WO2007076303A1

WO2007076303A1 - Implantable cell/tissue-based biosensing device

Info

Publication number: WO2007076303A1
Application number: PCT/US2006/062144
Authority: WO
Inventors: Zhongping Yang; James D. Reinke
Original assignee: Medtronic, Inc.
Priority date: 2005-12-29
Filing date: 2006-12-15
Publication date: 2007-07-05
Also published as: US20070154893A1; US7519409B2

Abstract

An implantable cell/tissue-based biosensor device detects and/or monitors the amount of one or more specific analytes within a patient. Stimulation circuitry stimulates the cells/tissue of the biosensor device causing the cells/tissue to evoke a response that is altered by the presence of a specific analyte. Sensing circuitry detects the evoked response and the amount of analyte is determined based on the detected response.

Description

IMPLANTABLE CE LJL/TΪSS U E-BASED BIOSENSIINTG DEVICE

Field, .of the invention The present invention relates to sensots for detecting an analyte in a patient. In particular, the present invention relates to implantable cell/dssue-based sensors form vivv detection of an analyte

Background of the Invention Numerous diseases and pathophysiological states arc associated with deviations from normal concentrations of analytes in a patient's blood or tissues Congestive heart failure- (CHF), for instance, causes significant morbidity and mortality, and the healthcare expenditure for this disease is substantial. While in vitro diagnostic assays to measure various analyte levels in. the blood are now in use, these assessments arc point-ϊn-carc assessments that do not provide the clinician a complete piofile of a patient's changing status. The inability to determine when a patient's CHF is worsening (before a patient gains several pounds in weight and/or edema is greatly increased) until the patient has a doctor's appointment or requires hospitalization will result in a delay of treatment Moreover, lequired changes to the patient's therapy will be delayed. implantable biosensors ha\ e recently become an important tool foi analyzing and quantifying anaivte compositions in a patient's blood which could be used for initiating therapy, conducting diagnostics or monitoring Ceils and/or tissues within the patient's body may act as sensors to detect and monitor these anaiyte concentrations. For early detection of disease or change in disease such as CHF, it is desirable for the implantable biosensor to be sensitive to changes in analyte levels, brief Sum mat v of the Invention

The disclosure relates to a celf/tissue-based device and method for detecting and/or monitoring an analyte in a patient. A bioscnsing recognition element, which specifically interacts with the analjte, is implanted within the patient Stimulation circuitry stimulates the biosonsing iccognition element, which evokes a response that is altered when the biosensing recognition element interacts with the analyte. Sensing circuitry detects the response and produces a sensor signal, which is related to an amount or presence of the analyie.

Brief Description of the Drawings Fig, I is a schematic illustration of a first representative embodiment of a biosensor device.

Fig. 2A-2D are schematic, cross-sectional illustrations of representative embodiments of cells that may be used with the biosensor device.

Fig. 3 is a top view of a first representative embodiment of a bioseiising recognition element.

Fig. 4 A is a cross-sectional, side view and Fig. 4B is atop view of a second representative embodiment of a biosensing recognition element.

Fig. 5 is a schematic illustration of a second representative embodiment of a biosensor device, Fig. 6 is a schematic illustration of a representative embodiment of a biosensor device implanted in endocardium.

Fig. 7 is a schematic illustration of a representative embodiment of a biosensor device implanted in epicardium.

Fig. 8 is a schematic illustration of a representative embodiment, of a biosensor device implanted in subcutaneous tissue.

Detailed Description of the invention

The following detailed description is merely exemplary in nature and is not. intended to limit the invention or the application and uses of the invention. Furthermore_., there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description.

For the sake of brevity, conventional techniques related to implantable medical device telemetry,, implantable medical device data processing, data communication protocols, computer network architectures, user interface generation and manipulation, and other functional aspects of the systems (and the individual, operating components of the systems) may not be described in detail herein. Furthermore, the connecting lines shown in the various figures contained herein are intended to represent example functional relationships and/or physical couplings between the various elements. It should be noted that many alternative or additional functional relationships or physical connections may be present m a practical embodiment. Fig. ϊ is representative embodiment of biosensor device 10. Biosensor device 10 includes biosenslng recognition dement 12 with biologic agent 14 and permeable membrane 16; electrodes 18a, ISb and 18c; conductors 20a, 20b and 20c; and housing 22 with stimulation circuitry 24, sensing circuitry 26, power source 28 and telemetry circuitry 30. Biologic agent 14 is encapsulated within permeable membrane 16. Membrane 16 is a barrier to prevent cells of biologic agent 14 from migrating or being dislodged while allowing nutrients, waste products, etc, to diffuse to and from biologic agent 14, It also prevents large molecules and cells from interacting with biologic agent 14 that could result in immunological reactions and rejection of biologic agent 14, Typically, membrane 16 is about 10 mm or less at its largest diameter. However, the size will vary depending on the analyle being monitored nnά the placement of element 12. Suitable materials include, for example, about 50 m. to about 100 ni thick polysulfone, polyvmyicMoπde/poiyacylmtrile or a copolymer of polyvinyl chloride acrylic. The material should have a molecular weight cut-off no larger than about 100,000 Da but preferably about 30,000 Da to about 50,000 Da.

1Ά some embodiments, it may be suitable to include a vascularization-pronioting material on the outer surface of membrane 16. The architecture of this material promotes vascularization around bioseπsing recognition element 12 by allowing cellular penetration through the .material. The increased vascularization creates a healthier environment for maintenance of biologic agent 14.

Electrodes 18a, 18b and 18c, which are collectively an electrical interface, are attached to the outer surface of membrane 16. Conductor 20a connects electrode ISa to stimulation circuitry 24, conductor 20b connects electrode iSb to sensing circuitry 26 and conductor 20c connects electrode 18c to stimulation circuitry 24 and sensing circuitry 26. Stimulation circuitry 24 is connected to sensing circuitry 26 and power source 28. Sensing circuitry 26 is additionally connected to telemetry circuitry 30, which, in turn, is connected to power source 28. Device 10 may be configured with two electrodes. In this embodiment, both electrodes are shared for stimulation circuitry 24 and sensing circuitry 26. Alternatively, device 10 may be configured with four electrodes, where two electrodes are associated with stimulation circuitry 24 and two electrodes are associated with sensing circuitry 26. With the latter embodiment; a better measurement of the action potential may be obtained, because interference caused by polarization of tbe electrodes is reduced.

Power source 28 may be one or more batteries or another implanted medical device coupled via electrical leads, for example. Any power source adapted to provide long-term use may be used in conjunction with device 10. Bousing 22 is hermetically sealed to protect circuitry when implanted. It is initially programmed arid then device Ϊ0 is implanted into & patient. Biosensing recognition element 12 is positioned in an area of the body where interaction is likely with a specific analyte for detection and/or where detection in a specific location, such as in or around the heart, is desired. Implantation of element 12 may be in patient tissue or within the patient's vascular system. Examples of analytes that may be detected by device 50 include electrolytes, hormones, amino acids/poly peptides/proteins, carbohydrates, lipids, neurotransmitters, drugs, etc. Some specific examples Include glucose, lactate, creatinine, troponin T₅ troponin I₉ thrombin, B-type nutrient peptide_* catecholamine, potassium, calcium, etc. Once implanted, telemetry circuitry 30 allows device 22 to be reprogrammed as desired. Telemetry circuitry 30 may be capable of long range communication and can include a patient and /or external alert as described In commonly assigned U.S. Patent No. 6, I 69,925. The alert notifies the patient or a health care facility if anayϊte concentrations fall outside an acceptable range. To detect an analyte of interest, an electrical stimulus is generated by stimulation circuitry 24 and proceeds along conductors 20a and 20c to electrodes 18a and 18c, respectively. The electrical stimulus may be any of a number of types of waveforms such as monophasic- biphasic or multiphasic electrical voltage or current pulse. The electrical stimulus then propagates across biologic agent 14. Interaction between the analyte and biologic agent 14, which is discussed in more detail below, alters depolarization and repolarization initiated by the electrical stimulus thus altering the electrical response of biologic agent 14. The electrical response detected from biologic agent .14, which can be aa electrogram or impedance spectra, is detected by electrodes 1.8b and ISc and transmitted to sensing circuitry 26 via conductors 20b &xiά 20c, respectively.

Typically, sensing circuitry '26 processes the data representing the evoked response. For example, one or more parameters from each action potential would be extracted to determine whether or not the ρararneter(s) fall within an expected range. The data would be fmlher processed with algorithms and a microprocessor to describe the distribution of the parameters) and how the parameter(s) have changed over time.

The gathered and processed information is transmitted to telemetry circuitry 30 where it is stored and then transmitted to an external device and then, for example, to a healthcare facility for review. Periodic transmission would occur, for example, once a week. The Chronicle^{1 M} System and CareLink^1M Network, both from Medtronic, Inc., are systems that may be used to collect and transmit the information from device 10 to a healthcare facility.

Electrically stimulating biologic agent 14 prior to detection provides a more sensitive and accurate measurement of the effect of the analyte on the electrical response.

The electrical stimulus simultaneously delivers a depolarization signal to essentially all cells within biologic agent 14. Under these conditions, the maximum. amount of detected electrical response is larger than without prior stimulation. Thus, the spectrum between maximum, and minimum readings Is wider allowing more specific and accurate correspondence between the detected readings and the concentration of anaiyte.

Biologic agent 14, as described above, forms the basis of biosensor device 10 and is comprised of tissue or cells. Because of its importance, sensing circuitry 26 may also be used to monitor the viability of the tissue or cells to minimize risks that altered evoked responses are due to, for example, dead or dying cells or tissue instead of the presence of an anaiyte. Monitoring may be carried out by varying the timing of the stimulation from stimulation circuitry 24. The time from stimulation to the action potential is then measured and used to determine if biologic agent 14 is viable.

The tissue or cells of biologic agent Ϊ4 may be any of a number of types but are typically excitable such as cardiac myocytes or neurons or are genetically modified to produce a detectable electrical response.

The cells or tissue may be derived from various animal sources but are usually human. Cells or tissue derived from the patient may also be used. The cells or tissue may also be derived from allogeneic- or syngeneic stem, ceils. The stem ceils, which may or may not be genetically modified, are cultured to differentiate into an appropriate tissue or celϊ type.

The cells or tissue may be modified at a molecular, genetic and/or cellular level. Molecuiarly modified cells or tissue are treated either in vivo or in vitro with a component that modifies a function or activity of the tissue or cells. Such components include, for example, cytokines, growth factors and hormones.

Genetically modified ceils or tissue are engineered to include stable or transient sequence that is expressed by the cells or tissue. The expressed product is typically protein. The sequence may express a product normally expressed by the ceils or tissue such that the cells or tissue now overexpress the product, or the sequence may express a product that is foreign to the cells or tissue. Alternatively, the sequence may express a chimeric product that is a combination of the two or it may express a mutant/modified version of a normally expressed product. In addition, the cells or {issue may be genetically modified to alter the level of expression of a specific gene. For example, a gene may be regulated and normally only expressed under specific conditions. Regulatory elements of the gene can be modified such that the gene is constitutively expressed.

Cellularfy modified cells or tissue have altered intracellular and/or extracellular matrices or growth architecture that affect cellular activity or function. For example, cells may be cultured in specific geometric configurations such as in circular patterns.

Figures 2A-2D illustrate representative embodiments of cells useful in device 10. Figure 2A shows excitable cell 34. Cell 34 may, for example, be a myocardial cell or neuronal cell. Cell 34 includes membrane 36, intracellular space 3S₇ extracellular space 40 and ion channel 42 with subunits 44. Typically, ion channel 42 transports ions from extracellular space 40 into intracellular space 38, from intracellular space 38 into extracellular space 40 or both. Transported ions may be, for example, sodium, potassium, or calcium. During the resting phase, cell 34 has an electrical charge across membrane 36, with intracellular space 38 being negative with respect to extracellular space 40, Certain external stimuli, such as the electrical stimulation described above, initiate depolarization where the charge across membrane 36 is reduced. During depolarization, ion channel 42 opens to allow an influx, of ions into intracellular space 38. Depolarization of cell 34 occurs as a wave as each subsequent ion channel 42 is triggered along membrane 36. The cell subsequently repokrizes to its resting potential, and the combination of depolarization and repolarization constitute the action potential. The electrical signals generated by the action potential, as is well-known in the art, can be detected With respect to device 10, cell 34 is useful in detecting the effect of substances such as pharmaceutical agents or toxins. Many substances can effect cellular action potentials, Ia this embodiment of device 10, those effects can be monitored to indicate the effect of the substance, whether or not cells within the patient are responding appropriately or to titrate an appropriate dose of a particular substance to evoke a particular response. Bi addition, the effects of combining medications can be monitored..

In order to increase the sensitivity of the cells or tissue, cells may be genetically modified to overexpress channel proteins such as subunits 44. Figure 2B shows modified cell 46 having membrane 36 and ion channels 42a, 42h and 42c with summits 44a, 44b and 44c, respectively, ϊn this embodiment, because cell 46 has more ion channels than that of cell 44, cell 46 has greater sensitivity and creates a stronger electrical signal than thai of cell 44.

Figure 2C is a representative embodiment of a modified cell 48. Ia this embodiment, ion channels 42a, 42b and 42c are not only overexpressed by cell 48, but are also modified to include amilyte specific receptors 50a, 50b and 50c, The terra receptors also include antibodies, antibody fragments or any type of ligand. Receptors 50a_> 50b and

50c extend into extracellular space 40 for interaction with an anaiyte. For example, device 10 may be used to detect troponin I in vivo when receptors 50a, 50b and 50c specifically bind troponin ϊ. When bound, ion channels 42a, 42b and 42c open allowing ion flow- across membrane 36, which generates a detectable electrical signal. The concentration of troponin I directly relates to the amount of binding to one or more of receptors 50a, 50b and/or 50c and the resulting electrical signal that is evoked. By detecting and analyzing that electrical signal, the concentration of troponin I within the patient can be determined.

In some instances, it may be beneficial to detect two different or two forms of a protein. For instance, device 10 may be used to detect combined concentrations of troponin .1. and troponin T. A. cell type represented by cell 52 in Figure 2D may be used.

In this embodiment, oae of subunit 44a is now linked to receptor 54 (a. troponin T specific receptor), while subunits 44b md 44c are linked to receptors 50b and 50c, respectively. In this way, a single cell type detects combined concentrations of two different, proteins or two forms of the same protein.

Some examples of membrane channel proteins that are useful with the present invention are listed in Table I. Table 1 also indicates each proteins function and the corresponding gene from which it is expressed. Table I

As noted above, electrodes 1 Sa, 1 Sb and 18c may be attached to the outer surface of membrane 16. Fig. 3 is a top view of biosensing recognition element 12 showing electrodes ISa and I Sb. Electrodes ΪSa, ISb and iSc are fabricated from an inert metal and therefore, may also be contained wi thin membrane .16 and in direct contact, with biologic agent 14. ϊn addition, electrodes of the present invention may take on various configurations. Figs. 4A and 4B are side and top views illustrating a representative embodiment of biosensing recognition element 56. In this embodiment, electrode 18c is identical to the previous embodiment. Electrode 58a. however, is C-shaped, and electrode 58b is centered within electrode 58a. The configurations shown, here are only exemplary. Any of a number of configurations may be used in conjunction with device 10.

In another variation of the present, invention, an array of biosensing recognition, elements 12 may be used for detecting multiple analytes. Fig. 5 is a representative embodiment of biosensing array device 60. Device 60 includes housing 22 with leads 62, which connect to array 64, Array 64 includes lead switch 66 connected to biosensing recognition elements I2a-12f via leads 68a~6Sf, respectively.

Biosensing recognition elements 12a-i2f are each configured essentially identical to biosensing recognition element 12 shown in Fig. 1, except that each of elements S.2a- !2f contain a biologic agent 14 that is specific for a different analyte. Lead switch 66 allows stimulation of and detection via individual biosensing elements at specific times. Alternatively, switching between individual biosensing elements can be performed by switching circuitry within housing 22.

For example, element 12a detects anaiyte A₅ element 12b detects analyte B, etc. Device 10 can be programmed so that element 12a is stimulated aad Its response Is sensed first. Then, element 12b is stimulated and its response is sensed second. This process continues through .0 element 12f. Device 10 can be programmed for any pattern of switching between, biosensing recognition elements 12a.~12.f. In addition, array 64 can. accommodate additional or fewer biosensi&g recognition elements as desired. ia an alternate embodiment, a single membrane 16 may encompass array 64 instead of individual membranes 16 encompassing each of elements J 2a- i 2f Λ single rπembϊane to aiouπd auay 64 could be eavier to assemble but there would be incieas>ed risk of migration of the various biologic agents. As noted previously, biosensmg recognition element 12 can be implanted into any of a number of locations within a patient Fig 6 is a representative embodiment showing element 12 implanted into the endocardium of heart H. Leads 70 extend out of heart H to connect to circuitry within housing 22. in Fig. 7, biosensing recognition element 12 is implanted into the epicardium of heart H. Again, electrodes 70 connect clement 12 with circuitry within housing 22. ϊn another representative embodiment shown in Fig. S, biosensmg recognition clement 12 is implanted subcutaneous!}- into the torso of patient P. These embodiments are exemplary. Depending on the- analyte(s) being detected, element 12 could be positioned almost anywhere within patient P. In addition, housing 22 shown in any of the embodiments can contain components and circuitry for delivering therapy to patient P>

Device 10 or device 60 τiιa> be stand-alone pioducts or be integrated as part of a therapy delivery device. Such therapy delivery devices include implantable pacemakers, defibrillators, cardiac ^synchronization therapy systems, drug pumps or any other means known in the ail The integrated devices may be programmed such that patient treatment is automatically altered or initiated based on the detected anai>tes. Alternatively, treatment provided by the integiated devices may be altered or started by a clinician after analysis of data gathered from the integrated device.

The stimulation of cells in a cell/tissue-based sensor and detection of the evoked response provides more accurate and sensitive in vivo detection of an analyte. This not only results in earlier and/or better treatment for the patient but also potentially decreases healthcare costs. Without anaiyte detection, signs of disease or worsening conditions may only be seen after the disease or condition, has significantly progressed to later stages making treatment longer and more difficult.

Although the present invention has been described with reference to preferred embodiments, workeis skilled in the art will recognize that changes may be made in form and detail without departing from ihe spirit and scope of the invention

Claims

CLAMS

1. A biosensor device for sensing an analyte in a patient, the biosensor device comprising: a bioseosing recognition element capable of interacting with the analyte and carrying out a response that is alterable upon interaction with the analyte; an electrical interface contacting the biosemmg recognition clement; stimulation circuitry, associated with the electrical interface, for stimulating the biosensing recognition element; and sensing circuitry, associated with the electrical interface, for sensing the response of the btoscnsi ng rccogniti on clement

2. The biosensor device of claim 1 wherein the biosensing recognition element comprises: a biologic agent; and a permeable membrane encapsulating the biologic agent.

3 The biosensor device of claim 2 wherein the biologic agent h moleeulariy, genetically or cellularly modified.

4. The biosensor device of claim 1 therein, the response sensed by tfie sensing circuitry is cellular action potential, impedance or both.

5. The biosensor device of claim 1 operably connected to a therapy delivery device.

6. The biosensor device of claim 5 wherein the therapy delivery device is one of a pacemaker, defibrillator, cardiac resynchronbation Therapy systerø and drug pump.

7. The biosensor device of claim 1 wherein stimulation circuitry provides one of monophasic voltage, triphasic voltage, multiphasic voltage and current pulses.

8. The biosensor device of claim 1 and further comprising: telemetry circuitry in communication with the sensing circuitry.

9. The biosensor device of claim I wherein the hiosensing recognition element further comprises a biologic agent, and the sensing circuitry inonitors viability of the biologic agent.

10. An implantable biosensor device for sensing a plurality of analytes, the implantable biosensor device comprising: a plurality of biosensing recognition elements, each biosensing recognition element capable of interacting with at least one of the plurality of analytes and carrying out a response that is alterable upon interaction with at least one of the plurality of analytes; a plurality of electrical Interfaces contacting the plurality of biosensing recognition elements; stimulation circuitry, associated with the plurality of electrical interfaces, for stimulating the plurality of biosensing recognition elements; and sensing circuitry, associated with the plurality of electrical interfaces, for sensing the response of the plurality of biosensing recognition elements.

11. The implantable biosensor device of claim 10 wherein each biosensing recognition element includes a biologic agent that is specific for at. least, one of the plurality of anaiytes.

12. The implantable biosensor device of claim 11 wherein the biologic agent is derived from stem ceils.

13. The implantable biosensor device of claim 1 1 wherein the biologic agent is røolecularly, genetically or cell daily modified.

14, The implantable biosensor device of claim 1 1 wherein the biologic agent is encapsulated in a permeable .membrane.

i S. The implantable biosensor device of claim 10 and further comprising: a lead switch, operably connected to the plurality of electrical interfaces.

16. A. method of sensing an analyte in a patient, the method comprising: implanting a biosensing recognition element In the patient, the bioseπsing recognition element being capable of interacting with the anaiyte and carrying out a response that is alterable upon interaction with the analyte; electrically stimulating the biosensing recognition element; detecting the response of the bioseusing recognition element; and reiati Jig the detected response Λvith an amount or presence of the analyte.

17. The method of claim 16 wherein the response includes a cellular action potential or impedance,

S S, The method of claim 16 and further comprising: altering or initiating treatment of the patient based on the detected amount or presence of the anslyte.

i 9. The method of claim 15 an<l further comprising:

.monitoring viability of the bioseiising recognition element.

20. The method of claim .16 wherein the response is implemented as a diagnostic,, monitoring or both tools.