Implantable Biosensor and Methods of Use Thereof

• US 20080154101A1
• Filed: 09/27/2007
• Published: 06/26/2008
• Est. Priority Date: 09/27/2006
• Status: Active Grant

• Current Assignee: University of Connecticut (State of Connecticut)
• Original Assignee: University of Connecticut (State of Connecticut)
• Inventors: Jain, Faquir, Grantham, Daniel H., Grantham, Deborah G., Burgess, Diane, Papadimitrakopoulos, Fotios
• Granted Patent: US 8,914,090 B2
• Time in Patent Office: Days
• US Class Current: 600/309
• CPC Class Codes: A61B 1/04 combined with photographic or television appliances
• CPC Class Codes: A61B 17/3403 Needle locating or guiding means guides for suture needles A61B17/0482; guiding or tracking by nuclear magnetic resonance G01R33/285
• CPC Class Codes: A61B 17/3468 for implanting or removing devices, e.g. prostheses, implants, seeds, wires devices for implanting seeds A61M37/0069
• CPC Class Codes: A61B 2017/00367 Details of actuation of instruments, e.g. relations between pushing buttons, or the like, and activation of the tool, working tip, or the like
• CPC Class Codes: A61B 2034/2057 Details of tracking cameras
• CPC Class Codes: A61B 2560/0214 of power generation or supply
• CPC Class Codes: A61B 2560/0219 of externally powered implanted units
• CPC Class Codes: A61B 2560/0475 Special features of memory means, e.g. removable memory cards
• CPC Class Codes: A61B 34/20 Surgical navigation systems; Devices for tracking or guiding surgical instruments, e.g. for frameless stereotaxis
• CPC Class Codes: A61B 5/0017 transmitting optical signals transmission by light H04B10/00
• CPC Class Codes: A61B 5/0031 Implanted circuitry
• CPC Class Codes: A61B 5/076 Permanent implantations telemetry using implanted circuitry A61B5/0031; implanted stimulators for therapy A61N1/3605, A61N1/362, A61N1/372
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14539 for measuring pH
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: A61B 5/7264 Classification of physiological signals or data, e.g. using neural networks, statistical classifiers, expert systems or fuzzy systems neural networks per se G06N3/00; expert systems per se G06N5/00
• CPC Class Codes: A61B 5/742 using visual displays A61B5/339 takes precedence

Abstract

Disclosed herein is an analyte sensing device capable of continuously monitoring metabolic levels of a plurality of analytes. The device comprises an external unit, which, for example, could be worn around the wrist like a wristwatch or could be incorporated into a cell phone or PDA device, and an implantable sensor platform that is suitable, for example, for implantation under the skin. The external device and the internal device are in wireless communication. In one embodiment, the external device and the internal device are operationally linked by a feedback system. In one embodiment, the internal device is encapsulated in a biocompatible coating capable of controlling the local tissue environment in order to prevent/minimize inflammation and fibrosis, promote neo-angiogenesis and wound healing and this facilitate device functionality.

Claims

1. An analyte sensing device comprising:

an external control unit and an implantable sensor platform in wireless optical operable communication, wherein the sensor platform can pass though a 14 gauge or smaller bore needle,

wherein the implantable sensor platform comprises, in operable communication,

a photovoltaic device to receive optical power from the external control unit to serve as a power source for powering said implantable sensor platform,

an optical receiver for detecting signals produced by the external control unit,

a plurality of sensor elements operable for sensing of one or more analytes

an interfacing circuit in operable communication with the sensor elements providing operating conditions to the sensor elements and controlled feedback for their operation, wherein the sensor element generates a sensor output signal proportional to the amount of analyte present,

a signal processing circuit interfaced with the sensor output signal, wherein the signal processing circuit converts the sensor output current signal to digital pulses, converter in operable communication with the signal processing circuit, wherein the electrical to optical converter converts the digital pulses to optical pulses and transmits the optical pulse to the external control unit,

a switching, multiplexing, demultiplexing logic circuits providing at least one function selected from initialization, power level check, circuit check, sensor selection, and sensor calibration,

one or more optical components for facilitating wavelength selection, transmission and/or reflection, for the purpose of demultiplexing optical sources or signals of different wavelengths, and

a biocompatible coating surrounding at least a portion of the sensor platform,

wherein the external control unit comprises, in operable communication,

an optical source suitable for powering the photovoltaic device of the implantable sensor platform,

an optical receiver suitable for receiving one or more optical pulses from the implantable sensor platform and converting the optical pulses to electrical pulses,

an optical transmitter suitable to transmit one or more optical pulses to the optical receivers of the implantable sensor platform, wherein the optical pulse relays instructions to the switching, multiplexing, demultiplexing and logic circuits of the implantable sensor platform to provide at least one function selected from initialization, power check, potentiostat circuit reconfiguration, sensor selection for analyte level measurement, and sensor calibration,

an integrated circuit for processing and displaying the electrical pulses, wherein the integrated circuits are in operable communication with the opto-electronic receivers,

a microcontroller comprising a program code, programmable memory, and means to display output and communicate with other devices, means of interfacing with the optical source, optical receivers and optical transmitters, to establish and operable communication with the implantable sensor platform,

a power supply to power the external unit,

one or more optical components providing wavelength selection, transmission or reflection functions, and

a miniaturized camera to align the implantable sensor platform with the optical components of the external control unit.

2. The analyte sensing device of claim 1, wherein the implantable sensor platform comprises three sub-chips in operable communication, wherein

sub-chip#1 comprises

the photovoltaic device,

an optical transmitter for transmitting information in the form of optical pulses to the external unit, and

the optical receiver;

sub-chip#2 comprises

the interfacing circuits including initialization, sensor select, and sensor calibration,

the potentiostat and signal processing circuits,

the electrical to optical transmitters; and

sub-chip#3 comprises the sensor elements.

3. The analyte sensing device of claim 2, wherein the three sub-chips are integrated with interconnects.

4. The analyte sensing device of claim 1, wherein the interfacing circuit comprises a voltage control logic unit, the signal processing circuit comprises a potentiostat, and the electrical to optical converter comprises an analog to digital converter.

5. The analyte sensing device claim 1, wherein the internal unit comprises a plurality of sensor elements that monitor a plurality of analytes.

6. The analyte sensing device of claim 5, further comprising sensor-select and potentiostat circuits that sequentially address the plurality of sensor elements.

7. The analyte sensing device of claim 1, wherein the sensor element comprises a body temperature sensor, a blood pressure sensor, a pH sensor, an oxygen sensor, a glucose sensor, a lactate sensor, or a combination of two or more of the foregoing sensors.

8. The analyte sensing device of claim 1, further comprising a feedback system between the internal unit and the external unit.

9. The analyte sensing device of claim 1, wherein the biocompatible coating is a hydrogel.

10. The analyte sensing device of claim 1, wherein the biocompatible coating comprises an agent suppress and control inflammation, and agent to suppress and control fibrosis, an antibiotic, an agent to prevent and control infection, an agent to promote angiogenesis, an agent to maturate blood vessels encapsulated, or a combination of two or more of the foregoing agents.

11. The analyte sensing device of claim 10, wherein the agent to suppress and control inflammation or fibrosis comprises dexamethasone, ibuprofen, triamcinalone, mitomycin C, anti-fibroblast antibody (anti-CD44), anti-transforming growth factor-β

(anti-TGF-β

) receptor antibody, or transforming growth factor-a (TGF-a).

12. The analyte sensing device of claim 11, wherein the agent is provided by a gene therapeutic.

13. The analyte sensing device of claim 10, wherein the agent to promote angiogenesis and blood vessel maturation agents comprise vascular endothelial growth factor (VEGF), transforming growth factor-a (TGF-a), anti-thrombospondin-2, or platelet derived growth factor PDGF.

14. The analyte sensing device of claim 10, wherein the antibiotic comprises Amikacin, Gentamycin, Kanamycin, Neomycin, Netilmicin, Paromomycin, Streptomycin, Tobramycin, Ertapenem, Imipenem, Meropenem, Chloramphenicol, Ciprofloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Trovafloxacin, Vancomycin;

Clindamycin;

Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Telithromycin, Cefadroxil, Cefazolin, Cephalexin, Cephalothin, Cephapirin, Cephradine, Cefaclor, Cefamandole, Cefonicid, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef, Cefdinir, Cefditoren, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Aztreonam, Metronidazole, Linezolid, Amoxicillin, Amoxicillin/Clavulanate, Ampicillin, Ampicillin/Sulbactam, Bacampicillin, Carbenicillin, Cloxacillin, Dicloxacillin, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Piperacillin/Tazobactam, Ticarcillin, Ticarcillin/Clavulanate, Quinupristin, Dalfopristin, Sulfamethoxazole/Trimethoprim, Demeclocycline, Doxycycline, Minocycline, Tetracycline, or a combination of one or more of the foregoing antibiotics.

15. The analyte sensing device of claim 1, wherein the biocompatible coating comprises a drug delivery device selected from microspheres, nanoparticles, liposomes, lipid complexes, micelles, or a combination of two or more of the foregoing drug delivery devices.

16. The analyte sensing device of claim 15, wherein the microspheres comprise a polymer selected from polylactide (PLA), polyglycolide (PGA), lactide-glycolide copolymers (PLGA), polycaprolactone, lactide-caprolactone copolymers, polyhydroxybutyrate, polyalkylcyanoacrylates, polyanhydrides, polyorthoesters, albumin, collagen, gelatin, dextrans, starches, acrylate polymers, methyl methacrylate, methacrylic acid, hydroxyalkyl acrylates, methacrylates, methylene glycol dimethacrylate, acrylamide, bisacrylamide, cellulose-based polymers, ethylene glycol polymers, ethylene glycol copolymers, oxyethylene, oxypropylene polymers, poly(vinyl alcohol), polyvinylacetate, polyvinylpyrrolidone, polyvinylpyridine or a combination of two or more of the foregoing polymers.

17. The analyte sensing device of claim 15, wherein the nanoparticles are copolymers of PLGA and PEG.

18. The analyte sensing device of claim 15, wherein the lipid comprises 1,2-Dilauroyl-sn-Glycero-3-Phosphocholine (DLPC);

1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC);

1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC);

1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC);

1,2-Dioleoyl-sn-Glycero-3-Phosphocholine (DOPC);

1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine (DMPE);

1,2-Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine (DPPE);

1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine (DOPE);

1,2-Dimyristoyl-sn-Glycero-3-Phosphate (Monosodium Salt) (DMPA);

1,2-Dipalmitoyl-sn-Glycero-3-Phosphate (Monosodium Salt) (DPPA);

1,2-Dioleoyl-sn-Glycero-3-Phosphate (Monosodium Salt) (DOPA);

1,2-Dimyristoyl-sn-Glycero-3-[Phospho-rac-(1-glycerol)] (Sodium Salt) (DMPG);

1,2-Dipalmitoyl-sn-Glycero-3-[Phospho-rac-(1-glycerol)] (Sodium Salt) (DPPG);

1,2-Dioleoyl-sn-Glycero-3-[Phospho-rac-(1-glycerol)] (Sodium Salt) (DOPG);

1,2-Dimyristoyl-sn-Glycero-3-[Phospho-L-Serine] (Sodium Salt) (DMPS);

1,2-Dipalmitoyl-sn-Glycero-3-[Phospho-L-Serine] (Sodium Salt) (DPPS);

1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine] (Sodium Salt) (DOPS);

1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N-(glutaryl) (Sodium Salt);

1,1′

,2,2′

-Tetramyristoyl Cardiolipin (Ammonium Salt);

1,2-Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000] (Ammonium Salt);

1,2-Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000] (Ammonium Salt);

1,2-Dioleoyl-3-Trimethylammonium-Propane (Chloride Salt) (DOTAP), cholesterol, or a combination of two or more of the foregoing lipids.

19. The analyte sensing device of claim 9, wherein the hydrogel comprises anionic polymers;

cationic polymers;

amphipathic polymers;

neutral polymers, synthetic polymers, or a combination of two or more of the foregoing polymers).

20. The analyte sensing device of claim 1, comprising a Pt working electrode comprising a Au/Ti/Pt layer or a Au/Ti/Pt/Ti/Ag layer.

21. The analyte sensing device of claim 2, wherein each of the sub-chips comprises a silicon circuit, a silicon-oxide coated light emitting and a silicon-oxide coated photodetecting device.

22. The analyte sensing device of claim 2, wherein the transmitters, receivers and photovoltaic cells operating at different wavelengths to avoid interference and optimize their respective performance.

23. The analyte sensing device of claim 1, wherein the implantable sensor platform comprises a converter in operable communication with the signal processing unit, where in an ultrasound transmitter converts digital electrical pulses into ultrasound pulse and transmit it to the external control unit.

24. The analyte sensing device of claim 1, wherein the device is designed to operate in manner which accepts various coding schemes for sensor selection, calibration, initialization, and power level check.

25. A method of using the analyte sensing device of claim 1, comprising subcutaneously implanting the implantable sensor platform.

26. The method of claim 25, wherein the implantable sensor unit is implanted using a 14 gauge or smaller needle.

27. The analyte sensing device of claim 1, wherein the external unit is capable of continuous monitoring of the level of an analyte within a host, and

wherein the device comprises a feedback system between the implantable sensor platform and the external unit.

28. The analyte sensing device of claim 27, wherein the feedback system has a function selected from verifying power levels in the implantable device, adjusting sensor calibration, selecting a sensor for data retrieval, or a combination comprising one or more of the foregoing functions.

29. A method of monitoring an analyte level in a host, comprising providing the analyte sensing device of claim 1;

determining the metabolic level of the analyte in a host;

transmitting a signal proportional to a metabolic level of the analyte to the external unit; and

displaying information regarding the metabolic level of the analyte on the external unit.

30. The analyte sensing device of claim 1, wherein a sensor current signal is converted by the signal processing unit into a voltage signal,

this voltage signal is converted by a voltage control oscillator (VCO) and logic circuits into an RF signal whose frequency is proportional to the analyte level, and which is wirelessly transmitted using an antenna on a subchip, wherein

the signal transmitted by the antenna is received by an electronic receiver located in the external unit.

31. The analyte sensing device of claim 1, wherein the implantable sensor platform comprises two sub-chips in operable communication, wherein

sub-chip#1 comprises

the photovoltaic device, a first photodetector for power monitoring, and a second photodetector for a function selected from initialization, sensor selection, control feedback, calibration of sensors, and potentiostat voltage check;

and

sub-chip#2 comprises

the interfacing circuit, and the sensing elements,

the signal processing circuits,

the electrical to optical converter,

a calibration and initializing circuit; and

one or more sensor elements,

wherein sub-chip#1 is hermetically sealed; and

wherein a portion of sub-chip#2 is hermetically sealed in a manner such that the sensor electrodes are exposed to body fluids.

32. The analyte sensing device of claim 1, wherein a sensor current signal is converted into an electronic voltage signal which drives an ultrasound transducer, and the ultrasound produced by the ultrasound transducer is received by a receiver located in the external unit.

33. An analyte sensing device comprising:

an external control unit and an implantable sensor platform in wireless optical operable communication, wherein the sensor platform can pass though a 14 gauge or smaller bore needle,

wherein the implantable sensor platform comprises sub-chip#1, sub-chip#2 and sub-chip#3 and a biocompatible coating surrounding at least a portion of the sensor platform,

wherein sub-chip#1 comprises

a photovoltaic device that powers the devices and the circuits sub-chip#1, sub-chip#2 and sub-chip#3,

a first optical receiver to receive instructions from a mode select unit via an external unit optical transmitter, wherein the external unit optical transmitter operates in the 800-1000 nm spectral range and is located in the external unit, and

a second optical receiver for providing information regarding received from light-emitting diodes operating at 719 nm and located in the external unit;

wherein the first and second optical receivers operate at wavelengths such that the first and second optical receivers do not interfere with each others operation,

a sensor platform optical transmitter operating at 1.55 micron, relaying information selected from relaying sensor output, calibration, potentiostat check, or solar power level check received from the driver located on subchip#2,

one or more optical components, and

one or more coatings providing wavelength selection, transmission or reflection functions,

wherein sub-chip#2 comprises

a plurality of interfacing circuits selected from initialization circuits, sensor select circuits, and sensor calibration circuits,

a potentiostat,

a signal processing circuit,

a logic circuits, a demultiplexer, a multiplexer, and a driver to enable transmission of feedback signals selected from a level of radiation intensity received by a plurality of photovoltaic cells, a reference voltage of the potentiostat, or a sensor reading, and

wherein the driver on subchip#2 feeds a plurality of pulses to the sensor platform optical transmitter located on subchip#1, and wherein the sensor platform optical transmitter does not interfere with 719 nm and 800-1000 nm signals,

wherein sub-chip#3 comprises a plurality of sensor elements,

wherein the sensor elements comprise a plurality of sensor elements electrode in contact with the potentiostat located on subchip #2,

wherein sub-chip#1, sub-chip#2 and sub-chip#3 are electrically interconnected and integrated in a manner to operate in the presence of body fluids with substantially no leaks;

wherein the external control unit comprises, in operable communication,

an optical source comprising light-emitting diodes and laser diodes operating at about 719 nm, wherein the optical source powers the photovoltaic device on sub-chip#1,

a third optical receiver for receiving one or more optical pulses at a wavelength of 1.55 micron from the optical transmitter on subchip #1 of implantable sensor platform,

wherein the external unit optical transmitter transmits one or more optical pulses in the 800-1000 nm spectral range to the first optical receiver, wherein the optical pulse relays instructions to sub-chip#2 for the switching, multiplexing, demultiplexing and logic circuits of sub-chip#2 to provide at least one function selected from initialization, power check, potentiostat circuit reconfiguration, sensor selection for analyte level measurement, and sensor calibration,

an integrated circuit for processing and displaying an electrical pulse, wherein the integrated circuit is in operable communication with an opto-electronic receiver,

a microcontroller comprising a program code;

programmable memory;

a means to display the output and communicate with other devices;

a means of interfacing with the optical source operating at 719 nm, the optical receiver operating at 1.55 micron and the optical transmitter at 800-1000 nm,

a power supply to power the external unit,

one or more optical components providing wavelength selection, transmission, or reflection functions, and

a miniaturized camera to align the implantable sensor platform with the optical components of the external control unit.

34. The analyte sensing device of claim 33, wherein the optical component located in the external unit operates at spectral wavelength other than 719 nm and 800-1000 nm,

the optical transmitter operates at a wavelength other than 1.55 micron, and

the operating wavelengths of the optical component and the optical transmitter are selected so that there is substantially no interference in a processed signals, and

a receiver meets the wavelength of the optical component or the optical transmitter.

35. The analyte sensing device of claim 33 wherein the optical transmitter operating at 1.55 micron located on subchip#2 is located substantially near the driver circuit providing information selected from initialization, power check, potentiostat circuit reconfiguration, sensor selection for analyte level measurement, and sensor calibration.

36. The analyte sensing device of claim 33, wherein the sensor element comprises a body temperature sensor, a blood pressure sensor, a pH sensor, an oxygen sensor, a glucose sensor, a lactate sensor, or a combination of two or more of the foregoing sensors.