the present invention describes the formation and use of electrically isolated cells to form part of a sensor . it should be understood that the isolated cells may be formed from part of the existing tissue , and , therefore the term isolated cell sensor , isolated tissue sensor , and isolate cell / tissue sensor , and the like , refer to the constructed cells wherein the utilized cells have been electrically isolated by the techniques described herein . in the drawings similar reference characters denote similar elements throughout the several views . the attached figures illustrate a method and device to form a sensor using a cardiomyocyte , which comprises an ablation catheter and a sensing lead . catheter 1 is a hollow conductor that carries rf power from the external generator to the myocardium 2 to form a cone - shaped ablation zone 3 to electrically isolate a part of myocardium 5 from the rest of the tissue . sensing lead 4 is a conductor that carries electrical signals from the isolated myocardium 5 back to the implanted monitoring device 6 . implantable device 6 is the main unit for processing the signals coming back from the sensing lead . the catheter used can be , as shown , a hollow catheter 1 with walls 7 and 8 . the catheter carries the high frequency electromagnetic waves between its walls . it is preferred that both the inner wall 7 and the outer wall 8 are formed by conductors , such as metals , metal coated polymers or conductive polymers . the space between the conductors 9 are air - filled and sealed at both ends with dielectric materials to keep the fluids from seeping in , but allowing the passage of the electromagnetic waves . using a stylet , the catheter 1 can be positioned within the ventricular cavity , against a healthy region of the myocardium 2 . the stylet is later removed while keeping the catheter 1 in place , and the proximal end of the catheter 1 is connected to a high frequency signal generator . the tip of the electrode that is in contact with the myocardium 2 is shown schematically in fig3 , optionally containing sensing electrode 4 , which would be introduced later on . electromagnetic waves produced by the generator travel between the walls 7 and 8 forming the shell of the catheter 1 and reaching to the distal end . before the waveguide formed by walls 7 and 8 terminates at the tissue , catheter 1 splits into multiple branches , shown as four different bands at the end of the catheter 1 . path lengths for these branches are calculated to provide the desired transmission delay , for example , the phase shift needed to form a phased array to create penetrating waves into the tissue are shown turned toward the central axis of the catheter 1 . this would expose a cone - shaped region of the myocardium to the electromagnetic waves and ablate it . however , the isolated cells of the myocardium 5 not directly in the ablation path 3 will be spared , electrically isolating viable tissue from the rest of the myocardium . sensing lead 4 is a conductor that carries electrical signals from the isolated myocardium 5 back to the implanted monitoring device 6 . following ablation , the hollow lumen of the catheter 1 can be used to advance a sensing electrode 4 for attachment to the electrically isolated myocardial cells 5 , preferably with an active fixation mechanism . finally , the catheter 1 is removed , leaving the sensing electrode 4 in contact with the electrically isolated myocardium 5 . the isolated cells and sensing electrode form the cell - based sensor . sensing lead 4 could contain a single electrode and be configured in unipolar fashion , or could contain two electrodes and be configured in bipolar fashion . furthermore , the cell - based sensor could have passive fixation using tines , or could contain active fixation to the myocardium 2 via screw - in process . implantable device 6 is the main unit for processing the signals coming back from the sensing lead 4 . an implantable device 6 with three ports is utilized to take advantage of the cell - based sensor . atrial leads 10 and ventricular leads 11 are utilized in their usual fashion , e . g ., for use in sensing intrinsic activities of the atria and ventricles , and for pacing . the third electrode 4 , labeled with letter “ s ” in fig4 , is used to sense the electrophysiological activity of the tissue segment 5 electrically isolated from the rest of the myocardium 5 . this isolated segment is not under the chronotropic influence of the rest of the myocardium 2 , but still receives the pharmaceuticals from the coronary circulation . hence , the implantable device 6 can detect the level of effects of drugs from the measured electrophysiologic activity of the isolated myocardium . furthermore , the availability of the ventricular lead 11 will allow the elimination of the far field r - waves from the sensing signal . such a device could be used for enhancing the monitoring capabilities of the implantable devices , and can also be used to provide feedback to an implantable drug pump . implantable device 6 could be a pacemaker , a defibrillator , or a simple monitoring device . it could also be an implantable drug delivery device , or a combination of any of the above . the purpose of catheter ablation is to destroy myocardial tissue 3 by delivering electrical energy using electrodes of a catheter 1 placed on the myocardium 2 . radio frequency ( rf ) energy delivered by the electrodes is provided by an external generator and destroys the tissue by controlled heat production . rf energy is delivered between the distal ( tip ) electrode of the catheter 1 and an indifferent electrode placed elsewhere on the patient &# 39 ; s body , usually as an external pad on the skin of the patient &# 39 ; s thigh . in the human body , electrical conduction is achieved by ions , which are too large to move back and fourth at the radio frequencies . instead , rf energy causes resistive heating of the cells surrounding the tip electrode of the catheter 1 . once tissue temperature exceeds 50 ° c ., irreversible cellular damage and tissue death occurs . newly formed scar tissue is not able to conduct the electrical impulses of the myocardium . electromagnetic waves travel in free space and in air without requiring a conductive medium . since air and free space do not conduct electricity , there is no power dissipation in either medium ( recall that p = v 2 / r , where r =∞). in the tissue , however , the resistance is not infinite ; therefore , the power is dissipated in the form of heat . as a result , wave amplitude would decrease once the electromagnetic waves leave the air and enter the tissue . electromagnetic waves could be guided and directed in a preferred direction by the use of special structures called waveguides which could be formed by the inner 7 and outer walls 8 of the hollow catheter 1 . waveguides can be constructed using conductors , such as metals , or dielectrics like glass as in the case of optical fibers , or combinations , as in the case of micro - strip lines . transmission of waves within these guides can be explained as multiple reflections from the walls 7 and 8 of the waveguide . electromagnetic waves travel through the cavity of the waveguide until they reach the load end , which is the end opposite to the source end connected to the generator . waves reaching the load end would be freed from the restriction imposed by the walls 7 and 8 of the waveguide and would disperse into the external medium . this condition is shown on fig1 . as waveguides focus the electromagnetic waves inside them toward the direction of the waveguide , steerable beam antennas ( phased array antennas and linear antenna arrays ) influence the direction of the waves upon the termination of the guide . principle of such an arrangement is shown in fig2 . in one implementation , four sources 12 , 13 , 14 and 15 simultaneously transmit electromagnetic waves at the same frequency , f 0 , but with some phase shift , or time delay . in the implementation shown in fig2 , the transmitter 15 transmits electromagnetic waves with no delay , allowing the waves emanating from this transmitter to travel farther in space before the other transmitters 12 , 13 and 14 begin to send out the same wave . this is indicated by circle 19 representing the traveling wave , centered on the bottom transmitter , having the largest radius . remaining transmitters 12 , 13 , and 14 transmit with linearly increasing delays , as shown with waves 16 , 17 and 18 , which traveled shorter distances and therefore have reduced radii . this arrangement allows the formation of a wavefront 20 where the direction of travel for the beam is controlled by adjusting the phase - shift ( time delay ) between the transmitters 12 , 13 , 14 and 15 . although the above description included a method where a single external rf source was used to feed rf signals to the catheter 1 which in turn generated the phase shifted signals at the distal end for phased array , it is also possible to generate the phase shifted signals at the source and carry them to the distal end using separate waveguides . it is also possible to place the rf oscillators at the distal end and power them from an external source placed at the proximal end . one operation of the present invention can be summarized as follows : a suitable portion of the myocardium 2 is identified as a candidate region for the formation of the cell - based sensor . its suitability is confirmed by electrogram to assure that the region contains viable tissue and ablation around the region would not cause re - entrant arrhythmias . catheter 1 is advanced to the position and rf power is applied to form the cone - shaped isolation zone 3 . afterwards , the sensing electrode 4 is attached to the isolated myocardium 5 and the isolation is confirmed with the a synchronous rates of depolarizations observed from the ventricular 11 and the sensing leads 4 shown on fig3 . atrial 10 and ventricular leads 11 , as well as the sensing lead 4 , are all connected to the implantable device 6 . under ambulatory conditions , implantable device 6 receives electrical signals from both the ventricular 11 and sensing leads 4 . the rate of depolarization measured from the ventricular lead 11 would be controlled by the chronotropic influence of the cardiovascular physiology as well as the administered pharmaceuticals . signals from the isolated myocardium 5 would show the influence of the pharmaceuticals primarily , and would indicate the independent effects of the anti - arrhythmic drugs on the cardiomyocytes . the foregoing description is considered as illustrative of the principles of the invention . numerous modifications and changes will be readily apparent to one skilled in the art . an example problem that the invention is designed to solve is presented : many anti - arrhythmic drugs have a very narrow range of effectiveness . for example , effective plasma concentration of quinidine is 3 - 6 μg / ml . it is eliminated by the liver , and its half life in the blood is 5 - 9 hours . patients take 300 - 600 mg every 6 hours to maintain the drug within the effective range , which causes the concentrations in the blood to swing from the maximum to the minimum of this range ( 3 - 6 μg / ml ) between administrations . if the patient delays the administration , or forgets it altogether , then the drug concentration in blood will fall below the therapeutic range , and the patient would be vulnerable to life - threatening arrhythmias . a sensor which can sense the anti - arrhythmic effects of drugs in the blood , such as the one described in this invention , would warn the patient or trigger an implantable drug pump to release additional drugs , quinidine in this case , into the bloodstream . an example sensor system was formed by edelberg et al ., where hearts from donor mice were implanted into the ears of recipient mice . in this experiment , endogenous and exogenous hearts were not in electrical contact . when propranolol , a β - blocker , was administered , r - r interval ( time between the two successive qrs complexes of the ecg , measured to determine the duration of the cardiac cycle ) of the exogenous heart was more than doubled in three minutes , where the increase in the r - r interval of the endogenous heart was less than 20 percent , showing that the isolated cardiomyocytes in the ear were much more sensitive to the drugs in the circulation . since the isolated myocytes were not influenced by other factors such as filling pressures and arterial loads , the changes in the electrical behavior of the isolated cells would be more specific . a change in the endogenous heart rate would not be specific to the drug administration , whereas a change in the rate of isolated heart cells would be specific to the drugs in the blood . the present invention utililes this fact in the design of the present invention . cells in the electrically isolated region of the myocardium can be converted into rhythmically depolarizing cells by molecular interventions . for example , it was shown by e . marbá cun et al ( nature , 12 sept . 2002 ) that the molecular suppression of kir2 channel unleashes pacemaker activity in ventricular myocytes . conversion of atrial myocytes into oscillators was also demonstrated by m . rosen et al ( circ , feb 2003 ) where the administration of adv - hcn2 initiated sa nodal activity in canine left atrium . since the cells in this isolated region are not in electrical contact with the rest of the myocardium , their rhythmic behavior does not lead to arrhythmias . however , the cells in this region are not under any of the usual chronotropic input as the sinus - atrial ( sa ) node . therefore , the isolated cells respond more specifically to the drugs which control the heart rate and the arrhythmias , but do not respond either to the changes in the systemic oxygen consumption or to the changes in total peripheral arterial resistance . above described sensor would show high specificity to drugs which block beta - adrenergic receptors , such as propranonol , timolol , metoprolol , etc . the rate observed from this region 5 as sensed by the lead 4 , as shown in figure , would primarily correspond to the concentration of β - blockers in the bloodstream , while the rate sensed by the lead 11 in fig4 would be affected by physiologic condition of the patient as well as pharmacological inputs . in fig5 , the solid line shows the rate of the ventricular myocardium being sensed from lead 1 1 and the dashed line shows the rate of the isolated region from lead 4 being sensed . the electrically isolated region does not contain cells with intrinsic oscillatory behavior . although these cell do not depolarize rhythmically , they would respond to electrical stimulation applied via lead 4 in fig4 . amplitude of the electrical stimulation can be chosen such that it is sufficient to depolarize the isolated region 5 in fig4 , but not sufficient to conduct through the necrotic tissue ( 3 ) and excite the remaining myocardium ( 2 ). once the electrical stimulation amplitude and pulse - width is chosen as explained above , one can measure the refractory period at the isolated region . two stimuli are delivered to the region in rapid succession ( e . g . δt = 150 msec ), and the evoked response is detected . if both stimuli capture and excite the isolated region , as evidenced by the presence of evoked response following each pulse , it would be concluded that the refractory period is shorter than δt . in this case , δt will be reduced , and the procedure is repeated . if only the first pulse captures , then it can be assumed that the refractory period is longer than δt , and the procedure will be repeated with a longer δt . measurement of refractory period would indicate the concentration of sodium channel blockers such as quinidine , procainamide and disopyramide , as well as potassium channel blockers such as bretylium and sotalol , as they directly alter the duration of the refractory period . the method described above for the measurement of the refractory period using two successive pulses is only applicable to the isolated region of the heart , since the paired pulses applied to the remaining myocardium ( 2 ) via the ventricular lead ( 11 ) could cause fibrillation and death of the patient if the second pulse were to coincide with the t - wave . fig6 shows the expected response from the leads 4 and 11 of fig4 . in part ( a ) δt & lt ; refractory period , as indicated by the lack of evoked response following the second stimulus , and ( b ) δt & gt ; refractory period indicated by the presence of evoked responses following both stimulation pulses .
a method and device are described to form a sensor using a cardiomyocyte by advancing a catheter into the tissue of interest , cardiac in the preferred embodiment , and using the catheter to ablate a cone - or a dome - shaped region to form an electrically isolated section of tissue . an electrode is later fixed to the region encompassed by the dome - shaped area of tissue and used to detect the electrophysiological activity of this electrically independent cluster of cells . these cells combined with the electrode and a detection circuitry will form a cell - based sensor to monitor the effects of the anti - arrhythmic drugs in the circulation . the inventive device includes an ablation catheter and a sensing lead . catheter is a hollow conductor which used to carry rf power from the external generator to the myocardium and to form a cone - shaped ablation zone to electrically isolate a part of myocardium from the rest . sensing lead is a conductor that carries electrical signals from the isolated myocardium back to the implanted monitoring device . implantable device is the main unit for processing the signals coming back from the sensing lead .