premixed calcium cement pastes for use in bone graft and similar medical repair applications are provided . the pastes may be injectable for delivery to the bone or tooth defect site . the pastes may include a non - toxic , calcium - containing and / or calcium phosphate - containing powder , a non - toxic organic acid capable of forming calcium complexes , and a non - toxic , non - aqueous , water - miscible liquid . non - aqueous liquids are preferred to limit premature hardening of the pastes , which may harden in aqueous environments . a preferred liquid is glycerin ( also sometimes referred to as “ glycerol ”). the organic acid is used to accelerate the hardening time of the paste upon delivery . gelling agents , such as hmc , carboxymethyl cellulose (“ cmc ”), alginate , chitosan , and the like , also can be mixed with the powders to enhance paste cohesiveness and washout resistance . because the hardening of these cements results from calcium - complex formation , it is contemplated that self - hardening cements can also be formulated using calcium - containing compounds instead of , or in combination with , calcium phosphate compounds . the calcium phosphate and / or calcium - containing compound powder can include monocalcium phosphate monohydrate (“ mcpm ”), mono calcium phosphate anhydrous (“ mcpa ”), dicalcium phosphate anhydrous (“ dcpa ”), dicalcium . phosphate dehydrate (“ dcpd ”), octacalcium phosphate (“ ocp ”), α - tcp , β - tricalcium phosphate (“ β - tcp ”), amorphous calcium phosphate (“ acp ”), calcium deficient ha , non - stoichiometric ha , ttcp , caso 4 , caso 4 . o . 5h 2 o , caso 4 . 2h 2 o , cao , ca ( oh ) 2 , and caco 3 and combinations thereof . preferred calcium phosphate powders include ttcp , dcpa , α - tcp and β - tcp . the ca / p molar ratio of ttcp is preferably between about 1 . 67 to about 2 , of α - tcp is between about 1 . 5 to about 1 . 67 , and of β - tcp is between about 1 . 50 to about 1 . 67 . the particle sizes of the calcium phosphate and / or calcium - containing compounds are between about 1 to about 200 μm and more preferably between about 2 to about 50 μm . any suitable , non - toxic , non - aqueous , water - miscible liquid may be used in preparing the pastes . possible liquids include glycerin , as well as related liquids , such as glycerin compounds , derivatives , substitutes and the like , that are non - toxic , non - aqueous , and watermiscible . certain alcohols also may be suitable for use as the non - toxic , non - aqueous , watermiscible liquid . preferably , the liquid is selected from glycerin , propylene glycol , polypropylene glycol ), poly ( ethylene glycol ), and combinations thereof . preferred organic acids are non - toxic , organic carboxylic acids . a number of carboxylic acids form calcium complexes that are not highly soluble . these acids include glycolic , citric , tartaric , malonic , malic , and maleic acids . some of these acids , when mixed with a powder containing one or more of calcium phosphate compounds and / or calcium - containing compounds produce relatively fast hardening cements . thus , it is possible that the use of these acids can produce faster setting premixed cements . one or more of these acids are mixed with the powder to provide a stable paste that will harden only upon contact with an aqueous fluid . without wishing to be bound by any theories , it is believed that the calcium phosphate compounds and / or calcium - containing compounds react with the organic acids in the presence of water to initially form calcium complexes that are not highly soluble , rather than to directly form hydroxyapatite . this then results in more rapid hardening of the paste . the compositions also may include a non - toxic gelling agent to enhance paste cohesiveness and washout resistance . the gelling agent may include hmc , cmc , chitosan , collagen , gum , gelatin , and alginate , and combinations thereof . the compositions are prepared and stored under substantially anhydrous conditions to limit premature hardening of the cement pastes . the compositions may be employed as self - hardening cement pastes in a variety of medical and dental procedures for repairing or restoring missing or defective bone or tooth tissue . the cement pastes may be applied to the defect site using any suitable methods , including injecting with a syringe or depositing with a spatula , and also molded or sculpted in vivo as desired . when the cement pastes are exposed to physiologic fluids , which contain water , or another aqueous environment at the defect site , they will harden relatively rapidly . an aqueous fluid may be contacted with the compositions either prior to or after application of the cement pastes at the defect site to enhance the rate of hardening of the cement pastes . as an example , a sodium phosphate or saline solution may be sprayed over the surface of the cement paste after it is delivered to the defect site to promote hardening of the outer surface of the cement paste , which will also assist with maintaining the shape of the cement paste as applied and molded . as another example , water may be mixed with the cement pastes prior to application of the pastes at the defect site to initiate hardening . for most clinical applications , a cement hardening time of more than 60 minutes is too long . premixed pastes or self - hardening bone graft pastes (“ bgps ”) in accordance with the various embodiments of the present invention will have an ht of no more than about 35 minutes , preferably no more than 20 minutes and even more preferably between about 5 to about 15 minutes . the following examples further illustrate preferred embodiments of the present invention but are not be construed as in any way limiting the scope of the present invention as set forth in the appended claims . various premixed self - hardening pastes were prepared . hardening times and other properties of the pastes were evaluated . preparation of the solid ingredients of premixed paste : ttcp was prepared by heating an equimolar mixture of commercially obtained dcp a ( baker analytical reagents , j . t . baker chemical co ., phillipsburg , n . j .) and caco 3 ( j . t . baker chemical co .) at 1500 ° c . for 6 hours in a furnace and quenched at room temperature . the ttcp and dcpa powders of the paste compositions were ground individually in a planetary ball mill in cyclohexane , ethanol , or without a liquid to obtain the desired median particle sizes , which typically is about 15 μm as disclosed in the prior art for making cpc powders . the median particle sizes of ttcp and dcpa were about 17 . 1 μm and about 1 . 7 μm , respectively . α - tcp was prepared by heating a mixture that contained 2 mol of dcpa and 1 mol of caco 3 to 1500 ° c . for 6 hours and then quenched in air . the powders were ground individually in a planetary ball mill in cyclohexane , ethanol , or without a liquid to obtain the desired median particle sizes based on data from previous studies . the median particle sizes of α - tcp and caco 3 were 4 . 6 and 3 . 9 μm , respectively . the median particle size of ca ( oh ) 2 was 2 . 2 μm . the particle sizes of the components of the pastes prepared in accordance with the present invention generally can be in the range of 1 to 50 μm . liquid ingredients of controls and premixed pastes : all ingredients were obtained commercially . a homogeneous mixture of a carboxylic acid , hmc or cmc , and glycerin was produced by blending the mixture in a ball mill . preparation of premixed pastes : premixed paste compositions were prepared by mixing a powder and a liquid at desired powder - to - liquid mass ratios ( p / l ) on a mixing block until a smooth and homogenous paste was obtained . the compositions , with components expressed in mass fraction (%) are presented in table 1 . washout resistance test : the washout resistance of the premixed pastes was tested as follows . premixed paste samples were shaped into a small sphere by hand , and then placed immediately in a 5 ml of physiologic - like solution (“ pls ”) ( 1 . 15 mm ca , 1 . 2 mm p , 133 mm nacl , 50 mm hepes , ph = 7 . 4 ) at 37 ° c . the sample was considered to pass the washout resistance test if it did not visibly disintegrate in the pls . all samples exhibited excellent washout resistance . diametral tensile strength (“ dts ”) measurement : dts samples were prepared by placing the premixed paste into a mold ( 6 mm diameter by 3 mm height ) with about 2 mpa of applied pressure . the mold was covered with two fritted glass slides ( pore size of about 40 μm to about 60 μm , thickness of about 3 . 5 mm ) and immersed in pls at 37 ° c . glycerol - pls exchange occurred through the fitted glass , allowing the paste to harden . samples were removed from molds at about 4 hours , and then each sample was immersed in 30 ml of pls for an additional 20 hours . in some cases , additional samples were prepared and samples were immersed in pls for an additional 6 days with the pls being changed daily ( 30 ml / specimen at 37 ° c .) to investigate the effect of pls immersion on physicochemical properties . dts values ( standard uncertainty equals 5 %) were measured on a universal testing machine ( united calibration corp , garden grove , calif .) using a loading rate of 10 mm / min , hardening time measurements : the gilmore needle method ( standard uncertainty equals 5 %) was used to measure hardening time on samples prepared as described above for dts measurements . all samples exhibited short hardening times . the hardening times were as shown in table 2 . assessments of hydroxyapatite formation : powder x - ray diffraction (“ xrd ”) analysis was used to estimate the extent of paste conversion to ha . the estimated standard uncertainty in 28 measurements is 0 . 01 ° and the minimum mass fraction of a calcium phosphate phase that can be detected by xrd is about 3 %. dts of some of the premixed paste samples were determined as given in table 3 . hydroxyapatite (“ ha ”) formation : conversion of the initial cement compositions to ha was incomplete in 1 - day samples . complete and near complete conversion of the initial cement compositions to ha was found in all 7 - day samples of premixed pastes using xrd . in sum , formation of a bone replacement or dental replacement paste results by combining dry powder constituents , characterized by their conversion - to calcium complexes in the presence of carboxylic acids and water . a gelling agent , such as hydroxypropyl methyl cellulose , can be mixed with the powder to improve the cohesiveness of the paste . the ratio of combined constituents is broad and the resulting paste can be formulated to control rather precisely the physical properties of the paste , including injectability , porosity and hardening time . while particular embodiments of the present invention have been described and illustrated , it should be understood that the invention is not limited thereto as modifications may be made by persons skilled in the art . the present application contemplates any and all modifications that fall within the spirit and scope of the underlying invention disclosed herein .
a bone or dental implant material in the form of a paste includes a mixture of calcium phosphate and / or calcium - containing powders , liquid glycerol , organic acid and gelling agent . the paste is stable , resistant to washout and will harden upon exposure to water . physical characteristics of the paste , including consistency , porosity , and hardening time , are controlled by the choice and ratio of constituents .