic instability and limited ability to permeate through biological membranes . in the present invention , encapsulation of hydrophilic macromolecules is demonstrated for exenatide and insulin . the first objective is entrapment of exenatide in the matrix of the nanoparticles at a reasonable level , with an aim at increasing the loading of the nanoparticles in the microparticles for oral administration , in order to ensure that the drug content in the final powdered formulation is the highest possible . the present invention further provides the incorporation of peptidic drugs into primary nanocapsules or nanoparticles that are further embedded in larger nanocapsules , resulting in the formation of double - coated nanoparticulate delivery systems that are designed to protect the peptide from the detrimental effects of the external environmental for prolonged release using parenteral route of administration . peptide loaded primary nanocapsules are encapsulated within larger secondary nanocapsules . it should be noted that in a nanocapsule having a diameter of 400 or 600 nm , it is theoretically possible to incorporate at least 64 and 216 nanocapsules of 100 nm diameter respectively based on volume calculations . the secondary microparticles , i . e . carriers encapsulating the primary nanoparticles of the invention , were obtained by a spray drying technique . spray drying is a process that converts liquids or suspensions into dry powders at a continuous single step process . spray drying was carried out by using buchi laboratory scale spray dryers that can generate microparticles in the size range of 1000 nm to 20 μm for small samples quantities ( few milligrams or milliliters ) at high yields (& gt ; 70 %), thereby forming microparticles at a relatively high yield . the secondary microparticles generally have a size ( diameter ) of between 1 and 30 microns . bovine serum albumin ( bsa ) and dextran 12 kda were purchased from sigma - aldrich ( rehovot , israel ). exenatide was kindly donated by teva pharmaceuticals ( jerusalem , israel ). glutaraldehyde 8 % in water was purchased from sigma - aldrich ( rehovot , israel ). sodium trimetaphosphate ( stmp ) was purchased from alfa aesar ( haverther chemicals and hill , ma , usa ). poly ( methacrylic acid , ethyl acrylate 1 : 1 ( eudragit ® l100 - 55 ) was obtained from rohm ( dramstadt . gmbh , germany ). hydroxypropylmethylcellulose ( methocel e4m premium ) was purchased from dow chemical company ( midland , mich ., usa ). sodium phosphate monobasic , monohydrate was purchased from mallinckrodt chemicals ( phillipsburg , n . j ., usa ). all organic solvents were hplc grade and purchased from j . t . baker ( deventer , holland ). the first line of protection on the sensitive biomacromolecule , exenatide , was achieved by loading the peptide into primary bsa nps . two different types of nps were prepared : bsa nps cross - linked with glutaraldehyde 8 % and bsa combined with dextran 12 kda nps cross - linked with stmp . the bsa nps cross - linked with glutaraldehyde , were prepared by an established desolvation method as previously described by weber et . al [ ref - desolvation process and surface characterisation of protein nanoparticles ]. 200 mg of bsa and 4 or 8 mg of exenatide were dissolved in 20 ml of bi - distilled water ( ddw ). after 0 . 5 hour , the ph of the solution was adjusted to 8 . 5 by 0 . 1m naoh . then , 40 ml of acetone were slowly added to the aqueous phase . an o / w emulsion was formed as evidenced by the rapid formation of opalescence in the dispersion medium . bsa nps were then cross - linked using 12 . 5 μl of glutaraldehyde 8 % solution over 2 hours . following cross - linking reaction completion , the acetone was evaporated under laminar air flow . this formulation was denominated glut - 1 . the bsa / dextran nps were similarly prepared by dissolving in 20 ml ddw , the following compounds : 200 mg of bsa , 50 mg of dextran 12 kda and 4 or 8 mg of exenatide when needed . after 0 . 5 hour , the ph of the solution was adjusted to 8 . 5 by 0 . 1m naoh to make sure that the adjacent hydroxyl groups on dextran are available for the reaction with the stmp cross - linker . then , 20 ml of acetone were slowly added to the aqueous phase . bsa / dextran nps were then cross linked using 50 mg of stmp over 3 hours and acetone was evaporated as described above . preliminary formulations were prepared and evaluated by varying the process parameters . two formulations that differ in the dextran amount were selected for further animal studies : 50 and 150 mg . the formulation with 50 mg was denominated as dx - 50 - and 150 mg as dx - 150 . the microspheres ( mps ) were formed by microencapsulating the exenatide containing nps using the spray drying technique . for the purpose of microencapsulation , 100 ml of nah 2 po 4 buffer was prepared . ph of the buffer was adjusted to 6 . 5 by 1m naoh solution . an amount of 750 mg of eudragit was dissolved in that solution maintaining ph at 6 . 5 . in addition , 1 % w / v hydroxypropylmethylcellulose ( hpmc ) solution was prepared by adding 1000 mg of hpmc to 100 ml of pre - heated (˜ 80 ° c .) ddw . then , the eudragit solution was added via funnel with a gaza band ( to filter eudragit particles that might have not dissolved ) to the hpmc solution . once the acetone was evaporated from the nps suspension , the combined solution of the microparticle polymers was added to the nps suspension . the suspension was then spray - dried with a buchi mini spray - drier b - 190 apparatus ( flawil , switzerland ) under the following conditions : inlet temperature 160 ° c . ; outlet temperature 85 ° c . ; aspiration 100 %; feeding rate of the suspension was 7 ml / min ; the powder was collected in the cyclone separator and the outlet yield was calculated . the mean diameter and zeta potential of the various nps were characterized using malvern &# 39 ; s zetasizer ( nano series , nanos - zs , uk ) at 25 ° c . and using water as diluent . morphological evaluation was performed using cryo - transmission electron microscopy ( cryo - tem ). in the cryo - tem method , a drop of the solution is placed on a carbon - coated holey polymer film supported on a 300 - mesh cu grid ( ted pella ltd ., redding , calif ., usa ), and the specimen is automatically vitrified using vitrobot ( fei ) by means of a fast quench in liquid ethane to − 170 ° c . the samples were studied using an fei tecnai 12 g2 tem , at 120 kv with a gatan cryo - holder maintained at − 180 ° c ., and images were recorded on a slow scan cooled charge - coupled device camera . morphological and size evaluation of spray dried mps were carried out using extra high resolution scanning electron microscopy ( model : magellan 400 l , fei , germany ). the samples were fixed on a sem - stub using double - sided adhesive tape and then made electrically conductive following standard coating by gold spattering ( pilaron e5100 ) procedure under vacuum . the total amount of exenatide in the powder was analyzed by dissolving the sample in 2 ml of water overnight . afterwards , the mixture was centrifuged at 14000 rpm for 2 min 1 ml from the supernatant was injected into hplc under the following conditions : column restek viva c4 ( 5 μm ), 250 / 4 . 6 mm . column temperature was kept at 45 ° c . mobile phase a was acetonitrile ( acn ), and mobile phase b was potassium dihydrogen phosphate ( kh 2 po 4 , 20 mmol / l ) adjusted to ph 2 . 5 by phosphoric acid . the kh 2 po 4 buffer was filtered through a 0 . 2 μm membrane filter prior to use . the following gradient conditions were used for exenatide : from 30 % to 45 % mobile phase a in 15 min , and re - equilibrated back to 30 % mobile phase a for 3 min . flow rate was 1 . 5 ml / min . injection volume was 20 μl . uv signal was detected at 215 nm . the exenatide content was calculated using a calibration curve constructed from exenatide concentrations ranging between 0 to 20 μg / ml that yielded a linear correlation ( r 2 = 0 . 999 ). all the animal studies were approved by the local ethical committee of laboratory animal care at the hebrew university of jerusalem ( md - 13575 - 4 ). sprague dawley male rats ( 300 - 350 g ) were used in this study . the animals were housed in spf conditions , fasted and had free access to drinking water . seven groups of 3 rats were randomly divided to evaluate the oral absorption and exenatide plasma levels over time . exenatide was injected subcutaneously as a solution or formulated in byetta ® at a dose of 65 μg / kg ( 20 μg / rat ). the third and fourth groups of rats were orally administrated with either 31 mg of blank mps spiked externally with exenatide or exenatide solution at a dose of 165 μg / kg ( 50 μg / rat ) to determine whether the blank formulation has an effect . finally , 35 , 33 and 32 mg of glut - 1 , dx - 50 and dx - 150 , respectively , were orally administrated at a dose of 165 μg / kg ( 50 μg / rat ). all oral suspensions were dispersed in 2 ml ddw , while the volume of subcutaneous injection was 200 μl . blood samples ( 500 μl ) were taken from the rat tail at 0 , 0 . 5 , 1 , 2 , 4 , 6 , 8 and 24 h . the blood samples were collected in edta and aprotinin containing tubes . the samples were centrifuged at 10 , 000 rpm , 4 ° c . for 10 min , after which 250 μl of plasma samples were transferred to new tubes and stored at − 80 ° c . until analyzed . exenatide levels were determined using cek - 0130 - 01 elisa kit ( ab biolabs , usa ) following the protocol suggested by the company . the pharmacokinetic parameters were calculated using winnonlin software , applying the trapezoid rule for calculation of auc . the auc values were adjusted following size dose corrections . the relative bioavailability of the different oral formulations compared to the standard marketed formulation byetta ® injected subcutaneously was calculated using the following equation : relative ⁢ ⁢ bioavailability = [ auc ⁢ ⁢ oral ] [ auc ⁢ ⁢ sc ] * 100 200 mg bsa ( sigma - a7906 ) and 50 mg of dextran 12 kda ( sigma - 31418 ) were dissolved in 10 ml ddw . 4 mg of exenatide were separately dissolved in 10 ml ddw . albumin / dextran solution was added to the exenatide solution to complete peptide dissolution ( solution a ). the ph 6 . 8 was adjusted with naoh 0 . 1m to reach ph of ˜ 8 . 5 . 20 ml acetone were injected to solution - a during strong stirring to elicit formation of bsa - dextran nps comprising most of exenatide . dextran cross - linking was obtained by addition of 5 % ( 1 ml ) of sodium trimetaphosphate ( stmp ) and the solution was agitated at 900 rpm at room temperature over 3 hours . a schematic representation of the synthesis of formulation f - 1 is shown in fig1 a - 1b . 200 mg bsa ( sigma - a7906 ) were dissolved in 10 ml ddw . 4 mg of exenatide were separately dissolved in 10 ml ddw . albumin solution was added to the exenatide solution to complete peptide dissolution . ph was adjusted with naoh 0 . 1m to reach ph between of 8 . 5 . 15 ml acetone were injected to solution - a during strong vortex to elicit formation of bsa - exenatide nps comprising most of exenatide . bsa cross - linking was obtained by addition of 25 μl glutaraldehyde 4 % and the solution was agitated at 900 rpm at room temperature over 3 hours . a schematic representation of cross linking of formulation f - 2 is shown in fig2 . exenatide activation was carried out by reacting 4 mg of exenatide with the spacer sulfo - smcc ( sulfosuccinimidyl - 4 -( n - maleimidomethyl ) cyclohexane - 1 - carboxylate ) for 2 hours at room temperature . for preparing the nanoparticles , 150 mg plga ( 50k ) ( resomer rg 504h , boehringen ingelheim ), 150 mg plga - co - peg ( 45k and 5k ) ( resomer rgp d 50105 ) and 10 mg oleyl cysteinamide were dissolved in 50 ml acetone . 100 mg solutol hs 15 ( basf ) was dissolved in 100 ml ddw while stirring . the organic phase was added to the aqueous phase under stirring ( 900 rpm ) and allowed to mix over 15 min . the formulation was evaporated to less that 10 ml on 37 ° c . using rotor evaporator under reduced pressure . ph was adjusted to 6 . 7 - 6 . 8 using naoh 0 . 1m and volume was adjusted to 10 ml . the formulation was centrifuged at 4000 rpm to sediment large particles ( 3 - 4 %). only the colloidal supernatant was used for final formulation . the activated exenatide was incubated immediately with the preformed formulation . incubation was performed at room temperature , overnight on magnetic stirrer . the maleimide groups of the lc - smcc reacted with the sulfhydryl groups of the oleyl cysteinamide at ph = 6 . 5 - 7 . 5 to form stable thioether bonds . 100 mg bsa ( sigma - a7906 ) were dissolved in 2 ml ddw . 5 mg of exenatide were separately dissolved in 3 ml ddw . albumin solution was added to the exenatide solution to complete peptide dissolution . ph was adjusted with naoh 1m to 7 . 4 - 8 . 10 ml acetone was injected into the solution during strong stirring to elicit formation of bsa nanoparticles comprising most of exenatide . 128 mg plga ( 50k ) was dissolved in 93 ml acetonitrile . 6 ml of bsa nanoparticles formulation was added during stirring to form double encapsulation ( nanospray conditions : 4 μm mesh , in temperature : 50 ° c .). 500 mg of hpmc were dissolved in 100 ml preheated ddw , and 500 mg of eudragit ( anionic ) were dissolved in 100 ml pbs . to the nanoparticles solution , eudragit solution and hpmc solution were added . the combined solutions were stirred for 30 minutes at 500 rpm in room temperature ; the combined dispersion was evaporated by spray drier at the following conditions : inlet temp = 160 ° c . ; outlet temp = 100 ° c . microparticles comprising drug - loaded nanoparticles were obtained . the physicochemical characterization of the drug - loaded nanoparticles is shown in table 1 . acclimation of the mice for few days was carried out by giving glucose and monitored glucose levels over 6 hours . afterwards , all mice were injected with byetta ( commercial exenatide injectible formulation ) at a dose of 20 μg / kg and monitoring blood glucose levels over 6 hours . evaluation of the glucose lowering effect of exenatide in various formulations on ob / ob mice was carried out for a group size of n = 8 per group of animals . each group of ob / ob mice was provided with one of the following : on 1st day , all animals were fasted 18 hours prior to the experiments then after fasting , blood glucose was monitored . glucose was injected ( 18 mm / kg ) by i . p . to all animals ; 60 min after glucose injection the following parameters were examined : blood glucose measurement , blood collection for elisa , body weight measurement . then , formulations f1 - f5 were orally administered ( byetta was administered by s . c .). after administration , blood glucose levels were monitored at 30 min , 1 hr , 1 . 5 hr , 2 hr , 3 hr and 6 hr from administration . from 2nd day to 9th day , body weight was measured at time zero and blood was collected for elisa . this was followed by administration of the formulations , and measuring blood glucose levels within 1 hr from drug administration ( as well as blood collection for elisa ). on 10th day , prior to administration the last doses of the tested formulations , glucose was given again followed by body weight measurement and blood collection of for elisa . after this , the formulations were administered in double dose ( to check the potentiation of these formulations ) to the respective animals and then after 1 hr of drug administration , blood glucose levels were measured and blood was collected for elisa . body weight measurements were carried out at the same time for each mouse . the results of the different formulation of exenatide ( f1 - f5 ) and byetta are shown in fig3 . blood samples were collected on day 1 to 10 . animals at 15 - 19 weeks of age were fasted overnight ( up to 16 h ) prior to blood glucose measurement procedures , by transferring mice to a clean cage base with clean nesting material and a small amount of soiled bedding and environmental enrichment from their old cage . the change of cage and bedding obviated the possibility that mice may access spilled food . water remained freely available throughout the entire fasting period . food was returned following collection of the final blood sample . a drop of blood was obtained from unrestrained mice by nicking the tail tip with a blade . measurements were taken using a handheld blood glucose meter ( accu - chek aviva , roche diagnostics , uk ). the blood glucose levels from preliminary experiments with byetta are shown in fig4 , while the blood glucose levels for different formulation of exenatide ( f1 - f5 ) and byetta are shown in fig5 . for insulin determination , 150 ml of blood was sampled from the tail vein ( blood was processed in a centrifuge at 3000 cycles / min for 10 and 5 min ). blood plasma was separated into two heparin - coated tubes for blood parameters and insulin measurements ( 30 ml each ). plasma insulin levels were measured using a mouse insulin enzyme - linked immunosorbent assay kit ( mercodia , sylveniusgatan , sweden ). the plasma insulin levels of the different groups at different days are shown in fig6 . collect plasma using edta as an anticoagulant . centrifuge samples for 15 minutes at 1000 × g within 30 minutes of collection . remove plasma and assay immediately or store samples in aliquot at − 20 ° c . or − 80 ° c . glycosylate hemoglobin levels were measured using a mouse insulin enzyme - linked immunosorbent assay kit ( life science , inc , florida , usa ). the glycosylate hemoglobin levels of the different groups at different days are shown in fig7 . bovine serum albumin ( bsa ) is a well - known and abundant protein carrier for oral drug delivery ( except peptides and proteins ). its major advantages are biodegradability , biocompatibility , safety , non - antigenicity , well tolerability and availability . furthermore , incorporation of peptides and proteins in primary nps is challenging as most of the coating polymers are soluble in water and need to be cross - linked to elicit in - vitro prolonged release of the peptides under sink conditions . in the case of bsa nps , widely accepted as nanocarriers , the issue is even more complicated . any denaturation process of albumin , including cross linking with glutaraldehyde , denaturation by heat or use of organic solvents will obviously affect the chemical integrity of the peptide or protein as observed also in the present work . to avoid such a drawback , the bsa matrix was combined with the polysaccharide dextran which can be cross - linked via its reactive hydroxyl groups as shown in fig8 [** polysaccharides as building blocks for nanotherapeutics ]. to achieve a stable nanoparticulate system , the reactive hydroxyl groups of dextran were cross - linked using tsmp , under suitable ph conditions . various formulations were prepared by varying different parameters , such as ph , type of cross - linking molecule , tsmp amount , dextran amount . the bsa nps containing exenatide prepared with glutatraldehyde as cross - linker exhibited a mean diameter size of 59 . 34 ± 0 . 32 nm based on triplicate measurement with a poly dispersity index ( pdi ) value of 0 . 138 reflecting a narrow size range and a zeta potential value of − 50 . 3 ± 3 . 03 mv . the properties of the nps formulations composed of bsa : dextran blend are presented in table 2 . based on the data depicted in table 2 , two formulations differing in dextran amount : 50 mg and 150 mg were selected as previously mentioned . the mean diameter of the nps , irrespective of the formulation , ranged from 190 to 210 nm , with a relative narrow distribution range as reflected by the relative low pdi values observed . visualization of the primary nps composed of the bsa / dextran blend was carried out using cryo tem ( fig1 a - b ). the images show a spherical morphology of the nps regardless the difference in composition with a diameter size similar in range value to the range observed with zetasizer measurements . the various np - loaded mps characterization was mainly visualized by xhr sem analysis ( fig9 a , b , c ). the microencapsulated nps , showed that the coating of the mps is smooth , ranging qualitatively in size from 1 to 15 μm and the mps are deflated as a result of the vacuum applied for sem visualization . the final exenatide content in glut - 1 , dx - 50 and dx - 150 was 0 . 147 , 0 . 153 and 0 . 158 % w / w respectively , leading to an encapsulation yield efficiency of approximately 40 % irrespective of the formulation . exenatide plasma levels from 3 rats , for each treatment are presented in fig1 . at 8 and 24 hours , exenatide plasma concentrations were below the detection limit of the kit irrespective of the formulation , hence data are not shown . furthermore , it can noted from the results presented in fig1 that the blank mps formulation ( prepared with dx - 50 nps with no exenatide ) spiked with exenatide solution , the glut - 1 formulation and the free exenatide solution administered orally did not elicit any detectable exenatide plasma level . it was also observed that the actual exenatide elicited a plasma profile close to the profile of the commercial byetta ™ product whereas the formulation dx - 50 elicited a higher pharmacokinetic profile than dx - 150 but both were administered at much higher dose that the injectable preparations ( 165 μg / kg versus 65 μg / kg respectively ). indeed , following calculations of the pharmacokinetic parameters it can clearly be noted following normalization of the dose that the highest auc value was elicited by the byetta injection , followed by the exenatide injected solution , the dx - 50 and dx - 150 formulation . furthermore , irrespective of the dose all the formulations elicited c max values higher than 1 , 000 ng / ml and no difference in the t max values . more importantly , anova analysis pointed out that there is no significant difference between the normalized auc values between byeatt and exenatide solution and the dex - 50 oral suspension . the only significant difference was with dex10 - 50 which elicited a relative oral bioavailability of 46 . 5 %. all the procedures related to animal handling , care , and the treatment in this study were performed according to the guidelines approved by the institutional animal care and use committee ( iacuc ) following the guidance of the association for assessment and accreditation of laboratory animal care ( aaalac ). all values in the figures and text are expressed as mean standard error ( s . e . m .) of the mean of n observations . for the in vivo studies , n represents the number of animals studied . in the experiments involving histology the figures shown are representative at least three experiments ( histological coloration ) performed on different experimental days on the tissues section collected from all the animals in each group . data sets were examined by one - or two - way analysis of variance , and individual group means were then compared with student &# 39 ; s unpaired t test . a p - value less than 0 . 05 was considered significant . the therapeutic efficacy and safety of different formulations of exenatide ( f1 - f5 ) was evaluated in ob / ob mice . in particular , there were no significant differences in body weight after administration of exenatide ( f1 - f5 ) and byetta ( fig3 ). in the preliminary experiments with byetta , after 1 h of glucose injection , mice were administered with byetta , as shown in fig4 ; a reduction in blood glucose levels is demonstrated until 6 h . this result supports the idea that byetta represent a goal standard in the treatment of diabetes . in addition , different formulations of exenatide ( f1 - f4 ) were compared with byetta treatment . it is of note that the exenatide formulations ( f1 - f4 ) were orally administered , while the byetta composition was administered by injection . the results showed that , daily oral administration of f - 1 and f - 2 are able to reduce the increase of blood glucose levels in ob / ob mice ( fig5 ). on this basis , it is speculated that these two formulations show the most interesting results . the data in fig6 demonstrates the plasma insulin levels of the different groups at different days . as can be observed , the treatment with the different formulations of exenatide ( f1 - f5 ) is able to increase the insulin levels as well as treatment with byetta . moreover , during the 10 days treatment , it was found that byetta injection reduces the levels of glycosylated hemoglobin ( hba1c ) in ob / ob mice ( fig7 - 11 ). the rate of glycosylated hemoglobin clarified , as compared to fig5 , shows that only two formulations of exenatide f - 1 and f - 2 show an effect in the reduction of glycosylated hemoglobin levels . from this it was concluded that daily oral administration of exenatide f - 1 ( and to a much lesser extent oral administration of f - 2 , because the peptide is cross - linked by glutaraldehyde and loss part of its activity ), may have a beneficial effect in the symptomatic treatment of diabetes . double nanoencapsulated samples comprising h - insulin were prepared for obtaining an injectable dry powder , for eliciting prolonged release of the peptide in vivo . 200 mg of human serum albumin ( hsa ) were dissolved in 5 ml of ddw under stirring . separately , 20 mg of human or bovine insulin were dissolved in 5 ml of ddw and vortexed for 30 seconds . the h - insulin solution was then added to the hsa solution and stirred for 30 minutes to complete peptide dissolution . the ph of the resulted solution was adjusted to 7 . 4 - 8 with naoh 0 . 1m . then , 20 ml of acetone were injected quickly ( within 20 seconds ) under vigorous stirring ( 900 rpm ) to elicit formation of hsa nanocapsules load with h - insulin ( solution a ). solution a was covered with aluminum foil to avoid acetone evaporation and was stirred over 1 hour at 900 rpm . samples ( 50 - 100 μl ) were withdrawn following one hour stirring for zeta potential and size measurements . separately , a solution of plga 100k ( 50 : 50 ) was dissolved in 80 ml of acetonitrile and added to solution a . nanoencapsulation of hsa / h - insulin nanoparticles into by plga using nanospray dryer — organic mode nanocapsules were prepared via spray drying on the nsd b - 90 operating at ‘ closed loop ’ mode , hence , n 2 ( g ) and co 2 ( g ) were flowed in the system instead of air . in all experiments , gas flow was about 120 l / min . the air was soaked with volatile vapors and humidity transferred to a dehumidifier unit for drying and condensation , then was returned dry to the system in a circular path . spray drying was carried out at low temperatures ( t m = 30 °- 60 ° c .) with mesh size membrane 4 μm . various formulations of different hsa / h - insulin / plga ratios were prepared . unlike conventional spray dryers that operate on turbulent flow , the nsd b - 90 operates on a laminar flow ; hence gentle heating is achievable , thus making the system compatible for heat - sensitive biopharmaceutical products . an appropriate analytical method by hplc was developed at the following conditions : a c4 column was used for separation and analyzing h - insulin ( restek viva 4 . 6 mm × 250 mm , i . d ., 5 μm particles , bellefonte , pa . usa ). column temperature was kept at 45 ° c . mobile phase a was acetonitrile ( acn ), and mobile phase b was potassium di - hydrogen phosphate ( kh 2 po 4 , 20 mmol / l ) adjusted to ph 2 . 5 with phosphoric acid . the mobile phase was filtered through a 0 . 45 μm membrane filter and degassed via vacuum prior to use . the following gradient conditions were used for h - insulin : from 30 % to 45 % mobile phase a in 15 min , and re - equilibrated back to 30 % mobile phase a for 3 min . flow rate was 1 . 5 ml / min . injection volume was 20 uv signal was detected at 215 nm . table 5 the zeta potential and particle size of the primary nanocapsules of various formulations zeta size potential formulation nanoparticles method ( nm ) pdi ( mv ) dehi - 002 plga 100k ( 3x ), 151 . 1 0 . 17 − 59 . 6 insulin ( 3x ) double nanoencapsulation dehi - 003 plga 100k ( 3x ), 150 . 1 0 . 17 − 61 . 9 insulin ( 1x ) nanoencapsulation dehi - 004 plga 100k ( 1x ), 160 . 9 0 . 10 insulin ( 1x ) nanoencapsulation samples were suspended in ultra pure water + vortex , and then were shaken for at least 30 minutes , prior to freezing . a suspension volume of 1 . 5 μm was sandwiched between two flat aluminum platelets with a 200 mesh tem grid used as a spacer between them . the sample was then high - pressure frozen in a hpm010 high - pressure freezing machine ( bal - tec , liechtenstein ). the frozen samples were mounted on a holder and transferred to a baf 60 freeze fracture device ( bal - tec ) using a vct 100 vacuum cryo transfer device ( bal - tec ). after fracturing at a temperature of − 120 ° c . samples were etched at − 110 ° c . for 5 minutes and coated with 3 nm pt / c by double axis rotary shadowing . samples were transferred to an ultra 55 sem ( zeiss , germany ) using a vct 100 and were observed using a secondary electrons in - lens detector at 1 . 5 kv at a temperature of − 120 ° c . the sem images are shown in fig1 a - 11c . the dm was induced in the rats by intravenous injection of streptozotocin ( stz ) diluted in 0 . 05m citrate buffer ( 50 mg / kg body weight ). two weeks afterwards , animals selected as diabetic were those that exhibited fasting glycemia above 250 mg / dl . glycemia was measured by the glucose oxidase method ( bergmeyer and bernt , 1974 ) using a clinical glucometer ( contour ™, bayer ). the diabetic rats were then used to evaluate the hypoglycemic effects of different formulations containing insulin nanocapsules via oral feeding at 5 ; 10 iu /( 175 ; 350 μg ) and subcutaneous injection at 5 iu ( 175 μg ) per animal in different conditions ( fasted and non fasted ). fig1 - 13 show the blood glucose levels following subcutaneous administration of the various insulin loaded nanoparticles formulations in fasting and non - fasting conditions ( n = 3 ), respectively . it can be seen from the sem images that primary hsa nanocapsules of h - insulin are nanoencapsulated in larger nanocapsules of plga . these primary nanocapsules are also coated internally by the polymer pla suggesting that the insulin release may be controlled upon i . m . or s . c . injection . this assumption was verified ( as can be seen in fig1 - 13 ), as the injection of both types of insulin in double nanocapsules elicit a marked prolonged decrease in blood glucose over 24 h in fasting conditions , whereas in non fasting conditions the effect is shorter . it can be concluded that the novel technique does not affect at least markedly the pharmacological activity of the insulin .	provided is a nanoparticle including a water - soluble protein , a glucan and a hydrophilic active agent , the glucan being at least partially cross - linked by a metaphosphate .