MEMS AFFINITY SENSOR FOR CONTINUOUS MONITORING OF ANALYTES

• US 20140134607A1
• Filed: 01/21/2014
• Published: 05/15/2014
• Est. Priority Date: 07/29/2011
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: LIN, Qiao, HUANG, Xian
• Granted Patent: US 9,364,174 B2
• Time in Patent Office: Days
• US Class Current: 435/5
• CPC Class Codes: A61B 2562/028 Microscale sensors, e.g. electromechanical sensors [MEMS]
• CPC Class Codes: A61B 5/0015 characterised by features of the telemetry system
• 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: B01L 2200/10 Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
• CPC Class Codes: B01L 2200/147 Employing temperature sensors
• CPC Class Codes: B01L 2200/148 Specific details about calibrations
• CPC Class Codes: B01L 2300/023 Sending and receiving of information, e.g. using bluetooth
• CPC Class Codes: B01L 2300/0645 Electrodes
• CPC Class Codes: B01L 2300/0663 Whole sensors
• CPC Class Codes: B01L 2300/0874 Three dimensional network
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2400/043 magnetic forces
• CPC Class Codes: B01L 2400/0433 vibrational forces
• CPC Class Codes: B01L 3/502753 characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation separation in general B01D; microapparatus for analysis using electrophoresis G01N27/44791; sample preparation G01N1/28
• CPC Class Codes: G01N 27/226 Construction of measuring vessels; Electrodes therefor
• CPC Class Codes: G01N 27/327 Biochemical electrodes , e.g. electrical or mechanical details for in vitro measurements
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose

Abstract

Techniques for monitoring a target analyte in a sample using a polymer capable of binding to the target analyte are disclosed. A microdevice useful for the disclosed techniques includes a semi-permeable membrane structure, a substrate, a first and second microchambers formed between the membrane structure and the substrate. The first microchamber can be adapted to receive a solution including the polymer, and the second microchamber can be adapted to receive a reference solution. Environmental target analyte can permeate the semi-permeable membrane structure and enters the first microchamber and the second microchamber. Based on the difference in a property associated with the polymer solution that is responsive to the target analyte-polymer binding, and the corresponding property associated with reference solution, the presence and/or concentration of the target analyte can be determined.

Claims

1. A microdevice for monitoring a target analyte in a sample using a polymer capable of binding to the target analyte, the microdevice comprising:

a semi-permeable membrane structure;

a substrate;

a first microchamber and a second microchamber, each formed between the semi-permeable membrane structure and the substrate, and including a suspended element positioned to be spaced apart from the substrate;

wherein the first microchamber is adapted to receive a solution including the polymer;

wherein the second microchamber is adapted to receive a reference solution for screening effects not caused by the target analyte;

wherein the semi-permeable membrane structure is permeable to the target analyte and impermeable to the polymer, thereby when the sample is placed in contact with the semi-permeable membrane structure, the target analyte, if present in the sample, permeates the semi-permeable membrane structure and enters the first microchamber and the second microchamber, respectively, and the polymer is prevented from escaping from the first microchamber through the semi-permeable membrane structure.

2. The microdevice of claim 1, wherein the binding of the polymer with the target analyte causes a change in the permittivity of the polymer solution.

3. The microdevice of claim 1, wherein the suspended element of each of the first microchamber and the second microchamber comprises a vibrational element, and wherein the binding of the polymer with the target analyte causes a change in the vibration of the vibrational element in the first microchamber.

4. The microdevice of claim 3, wherein the vibration of the vibrational element is actuable by an external magnetic field.

5. The microdevice of claim 4, wherein the vibrational element comprises permalloy.

6. The microdevice of claim 1, wherein each of the first microchamber and the second microchamber further comprises a top electrode and a bottom electrode, respectively.

7. The microdevice of claim 6, wherein the top electrode is included in the suspended element and the bottom electrode is included in the substrate.

8. The microdevice of claim 7, wherein the top electrode in each of the first microchamber and the second microchamber is supported by at least one anti-stiction post formed from the substrate.

9. The microdevice of claim 8, wherein the top electrode is perforated.

10. The microdevice of claim 1, wherein the semi-permeable membrane structure includes at least two semi-permeable membrane portions each forming a cover for the first microchamber and the second microchamber, respectively.

11. The microdevice of claim 1, further including the polymer solution in the first microchamber and the reference solution in the second microchamber.

12. The microdevice of claim 11, further comprising a capacitive sensor coupled with each of the first microchamber and the second microchamber, the capacitive sensors configured to detect the difference in capacitance between (A) the capacitor formed by the suspended element, the substrate, and the polymer solution sandwiched therebetween in the first microchamber;

and (B) the capacitor formed by the suspended element, the substrate, and the reference solution sandwiched therebetween in the second microchamber.

13. The microdevice of claim 12, wherein the capacitive sensors each comprise a top electrode included in the suspended element and a bottom electrode included in the substrate.

15. The microdevice of claim 13, wherein the perforated electrode is supported by at least one post formed from the substrate.

16. The microdevice of claim 1, wherein the polymer comprises a plurality of boronic acid moieties.

17. The microdevice of claim 16, wherein the polymer comprises poly(N-hydroxyethylacrylamide-ran-3-acrylamidophenylboronic acid) (PHEA-ran-PAAPBA).

18. The microdevice of any of claim 1, wherein the polymer reversibly binds with the target analyte.

19. The microdevice of claim 1, wherein the analyte is glucose.

20. The microdevice of claim 1, adapted to be implantable in a subcutaneous tissue of a subject.

21. The microdevice of claim 1, further comprising a microheater.

22. The microdevice of claim 1, further comprising a temperature sensor.

23. An implantable monitor for monitoring a target analyte in the interstitial fluid of a subject, comprising a microdevice of claim 1 coupled with a wireless interface.

24. The implantable monitor of claim 23, wherein the wireless interface comprises:

a capacitance digital converter coupled with the microdevice and adapted to produce a digital signal representing a measurement of the target analyte in the interstitial of the subject;

a microcontroller coupled with the capacitance digital converter; and

a transponder coupled with the microcontroller to transmit the digital signal received from the capacitance digital converter to an external reader.

14. A microdevice for monitoring a target analyte in a sample using a polymer capable of binding to the target analyte, the microdevice comprising

a semi-permeable membrane structure;

a substrate;

a microchamber formed between the semi-permeable membrane structure and the substrate, the microchamber adapted to receive a solution including the polymer, and including a suspended element positioned to be spaced apart from the substrate,

wherein the suspended element comprises a perforated electrode; and

wherein the semi-permeable membrane structure is permeable to the target analyte and impermeable to the polymer, thereby when the sample is placed in contact with the semi-permeable membrane structure, the target analyte, if present in the sample, permeates the semi-permeable membrane and enters the microchamber, and the polymer is prevented from escaping from the microchamber through the semi-permeable membrane structure.

25. A method for monitoring a target analyte in a sample using a polymer capable of binding to the target analyte, comprising:

loading a solution including the polymer into a first microchamber and a reference solution into a second microchamber;

placing the sample in contact with a membrane structure having permeability to the target analyte and impermeability to the polymer such that the target analyte, if any, permeates the membrane structure and enters the first microchamber and the second microchamber, thereby effecting the binding of the target analyte with the polymer in the first microchamber;

detecting a difference, if any, in a property associated with the polymer solution upon the binding between the polymer and the target analyte in the first microchamber and the corresponding property associated with the reference solution in the second microchamber; and

based on the detected difference, determining a presence and/or concentration of the target analyte in the sample.

26. The method of claim 25, wherein the binding of the polymer with the target analyte causes a change in the permittivity of the polymer solution, and wherein the detecting comprises:

applying an alternating electric field at a predetermined frequency to the polymer solution in the first microchamber and the reference solution in the second microchamber; and

detecting a difference in permittivity of the polymer solution in the first microchamber and the reference solution in the second microchamber at the predetermined frequency.

27. The method of claim 25, wherein the first microchamber and the second microchamber each include a suspended vibrational element, wherein the binding of the polymer with the target analyte causes a change in the viscosity of the polymer solution, and wherein the detecting comprises:

actuating the vibrations of the vibrational element in each of the first microchamber and the second micro chamber; and

detecting a difference in the vibrations of the vibrational element in the first microchamber and the vibrational element in the second microchamber.

28. The method of claim 27, wherein the actuating comprises actuating the vibrations of the vibrational element in each of the first microchamber and the second microchamber by an alternating electromagnetic field.

33. The method of claim 25, wherein the analyte is glucose.

34. The method of claim 25, wherein the detection is continuous over time.

35. The method of claim 25, wherein placing the sample in contact with the semi-permeable membrane structure comprises subcutaneously implanting a microdevice containing the membrane structure enclosing the first microchamber and the second microchamber in a subject.

36. The method of claim 35, wherein the sample comprises intestinal fluid of the subject.

37. The method of claim 35, wherein the sample comprises venous blood.

29. A method for monitoring a target analyte in a sample using a microdevice comprising a substrate, a semi-permeable membrane structure, and a microchamber formed between the semi-permeable membrane structure and the substrate, the microchamber including an suspended element including a perforated electrode, comprising:

placing the sample in contact with the semi-permeable membrane structure of the microdevice such that the target analyte, if any, in the sample permeates the membrane structure and enters the microchamber to bind with the polymer in the polymer solution;

detecting the permittivity of the polymer solution using an alternating electric field applied across at least a portion of the polymer solution; and

based on the detected permittivity, determining a presence and/or concentration of the target analyte in the sample.

30. The method of any of claims 29, wherein the polymer comprises a plurality of boronic acid moieties.

31. The method of claim 30, wherein the polymer comprises poly(N-hydroxyethylacrylamide-ran-3-acrylamidophenylboronic acid) (PHEA-ran-PAAPBA).

32. The method of any of claims 29, wherein the polymer reversibly binds with the target analyte.

38. A method for monitoring a target analyte in a sample using a polymer capable of binding to the target analyte, comprising:

placing the sample in contact with a semi-permeable membrane structure having permeability to the target analyte and impermeability to the polymer such that the target analyte, if any, in the sample permeates the membrane structure and enters the first microchamber loaded with a solution containing the polymer and the second microchamber loaded with a reference solution, respectively, thereby effecting the binding of the target analyte with the polymer in the first microchamber;

detecting a difference, if any, in a property associated with the polymer solution upon the binding between the polymer and the target analyte in the first microchamber and the corresponding property associated with the reference solution in the second microchamber; and

based on the detected difference, determining a presence and/or concentration of the target analyte in the sample.