Canary on a chip: embedded sensors with bio-chemical interfaces

• US 10,820,844 B2
• Filed: 07/21/2016
• Issued: 11/03/2020
• Est. Priority Date: 07/23/2015
• Status: Active Grant

• Current Assignee: California Institute of Technology, The Trustees of Dartmounth College (Dartmouth College)
• Original Assignee: California Institute of Technology
• Inventors: Scherer, Axel, Gaur, Arti
• Primary Examiner(s): Dejong, Eric S
• Application Number:
  US15/216,662
• Publication Number:
  US 20170020415A1
• Time in Patent Office: 1,566 Days
• Field of Search: None
• 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 2560/0219 of externally powered implanted units
• CPC Class Codes: A61B 2562/0209 Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
• CPC Class Codes: A61B 2562/028 Microscale sensors, e.g. electromechanical sensors [MEMS]
• CPC Class Codes: A61B 2562/04 Arrangements of multiple sensors of the same type
• CPC Class Codes: A61B 2562/125 characterised by the manufacture of electrodes
• 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 5/1451 for interstitial fluid
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• 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 5/1473 invasive, e.g. introduced into the body by a catheter A61B5/1482 takes precedence
• CPC Class Codes: A61B 5/14735 comprising an immobilised reagent
• 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 5/4839 combined with drug delivery
• CPC Class Codes: A61M 2205/3523 using telemetric means
• CPC Class Codes: A61M 2205/8237 Charging means
• CPC Class Codes: A61M 2207/00 Methods of manufacture, assembly or production
• CPC Class Codes: A61M 5/14276 specially adapted for implantation
• CPC Class Codes: A61M 5/172 : electrical or electronic A61M5/16804, A61M5/16831 take precedence
• CPC Class Codes: A61M 5/1723 : using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00

Abstract

Wireless electrochemical measurements methods using minimally invasive micro-sensors that monitor response of cells to specific analytes are described. Micro-actuators integrated on a same chip as the micro-sensors are used to provide closed loop in-vivo local therapy on demand. An in-vivo bio-electronic system that can monitor the health of cell colonies and accordingly dispense corresponding therapeutic drugs is also described.

Claims

1. A method for in-vivo measuring of metabolic health of cells, the method comprising:

providing a miniaturized wireless implantable device comprising an electrochemical sensor comprising electrodes covered with a functionalization layer that comprises an oxidoreductase for sensing a chemistry of interest;

selecting a cell culture or colonies specific to an analyte of interest;

confining the cell cultures or colonies, and the miniaturized wireless implantable device in a semi-permeable cell containment barrier;

implanting the semi-permeable cell containment barrier into a living body comprising the analyte of interest;

based on the implanting, subjecting the cell cultures or colonies to the analyte of interest;

based on the subjecting, obtaining a metabolic reaction of the cell cultures or colonies with the analyte;

based on the obtaining, releasing the chemistry of interest; and

based on the releasing, sensing the chemistry of interest via the electrochemical sensor of the miniaturized wireless implantable device, thereby measuring metabolic health of cells of the cell cultures or colonies.

2. The method according to claim 1, wherein the semi-permeable cell containment barrier is one of:

a) and organic pouch, and b) parylene.

3. The method according to claim 1, wherein the cell cultures or colonies are specifically selected for sensing one or more of:

a) genomic markers like micro-RNAs and circulating DNAs, and b) exosomes and cytokine molecules in blood, interstitial fluid, urine or saliva.

4. The method according to claim 1, wherein the miniaturized implantable device is further configured for delivery of a payload via one or more integrated delivery modules.

5. The method according to claim 4, further comprising:

based on the measuring, delivering a payload of the one or more integrated delivery modules to the cell cultures or colonies; and

based on the delivering, affecting the metabolic health of the cell cultures or colonies.

6. The method according to claim 5, wherein the measuring further comprises:

wirelessly transmitting metabolic health data to a remote controller; and

wirelessly receiving control data from the remote controller to initiate an amount of the payload to be delivered.

7. The method according to claim 1, wherein the cell cultures or colonies comprise genetically engineered cells.

8. The method according to claim 7, wherein the genetically engineered cells are designed for longevity and selectivity to specific molecules.

9. The method according to claim 8, wherein the specific molecules comprise one or more of:

a) cytokines, and b) microRNAs.

10. The method according to claim 1, wherein the cell cultures or colonies comprise fluorescent protein markers and the miniaturized wireless implantable device is configured to detect an optical signal in correspondence of the metabolic reaction of the cell cultures or colonies with the analyte.

11. The method according to claim 10, wherein the wireless implantable device is further configured to transmit and receive data through an external light source.

12. The method according to claim 11, wherein the external light source is further configured to excite the fluorescent protein markers for generation of the optical signal.

13. An in-vivo implantable bio-electronic system comprising:

a semi-permeable cell containment barrier comprising;

i) wireless implantable device comprising an electrochemical sensor comprising electrodes covered with a functionalization layer that comprises an oxidoreductase to sense a chemistry of interest;

ii) a cell culture or colonies specific to an analyte of interest,

wherein;

when the in-vivo implantable bio-electronic system is implanted into a living body comprising the analyte of interest and a metabolic reaction of the cell cultures or colonies with the analyte releases the chemistry of interest, the electrochemical sensor of the wireless implantable device senses the released chemistry of interest.

14. The in-vivo implantable bio-electronic system according to claim 13, wherein the semi-permeable cell containment barrier is one of:

a) and organic pouch, and b) parylene.

15. The in-vivo implantable bio-electronic system according to claim 13, wherein the cell cultures or colonies are specifically selected for sensing one or more of:

a) genomic markers like micro-RNAs and circulating DNAs, and b) exosomes and cytokine molecules in blood, interstitial fluid, urine or saliva.

16. The in-vivo implantable bio-electronic system according to claim 13, wherein the miniaturized implantable device is further configured for delivery of a payload via one or more integrated delivery modules.

17. The in-vivo implantable bio-electronic system according to claim 16, wherein the delivery of the payload is configured to affect metabolic health of the cell cultures or colonies.

18. The in-vivo implantable bio-electronic system according to claim 17, wherein an amount of the payload to be delivered is based on received wireless control data responsive to transmitted wireless data corresponding to the sensed chemistry of interest.

19. The in-vivo implantable bio-electronic system according to claim 13, wherein the cell cultures or colonies comprise genetically engineered cells.

20. The in-vivo implantable bio-electronic system according to claim 19, wherein the genetically engineered cells are designed for longevity and selectivity to specific molecules.

21. The in-vivo implantable bio-electronic system according to claim 20, wherein the specific molecules comprise one or more of:

a) cytokines, and b) microRNAs.

22. The in-vivo implantable bio-electronic system according to claim 13, wherein the cell cultures or colonies comprise fluorescent protein markers and the miniaturized wireless implantable device is configured to detect an optical signal in correspondence of the metabolic reaction of the cell cultures or colonies with the analyte.

23. The in-vivo implantable bio-electronic system according to claim 22, wherein the wireless implantable device is further configured to transmit and receive data through an external light source.

24. The in-vivo implantable bio-electronic system according to claim 23, wherein the external light source is further configured to excite the fluorescent protein markers for generation of the optical signal.

25. The in-vivo implantable bio-electronic system of claim 13, wherein the oxidoreductase comprises at least one of:

a) lactate oxidase;

b) glucose oxidase;

c) glucose dehydrogenase;

d) horseradish peroxidase;

e) uricase;

f) urease;

g) ascorbate oxidase;

h) sarcosine oxidase;

i) alcohol oxidase;

j) malate dehydrogenase;

k) glucoamylase;

l) glutamate oxidase;

or m) cholesterol dehydrogenase.