Fabrication of implantable fully integrated electrochemical sensors

• US 9,173,605 B2
• Filed: 07/24/2014
• Issued: 11/03/2015
• Est. Priority Date: 12/13/2012
• Status: Active Grant

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Mujeeb-U-Rahman, Muhammad, Scherer, Axel, Honarvar Nazari, Meisam, Sencan, Mehmet
• Primary Examiner(s): FOURSON III, GEORGE R
• Application Number:
  US14/340,498
• Publication Number:
  US 20140336485A1
• Time in Patent Office: 467 Days
• Field of Search: 438/49, 257/414
• US Class Current: 1/1
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1473 invasive, e.g. introduced into the body by a catheter A61B5/1482 takes precedence
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: G01N 27/48 using polarography, i.e. measuring changes in current under a slowly-varying voltage
• CPC Class Codes: H01L 21/77 Manufacture or treatment of devices consisting of a plurality of solid state components or integrated circuits formed in, or on, a common substrate electrically programmable read-only memories or multistep manufacturing processes therefor H10B69/00
• CPC Class Codes: H01L 25/16 the devices being of types provided for in two or more different main groups of groups H01L27/00 - H01L33/00, or in a single subclass of H10K, H10N, e.g. forming hybrid circuits
• CPC Class Codes: H01L 27/04 the substrate being a semiconductor body
• CPC Class Codes: H01L 28/10 Inductors
• CPC Class Codes: H01L 29/0676 oriented perpendicular or at an angle to a substrate
• CPC Class Codes: H01L 29/413 Nanosized electrodes, e.g. nanowire electrodes comprising one or a plurality of nanowires nanosized carbon materials, e.g. carbon nanotubes, per se C01B32/15; transparent electrodes comprising carbon nano-tubes H10K30/821, nanotechnology per se B82B
• CPC Class Codes: H01L 2924/00 Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
• CPC Class Codes: H01L 2924/0002 Not covered by any one of groups H01L24/00, H01L24/00 and H01L2224/00
• CPC Class Codes: Y10T 29/49018 with other electrical component

Abstract

A fully integrated small size implantable sensing device is described, which can include a sensor and an electronic circuit to interface with the sensor and communicate with an external device. Various fabrication methods for the sensing device are described, including provision of wells, created using same fabrication technology as the electronic circuit, to contain electrodes of the sensor and corresponding functionalization chemicals. Such implantable sensing device can be used for a variety of electrochemical measuring applications within a living body as well as actuation by injecting a current into the living body.

Claims

1. A method for fabricating a miniaturized implantable device:

fabricating an electronic system by monolithically integrating the electronic system on a first face of a substrate, the electronic system being configured, during operation of the implantable device, to communicate with an external device over a wireless communication link and to extract power for the implantable device from the wireless communication link;

fabricating a coil by monolithically integrating the coil on the first face of the substrate, the coil being configured to provide the wireless communication link;

fabricating a plurality of electrodes of an electrochemical sensor on a first metal layer separate from metal layers used to fabricate the electronic system by monolithically integrating the plurality of electrodes on the first face of the substrate, the plurality of electrodes being configured to provide electrical interface between the electrochemical sensor of the implantable device and the electronic system; and

creating a plurality of wells in correspondence of the plurality of electrodes.

2. The method of claim 1, wherein one or more of the plurality of electrodes are distributed electrodes and/or are patterned electrodes.

3. The method of claim 1, wherein the first metal layer is a top metal layer of the substrate, and wherein the creating the plurality of wells comprises etching all or some of the top metal layer in correspondence of the plurality of wells.

4. The method of claim 1, wherein the first metal layer is a lower metal layer of the substrate, and wherein the creating the plurality of wells comprises etching of top insulating layers and etching all or some of the lower metal layer in correspondence of the plurality of wells.

5. The method of claim 1, wherein the fabricating of the plurality of electrodes further comprises depositing a metal in correspondence of an electrode of the plurality of electrodes different from a metal of the first metal layer.

6. The method of claim 5, wherein the deposited metal is a metal based on a noble metal and/or a noble metal oxide.

7. The method of claim 5, wherein the deposited metal is one of:

a) platinum, and b) platinum oxide.

8. The method of claim 6, wherein the depositing of the metal comprises using a cleanroom procedure comprising deposition under oxygen plasma.

9. The method of claim 6, wherein the depositing of the metal comprises using a cleanroom procedure comprising electrochemical oxidation in a mixture of strong oxidizers.

10. The method of claim 9, wherein the mixture of strong oxidizers comprises one or more of:

a) sulfuric acid, and b) hydrogen peroxide, and wherein the electrochemical oxidation comprises repeatedly subjecting a first electrode of the plurality of electrodes to a high oxidative potential followed by a low reductive potential with respect to a potential of a second electrode of the plurality of electrodes.

11. The method of claim 7, wherein the electrode of the plurality of electrodes is one or more of:

a) a working electrode of the plurality of electrodes, and b) a reference electrode of the plurality of electrodes.

12. The method of claim 11, wherein a metal deposited in correspondence of a counter electrode of the plurality of electrodes is different from a metal deposited in correspondence of the working electrode and the reference electrode.

13. The method of claim 5, further comprising depositing a functionalization layer comprising functionalization chemistry before dicing the substrate using one or a combination of:

a) a fluid dispensing robot, b) spin coating, c) spray coating, d) stencil coating, and e) whole substrate coating followed by stencil protected removal.

14. The method of claim 13, wherein the functionalization chemistry comprises an oxidoreductase.

15. The method of claim 14, wherein the oxidoreductase comprises one of:

a) lactate oxidase, b) glucose oxidase, c) glucose dehydrogenase, d) a mixture comprising any one of a)-c) with horseradish peroxidase, e) uricase, f) urease, g) ascorbate oxidase, h) sarcosine oxidase, i) alcohol oxidase, j) malate dehydrogenase, k) glucoamylase, I) glutamate oxidase, and m) cholesterol dehydrogenase.

16. The method of claim 1, wherein the fabricating of the electronic system comprises creating vias to connect the electronic system to the plurality of electrodes, wherein the vias are created using a metal material different from a metal material used in fabricating of the electronic system.

17. The method of claim 1, wherein the fabricating of the coil comprises fabricating a plurality of concentric patterns on the first metal layer.

18. The method of claim 1, wherein the fabricating comprises a CMOS fabrication technology.

19. The method of claim 1, wherein a larger side of the miniaturized implantable device is not larger than 1.4 mm, a larger side of the electrochemical sensor is not larger than 500 μ

m and a thickness of the miniaturized implantable device is not more than 250 μ

m.

20. The method of claim 19, wherein during operation, the miniaturized implantable device is adapted to consume not more than 6 μ

W of power.

21. The method of claim 20, wherein the wireless communication link is an inductive coupling link.

22. The method of claim 21, wherein a data modulation method used in the wireless communication link is a load-shift keying method (LSK).

23. The method of claim 21, wherein the wireless communication link operates at a frequency band of the industrial, scientific and medical (ISM) radio band.

24. The method of claim 20, wherein the electronic system comprises:

a potentiostat configured, during operation of the miniaturized implantable device, to interface with the plurality of electrodes;

a trans-impedance amplifier (TIA) connected to a working electrode (WE) of the plurality of electrodes, wherein the TIA allows a bidirectional current measurement;

a dual-slope analog-to-digital converter (ADC) comprising a programmable integration time, operatively coupled to the trans-impedance amplifier and configured to measure a current from the working electrode over a range of 80 dB.

25. A method for implanting an electrochemical sensor in a mammal, the method comprising:

providing a miniaturized implantable device fabricated using the method of claim 1;

injecting the miniaturized implantable device in the mammal; and

based on the injecting, completely embedding the miniaturized implantable device within tissue of the mammal.

26. The method of claim 25, wherein the injecting is performed using an appropriate gauge needle or an appropriate gauge trocar.

27. The method of claim 25 further comprising:

providing the external device comprising a plurality of coils configured to provide power to the implantable device;

positioning the external device at a distance of the implantable device outside the tissue of the mammal;

based on the positioning, powering the implantable device via a coil of the plurality of coils;

based on the powering, measuring an amplitude of a signal received from the implantable device;

repeating the powering and the measuring for each coil of the plurality of coils;

based on the repeating, determining a max amplitude signal received from the implantable device;

based on the determining, effectively powering the implantable device using a coil of the plurality of coils in correspondence of the max amplitude; and

based on the effectively powering, operating the implantable device.

28. The method of claim 25 further comprising:

powering the implantable device via an external coil inductively coupled to the implantable device;

based on the powering, charging a bank of capacitors of the electronic system; and

based on the charging, injecting, via one or more electrodes of the plurality of electrodes, a current to the tissue.

29. A monolithically integrated miniaturized implantable device comprising:

a substrate for monolithic integration of the miniaturized implantable device comprising a plurality of metal layers separated via a plurality of insulating layers;

a monolithically integrated electrochemical sensor comprising a plurality of electrodes;

a monolithically integrated electronic system;

a plurality of wells in correspondence of the plurality of electrodes, wherein a depth of a well of the plurality of wells extends across one or more metal layers of the plurality of metal layers and/or one or more insulating layers of the plurality of insulating layers; and

a monolithically integrated coil,

wherein during operation of the implantable device, the electronic system is configured to;

interface with the electrochemical sensor and sense a current in correspondence of a reaction,

communicate with an external device over a wireless communication link provided by the coil, and,

extract power for the miniaturized implantable device from the wireless communication link.

30. The miniaturized implantable device of claim 29, wherein the depth is in a range of 4 μ

m to 6 μ

m.

31. The miniaturized implantable device of claim 29, wherein the well comprises an electrode metal different from a metal of the one or more metal layers.

32. The miniaturized implantable device of claim 31, wherein the electrode metal is a noble metal and comprises a top oxidized layer of the noble metal.

33. The miniaturized implantable device of claim 32, wherein the well further comprises a functionalization chemistry of the electrochemical sensor.

34. The miniaturized implantable device of claim 29, wherein a larger side of the miniaturized implantable device is not larger than 1.4 mm, and a thickness of the miniaturized implantable device is not more than 250 μ

m.

35. The miniaturized implantable device of claim 29, wherein the coil and the plurality of electrodes are on a top metal layer of the plurality of metal layers.

36. The miniaturized implantable device of claim 35, wherein the coil comprises a plurality of concentric metal patterns and wherein the coil surrounds the electrochemical sensor.

37. The miniaturized implantable device of claim 29, wherein the electronic system comprises a dual-slope analog-to-digital converter (ADC) operatively coupled to the electrochemical sensor and configured to measure a current from the electrochemical sensor over a range of 80 dB.

38. The miniaturized implantable device of claim 37, wherein the dual-slope ADC comprises a programmable integration time.

39. The miniaturized implantable device of claim 29, wherein the electronic system comprises and actuator circuitry comprising a bank of capacitors, configured, during operation of the miniaturized implantable device, to provide a current based on an energy stored in the bank of capacitors to one or more electrodes of the plurality of electrodes.

40. The miniaturized implantable device of claim 39, wherein the actuator circuity further comprises a waveform shaping circuit configured, during operation of the miniaturized implantable device, to control a waveform signal in correspondence of the current.