Implantable medical device with chemical sensor and related methods (2025)

U.S. patent number 7,809,441 [Application Number 11/383,933] was granted by the patent office on 2010-10-05 for implantable medical device with chemical sensor and related methods. This patent grant is currently assigned to Cardiac Pacemakers, Inc.. Invention is credited to James Gregory Bentsen, Michael John Kane, Jonathan Kwok, Jeffrey Allen Von Arx.

Implantable medical device with chemical sensor and relatedmethods

Abstract

In an embodiment, the invention includes an implantable medicaldevice with a pulse generator and a chemical sensor incommunication with the pulse generator, the chemical sensorconfigured to detect an ion concentration in a bodily fluid. In anembodiment, the invention includes a method for providing cardiacarrhythmia therapy to a patient including sensing a physiologicalconcentration of an analyte, communicating data regarding thephysiological concentration of the analyte to an implanted pulsegenerator, and delivering therapy to the patient based in part onthe physiological concentration of the ion. In an embodiment, theinvention includes a method for monitoring diuretic therapy. In anembodiment, the invention includes a method for controllingdelivery of an active agent into a human body. Other aspects andembodiments are provided herein.

Prior Publication Data

References Cited [Referenced By]

U.S. Patent Documents

Foreign Patent Documents

Other References

Primary Examiner: Layno; Carl H.
Assistant Examiner: Heller; Tammie K
Attorney, Agent or Firm: Pauly, Devries Smith & Deffner,L.L.C.

Claims

What is claimed is:

1. An implantable medical device comprising: a cardiac rhythmmanagement system comprising an implantable pulse generatorcomprising a power source, circuitry for delivering at least one ofcardiac pacing and cardiac shock therapy; and an implantablehousing configured to encapsulate the circuitry for delivering atleast one of cardiac pacing and cardiac shock therapy; and achronically implantable chemical sensor in communication with thepulse generator, the chemical sensor configured to detect an ionconcentration in a bodily fluid, the chemical sensor comprising: anoptical sensing element selective for potassium ion comprising apolymeric matrix permeable to sodium ions, potassium ions, andhydronium ions; an optical excitation assembly configured toilluminate the optical sensing element; an optical detectionassembly configured to receive light from the optical sensingelement, and an opaque cover layer disposed over a side of thesensing element.

2. The implantable medical device of claim 1, the polymeric matrixcomprising a polymer selected from the group consisting ofcellulose, polyvinyl alcohol, dextran, polyurethanes, quaternizedpolystyrenes, sulfonated polystyrenes, polyacrylamides,polyhydroxyalkyl acrylates, polyvinyl pyrrolidones, polyamides,polyesters, and mixtures and copolymers thereof.

3. The implantable medical device of claim 1, the optical sensingelement having a first side and a second side, the first sideopposite the second side, the optical excitation assembly and theoptical detection assembly both disposed on the first side.

4. The implantable medical device of claim 1, the chemical sensorcomprising a communication interface configured to communicatewirelessly with the pulse generator.

5. The implantable medical device of claim 1, the chemical sensorcomprising a communication interface configured to communicate withthe pulse generator via a radio frequency link, an ultrasonic link,or an acoustic link.

6. The implantable medical device of claim 1, the chemical sensorelectrically or optically coupled to the pulse generator.

7. The implantable medical device of claim 1, the chemical sensorfurther configured to detect an ion selected from the groupconsisting of sodium, chloride, calcium, magnesium, lithium andhydronium.

8. The implantable medical device of claim 7, the optical sensingelement comprising an ion selective complexing moiety and afluorescing moiety, the fluorescing moiety exhibiting differentialfluorescent intensity based upon selective binding of an ion to theion selective complexing moiety.

9. The implantable medical device of claim 8, the ion selectivecomplexing moiety selected from the group consisting of cryptands,crown ethers, bis-crown ethers, calixarenes, noncyclic amides, andhemispherands.

10. The implantable medical device of claim 8, the optical sensingelement comprising a fluoroionophore selected from the groupconsisting of lithium specific fluoroionophores, sodium specificfluoroionophores, and potassium specific fluoroionophores.

11. The implantable medical device of claim 7, the optical sensingelement comprising an ion selective complexing moiety and acolorimetric moiety, the colorimetric moiety exhibitingdifferential light absorbance on selective binding of an ion to theion selective complexing moiety.

12. The implantable medical device of claim 11, the complexingmoiety selected from the group consisting of cryptands, crownethers, bis-crown ethers, calixarenes, noncyclic amides, andhemispherands.

13. The implantable medical device of claim 7, the optical sensingelement comprising an ionophore selected from the group consistingof sodium specific ionophores, potassium specific ionophores,calcium specific ionophores, magnesium specific ionophores, andlithium specific ionophores.

14. The implantable medical device of claim 1, the optical sensingelement configured to fluorescently emit light at two differentwavelengths.

15. The implantable medical device of claim 1, the bodily fluidselected from the group consisting of blood, interstitial fluid,serum, lymph, and serous fluid.

16. The implantable medical device of claim 1, the excitationassembly comprising a light source, the light source comprising alight emitting diode.

17. The implantable medical device of claim 1, the excitationassembly comprising a first light emitting diode; and a secondlight emitting diode; the first and second light emitting diodesconfigured to emit light at different wavelengths.

18. The implantable medical device of claim 1, the detectionassembly comprising a component selected from the group consistingof a photodiode, a charge-coupled device (CCD), a junction fieldeffect transistor (JFET) optical sensor, and a complementarymetal-oxide semiconductor (CMOS) optical sensor.

19. The implantable medical device of claim 1, the chemical sensorcoupled to the implantable housing.

20. The implantable medical device of claim 19, the implantablehousing defining an aperture occluded by a transparent member, theoptical sensing element in optical communication with theexcitation assembly and the detection assembly through thetransparent member.

21. The implantable medical device of claim 1, further comprising:a cardiac pacing lead; and a device header coupled to theimplantable housing, the device header configured to provide anelectrical connection between the cardiac pacing lead and the pulsegenerator; the chemical sensor coupled to the device header.

22. The implantable medical device of claim 1, further comprising:a cardiac pacing lead, the chemical sensor coupled to the cardiacpacing lead.

23. The implantable medical device of claim 1, the cardiac rhythmmanagement system comprising one of a pacemaker, a cardiacresynchronization therapy (CRT) device, a remodeling controltherapy (RCT) device, a cardioverter/defibrillator, apacemaker-cardioverter/defibrillator, and a hemodynamicmonitor.

24. The implantable medical device of claim 1, the chemical sensorfurther configured to selectively detect a physiological analyteselected from the group consisting of glucose, creatinine, lactate,urea, brain-neural peptide (BNP), nitric-oxide, and troponin.

25. The implantable medical device of claim 1, the chemical sensorfurther configured to selectively detect a concentration of aphysiological analyte indicative of renal function.

26. The implantable medical device of claim 1, further comprising atelemetry circuit.

27. The implantable medical device of claim 1, the chemical sensorfurther configured to selectively detect a concentration of atleast one of creatinine and urea.

28. An implantable cardiac rhythm management system comprising: apulse generator comprising circuitry for delivering at least one ofcardiac pacing and cardiac shock therapy; and a chronicallyimplantable optical chemical sensor in communication with the pulsegenerator, the chemical sensor configured to detect an analyteconcentration in a bodily fluid, the chemical sensor comprising: anoptical sensing element specific for potassium ion comprising aplurality of beads; an optical excitation assembly configured toilluminate the optical sensing element; and an optical detectionassembly configured to receive light from the optical sensingelement.

Description

TECHNICAL FIELD

This disclosure relates generally to implantable medical devicesand, more particularly, to implantable medical devices with achemical sensor and related methods.

BACKGROUND OF THE INVENTION

Implantable medical devices (IMDs), such as cardiac rhythmmanagement systems, are commonly used to provide treatment ortherapy to patients. Cardiac rhythm management systems can includepacemakers. Pacemakers deliver timed sequences of low energyelectrical stimuli, called pacing pulses, to the heart, via anintravascular lead wire or catheter (referred to as a "lead")having one or more electrodes disposed in or about the heart. Heartcontractions are initiated in response to such pacing pulses.Pacemakers are often used to treat patients with bradyarrhythmias,that is, hearts that beat too slowly, or irregularly. Suchpacemakers may also coordinate atrial and ventricular contractionsto improve pumping efficiency.

Cardiac rhythm management systems can also include cardiacresynchronization therapy (CRT) devices for coordinating thespatial nature of heart depolarizations for improving pumpingefficiency. For example, a CRT device may deliver appropriatelytimed pacing pulses to different locations of the same heartchamber to better coordinate the contraction of that heart chamber,or the CRT device may deliver appropriately timed pacing pulses todifferent heart chambers to improve the manner in which thesedifferent heart chambers contract together.

Cardiac rhythm management systems also include defibrillators thatare capable of delivering higher energy electrical stimuli to theheart. Such defibrillators include cardioverters, which synchronizethe delivery of such stimuli to sensed intrinsic heart activitysignals. Defibrillators are often used to treat patients withtachyarrhythmias, that is, hearts that beat too quickly. Adefibrillator is capable of delivering a high energy electricalstimulus that is sometimes referred to as a defibrillationcountershock, also referred to simply as a "shock." Thecountershock interrupts the tachyarrhythmia, allowing the heart toreestablish a normal rhythm for the efficient pumping of blood. Inaddition to pacers, CRT devices, and defibrillators, cardiac rhythmmanagement systems can also include devices that combine thesefunctions, as well as monitors, drug delivery devices, and otherimplantable or external systems or devices for diagnosing ortreating the heart.

Certain physiological analytes impact many of the problems thatimplantable medical devices are designed to treat. As one example,potassium ion concentrations can affect a patient's cardiac rhythm.Therefore, medical professionals frequently evaluate physiologicalpotassium ion concentration when diagnosing a cardiac rhythmproblem. However, measuring physiological concentrations ofanalytes, such as potassium, generally requires drawing blood fromthe patient. Blood draws are commonly done at a medical clinic orhospital and therefore generally require the patient to physicallyvisit a medical facility. As a result, despite their significance,physiological analyte concentrations are frequently measured onlysporadically.

SUMMARY OF THE INVENTION

Disclosed herein, among other things, is an implantable medicaldevice (IMD) for sensing chemical concentration in a bodily fluid.In an embodiment, the invention includes an implantable medicaldevice with a pulse generator and a chemical sensor incommunication with the pulse generator, the chemical sensorconfigured to detect an ion concentration in a bodily fluid. Thechemical sensor can include a sensing element, an opticalexcitation assembly, and an optical detection assembly.

In an embodiment, the invention includes an implantable cardiacrhythm management system having a pulse generator and a chemicalsensor in communication with the pulse generator, the chemicalsensor configured to detect an ion concentration in a bodily fluid.The chemical sensor can include a sensing element, an opticalexcitation assembly, and an optical detection assembly.

In an embodiment, the invention includes a method for providingcardiac arrhythmia therapy to a patient. The method can includeoptically measuring a physiological concentration of an ion in abodily fluid of the patient with an implanted chemical sensor. Themethod can further include transmitting data regarding thephysiological concentration of the ion to an implanted pulsegenerator. The method can also include delivering therapy from theimplanted pulse generator to the patient based in part on thephysiological concentration of the ion.

In an embodiment, the invention includes a method of monitoringdiuretic therapy. The method can include optically sensing aphysiological concentration of an ion in a bodily fluid of thepatient with an implanted chemical sensor. The method can alsoinclude communicating data regarding the physiologicalconcentration of the ion to an implanted pulse generator. Themethod can further include altering the delivery of the diuretictherapy to the patient based in part on the physiologicalconcentration of the ion.

In an embodiment, the invention includes a method for controllingdelivery of an active agent into a human body. The method caninclude measuring a physiological concentration of one or moreanalytes with an implanted system comprising a pulse generator anda chemical sensor, the chemical sensor comprising a sensingelement, an excitation assembly, and a detection assembly. Themethod can further include varying delivery of the substance atleast in part as a function of the measured concentration of theone or more analytes.

This summary is an overview of some of the teachings of the presentapplication and is not intended to be an exclusive or exhaustivetreatment of the present subject matter. Further details are foundin the detailed description and appended claims. Other aspects willbe apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which is not to be takenin a limiting sense. The scope of the present invention is definedby the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates aspects of an implantable medicaldevice (IMD) with a chemical sensor in accordance with anembodiment of the invention.

FIG. 2 schematically illustrates an IMD with a chemical sensor inaccordance with another embodiment of the invention.

FIG. 3 schematically illustrates an IMD with a chemical sensor inaccordance with another embodiment of the invention.

FIG. 4 schematically illustrates an IMD with a chemical sensor inaccordance with another embodiment of the invention.

FIG. 5 schematically illustrates an IMD with a chemical sensor inaccordance with another embodiment of the invention.

FIG. 6 illustrates an implantable medical device (IMD) with achemical sensor in the header, according to variousembodiments.

FIG. 7 illustrates an implantable medical device (IMD) with achemical sensor integrated with the body of the device, accordingto various embodiments.

FIG. 8 is a cross-sectional view of a sensing element, according tovarious embodiments.

FIG. 9 is a cross-sectional view of a sensing element, according toanother embodiment of the invention.

FIG. 10 is a cross-sectional view of a sensing element, accordingto another embodiment of the invention.

FIG. 11 schematically illustrates an embodiment of a device formeasuring a physiological analyte concentration.

FIG. 12 schematically illustrates a duty cycling scheme foroperation of an optical sensor in accordance with an embodiment ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

The disclosures of commonly-owned U.S. Pat. No. 7,225,024, filed onSep. 30, 2003, and U.S. Publication No. 2004-0133079, filed on Jan.2, 2003, are herein incorporated by reference.

Physiological analyte concentrations are important data points forboth the diagnosis and treatment of many medical problems. Forexample, knowledge of potassium ion concentrations can be importantto the correct diagnosis of cardiac arrhythmias. The excitationcycle of cardiac cells is influenced by their resting electricalpotential, and by the activity of ion channels (such as potassium,sodium, and calcium) in the cell membrane of the cardiac cells. Byway of example, potassium ion channels play an important role inreturning a cardiac cell to a resting electrical potentialfollowing an action potential. When the concentration of potassiumin the plasma is within a normal physiological range, the potassiumion channels can function effectively. Unfortunately, when thepotassium concentration in the plasma is elevated ("hyperkalemia")the concentration gradient of potassium across the cardiac cellmembrane is reduced and the cardiac cell generally becomesdepolarized and inexcitable. In contrast, when the potassiumconcentration is low ("hypokalemia"), the concentration gradient ofpotassium across the cardiac cell membrane is increased resultingin hyperpolarization of the resting electrical potential.Hypokalemia can lead to arrhythmias, such as atrial fibrillation.Thus, knowledge of potassium ion concentrations can be valuable informing a correct diagnosis of a cardiac rhythm problem. Likewise,the concentrations of other physiological ions, such as sodium andcalcium, can also be important in the diagnosis and treatment ofcardiac arrhythmias.

Beyond cardiac rhythm problems, ion sensing can also be useful inthe context of monitoring drug therapy, monitoring renal function,titrating drugs (such as hearth failure medications), monitoringfor heart failure decompensation, and observing primary electrolyteimbalance subsequent to dietary intake or renal excretionvariations.

Embodiments of the present invention can be used to gatherconcentration data regarding medically relevant analytes in bodilyfluids. Specifically, embodiments of the present invention caninclude an implantable medical device including a pulse generatorto deliver electrical pulses and/or shock therapy and a chemicalsensor in communication with the pulse generator. The chemicalsensor can be configured to detect an ion concentration in a bodilyfluid, and can include a sensing element, an excitation assembly,and a detection assembly configured to receive light from thesensing element.

Integrating the functionality of chemical sensors with implantablecardiac rhythm management devices can offer therapeutic advantages.The data generated by an implantable cardiac rhythm device and thedata generated by a chemical sensor offer mutually orthogonal butlinked views of the physiologic state of the patient. Combiningthese views can provide a health professional with additionalinsight into the patient's health. As just one example, an erraticheart-rate in the presence of very high or very low potassiumconcentrations indicates a greater level of risk to the patientthan either condition presented separately. Various embodiments ofthe present invention can detect both analyte concentrations, suchas potassium concentration, and cardiac arrhythmias so that riskscan be quickly identified and, in some embodiments, conveyed to ahealth professional when appropriate.

Continuous or near-continuous monitoring of physiological analytescan offer therapeutic benefits. Typically, the process formeasuring physiological concentrations of analytes involves drawingblood from the patient. Blood draws are typically done at a medicalclinic or hospital. Therefore, the patient must generally visit amedical facility, and as a result, physiological analyteconcentrations are generally measured only sporadically.Accordingly, the clinician is usually presented with only sporadicsnapshot data representing a patient's condition only on particulardays. While this snapshot data is valuable, having data stretchingover a longer continuous period of time can be of greater valuebecause it can more accurately reflect trends as well as periodicfluctuations that could be caused by diet, activity, medications,etc. Various embodiments of the invention, including an implantablemedical device with a chemical sensor, can be used to provideclinicians with continuous or semi-continuous data regardinganalyte concentrations.

When a medical device is implanted within a host, the immune systemof the host senses the presence of the foreign body and starts whatis referred to as a foreign body response. Within hours, there isadherence and activation of platelets in the area of the inserteddevice, followed by the release of growth factors and chemotacticagents from platelet granules. Granulocytes and mononuclearphagocytes then migrate into the area. Subsequently, the site isinfiltrated by fibroblasts. Within the first few weeks, thefibroblasts multiply and lay down collagen that begins to form anavascular connective tissue envelope or "pocket". This process cancontinue for months and generally results in the completeencasement of the medical device in an avascular pocket with wallsthat are 50 .mu.m to 200 .mu.m thick.

Unfortunately, chronically implanted medical devices with chemicalsensors can suffer from problems as a result of the foreign bodyresponse. The pocket wall itself is poorly vascularized and servesto prevent the medical device from interfacing with highlyvascularized tissues. Without interfacing with highly vascularizedtissues, the medical device may not be able to accurately detectphysiological conditions outside of the pocket. As an example,glucose is known to traverse the pocket wall relatively poorly andtherefore glucose levels within the pocket do not accuratelyreflect physiological glucose levels outside of the pocket.Therefore most implanted glucose sensors become increasinglyinaccurate as the avascular pocket forms around them. However, asdetailed in Example 1 below, the Applicants have discovered thations, such as sodium and potassium ions, behave differently thanglucose in traversing the pocket wall. Specifically, Example 1shows that ions such as sodium and potassium are able to traversethe pocket wall sufficiently well to enable accurate measurementsregarding their physiological concentrations to be taken fromwithin the pocket wall. Therefore, chemical sensors that detectphysiological ions, such as sodium and potassium, can be integratedwith chronically implanted medical devices, such as implantablecardiac rhythm management devices.

Closely related to the issues associated with the foreign bodyresponse are issues associated with biofouling of implanted medicaldevices. Biofouling can include the accumulation of biomoleculessuch as proteins, fats, and/or carbohydrates on the surfaces of animplanted device. While not intending to be bound by theory,biofouling is believed to lead to drift and loss of responsivenessin the context of electrochemical (such as potentiometric) chemicalsensors that are implanted chronically. For ion selectiveelectrodes, the measured electromotive force primarily depends onthe potential change across the interface of the sample andmembrane phases. This interfacial measured electromotive force canbecome compromised by the deposition of proteins and otherbiomolecules on the sensor surface. Furthermore, in ion-selectiveelectrodes, the bulk of the sensor membrane is generallyimpregnated with a known excess of an analyte. The Nernstianresponse is only observed if the organic phase boundaryconcentration is not significantly altered as a function of thesample concentration. For acute measurements, this condition ismaintained. However, for chronic monitoring, preloaded analyte canleach from the sensor film, compromising calibration.

In contrast, both non-carrier and carrier based optical sensingelements rely on concentration changes within the bulk of thesensing element. Therefore, optical sensing approaches are believedto be generally less susceptible to biofouling problems thanelectrochemical chemical sensors relying on interfacialphenomena.

It will be appreciated that the sensing of analyte concentrationscan be directed at a specific analyte or a plurality of differentanalytes. In an embodiment, the analyte sensed is one or moreanalytes relevant to cardiac health. In an embodiment, the analytesensed is one or more analytes indicative of renal health. Theanalyte sensed can be an ion or a non-ion. The analyte sensed canbe a cation or an anion. Specific examples of analytes that can besensed include acetic acid (acetate), aconitic acid (aconitate),ammonium, blood urea nitrogen (BUN), B-type natriuretic peptide(BNP), bromate, calcium, carbon dioxide, cardiac specific troponin,chloride, choline, citric acid (citrate), cortisol, copper,creatinine, creatinine kinase, fluoride, formic acid (formate),glucose, hydronium ion, isocitrate, lactic acid (lactate), lithium,magnesium, maleic acid (maleate), malonic acid (malonate),myoglobin, nitrate, nitric-oxide, oxalic acid (oxalate), oxygen,phosphate, phthalate, potassium, pyruvic acid (pyruvate), selenite,sodium, sulfate, urea, uric acid, and zinc. Inorganic cationssensed by this method include but not limited to hydronium ion,lithium ion, sodium ion, potassium ion, magnesium ion, calcium ion,silver ion, zinc ion, mercury ion, lead ion and ammonium ion.Inorganic anions sensed by this method include but not limited tocarbonate anion, nitrate anion, sulfite anion, chloride anion andiodide anion. Organic cations sensed by this method include but arenot limited to norephedrine, ephedrine, amphetamine, procaine,prilocaine, lidocaine, bupivacaine, lignocaine, creatinine andprotamine. Organic anions sensed by this method include but notlimited to salicylate, phthalate, maleate, and heparin. Neutralanalytes sensed by this method include but not limited to ammonia,ethanol, and organic amines. In an embodiment, ions that can besensed include potassium, sodium, chloride, calcium, and hydronium(pH). In a particular embodiment, concentrations of both sodium andpotassium are measured. In another embodiment, concentrations ofboth magnesium and potassium are measured.

In some embodiments, the physiological concentration of an analyteis sensed directly. In other embodiments, the physiologicalconcentration of an analyte is sensed indirectly. By way ofexample, a metabolite of a particular analyte can be sensed insteadof the particular analyte itself. In other embodiments, an analytecan be chemically converted into another form in order to make theprocess of detection easier. By way of example, an enzyme can beused to convert an analyte into another compound which is easier todetect. For example, the hydrolysis of creatinine into ammonia andN-methylhydantoin can be catalyzed by creatinine deiminase and theresulting ammonia can be detected by a chemical sensor. As anotherexample, the oxidation of glucose into gluconolactone and hydrogenperoxide can be catalyzed by glucose oxidase and the resultinghydrogen peroxide can be detected by a chemical sensor. In someembodiments, the enzyme is immobilized to prevent it from leachingout of the chemical sensor.

Referring now to FIG. 1, a schematic view of an implantable medicaldevice (IMD) 102 with a chemical sensor 104 is shown. In variousembodiments, the IMD 102 can include a cardiac rhythm managementdevice, such as a pacemaker, a cardiac resynchronization therapy(CRT) device, a remodeling control therapy (RCT) device, acardioverter/defibrillator, or apacemaker-cardioverter/defibrillator. One exemplary cardiac rhythmmanagement device is disclosed in commonly assigned U.S. Pat. No.6,928,325, issued Aug. 9, 2005, the contents of which is hereinincorporated by reference. In the embodiment shown in FIG. 1, thechemical sensor 104 is integrated with the IMD 102. The chemicalsensor 104 is configured to detect a concentration of an analyte,such as an ion, in a bodily fluid. Bodily fluids can include blood,interstitial fluid, serum, lymph, and serous fluid. The chemicalsensor 104 includes a sensing element 108. The chemical sensor 104also includes an excitation assembly 106 and a detection assembly110. The chemical sensor 104 can be configured to operate invarious ways including calorimetrically and/orfluorimetrically.

It will be appreciated that chemical sensors can be configured tooperate in various other ways. For example, optical chemicalsensors can be configured to directly illuminate tissues or fluidsof the body and then analyze the resulting spectral response todetermine analyte concentrations (e.g., a direct spectroscopicapproach). However, while not intending to be bound by theory, itbelieved that such direct spectroscopic approaches generally sufferfrom issues that can impair accuracy including backgroundinterference and/or temporal signal drift associated withbiofouling.

The excitation assembly 106 can be configured to illuminate thesensing element 108. In an embodiment, the excitation assembly 106includes a light-emitting diode (LED). In some embodiments, theexcitation assembly includes solid state light sources such asGaAs, GaAlAs, GaAlAsP, GaAlP, GaAsP, GaP, GaN, InGaAlP, InGaN,ZnSe, or SiC light emitting diodes or laser diodes that excite thesensing element(s) at or near the wavelength of maximum absorptionfor a time sufficient to emit a return signal. In otherembodiments, the excitation assembly can include other lightemitting components including incandescent components. In someembodiments, the excitation assembly 106 can include a waveguide.The excitation assembly 106 can also include one or more bandpassfilters and/or focusing optics.

In some embodiments, the excitation assembly includes a pluralityof LEDs with bandpass filters, each of the LED-filter combinationsemitting at a different center frequency. According to variousembodiments, the LEDs operate at different center-frequencies,sequentially turning on and off during a measurement, illuminatingthe sensing element. As multiple different center-frequencymeasurements are made sequentially, a single unfiltered detectorcan be used.

The sensing element 108 can include one or more ion selectivesensors. Physiological analytes of interest can diffuse into thesensing element 108 and bind with an ion selective sensor to resultin a fluorimetric or calorimetric response. Exemplary ion selectivesensors are described more fully below.

The detection assembly 110 can be configured to receive light fromthe sensing element 108. In an embodiment, the detection assembly110 includes a component to receive light. By way of example, insome embodiments, the detection assembly 110 includes acharge-coupled device (CCD). In other embodiments, the detectionassembly can include a photodiode, a junction field effecttransistor (JFET) type optical sensor, or a complementarymetal-oxide semiconductor (CMOS) type optical sensor. In anembodiment, the detection assembly 110 includes an array of opticalsensing components. In some embodiments, the detection assembly 110can include a waveguide. The detection assembly 110 can alsoinclude one or more bandpass filters and/or focusing optics. In anembodiment, the detection assembly 110 includes one or morephotodiode detectors, each with an optical bandpass filter tuned toa specific wavelength range.

The excitation and detection assemblies can be integrated usingbifurcated fiber-optics that direct excitation light from a lightsource to one or more sensing elements, or simultaneously tosensing elements and a reference channel. Return fibers can directemission signals from the sensing element(s) and reference channelsto one or more optical detectors for analysis by a processor. Inanother embodiment, the excitation and detection assemblies areintegrated using a beam-splitter assembly and focusing opticallenses that direct excitation light from a light source to thesensing element and direct emitted or reflected light from thesensing element to an optical detector for analysis by aprocessor.

In some embodiments, the detection assembly 110 is disposed on thesame side of the sensing element 108 as the excitation assembly106. In other embodiments, the detection assembly 110 is on theopposite side of the sensing element 108 from the excitationassembly 106. It will be appreciated that many different physicalarrangements of the components are possible.

Embodiments of the invention can include an implantable medicaldevice having a chemical sensor co-located with a pulse generatorbody, located on a lead connected to a pulse generator body througha header, or separately located in a sensor module in wired orwireless communication with a pulse generator body.

FIG. 2 schematically illustrates an implantable system 200 having apulse generator 202 co-located with an integrated chemical sensor203, according to various embodiments. The term "pulse generator"as used herein shall refer to the part or parts of an implantedsystem, such as a cardiac rhythm management system or aneurological therapy system, containing the power source andcircuitry for delivering pacing and/or shock therapy. The pulsegenerator 202 can include a controller circuit 210 (includingcomponents such as a pulse generator circuit) to communicate withthe chemical sensor 203, a telemetry circuit 212 to communicatewith the controller circuit 210 and an external module 220 (such asa programmer module), and a memory circuit 214 to communicate withthe controller circuit 210. The chemical sensor 203 includes asensing element 204, an optical excitation assembly 206, and anoptical detection assembly 208. The implantable system 200 caninclude at least one implantable lead 222 coupled to the pulsegenerator 202 via the controller circuit 210 (or pulse generatorcircuit), the at least one implantable lead 222 configured to beconnected to at least one implantable electrode 224 capable ofelectrically stimulating tissue. However, it will be appreciatedthat embodiments of the invention can also include implantablesystems, such as cardiac rhythm management systems, that do notinclude pacing leads, such as leadless implantablecardioverter-defibrillators.

In various embodiments, the controller circuit, telemetry circuit,and memory circuit are within a device body or housing. In someembodiments, the chemical sensor 203, or some of the componentsthereof, are disposed within the device body or housing. In someembodiments, the chemical sensor 203, or some of the componentsthereof are disposed on the device body or in an aperture in thedevice body. In an alternative embodiment, the optical excitationassembly 206 and the optical detection assembly 208 can be disposedwithin the device body, while the sensing element 204 is disposedoutside of the device body. In such an embodiment, opticalcommunication between the optical excitation assembly 206, thesensing element 204, and the optical detection assembly 208 ismaintained by waveguides, optical lenses, or optical windows. Forexample, an optical lens or an optical window (transparent member)can be disposed within an aperture on the device body, the sensingelement can be optically coupled to the outside of the lens orwindow, and the optical excitation assembly and optical detectionassembly can be optically coupled to the inside of the lens orwindow.

FIG. 3 illustrates an embodiment of an implantable system 300having a pulse generator 302 coupled to (such as electrically oroptically), but separate from, a chemical sensor 303. The pulsegenerator 302 can include a controller circuit 310 to communicatewith the chemical sensor 303, a telemetry circuit 312 tocommunicate with the controller circuit 310 and an external module320 (such as a programmer module), and a memory circuit 314 tocommunicate with the controller circuit 310. The chemical sensor303 includes a sensing element 304, an optical excitation assembly306, and an optical detection assembly 308. The implantable system300 can include at least one implantable lead 322 connected to thepulse generator 302, the at least one implantable lead 322configured to be connected to at least one implantable electrode324 capable of electrically stimulating tissue. The implantablesystem 300, can include a chemical sensing lead to electrically oroptically couple the pulse generator 302 with the chemical sensor303.

FIG. 4 illustrates an embodiment of an implantable system 400having a pulse generator 402 in wireless communication with achemical sensor 403. The pulse generator 402 can include acontroller circuit 410, a telemetry circuit 412 to communicate withthe controller circuit 410, the chemical sensor 403, and anexternal module 420 (such as a programmer module), and a memorycircuit 414 to communicate with the controller circuit 410. Thechemical sensor 403 includes a sensing element 404, an opticalexcitation assembly 406, and an optical detection assembly 408. Theimplantable system 400 can include at least one implantable lead422 connected to the pulse generator 402, the at least oneimplantable lead 422 configured to be connected to at least oneimplantable electrode 424 capable of electrically stimulatingtissue. In this embodiment, the pulse generator 402 is in wirelesscommunication with the chemical sensor 403. It will be appreciatedthat wireless communication can be achieved through variousapproaches including radio frequency links, ultrasonic links,acoustic links, and the like. In some embodiments, the chemicalsensor 403 can be in a self-contained device with its own internalpower supply and radio frequency or acoustic communicationcapability (having a radio frequency communication link, anultrasonic communication link, and/or an acoustic communicationlink).

FIG. 5 illustrates an embodiment including a system 500 having apulse generator 502 and a chemical sensor 503 integrated with alead 522. The lead 522 is coupled to the pulse generator 502. Thechemical sensor 503 can be coupled to the lead 522 at any pointbetween the proximal and distal ends of the lead 522. In anembodiment, the chemical sensor 503 is coupled to the distal end ofthe lead 522. The chemical sensor includes at least one sensingelement 504, at least one optical excitation assembly 506 and atleast one optical detection assembly 508.

FIG. 6 illustrates an embodiment of an implantable medical device(IMD) 600 with an integrated chemical sensor 603 in the header 652.The IMD 600 includes a housing or body 654. In this embodiment, thechemical sensor 603 is located in the IMD device header 652 whichis in turn coupled to the housing 654. FIG. 7 illustrates anembodiment of an implantable medical device (IMD) 700 with anintegrated chemical sensor 703 disposed on the device housing 754.In this embodiment, the chemical sensor 703 is coupled to thedevice housing 754. According to various embodiments, circuitry forcorrection of cardiac arrhythmias uses a common battery with theexcitation assembly. Circuitry for correction of cardiacarrhythmias is configured to communicate with the detectionassembly directly or indirectly, according to variousembodiments.

It will be appreciated that the sensing element may take on variousstructural configurations. Referring now to FIG. 8, across-sectional view of a sensing element 800 for measuring ionconcentration is shown according to some embodiments. The sensingelement 800 includes an optically transparent backing layer 825, anadhesive or bonding layer 827 under the backing layer 825, anindicator element 815 attached to the membrane, and an overcoatlayer 805.

The indicator element 815 can include a polymeric support matrixand one or more ion selective sensors as described more fullybelow. Physiological analytes can diffuse through the overcoatlayer 805 and into the indicator element 815 where they can bindwith the ion selective sensor to produce a fluorimetric orcalorimetric response.

The backing layer 825 can be configured to provide support (e.g.stiffness and handling capability) for the sensing element 800. Thebacking layer 825 can be transparent and essentially impermeableto, or much less permeable than the overcoat layer 805 to thesolution in which a target analyte is present, such as blood,interstitial fluid, or a calibrating solution. The backing layer825 can allow the signal or signals, such as the optical signals,from the indicator element 815, to pass there-through. Particularlyuseful materials of construction for this backing layer 825 includepolymeric materials such as polyesters, polycarbonates,polysulfones including but not limited to polyethersulfones andpolyphenylsulfones, polyvinylidine fluoride, polymethylpentenes,and the like.

The backing layer 825 can be adhesively bonded or thermally fusedto the indicator element 815. In embodiments where the backinglayer 825 is adhesively bonded to the indicator element 815, thebonding adhesive can be essentially transparent to light used inexcitation of the sensing element 800 and to light emitted orreflected there-from. An exemplary adhesive is FLEXOBOND 431.TM.urethane adhesive (Bacon Co., Irvine, Calif.).

The adhesive or bonding layer 827 can serve to couple the sensingelement 800 to a substrate. The adhesive or bonding layer 827 caninclude a bonding adhesive. The bonding adhesive can be essentiallytransparent to light used in excitation of the sensing element 800and to light emitted or reflected there-from. An exemplary adhesiveis FLEXOBOND 431.TM. urethane adhesive (Bacon Co., Irvine,Calif.).

The overcoat layer 805 can include a material that is permeable tothe analyte of interest. The overcoat layer 805 can be opaque so asto optically isolate the indicator element 815 from the tissuessurrounding the sensing element 800 in vivo. Alternatively, aseparate opaque layer can be disposed over or under the overcoatlayer 805. The overcoat layer 805 can include a polymeric materialwith an opacifying agent. Exemplary opacifying agents can includecarbon black, or carbon-based opacifying agents, ferric oxide,metallic phthalocyanines, and the like. In a particular embodiment,the opacifying agent is carbon black. Opacifying agents can besubstantially uniformly dispersed in the overcoat layer 805, or ina separate layer, in an amount effective to provide the desireddegree of opacity to provide the desired optical isolation. Thesensing element 800 can also include an opaque ink coating appliedusing a variety of techniques, such as an inkjet technique or anink-screening technique. The sensing element 800 can also include ablack membrane. For example, it can include a black DURAPORE.RTM.membrane (available from Millipore as a white membrane which isthen treated with black ink).

FIG. 9 illustrates a cross-sectional view of a sensing element 850for measuring analyte concentration, according to variousembodiments. The sensing element 850 includes a first indicatorelement 865 and second indicator element 870. In an embodiment, thefirst indicator element 865 can be an analyte indicating elementwhile the second indicator element 870 can be an analyteinsensitive element for optical referencing purpose, or moregenerally, as a negative control. In another embodiment, the firstindicator element 865 is specific for one analyte while the secondindicator element 870 is specific for a different analyte ofinterest. In another embodiment, indicator elements 865 and 870 canbe accompanied by other indicator elements including analytesensitive and insensitive elements forming an indicator array. Insome embodiments, concentrations of a plurality of analytes can besensed. For example, concentrations of between 1 and 20 analytescan be sensed in some embodiments.

In the embodiment shown in FIG. 9, analytes from a bodily fluiddiffuse through a membrane 855 and reversibly bind with an ionselective sensor disposed within the indicator elements. Manydifferent ion selective sensors or systems can be used. Exemplaryion selective sensors and systems are described in greater detailbelow. The indicator element can include a polymeric support. Thepolymeric support can include an ion permeable polymeric matrix.Specifically, the polymeric support can include a polymeric matrixpermeable to sodium ions, potassium ions, and hydronium ions. Thepolymeric support can include a hydrophilic polymer. In anembodiment, the polymeric support can include one or more ofcellulose, polyvinyl alcohol, dextran, polyurethanes, quaternizedpolystyrenes, sulfonated polystyrenes, polyacrylamides,polyhydroxyalkyl acrylates, polyvinyl pyrrolidones, polyamides,polyesters, and mixtures and copolymers thereof.

The membrane 855 can include an ion permeable polymeric matrix. Forexample, the membrane 855 can include a polymeric matrix permeableto sodium ions, potassium ions, and hydronium ions. In someembodiments, the membrane 855 includes a hydrophilic polymer.Various types of polymers can be used to form the membrane 855. Byway of example, the membrane can include one or more of cellulose,polyvinyl alcohol, dextran, polyurethanes, quaternizedpolystyrenes, sulfonated polystyrenes, polyacrylamides,polyhydroxyalkyl acrylates, polyvinyl pyrrolidones, polyamides,polyesters, and mixtures and copolymers thereof.

In some embodiments, membrane 855 is opaque. For example, in someembodiments both an optical excitation assembly and an opticaldetection assembly are located on a side of the sensing element 850opposite the membrane 855. In such an embodiment, renderingmembrane 855 opaque can reduce background interference. In otherembodiments, an opaque cover layer is disposed over membrane 855.In will be appreciated that there are many way of developingopacity in a membrane or layer including those described above.

The housing 860 can be configured to separate indicator elements865 and 870. The housing 860 can include microwells ormicrocavities into which the indicator elements 865 and 870 fit.However, in some embodiments the indicator elements are disposedimmediately adjacent to one another. The housing 860 can beconstructed of various materials. In some embodiments, the housing860 includes a polymeric matrix. In an embodiment, the housing 860includes an ion permeable polymeric matrix. Base layer 875 isconfigured to be disposed between the indicator elements 865 and870 and the optical detection assembly. In an embodiment, the baselayer 875 is optically transparent over the wavelengths ofinterrogation and detection. Base layer 875 can be made of avariety of different materials including an optically transparentpolymer, glass, crystal, etc. In some embodiments, base layer 875is omitted such that components, such as the optical excitationassembly and/or optical detector assembly are in direct contactwith indicator elements 865 and 870.

According to an embodiment, dual wavelengths of light are used forillumination of the one or more sensing elements to allow fordifferential measurements. For example, one center wavelength canexcite the sensing element at an isobestic point on the spectralresponse curve and another center-wavelength can excite at amaximally sensitive wavelength. Another embodiment can excite thesensing element(s) using dual illumination wherein the two centerwavelengths are chosen for maximal excitability but withcomplimentary amplitude responses. The analyte insensitive opticalelement is then used as an optical system drift correction signaland thereby enhances long-term accuracy. Other embodiments employpH sensitive compartments to allow for cancellation of pHeffects.

FIG. 10 illustrates a cross-sectional view of a sensing element formeasuring analyte concentrations, according to various embodiments.The sensing element 900 includes a first indicator element 915 andsecond indicator element 920. The sensing element 900 includes ahousing 910, an ion permeable membrane 905, and a base layer 925.In this embodiment, the chemistries of the sensing element 900 areintegrated into or onto support beads for the purpose of increasingsurface area and optical scattering effects. The sensing element900 can be configured to be mated to the header of a pulsegenerator, to an optical window in the housing of a pulsegenerator, to a lead, or to an optical window on a sensor inwireless communications with the pulse generator (satellitesensor).

FIG. 11 illustrates one embodiment of a system for measuring ananalyte concentration. The analyte of interest, for examplepotassium, is present in a bodily fluid, for example interstitialfluid, in contact with the ion permeable membrane 586 of sensingelement 578. The analyte diffuses through the membrane 586 andbinds with an ion selective sensor in indicator element 580. Thebinding of the analyte results in an absorption spectral shiftand/or a change in the fluorescent intensity of the indicatorelement 580.

Indicator element 584 is also subject to the flux of analytediffusing through the membrane 586. However, in this embodimentindicator element 584 is designed to be optically invariant toanalyte concentrations and thus can serve as a negative control. Inthis embodiment, indicator element 584 can also be referred to asan optical reference element.

The diffuse reflectance spectra of indicator element 580 andoptical reference element 584 are detected by first illuminatingindicator element 580 and optical reference element 584 withemitters 562 and 564 (optionally in conjunction with opticalfilters.) Emitters 562 and 564, located within opto-electronicblock 560, can be configured to produce light at two differentcenter-wavelengths (e.g., wavelength 1 and wavelength 2respectively) selected to effectively interrogate the spectralreflectance changes of indicator element 580 as the analyteconcentration changes. Emitters 562 and 564 can be turned on andoff alternately, under control of microprocessor control unit (MCU)548 so that only one wavelength of reflectance is interrogated at atime. The light can be coupled from each of the emitters 562 and564 to each of the indicator element 580 and the optical referenceelement 584 by means of an optical routing block 576. Diffuselyreflected light, or emitted light in the case of a fluorescentsensor, is then routed from indicator element 580 and opticalreference element 584, through optically transparent membrane 582,to sensor optical detector 572 and reference optical detector 532,respectively, by means of the optical routing block 576. Theoptical routing is achieved by means of optical fibers, waveguides,integrated optical packing of emitter and detector subassemblies,by free-space optics, or by other means known by those skilled inthe art. The optical detectors 572 and 532 produce an electricalcurrent that can be amplified by circuits 574 and 534 respectivelyto result in voltage signals indicative of the reflected lightintensity returned from the indicator element 580 and the opticalreference element 584 respectively. These analog voltage signalscan then be processed by A/D converters 544 and 542, respectively,to produce digital signals and can then be routed through amultiplexer (MUX) 540. The resulting data is processed by MCU 548and stored in memory 550 or routed to telemetry unit 552.

As the concentration of the analyte changes, the opticalcharacteristics of indicator element 580 change, while the opticalcharacteristics of the optical reference element 584 do not change.In one embodiment, MCU 548 can take the digitized emission orreflectance signal at a particular wavelength associated withexcitation of the indicator element 580 and then calculates acorrected signal based upon the digitized signals associated withoptical reference element 584. The MCU 548 can then take thedigitized emission or reflectance signal at a second wavelengthassociated with excitation of the indicator element 580 andcalculates a second corrected signal based upon the digitizedsignals associated with optical reference element 584. The MCU 548can then use the ratio of corrected optical signals at the twowavelengths in estimating analyte concentration. This ratio isprocessed by MCU 548 by a program routine or lookup table intorepresentations of analyte concentration. Resulting data can bestored, transmitted to external devices, or integrated into thefunctions of an accompanying therapeutic device.

Embodiments of chemical sensors of the invention may be calibratedinitially and/or periodically after implantation to enhanceaccuracy. It will be appreciated that calibration can be performedin various ways. By way of example, after the chemical sensor isimplanted, blood can be drawn and analyte concentrations in theblood can be assessed using standard in vitro laboratorytechniques. The concentrations indicated by the in vitro testingcan then be compared with the concentrations indicated by theimplanted device, and the implanted device can then be corrected(offset correction) based on the difference, if any. The offsetcorrection value can be stored in circuitry in the pulse generatorand automatically applied to future measurements. In someembodiments, this correction procedure is performed after theforeign body response has formed a tissue pocket around theimplanted device. In some embodiments, this correction procedure isperformed at regular intervals.

The chemical sensor can measure the concentration of one or moreanalytes, such as sodium ions and potassium ions, at a programmablerate (using a programmable timer), according to an embodiment. Thechemical sensor can also be configured to measure concentrations ofanalytes on demand, as dictated by a program routine or asinitiated by an externally communicated command. The analyteconcentration measurements can be equally spaced over time, orperiodic, in an embodiment. For example, the optical excitationassembly can be configured to interrogate the sensing elementperiodically. The measurements can be taken at various times in anon-periodic manner, or intermittently, in an embodiment. In oneembodiment, a measurement is made approximately once per hour.

The power consumption of an optical chemical sensor system can besignificantly greater than that of an electrochemical sensor systemconfigured for similar performance. This is particularly true inthe context of an optical chemical sensor including an opticalexcitation assembly. Chemical sensors of the invention can bedesigned as part of a chronically implantable system and thereforepower consumption can be a performance limiting characteristic. Assuch, embodiments of the invention can include methods to reduceaverage and peak power consumption from an energy source, such as abattery.

Referring now to FIG. 12, a schematic illustration of a powermanagement system is shown that can reduce battery load whilepreserving system performance. In FIG. 12, interval "A" depicts theduration of observation of the sensed parameter. Interval "B"depicts the maximum duration between observations of the sensedparameter. Interval "B" should be as long as possible for the bestenergy savings, but it must be short enough so that rapid changesin the observed system are tracked by the detector. It will beunderstood that this system can be optimized based on the temporalcharacteristics of the analyte of interest. For example, if thesensor is intended to measure potassium levels, the maximum rate ofchange for potassium concentrations in the target physiologicalsystem can be taken into account. In other words, the particularanalyte being measured can directly impact factors such as themaximum duration between observations of the sensed parameter. Inan embodiment, the LED can be turned on for a portion of theduration of observation. The percentage of time that the LED isturned on during the duration of observation can be referred to asthe duty factor of sampling.

The ratio of A/B multiplied by the duty factor of samplingrepresents the fraction of energy used by the system compared to acontinuous mode detection scheme. For example, assuming theduration of observation is 100 milliseconds, the maximum durationbetween observations is 3600 seconds (1 hour), and the duty factoris 50%, then the final energy fraction is 0.0000138. In otherwords, based on these assumptions, the sensor will useapproximately 1/72,000th of the energy in a semi-continuous dutyfactor mode than in continuous mode. It will be appreciated thatmany different durations of observation are contemplated herein. Inaddition, many different maximum durations between observations arecontemplated herein such as 1 minute, 10 minutes, 30 minutes, 60minutes, 120 minutes, 180 minutes, etc.

In many embodiments, the dominant energy consuming portion of thesensor system will be the light source, if operated in a continuousmode. A typical light source can consume 2 milliAmps, an amountunacceptably high for most chronically implanted devices. However,using the described duty factoring scheme, in one example, theaverage current consumed can be reduced to 28 nanoAmps. It will beappreciated that the results of the duty factoring scheme willdepend on various factors including the particular duration ofobservation, the maximum duration between observations, and theeffective duty factor.

Embodiments of the invention can also include methods for reducingnoise and uncertainty in the system responses includingmodulation/demodulation and multiple sampling events. Modulationreduces the sensor susceptibility to external light sources and toDC offsets in the received signal. By way of example, thestimulating light source can be turned on at a specific frequency1204 "frequency f" and the receive circuit can have a filter thatrejects signals outside of a narrow band that includes frequency f.In addition, the receive circuit includes a demodulator thatresponds preferentially to signals of frequency f. These featurescan reduce or eliminate any system response to signals from sourcesother than the intended optical source.

Multiple sampling events 1202 within the sampling interval providelower peak current demands from the power supply during the sampleevent. These also provide multiple signals which can be integratedand averaged to reduce the effects of random noise sources andincrease accuracy. The generation of sample intervals, sampleevents, and the processing of the sensor information can beperformed by a microprocessor control unit/timer. Themicroprocessor control unit can then send the data to memory orcommunicate with other components of a patient managementsystem.

Embodiments of the invention can include a sensing elementincluding one or more ion selective sensors. Ion selective sensorsmay either rely on surface phenomena or on concentration changesinside the bulk of a phase. Ion selective sensors can includeoptical sensors, including both non-carrier optical sensors andcarrier-based optical sensors, and ion-selective electrodes(ISEs).

In an embodiment, the ion selective sensor is fluorimetric.Fluorimetric ion selective sensors exhibit differential fluorescentintensity based upon the complexing of an analyte to a complexingmoiety. In an embodiment, the ion selective sensor is calorimetric.Colorimetric ion selective sensors exhibit differential lightabsorbance based upon the complexing of an analyte to a complexingmoiety.

In some embodiments, the ion selective sensor comprises anon-carrier or carrier-based fluorescent or calorimetric ionophoriccomposition that comprises a complexing moiety for reversiblybinding an ion to be analyzed, and a fluorescing or calorimetricmoiety that changes its optical properties as the complexing agentbinds or releases the ion. The complexing agents of the inventioncan optionally be appended with one or more organic substituentschosen to confer desired properties useful in formulating the ionsensing composition. By way of example, the substituents can beselected to stabilize the complexing agent with respect to leachinginto the solution to be sensed, for example, by incorporating ahydrophobic or polymeric tail or by providing a means for covalentattachment of the complexing agent to a polymer support within theion selective sensor.

Non-Carrier Ion Sensors

In an embodiment, the ion selective sensor is a non-carrier opticalion sensor. Non-carrier optical ion sensors can include ahydrophilic indicator dye that is covalently attached to ahydrophilic polymer matrix (substrate), and which selectivelycomplexes the ion of interest to directly produce either acalorimetric or fluorescent response. In an embodiment of anon-carrier ion selective sensing element, a fluoroionophore iscovalently bonded to a suitable substrate. A fluoroionophore is acompound including both a fluorescent moiety and an ion complexingmoiety. As an example,(6,7-[2.2.2]-cryptando-3-[2''-(5''-carboethoxy)thiophenyl]coumarin,a potassium ion selective fluoroionophore, can be covalentlyattached to an azlactone functional hydrophilic porous polyethylenemembrane to produce a fluorescence-based K.sup.+ non-carrier ionsensor. As another example, hydroxypyrene trisulfonate, a hydrogenion selective fluoroionophore, can be covalently attached to anamine functional cellulose to produce a fluorescence-based pHnon-carrier ion sensor. The fluoroionophore can be covalentlybonded to a substrate by any useful reactive technique, which maydepend upon the chemical functionality of the particularfluoroionophore. The substrate can, in turn, be attached to abacking membrane or layer.

A specific example of a non-carrier potassium ion sensor includes asensing layer that includes6,7-[2.2.2]-cryptando-3-[2''-(5''-carboxy)furyl]coumarin (FCCC)covalently bonded to a crosslinked amine functional cellulosemembrane (CUPROPHAN.TM.; Enka AG, Ohderstrasse, Germany), thesensing layer being adhered to a polycarbonate backing membrane byFLEXOBOND 430.TM. urethane adhesive and the backing membrane havingcoated thereon CW14.TM. pressure-sensitive adhesive on a releaseliner. Another specific example of a non-carrier potassium ionsensor includes a sensing layer that includes6,7-[2.2.2]-cryptando-3-[2''-(5''-carboxy)furyl]coumarin covalentlybonded to a crosslinked azlactone functional hydrogel with a linkersuch as a diamine linker. The sensing layer can then bephotocrosslinked within the cavity of a substrate, such as amicrowell, or the gel capsule of a satellite sensor. The termsatellite sensor can be used to describe implanted chemical sensorsthat are remote from the pulse generator.

A specific example of a non-carrier sodium ion sensor includes asensing layer having6,7-[2.2.1]-cryptando-3-[2''-(5''-carboxy)furyl]coumarin covalentlybonded to a crosslinked amine functional cellulose membrane(CUPROPHAN.TM.; Enka AG, Ohderstrasse, Germany), the sensing layerbeing adhered to a polycarbonate backing membrane by FLEXOBOND430.TM. urethane adhesive and the backing membrane having coatedthereon CW14.TM. pressure-sensitive adhesive on a releaseliner.

A specific example of a non-carrier hydrogen ion sensor includes asensing layer that includes hydroxypyrene trisulfonate covalentlybonded to a crosslinked amine functional cellulose membrane(CUPROPHAN.TM.; Enka AG, Ohderstrasse, Germany), the sensing layerbeing adhered to a polycarbonate backing membrane by FLEXOBOND430.TM. urethane adhesive and the backing membrane having coatedthereon CW14.TM. pressure-sensitive adhesive on a releaseliner.

An exemplary class of fluoroionophores are the coumarocryptands.Coumarocryptands can include lithium specific fluoroionophores,sodium specific fluoroionophores, and potassium specificfluoroionophores. For example, lithium specific fluoroionophorescan include(6,7-[2.1.1]-cryptando-3-[2''-(5''-carboethoxy)furyl]coumarin.Sodium specific fluoroionophores can include(6,7-[2.2.1]-cryptando-3-[2''-(5''-carboethoxy)furyl]coumarin.Potassium specific fluoroionophores can include(6,7-[2.2.2]-cryptando-3-[2''-(5''-carboethoxy)furyl]coumarin and(6,7-[2.2.2]-cryptando-3-[2''-(5''-carboethoxy)thiophenyl]coumarin.

Suitable fluoroionophores include the coumarocryptands taught inU.S. Pat. No. 5,958,782, the disclosure of which is hereinincorporated by reference. Such fluorescent ionophoric compoundscan be excited with GaN blue light emitting diodes (LEDs) emittinglight at or about 400 nm. These fluorescent ionophoric compoundshave ion concentration dependent emission that can be detected inthe wavelength range of about 450 nm to about 470 nm.

The substrate can be a polymeric material that is water-swellableand permeable to the ionic species of interest, and insoluble inthe medium to be monitored. Exemplary substrate materials include,for example, ion-permeable cellulose materials, high molecularweight or crosslinked polyvinyl alcohol (PVA), dextran, crosslinkeddextran, polyurethanes, quaternized polystyrenes, sulfonatedpolystyrenes, polyacrylamides, polyhydroxyalkyl acrylates,polyvinyl pyrrolidones, hydrophilic polyamides, polyesters, andmixtures thereof. In an embodiment, the substrate is cellulosic,especially ion-permeable crosslinked cellulose. In an embodiment,the substrate comprises a regenerated cellulose membrane(CUPROPHAN.TM., Eenka AG, Ohderstrasse, Germany) that iscrosslinked with an epoxide, such as butanediol diglycidyl ether,further reacted with a diamine to provide amine functionalitypendent from the cellulose polymer. In an alternate embodiment, thesubstrate comprises azlactone functional hydrophilic porouspolypropylene that has been amine functionalized using a diaminefunctionality pendent to the azlactone.

In one approach to making a non-carrier ion selective sensor,aminoethylated cellulose is first activated by treatment with asodium bicarbonate solution. A fluoroionophore, such as6,7-[2.2.2]-cryptando-3-[2''-(5''-carboxyl)furyl]coumarin, is thencovalently bonded to the aminoethylated cellulose. Optionally, oncethe desired amount of the fluoroionophore is covalently bonded tothe aminoethylcellulose, remaining amino groups are blocked byacylation. Next, the fluoroionophore bearing cellulose is thentaken up into solution and then coated or deposited on an opticalfiber or in a microcavity of a housing.

Permeability enhancing agents can be added to the composition usedto form the sensing layer to increase the ion permeability of thesensing layer. Suitable permeability enhancing agents can includesmall molecular weight molecules which are hydrophilic and arewater soluble. Such agents can include sugars, polyols and thelike. As a specific example, glycerol can be used. Another specificexample includes low molecular weight water solublepolyvinylalcohol.

In some embodiments, the sensing layer materials can be preparedutilizing a photocrosslinkable hydrogel having reactive functionalgroups for covalently attaching chemically functionalizedfluoroionophores and chromoionophores. In an embodiment, thephotocrosslinkable hydrogel can include azlactone functionalcopolymers. The azlactone functional copolymers can be crosslinked(cured) using photocrosslinking agents such as bisazides,bisdiazocarbonyls, and bisdiazirines. This type of crosslinkingdoes not affect the azlactone groups, but creates a threedimensional hydrogel matrix. The azlactone functional polymers canthen be reacted with chromoionophores or fluoroionophores havingreactive functional groups (such as primary amines, secondaryamines, hydroxyl groups, and thiol groups). The reactive functionalgroups then react, either in the presence or absence of suitablecatalysts, with the azlactones by nucleophilic addition to producea covalent bond. The covalent bonding step can be carried outbefore or after coating, before or after curing, and before orafter patterning.

Optionally, after ion sensing molecules are covalently attached,capping groups can be added to occupy any unused functional groups,such as azlactone groups, and prevent later contamination of thegel by any unwanted material. The capping group may hydrophilic(e.g. water) to improve the swellability of the gel. Alternatively,the capping group can be hydrophobic to provide a microenvironmentcompatible with carrier based ion selective sensors, as describedmore fully below.

The sensing layer materials can be configured in various waysdepending on the particular application. In some embodiments, thesensing layer materials are configured in a substantially planarconfiguration. In other embodiments, the sensing layer materialsare configured as beads or microdots.

Curing of sensing layer compositions can be performed using lightor heat depending on the particular application and the chemicalmakeup of the sensing layer materials.

Carrier Based Ion Sensors

In an embodiment, the ion selective sensor is a carrier based ionsensor. Carrier based ion sensors include a compound, referred toas an ionophore, that complexes with and serves to carry the ion ofinterest. Carrier based ion sensors can include both optical ionsensors and ion selective electrodes. In some embodiments, carrierbased optical ion sensors include a lipophilic ionophore, and alipophilic fluorescent or calorimetric indicator dye, called achromoionophore. The chromoionophore and the ionophore can bedispersed in, and/or covalently attached to, a hydrophobic organicpolymeric matrix. The ionophore can be capable of reversiblybinding ions of interest. The chromoionophore can be a protonselective dye. In operation, ions of interest are reversiblysequestered by the ionophores within the organic polymer matrix. Tomaintain charge neutrality within the polymer matrix, protons arethen released from the chromoionophore, giving rise to a color orfluorescence change.

A specific example of a carrier based ion sensor includes potassiumionophore III, chromoionophore I, and potassiumtetrakis(4-chlorophenyl)borate dispersed in a polymer matrix madefrom polyvinylchloride and bis(2-ethylhexyl)sebacate surfactant toproduce a colorimetric K.sup.+ sensing element.

The hydrophobic organic polymeric matrix can include materials withsufficient tensile strength, chemical inertness, and plasticizercompatibility. Exemplary materials can include poly(vinylchloride), derivatives of polyvinyl chloride, polyurethane,silicone rubbers, polyalkylmethacrylates, and polystyrene.

In an embodiment, the hydrophobic organic polymer matrix is madepermeable to the analyte of interest with plasticizers. Suitableplasticizers can include 2-nitrophenyl octyl ether (NPOE), dioctylsebacate (DOS), bis(2-ethylhexyl)sebacate (BEHS), dibenzyl ether(DBE), and the like. However, it is known that plasticizers canleach out of the hydrophobic organic polymer matrix over time. Thismay lead to decreased functioning of the sensor. Accordingly, insome embodiments, the sensing element includes a polymeric matrixthat is self-plasticizing. Such polymers can include polyurethanes,polysiloxanes, silicone rubber, polythiophenes, epoxyacrylates, andmethacrylic and methacrylic-acrylic copolymers. In an embodiment,ion selective polymer materials are produced with an acrylatebackbone and a plurality of pendant lipophilic plasticizing groupsderived from acrylate co-monomers. The lipophilic plasticizinggroups can, for example be a pendant C.sub.3-7 alkyl group thatrenders the polymer matrix inherently soft (e.g. a glass transitiontemperature (Tg) of less than -10.degree. C.) and does not requireadditional plasticizers, i.e. the polymer is in effectself-plasticizing, so that the problem of leaching of theplasticizer does not arise.

In some embodiments, a lipophilic anion (ion-exchanger) is includedto improve ion selectivity by stabilizing the concentration of theion-ionophore complex. For example, tetraphenylborate derivativescan be used as an ion-exchanger in cation-selective polymermembrane electrodes and bulk optical sensors. In addition toreducing anion interference, tetraphenylborates can also decreasemembrane resistance, and improve ionophore selectivity bystabilizing the concentration of ion-ionophore complex. Thedelocalized monoanionic charge that these compounds possess, incombination with their sterically hindered molecular structure makethem very weakly coordinating. This is a characteristic that leadsto weak, non-specific ion pair formation and maximumionophore-mediated selectivity of the membrane. Specific lipophilicanions can include potassium tetrakis(4-chlorophenyl)borate),designated KTpClPB; sodiumtetrakis[3,5-bis(1,1,1,3,3,3-hexafluoro-2methoxy-2-propyl)phenyl]borate,designated NaHFPB; potassiumtetrakis[3,5-bis(trifluoromethyl)phenyl]borate, designated KTFPB;sodium tetrakis(4-fluorophenyl)borate, combinations thereof, andthe like. Compounds that can be suitable alternatives totetraphenylborates include 3,5[bis-(trifluoromethyl)phenyl]borate(NaTFPB), carboranes (such as closo-dodecacarboranes), andhalogenated carboranes (such as trimethylammoniumundecabromocarborane (TMAUBC), undecachloroinated (UCC),hexabrominated (HBC), and undecaiodinated (UIC) carboraneanions).

The chromoionophore in a carrier based ion sensor, as mentionedabove, can be a pH sensitive material. Exemplary pH sensitivechromoionophore dyes include include congo red, neutral red, phenolred, methyl red, lacmoid, tetrabromophenolphthalein,.alpha.-napholphenol, and the like. The chromoionophore can beimmobilized by covalent bonding to the polymer matrix. Thechromoionophore can be dissolved into the polymer matrix with theaid of a plasticizer as described above.

The ionophore and/or chromoionophore can be immobilized in thepolymeric matrix in various ways. For example, in one approach theionophore is directly grafted onto an existing polymer withreactive sites. In a second approach, two different polymers areblended together, with one of them containing the graft ionophore.A third approach includes polymerizing an acrylate functionalmonomer, including the ionophore as a side chain, with othermonomers in a one-step polymerization method. In a fourth approach,azlactone functional acrylate polymers can undergo nucleophilicaddition of an amine, hydroxyl, or thiol functional ionophores toprovide a covalently bonded ionophore.

Exemplary pH responsive chromoionophores can includeChromoionophore I,(9-(diethylamino)-5-(octadecanoylimino)-5H-benzo[a]phenoxazine),"ETH 5294" CAS No. 125829-24-5; Chromoionophore II,(9-diethylamino-5-[4-(16-butyl-2,14-dioxo-3,15ioxaeicosyl)phenylimino]benzo[a]phenoxazine), "ETH 2439" CAS No.136499-31-5; Chromoionophore III,(9-(diethylamino)-5-[(2-octyldecyl)imino]benzo[a]phenoxazine, "ETH5350" CAS No. 149683-18-1; Chromoionophore IV,(5-octadecanoyloxy-2-(4-nitrophenylazo)phenol), "ETH 2412" CAS No.124522-01-6; Chromoionophore V,(9-(diethylamino)-5-(2-naphthoylimino)-5H-benzo[a]phenoxazine), CASNo. 132097-01-9; Chromoionophore VI, (4',5'-dibromofluoresceinoctadecylester), "ETH 7075" CAS No. 138833-47-3; ChromoionophoreXI, (fluorescein octadecyl ester), "ETH 7061" CAS No.138833-46-2.

In an embodiment, the ion selective sensor is a carrier basedion-selective electrode (ISE). Carrier based ion-selectiveelectrodes can include many of the same materials as carrier basedoptical ion sensors, but without the chromoionophore. In thisembodiment, the ion selective hydrophobic polymer matrix containingthe ionophore can be placed on top of a reference electrode such asa Ag/AgCl electrode, with an intervening hydrogel layer containinga fixed amount of a reference electrolyte (e.g. KCl for a K+sensor). A reference electrode without the ionophore is alsoprovided in this embodiment. ISEs produce a measurablepotentiometric change upon contact with a fluid sample containingtarget ions. This is driven by phase boundary potentials at bothinterfaces, and the diffusion potential within the ion-selectivepolymer matrix.

Complexing Moieties

Compounds used in both non-carrier ion sensors and carrier-basedion sensors can include complexing moieties. Suitable complexingmoieties can include include cryptands, crown ethers, bis-crownethers, calixarenes, noncyclic amides, and hemispherand moieties aswell as ion selective antibiotics such as monensin, valinomycin andnigericin derivatives.

Those of skill in the art can recognize which cryptand and crownether moieties are useful in complexing particular cations,although reference can be made to, for example, Lehn and Sauvage,"[2]-Cryptates: Stability and Selectivity of Alkali andAlkaline-Earth Macrocyclic Complexes," J. Am. Chem. Soc, 97,6700-07 (1975), for further information on this topic. Thoseskilled in the art can recognize which bis-crown ether, calixarene,noncyclic amides, hemispherand, and antibiotic moieties are usefulin complexing particular cations, although reference can be madeto, for example, Buhlmann et al., "Carrier-Based Ion-SelectiveElectrodes and Bulk Optodes. 2. Ionophores for Potentiometric andOptical Sensors," Chem. Rev. 98, 1593-1687 (1998), for furtherinformation on this topic.

By way of example cryptands include a structure referred to as acryptand cage. For cryptand cages, the size of the cage is definedby the oxygen and nitrogen atoms and the size makes cryptand cagesquite selective for cations with a similar diameter. For example a[2.2.2] cryptand cage is quite selective for cations such asK.sup.+, Pb.sup.+2, Sr.sup.+2, and Ba.sup.+2. A [2.2.1] cryptandcage is quite selective for cations such as Na.sup.+ and Ca.sup.+2.Finally, a [2.1.1] cryptand cage is quite selective for cationssuch as Li.sup.+ and Mg.sup.+2. The size selectivity of cryptandcages can aid in the sensitivity of chemical sensing. When thesecryptand cages are incorporated into physiologic sensing systemsheavier metals such as Pb.sup.+2 and Ba.sup.+2 are unlikely to bepresent in concentrations which interfere with the analysis of ionsof broader physiological interest such as Na.sup.+ and K.sup.+.

For crown-ether moieties the size of the 15-crown-5 cage defined bythe oxygen atoms make the unit suitably selective for Na.sup.+; thesize of the 18-crown-6 cage makes it suitably selective forK.sup.+; the size of the 21-crown-7 cage makes it quite selectivefor K.sup.+ and nonselective for Na.sup.+. Li.sup.+ fits well intothe cavities formed by crown ethers of sizes in the range of12-crown-4 to 15-crown-4. Crown ethers can include lithium specificcrown ethers, sodium specific crown ethers, potassium specificcrown ethers, and calcium specific crown ethers. For example,lithium specific crown ethers can include 6,6-dibenzyl-14-crown-4,(7-tetradecyl-2,6,9,13-tetraoxatricyclo[12.4.4.0.sup.1,14]docosane,and((2S,3S)-(-)-2,3-bis(diisobutylcarbamoylmethyl)-1,4,8,11-tetraoxacyclotet-radecane. Sodium specific crown ethers can include(2,6,13,16,19-pentaoxopentacyclo[18.4.4.4.sup.7,12.0..sup.1,200.sup.7,12]-dotriacontane, designated 2,3:11,12-didecalino-16-crown-5 or"DD16C5";4'isopropyl-4'-OCH.sub.2CON(C.sub.8H.sub.17).sub.2-dibenzo-16-crown-5,designated Na.sup.+-18;4'-decanyl-4'-(4-hydroxy-5-methyl-nitrophenyl-5-oyl)-dibenzo-16-crown-5,designated Na.sup.+ 43; and15-methyl-15-stearyl-oxymethyl-1,4,7,10,13-pentaoxacyclohexadecane,designated "ODM16C5". Potassium specific crown ethers can includenaphtho-(15-crown-5); (hexanolyloxymethyl)benzo-15-crown-5;(octadecanoyloxymethyl)benzo-15-crown-5; and K.sup.+-35, an anioniccrown ether dye derived from benzo-15-crown-5 (nomenclature ofBuhlmann et al. supra). Calcium specific crown ethers can include4,13-di-N-octadecylcarbamoyl-3-oxabutyryl-1,7,10,16,tetra-oxa-4,13-diazac-yclooctadecane or10,19-bis[(octadecylcarbamoyl)methoxy-acetyl]-1,4,7,13,16-pentaoxa-10,1,9--diazacycloheneicosane; designated "K22E1".

Complexation of bis-(crown ether) and alkali metal ions is quitespecific when the size of the cation is slightly larger than theinternal cavity formed by one of the crown ether rings. This can beexplained by formation of intramolecular sandwich complexes. HighNa.sup.+ selectivity is, for example, obtained with bis(14-crown-4)and bis(12-crown-4) compounds, even though the 14-crown-4 and12-crown-4 cavities too small for Na.sup.+. In the same way,K.sup.+ selectivity is obtained with bis(15-crown-5) compounds.Bis-crown ethers can include sodium specific bis crown ethers andpotassium specific bis crown ethers. Sodium specific bis crownethers can includebis[(12-crown-4)methyl]-2-dodecyl-2-methyl-malonate;bis[(12-crown-4)methyl]-2,2-dibenzyl-malonate;1,1-bis[(12-azacrown-4)-N-methyl]dodecane. Potassium specific biscrown ethers can includebis[(benzo-15-crown-5)-4'-ylmethyl]pimelate;bis[(benzo-15-crown-5)-4'ylmethyl]-2-dodecyl-2-methylmalonate; and2,2-bis[3,4-(15-crown-5)-2-nitrophenylcarbamoxymethyl]tetradecane,designated "BME-44".

Hemispherands can be considered to be crown ether compounds with anextra bridge that enhances ligand preorganization. An example ofsodium specific hemispherand can include the compound sold underthe trade name HEMISODIUM (Na.sup.+-40, nomenclature of Buhlmann etal. supra). Potassium specific hemispherands can include K.sup.+-26(nomenclature of Buhlmann et al. supra) and K.sup.+-27(nomenclature of Buhlmann et al. supra).

Non-cyclic amides can include both sodium specific non-cyclicamides and calcium specific non-cyclic amide. Sodium specificnon-cyclic amides can includeN,N',N''-triheptyl-N,N',N''-trimethyl-4,4',4''-propylidynetris(3--oxabutyramide), designated "ETH 227";N,N'-dibenzyl-N,N'-diphenyl-1,2-phenylene-dioxydiacetamide,designated "ETH 157";N,N,N',N'-tetracyclohexyl-1,2-phenylenedioxy-diacetamide,designated "ETH 2120"; and4-octadecanoyloxymethyl-N,N,N',N'-tetracyclohexyl-1,2-phenylenedioxy-diac-etamide, designated "ETH 4120". Calcium specific non-cyclic amidescan include(-)-(R,R)--N,N'-bis-[11-(ethoxycarbonyl)undecyl]-N,N'-4,5-tetrame-thyl-3,6-dioxaoctane-diamide, designated "ETH 1001";N,N,N',N'-tetracyclohexyl-3-oxapentanediamide, "designated ETH129"; N,N-dicyclohexyl-N',N'-dioctadecyl-3-oxapentanediamide,"designated ETH5234".

Calixarenes can include sodium specific calixarenes and potassiumspecific calixarenes. Sodium specific calix[4]arenes can include25,26,27,28-tetrakis(ethoxycarbonylmethoxy),3,9,15,21-tert-butylcalix[4]arene; Na.sup.+-20 (nomenclature ofBuhlmann et al. supra); Na.sup.+-42 (nomenclature of Buhlmann etal. supra); Na.sup.+-33 (nomenclature of Buhlmann et al. supra);and Na.sup.+-34 (nomenclature of Buhlmann et al. supra). Potassiumspecific calix[6]arenes and calix[4]arenecrown-5 ionophores caninclude37,38,39,40,41,42-hexakis(ethoxycarbonylmethoxy)calix[6]arene;K.sup.+-32 (nomenclature of Buhlmann et al. supra); K.sup.+-33(nomenclature of Buhlmann et al. supra); and K.sup.+-34(nomenclature of Buhlmann et al. supra).

Coating and Patterning of Sensors

Sensing layer compositions, in the context of both carrier andnon-carrier ion sensors, can be coated with or without addition ofa solvent. In some embodiments, the sensing layer components areformulated as a liquid composition to facilitate coating of thesensing layer components onto substrates using coating techniquessuch as spray coating or dip coating. For example, in certainembodiments, it can be advantageous to incorporate the sensinglayer on the tip of a fiber optic lead or inside a capsuleassociated with a satellite sensor in wireless communication with apulse generator. In these cases, it can be advantageous to spraycoat or dip coat the sensing layer components onto the fiber opticlead or inside the capsule. Suitable coating methods can alsoinclude spin coating, knife coating, or roller coating.

The composition can be selectively coated to provide a patternedsurface. For example, techniques including ink jet printing,offset, flexographic printing, etc. can be used to selectively coatthe composition. The composition may also be knife coated onto amicrostructured surface (e.g. a surface having micron scaledepressions or channels) in such a way that the composition residesin microstructures, providing a patterned array of the composition.In some embodiments, the composition can be deposited intomicrowells or microcavities in a substrate using precisiondispensing techniques, such as pin-based precision dispensing.

Beyond selective coating, patterning can also be achieved bytechniques such as selective curing of the composition or selectiveremoval of the composition from a substrate. Selective curingtechniques can include selective exposure to UV light or heat.Selective UV exposure methods include exposure through a mask orphotographic negative or exposure by a directed beam of light, suchas a laser. After curing, remaining uncured composition can beremoved, e.g. by washing, to result in a patterned coating.

In some embodiments, the composition can be patterned onto asubstrate by a laser addressable thermal transfer imagingprocesses. In this process, a thermal transfer donor element isconstructed comprising a support layer, a light-to-heat conversionlayer, and a transfer layer comprising the composition to bepatterned. When the donor element is brought in contact with areceptor and image wise irradiated, a melt stick transfer processoccurs and the composition containing transfer layer is imaged ontothe receptor. As an example, the photocrosslinkable azlactonecomposition described earlier can be used in the transfer layer ofsuch a system. This photocrosslinkable azlactone composition can bereacted with chromoionophores or fluoroionophores beforeincorporation into the transfer layer, after incorporation into thetransfer layer, or after laser addressed thermal transfer to thereceptor. The azlactone composition can be thermally orphotochemically crosslinked before or after the transfer process.This process offers the opportunity to pre-pattern differentindictor elements onto a transfer layer comprising the azlactonecomposition prior to laser addressed thermal imaging of individualazlactone-indicator conjugates to the receptor substrate.Registration of the donor and receptor elements can be roboticallyaltered between any or all of the transfer steps to build updesired array spacings and sizes for transferred elements on thereceptor that is different from the patterning of the indicators onthe transfer layer.

Methods of Operation

An embodiment of the invention includes a method for using animplantable medical device including a pulse generator to monitorconcentrations of physiological analytes. The method includessensing analyte concentrations with a chemical sensor. Sensinganalyte concentrations with a chemical sensor can include exposinga sensing element to a bodily fluid. Sensing analyte concentrationswith a chemical sensor can also include illuminating a sensingelement with an optical excitation assembly to produce an opticalreturn signal. Sensing analyte concentrations with a chemicalsensor can further include receiving light reflected from oremitted from the sensing element using an optical detectionassembly.

Methods of the invention can include periodically interrogating asensing element to determine analyte concentrations. Methods canalso include storing a digitized representation of measured analyteconcentrations in a memory within the implantable medical device.In some embodiments, once the information is stored, it can beevaluated as a function of time to identify metabolic trends andevents. Some embodiments also include conveying data regardinganalyte concentrations and/or calculated risk indexes to anotherdevice. For example, one or more messages can be wirelesslycommunicated to a remote patient monitoring device, includinginformation on the stored measured analyte concentrations. In someembodiments, the method includes reading analyte concentrationperiodically using a home monitoring system, such as an advancedpatient management system (APM). A further embodiment includesproviding trending data to show the trend of analyte concentrationover time.

According to various method embodiments, a processor within theimplantable medical device can be used to calculate analyteconcentrations based on digitized optical signals collected from anoptical sensing element and a corresponding analyte insensitiveoptical reference element. The method can include first correctinganalyte dependent intensity readings from a sensing element at agiven center-wavelength for optical offsets as measured usingintensity readings from an optical reference element at thatcenter-wavelength. The method can also include using the correctedoptical signal, in conjunction with a lookup table to obtain theanalyte concentration. In an embodiment, the method includesadjusting the data based on calibration coefficients stored in thememory. In various embodiments, adjustments are made based ontemperature, as measured by a temperature sensor integrated intothe implantable medical device. The method can also includecalculating compensated analyte concentrations, taking into accountvarious adjustments, and then storing them in memory along with anassociated time stamp.

Methods of Use

In some current heart failure monitoring regimens, heart failurepatients take note of weight gain, blood pressure, and othersymptoms, and then self-report these symptoms via telephone to anurse or physician who treats their condition. If their reportedsymptoms indicate an adverse condition that requires diuretictherapy, the caregiver has to choose between prescribing treatmentover the phone, or bringing the patient to the clinic. Diuretictherapy can include the administration of diuretics as well as theadministration of agents such as ACE inhibitors, beta blockers,ionotropic agents, in various combinations.

A common recommendation, often given without a blood test tomeasure concentrations of physiological analytes, is to administeran increased dose of diuretics and a dose of potassium. The logicof administering the dose of potassium is that it is used to offsetincreased losses of physiological potassium due to the increaseddose of diuretics. Because actual physiological potassiumconcentrations are unknown in this scenario, there is a risk thatthe patient will end up with a potassium concentration that is toohigh or too low as a result. Specifically, if the patient alreadyhad high potassium levels, unknown to the caregiver, and ifpotassium ingestion and excretion are not properly balanced, thenit is possible to suffer from hyperkalemia (potassium concentrationtoo high). The consequences of hyperkalemia, as previouslydescribed, can include cardiac arrhythmias that sometimes result indeath.

In an embodiment, the invention includes a method of monitoringdiuretic therapy (such as diuretic therapy administered to apatient) using an implanted medical device. The method can includeoptically monitoring potassium ion concentration in a bodily fluidof a patient using an implanted medical device. The method caninclude determining whether the patient is suffering fromhypokalemia or hyperkalemia. In an embodiment, the patient is aheart failure patient. The method includes monitoring potassiumconcentrations with a chemical sensor. Monitoring potassiumconcentrations with a chemical sensor can include exposing asensing element to a bodily fluid. Monitoring potassiumconcentrations with a chemical sensor can also include illuminatinga sensing element with an optical excitation assembly to produce anoptical return signal. Monitoring potassium concentrations with achemical sensor can further include receiving light reflected fromor emitted from the sensing element using an optical detectionassembly. Some embodiments of the method also include conveyingdata regarding potassium concentrations and/or calculated riskindexes to a non-implant device via a telemetry link and/or to ahealth professional. For example, one or more messages can bewirelessly communicated to a remote patient monitoring device.

Methods of monitoring diuretic therapy using an implanted medicaldevice according to the invention can provide various benefits. Onebenefit is that a caregiver can more safely recommend a therapeuticdose of a diuretic and potassium while reducing the risk ofhyperkalemia and hypokalemia. The method can allow the correctbalance of diuretic and potassium to be prescribed without drawingblood from the patient. The information gathered by the implanteddevice can be coupled through a telemetry/remote patient managementsystem, allowing the patient to get the optimal prescriptionwithout entering the physician's office.

In addition, the risk posed to a patient by administering increaseddoses of diuretics along with doses of potassium can be compoundedby the patient's overall renal function. For patients with impairedrenal function, the risk of becoming hyperkalemic from a dose ofpotassium is much greater. Even a slight potassium dose imbalance,that would be completely safe for a patient with normal kidneyfunction, could have catastrophic destabilizing effects on apatient with impaired renal function. Therefore, methods ofmonitoring diuretic therapy using an implanted medical deviceaccording to some embodiments of the invention can also includeoptically monitoring a concentration of an analyte indicative ofrenal function with the implanted medical device. Specific analytesindicative of renal function can include creatinine, urea, and uricacid.

While an example of a method of monitoring diuretic therapy hasbeen described, it will be appreciated that embodiments of thepresent invention can also include monitoring of other types oftherapy. By way of example, embodiments of the invention caninclude a method for titrating drug therapy. In particular, anembodiment can include a method for controlling delivery of anactive agent into a human body. The method can include measuring aphysiological concentration of one or more analytes with animplanted system and varying delivery of the substance at least inpart as a function of the measured concentration of the one or moreanalytes. The implanted system can include a pulse generator and achemical sensor. The chemical sensor can include a sensing element,an excitation assembly, and a detection assembly. The one or moreanalytes can include potassium, sodium, chloride, calcium,magnesium, lithium or hydronium. The one or more analytes caninclude an analyte indicative of renal function. The one or moreanalytes can include an analyte indicative of cardiac function. Inan embodiment, the active agent can comprise a diuretic. Thephysiological concentration of the one or more analytes can beassessed by measuring the concentration in a bodily fluid selectedfrom the group including of blood, interstitial fluid, serum,lymph, and serous fluid.

Methods of the invention can also include providing cardiacarrhythmia therapy to a patent. By way of example, methods of theinvention can include optically sensing a physiologicalconcentration of an ion in a bodily fluid of a patient with animplanted chemical sensor. The method can further includecommunicating data regarding the physiological concentration of anion to an implanted pulse generator. The method can also includealtering the delivery of pulses from the implanted pulse generatorto the patient based in part on the physiological concentration ofan ion. Data regarding the physiological concentration of the ioncan then be reported to a non-implanted device via a telemetrylink. Data regarding the physiological concentration of the ion canbe combined with data regarding the patient's cardio-respiratorysystem to form a composite profile of the patient's cardiaccondition. Data regarding the patient's cardio-respiratory systemcan include an EKG signal, respiration rate, accelerometer data,trans-thoracic impedance, lead impedance, cardiac volume, bloodpressure, weight, and cardiac necrosis signals.

Methods of providing cardiac arrhythmia therapy can also includeoptically monitoring a physiological concentration of an ion in abodily fluid of the patient with an implanted chemical sensor,transmitting data regarding the physiological concentration of theion to an implanted cardiac rhythm device, and delivering pulsesfrom the implanted cardiac rhythm device to the patient based inpart of the physiological concentration of the ion.

Methods of Optimized Diagnostic Indication

It will be appreciated that the integration of an implantedchemical sensor with the functionality of an implanted cardiacrhythm management (CRM) device enables combinations of data to besynthesized into diagnostic indicators with previously unrealizedutility. As a specific example, the implanted chemical sensor canprovide data regarding analyte concentrations while the CRM devicefunctionality can provide cardiac data such as an EKG signal. Asdescribed above, the two types of data offer mutually orthogonalbut linked views of the physiologic state of the patient. These twotypes of data, or in some embodiments more than two types, can becombined to form a composite profile of a patient's condition orcomposite risk index.

The value of combining the chemical sensor data with the CRM devicedata can be illustrated in multiple examples. One example is amethod involving coordination of an electrolyte concentrationsignal with that of an EKG signal. A rapid or erratic heart rate iseasily identified by the CRM device functionality. This data iscoupled with the information from the chemical sensor, such aspotassium ion concentration. As described above, an erraticheart-rate in the presence of very high or very low potassiumconcentrations indicates a greater level of risk to the patientthan either condition separately. Methods of the invention caninclude embodying this logic as an algorithm and creating a warningindicator that can provide a local alert through an integratedtransducer, a proximal alert from a bedside or external device incommunication with the system, or a medical alert provided to acentral monitoring system.

Another example is a method involving coordination of anelectrolyte concentration signal with that of a respiration ratesignal. CRM device functionality can include observing andidentifying high respiration rates. Clinically, respiration ratescan be associated with the physiological concentration of sodiumions and can indicate fluid volume overload conditions for thepatient. Further, CRM device functionality can include data from anaccelerometer that can verify that exercise is not the respirationdriver. The combination of a volume overload signal with a verifiedhigh resting respiration rate is indicative of an imminentcardio-respiratory system crisis. Methods of the invention caninclude embodying this logic as an algorithm and creating a warningindicator that can provide a local alert through an integratedtransducer, a proximal alert from a bedside or external device incommunication with the system, or a medical alert provided to acentral monitoring system.

Yet another example is a method involving coordination of EKGsignal vector values with concentrations of analytes indicatingcardiac tissue necrosis. Specifically, CRM device functionality caninclude identifying the vector component values of the EKG waveformand then categorizing these into normal or abnormal vector patternbins. The chemical sensor can be configured to identifyconcentrations of troponin, cardiac specific troponin, or any otheranalyte that indicates cardiomyocyte necrosis. The method caninclude combination of the EKG vector analysis and the cardiacnecrosis analyte concentration signal as part of a formalizedalgorithm. This method can provide greater specificity foridentifying a cardiac infarct than a method based on analyzingeither signal in isolation. Methods of the invention can includeembodying this logic as an algorithm and creating a warningindicator that can provide a local alert through an integratedtransducer, a proximal alert from a bedside or external device incommunication with the system, or a medical alert provided to acentral monitoring system.

While several examples of specific methods of combining data froman implanted chemical sensor with data provided by CRM devicefunctionality have been provided, it will be appreciated that manyother methods are possible based on combining data in a similarfashion. By way of example, other methods can include combining oneor more of chemical sensor signals with the EKG, trans-thoracicimpedance, accelerometer indicated activity, accelerometerindicated posture, heart sounds, lead impedance, cardiac volume,and other signals obtained from the CRM device. In a particularembodiment, potassium ion concentration is combined with bloodpressure data.

Methods of Providing Automated Feedback

Methods described herein can be adapted to provide automaticfeedback (such as indications or recommendations) to a patientregarding behavioral or pharmaceutical interventions appropriate tothe stabilization, improvement, or maintenance of health. By way ofexample, methods can include the detection of an excessive orinadequate potassium level which can be fed into an algorithmresulting in the delivery of a message to the patient regarding thecondition without caregiver intervention. The algorithm can beconstructed to provide patients with recommendations for dietaryand/or activity modification within a range of analyte valueswherein the medical risk remains modest or negligible. The methodcan allow patients to reverse physiological trends before theybecome more serious or require the intervention of medicalprofessionals.

In some embodiments, the method can include providingrecommendations to the patient so that the patient can modulate thedose of a therapeutic agent to a more appropriate level. The methodcan also include providing a medical professional with data so thatthe medical professional can modulate the dose of a therapeuticagent and/or change the therapeutic agent.

The method can include categorizing a patient's current conditionas within the bounds of self-management or requiring theintervention of a medical professional. The boundaries of thesecategories can be predetermined, determined adaptively bymonitoring the patient norms, or set by a medical professional asdesired to yield the optimal patient benefit.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, uponreading and comprehending this disclosure, other methods within thescope of the present subject matter.

One of ordinary skill in the art will understand that the modules,circuitry, and methods shown and described herein with regard tovarious embodiments of the invention can be implemented usingsoftware, hardware, and combinations of software and hardware. Assuch, the illustrated and/or described modules and circuitry areintended to encompass software implementations, hardwareimplementations, and software and hardware implementations.

It should be noted that, as used in this specification and theappended claims, the singular forms "a," "an," and "the" includeplural referents unless the content clearly dictates otherwise. Itshould also be noted that the term "or" is generally employed inits sense including "and/or" unless the content clearly dictatesotherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase "configured" describes a system,apparatus, or other structure that is constructed or configured toperform a particular task or adopt a particular configuration. Thephrase "configured" can be used interchangeably with other similarphrases such as "arranged", "arranged and configured", "constructedand arranged", "constructed", "manufactured and arranged", and thelike.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications areherein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated by reference.

This application is intended to cover adaptations or variations ofthe present subject matter. It is to be understood that the abovedescription is intended to be illustrative, and not restrictive.The scope of the present subject matter should be determined withreference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

Aspects of the present invention may be better understood withreference to the following examples. These examples are notintended as limiting the scope of the invention.

EXAMPLES

Example 1

Determination of Ion Concentration within Pocket

The objective of this study was to evaluate the potential effectsof the fibrous capsule surrounding an Implantable CardiacDefibrillator (ICD) on sodium, potassium and glucose concentrationsimmediately surrounding the device. Twelve canines were implantedwith an ICD device and cared for in accordance with standardlaboratory procedures. After a period of time (specified in Table 1below), fluid was collected from inside the implant encapsulationtissue (or pocket) and compared with corresponding blood serum. Anamount of fluid sufficient for testing was drawn from eight of thetwelve canines (insufficient amounts of fluid were collected fromthe other four). K.sup.+, Na.sup.+, Glucose, and pH andconcentrations were measured using a Radiometer ABL 825 bloodanalyte monitor for samples from those eight canines. Serum sampleswere also drawn from the twelve animals and similarly analyzed withthe Radiometer ABL 800 blood analyte monitor. The data is shown inTable 1 below and summarized in Table 2 below:

TABLE-US-00001 TABLE 1 Relative Concentrations Pocket Age pH(T)c ID(Days) K.sup.+ (%) Na.sup.+ (%) Glu (%) (%) 1 61 128.6 96.8 7.498.7 2 61 153.8 99.3 2.5 102.0 3 57 119.4 100.7 0.86 97.6 4 61123.7 98.7 1.18 100.3 5 64 148.6 99.3 3.5 101.6 6 64 104.9 102.12.3 92.9 7** 74 127.0 98.6 29.8 98.0 8 55 114.3 100.7 1.05 97.7Range 55-74 104.9-153.8 96.8-102.1 0.86-29.8 92.9-106.3 * Pocketlevel compared to serum level, expressed in %. <100% indicatesthat the level was lower in the pocket. >100% indicates that thelevel was higher in the pocket. **Lead re-positioned at distal endone week after implant

TABLE-US-00002 TABLE 2 Concentration Ranges K.sup.+ Na.sup.+Glucose Range: (mmol/L) (mmol/L) (mg/dL) pH(T)c Normal* 3.4-5.6141-159 74-145 7.310-7.420 Blood Serum (n = 12) 3.5-4.2 146-15467-119 7.334-7.440 Pocket Fluid (n = 8) 4.0-6.0 144-150 1-316.859-7.846 *Normal ranges provided by Marshfield Labs, Marshfield,Wisconsin

The data show that relative to the reference range, K.sup.+ levelswere normal in the blood serum and normal to slightly elevated(average ratio of 127%.+-.16%) in the pocket fluid. The Na.sup.+levels were normal in the blood serum and the pocket fluid (averageratio 100%.+-.2%). The glucose levels were normal in the bloodserum and highly suppressed in the pocket fluid (average ratio6%.+-.10%). The pH levels were normal in the blood serum and variedbelow, within, and above the normal range in the pocket fluid. Thisexample shows that physiological ions such as K.sup.+ and Na.sup.+can be accurately measured from within an encapsulation pocket.

Example 2

Planar Ion Selective Optical Sensing Element

CUPROPHAN.RTM. cellulose sheets infiltrated with glycerol (AkzoNobel Chemicals; Chicago, Ill.) are washed with deionized water (10minutes) to remove the glycerol. Each sheet is stretched on a glassplate and dried at room temperature.

A. Overcoat

An overcoat solution is prepared by dissolving 4 g dextran (MW2,000,000) in 200 mL deionized water at 50.degree. C. Then, 2 gMARASPERSE DBOS-4.RTM. dispersing agent (Diashowa Chemicals, Inc.;Rothschild, Wis.) is added and the mixture is shaken. Thereafter, 4g MONARCH-700.RTM. carbon black (Cabot Corp.; Waltham, Mass.) isadded with sonication to produce a uniform aqueous dispersion ofcarbon-black. To the dispersion is added 4 g 50% (aq.) NaOHsolution with mixing. Subsequently, 6 g of a 50% ethylene glycoldiglycidylether (EGDGE) solution in deionized water is mixed in.The resulting overcoat solution is sprayed evenly onto theCUPROPHAN.RTM. membrane and allowed to dry.

B. Crosslinking

A solution of 3 g of 50% NaOH solution and 85 g DMSO in 350 mLdeionized water is prepared. 450 g of a 50% aqueous EGDGE solutionis added and mixed. This crosslinking solution is poured onto theCUPROPHAN.RTM. sheets and retained for 1 hr followed by rinsingwith deionized water.

C. HDA (1,6-Hexandediamine) Reaction

Crosslinked CUPROPHAN.RTM. membranes are immersed in a solution of120 g 70% HDA in 2.0 L deionized water for 2 hrs, rinsed withdeionized water to wash off excess HDA.

D. FCCC Coupling Reaction

A dye solution is prepared by dissolving 30 mg FCCC in 30 mL DMF.Subsequently, 0.8 mL of 1,3-diisopropylcarbodiimide (DIC) and 190mg benzotriazole hydrate (HOBt) are added and stirred for 15minutes, after which 0.4 mL N,N-diisopropylamine (DIEA) is addedwith stirring. HDA-functionalized CUPROPHAN.RTM. sheets are removedfrom the deionized water, towel dried and immersed in the dye bathfor 24 hours, after which the pieces are removed and washed withDMF, then dilute aqueous HCL (pH 2-3.5).

E. Sensor-Pulse Generator Assembly

A dye-coupled CUPROPHAN.RTM. sheet is laminated to a thin (0.175mm) polycarbonate sheet (Bayer AG; Leverkusen, Germany) using a2-part polyurethane adhesive such as FLEXOBOND.RTM. 430 (BaconIndustries, Inc.; Irvine, Calif.). On the polycarbonate side, aCW14.TM. pressure sensitive adhesive sheet (RSW Inc., SpecialtyTape Div.; Racine, Wis.) is attached and the release-liner isremoved. Discs are punched from the laminate using a hole-puncherand placed on an optical window of a pulse generator, configuredwith optoelectronics as described below for measuring potassiumdependent emissions from the sensing element.

F. Optical Response of Potassium Sensor

GaN LEDs from Nichia Chemical Industries, Tokushima, Japan, orToyoda Gosei Co., Ltd (under the brand name LEDTRONICS.TM.) aredisposed within the pulse generator and configured to be amplitudemodulated at a 30 kHz carrier frequency, with a burst duration of0.2 seconds, a repetition rate of 5 seconds, and an average outputpower of 2.5 mW. The light is focused, passed through a bandpassexcitation filter (e.g. 390 nm.+-.0.25 nm; % T=52%; out-of-bandblocking=0.001% T; available from SpectroFilm; Woburn, Mass.), andtransmitted to the sensing element through the optical window inthe pulse generator. The modulated fluorescent return is similarlycollected and passed through a bandpass emission filter (e.g.475.+-.0.35 nm; % T=64%; out-of-band blocking=0.001% T such as isavailable from SpectroFilm). The filtered optical signal is then befocused onto the active region of an S1337-33-BR.TM. photodiodedetector (available from Hamamatsu Corp.; Bridgewater, N.J.) housedwithin the pulse generator. A small fraction of the excitationlight is directly routed to the detector assembly and attenuatedwith a neutral density filter to provide a reference optical signalfrom the LED. In addition, an electronic switch is used toalternately sample the detector photo current and a 30 kHzelectrical reference signal from the frequency generator. Thedetector output is directed to an electronic circuit within thepulse generator or satellite sensor that converts the photocurrentfrom the photodiode detector to a voltage. A transimpedancepreamplification stage converts a photocurrent or the referenceelectrical signal to a voltage using an operational amplifiercircuit. The following stage is a two-stage Delyiannis-Friend stylebandpass filter designed to band limit the noise power whilefurther amplifying the signal. The amplified photosignal orreference electrical signal is then digitally sampled at 100 kHzand processed to obtain a fluorescence intensity that is indicativeof analyte concentration. Optionally, a pH sensor signal is alsosampled and used to correct for minor pH dependent variations inthe potassium sensor signal.

Example 3

Ion Selective Sensing Element in Hydrogel

A. Preparation of 1:1 Dimethylacrylamide:Vinyl Dimethylazlactone(DMA:VDM) Copolymer

A solution of 70 parts dimethylacrylamide (DMA) and 70 parts2-vinyl-4,4-dimethyl-2-oxazoline-5-one (vinyldimethylazlactone,VDM, commercially available from SNPE, Princeton, N.J.) in 210parts methylethyl ketone (MEK) is mixed with 0.7 partsN,N'-azobis(isobutyronitrile) initiator (AIBN, commerciallyavailable as VAZO.RTM. 64, Wako Chemicals USA, Inc., Richmond,Va.). The mixture is sparged with nitrogen for 5 minutes, thensealed in ajar and tumbled in at 60.RTM. C for 24 hours.

B. Lithographic Patterning of DMA:VDM Using 4-(p-Azidosalicyamido)Butylamine (ASBA)

Under low-lighting conditions, 25 mg of4-(p-azidosalicyamido)butylamine (ASBA, commercially available fromPierce Chemical Co., Rockford, Ill.) and 10 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide promoter (EDC, HClsalt, Pierce Chemical Co., Rockford, Ill.) is dissolved in 0.5 mlof 95:5 (v/v) isopropanol:water. This solution and one drop of aq.1N HCl are added to 1 mL of a 40% (w/w) solution of 50:50 DMA:VDMcopolymer (Example 1) in MEK. Thermal coupling of the butylamineportion of ASBA to azlactone functional groups is allowed to takeplace for 2 hour at room temperature. The MEK solution of theresulting mixture is spin-coated onto a PMMA substrate and dried ina vacuum desiccator for 15 minutes. The sample is lithographicallyexposed to UV irradiation at 10-30 mW/cm.sup.2 measured at 365 nmthrough a photomask for 3 minutes to photocrosslink through theazido portion of bound ASBA. The mask is removed and the sample iswashed thoroughly with pure isopropyl alcohol, leaving gel patternsthat match those of the photomask. This dual cure approachincreases the efficiency for crosslinking compared to a bisazidecrosslinker.

C: Preparation of Amine-Functional FCCC

The half-protected mono-N-tert-butyloxycarbonyl(t-BOC)-propylenediamine (Molecular Probes-Invitrogen) is usefulfor converting organic solvent-soluble carboxylic acids intoaliphatic amines. Following coupling of the half-protectedaliphatic diamine to the activated carboxylic acid of FCCC understandard conditions, the t-BOC group is quantitatively removed withtrifluoroacetic acid. The resultant aliphatic amine derivative ofFCCC is then reacted directly with azlactone functional polymer orhydrogel.

D: Preparation of FCCC Functional Hydrogel

To demonstrate the reactivity of the photo-crosslinked composition,a second sample of azlactone hydrogel is prepared and treated asfollows: 50 nM of amine-functionalized FCCC is dissolved in 20 uLof carbonate bicarbonate buffer (0.05 M, pH 9.2). The indicatorsolution is spotted onto the photo-cured DMA:VDM coating using aneedle. The sample is put in a sealed, humidified container for 2hours at room temperature before washing with DI water andincubating in DI water for 10 hours.

Example 4

Ion-Selective Optical Sensing Element in an Ion PermeableHEMA:PEGMA Hydrogel Film

A: Preparation of Acrylamide Functional FCCC

Amine-functional FCCC, prepared as described in Example 3 isreacted with the succinimidyl ester of 6-((acryloyl)amino)hexanoicacid (Molecular Probes-Invitrogen) under standard conditions toyield acrylamide functional FCCC.

B: Fabrication of Polyhema Layer

A solution of 40 wt. % hydroxyethyl methacrylate (HEMA), 8.3 wt. %poly(ethyleneglycol)methacrylate (PEGMA, Mn ca 360), 1.5 wt. %acrylamide functional FCCC, 50% deionized water and 0.2 wt. %Irgacure 651 is put into a mold consisting of two slide glasses,one having a hydrophobic octadecasilane treated surface, the otherhaving a trimethyoxysilylpropylmethacrylate treated surface andseparated by a spacer with 16 um thickness. After polymerization byexposure to UV light for 10 min the hydrophobically treated glassslide is removed, leaving a HEMA:PEGMA hydrogel film covalentlyattached to the remaining glass slide and comprising covalentlyincorporated FCCC fluoroionophore.

C: Optical Overcoat

Optionally, the optical overcoat as described in Example 2 isapplied over the HEMA:PEGMA hydrogel film according to procedure ofExample 2.

Example 5

Preparation of Sensing Elements Using Plasticized PVC Polymer

A: Preparation of Sensing Beads

Microscopic beads based on 30 wt. % of poly(vinyl chloride), PVCand 70 wt. % of bis(ethylhexyl)sebacate, BEHS are prepared using aspray dry method. A THF solution containing 1 wt. % PVC and 1 wt. %of BEHS is sprayed with a nebulizer under heated air stream from aheat gun and PVC/BEHS particles (2.5.+-.1 um in diameter) arecollected in a cyclone chamber.

50 mg of BEHS solution containing 0.5 mg of hydrogen ion selectivechromoionophore III, 1.6 mg of NaHFPB and 22.3 mg of sodiumionophore, bis(12-crown-4) are added to 300 mg of the PVC/BEHSbeads and thoroughly mixed, to form Na.sup.+/pH sensing microscopicbeads.

50 mg of BEHS, 0.5 mg of hydrogen ion sensitive chromoionophoreIII, 1.6 mg of NaHFPB and 6.3 mg of potassium ionophore III(BME-44) are dissolved in 0.5 ml of 1,1-dichloromethane (DCM). Theresulting solution is allowed to stand for 5 hours to evaporate theDCM. Into this cocktail, 300 mg of PVC/BEHS microscopic beads areadded and then thoroughly mixed to form K.sup.+/pH sensingmicroscopic beads.

50 mg of BEHS solution is added to 300 mg of the PVC/BEHS beads andthoroughly mixed to form optical white reference beads.

B: Suspension of Beads in Hydrogel

For both sensing and optical reference beads, to preventconglomerating of the sensing beads, the beads are suspended andfixed in a hydrogel matrix. Two milligrams of the sensing orreference beads are well mixed with 1 mg of PEG and 1 mg of aqueousmonomer solution containing 30 wt. % of acrylamide, 1 wt. % ofN,N'-methylene-bis-acrylamide and 0.5 wt. % of photoinitiator,Irgacure 2959. The suspension is placed in between two slideglasses and then photopolymerized upon UV light irradiation for 15min.

C: Fabrication of a polyHEMA-Based Sensor Body

HEMA (2-hydroxyethyl methacrylate) based sensor bodies are preparedby making a polymer plate using a photopolymerization methodapplied to the monomer solution in between two slide glassesseparated by a spacer. To prevent strong adhesion of the resultingpolymer to the glass surface, surface modified slide glasses withoctadecylsilane are used. The slides (25.times.75.times.1 mm) arecleaned in a 1N HNO.sub.3 solution at 70.degree. C. for 2 hours andafter cooling they were rinsed with milliQ water. After drying inan oven, cleaned slide glasses are placed into 1 L of toluene with1.5 g of octadecyltrichlorosilane and heated under reflux for 6hours. The thus surface modified slide glasses are washed byethanol and milliQ water, and used as substrates forphotopolymerization.

A solution of 80 wt. % HEMA, 8.0 wt. % PEGMA (poly(ethylene glycol)methacrylate), 2.0 wt. % DEGDMA (di(ethyleneglycol)dimethacrylate), 9.8 wt. % deionized water and 0.2 wt. %Irgacure 651 are transferred into a mold consisting of two surfacemodified slide glasses separated by a spacer with 400 um thickness.The solution is polymerized to form a crosslinked hydrogel byexposure to low intensity 365 nm UV light (ca 2 mW/cm.sup.2) for 10min. After polymerization, the thus prepared polyHEMA film isremoved from the mold. To prepare wells in the polyHEMA film foreach sensing capsule, an excimer laser is used with a mask made ofa brass plate 200 um thick in which four holes 1 mm in diameter arelinearly aligned with 1.3 mm distances in between holes to createsensor compartments in a single sensor body. After successful laserdrilling, the polyHEMA film with wells is washed with deionizedwater.

D: Fabrication of Sensor Window Membrane

To prepare the sensor window membrane, a solution of 32.9 wt. %HEMA, 16.9 wt. % PEGMA, 50 wt. % deionized water and 0.2 wt. %Irgacure 651 is put into a mold consisting of two slide glasseshaving hydrophobic surfaces separated by a spacer with 16 umthickness. After polymerization by exposure to UV light for 12 min,one of the slide glasses in the mold is carefully removed. In thiscase, the polyHEMA window membrane with 16 um thickness remains onthe surface of another slide glass.

E. Construction of Sensor Body with Wells

To adhere the sensor body with the window membrane, 10 uL of theabove mentioned monomer solution is applied to the surface of thethus prepared window membrane on the slide glass and spread. Thesensor body is then placed on the window membrane, covered with aslide glass and clamped with binder clips. By exposure to UV lightfor 15 min, the polyHEMA-based sensor body containing wells withsealed bottoms is successfully prepared.

F. Filling the Sensor Wells and Completing Construction of theSensor

The thus prepared sensor body is placed on a slide glass withsealed bottoms down and fixed with Scotch tape at the edges of thesensor body. In the respective sensor compartments Na.sup.+/pHsensing beads, K.sup.+/pH sensing beads and optical white beads fora sensor body with three wells are stuffed by using a tiny glassrod under a stereo microscope.

Another piece of window membrane on a slide glass with hydrophobicsurface is then prepared by using the same method mentioned above.Ten uL of the monomer solution mentioned above is applied on thesurface of the window membrane and then spread. After removing thetape, the sensor body stuffed with beads on the slide glass iscovered with the thus prepared window membrane together with theslide glass and cramped with binder clips. By exposure to UV lightfor 15 min, all wells with beads in the sensor body are sealed withanother window membrane. At this point the sensors are ready fortesting.

G. Optical Response of K.sup.+ Sensor

Reflectance spectra of the optical K.sup.+ sensor in Tris/HClbuffer at pH 7.4 are measured using an a fiber optic spectrometer(e.g. BIF400 UV-VIS, Ocean Optics, CA). As potassium ionconcentration increases over the range of 0 mM to 10 mM K+,reflectance at 505 nm (corresponding to the acidic form ofchromoionophore III) decreases while the reflectance at 580 nm(corresponding to the basic form of chromoionophore III) increases.The white beads can be used as an optical reference for thesemeasurements. Optionally, the ratio of the 505 and 580 nmreflectances can be used in calculating the potassium ionconcentration.

Alternatively, optical characterization of the films can be donevia fluorescence spectroscopy. When the film comes in contact withpotassium ions, the release of protons from the film leads to ameasurable change in it fluorescence properties. Emission peaks areobserved at 647 nm and 683 nm. The former corresponds to theprotonated form of chromoionophore III, while the lattercorresponds to the deprotonated form. When the concentration ofK.sup.+ in the sample increases, the protonated peak at 647 nmdecreases and the deprotonated peak at 683 nm increases. It hasbeen reported that ratiometric analysis can minimize the effects ofphotobleaching and variations in lamp intensity. Therefore theintensity ratio of the two peaks (647 and 683 nm) is used insteadof the absolute fluorescence.

H. Sensor Constructions

Precision coatable sensor constructions based on above describedsensor beads are fabricated. The process includes (1) mixingacrylamide and bis-acrylamide monomers and polyethylene glycololigomers with sensor beads or sensing dyes and a thermal orphoto-chemical curing agent (2) coating the mixture onto a sensorbacking (3) initiating cure to promote formation of a hydrogel andadhesion of the hydrogel to wells on the sensor backing (4)formation and adhesion of a HEMA window membrane to the resultinghydrogel compositions.

A multi-layer laminate sensor can be fabricated. The processincludes (1) cellulose acetate membrane optionally impregnated withthermal or photo-cross linked HEMA polymers as the window membrane(2) a partitioned spacer layer bonded to the dialysis membrane andcomprising void spaces filled with the sensor bead (3) an opticalwindow bonded to the partitioned spacer layer.

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