US20180289299A1

US20180289299A1 - Microfluidic Systems For Electrochemical Transdermal Analyte Sensing Using a Capillary-Located Electrode

Info

Publication number: US20180289299A1
Application number: US16/005,826
Authority: US
Inventors: Makarand Paranjape
Original assignee: Georgetown University
Current assignee: Georgetown University
Priority date: 2013-03-15
Filing date: 2018-06-12
Publication date: 2018-10-11
Also published as: WO2014149514A1; US10004434B1

Abstract

A sensing device, designed to be used in contact with the skin, contains a plurality of individually controllable sites for electrochemically monitoring an analyte, such as glucose, in interstitial fluid of a user. The device includes at least a hydrophobic layer designed to contact the skin; a capillary channel providing an opening adjacent the skin; a metal electrode layer having a sensor layer applied to an edge portion thereof such that it is exposed to the interior of said capillary channel, the sensing layer being effective to measure the analyte.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/834,199 filed Mar. 15, 2013 and titled “Microfluidic Systems For Electrochemical Transdermal Analyte Sensing Using a Capillary-Located Electrode,” which is incorporated herein by reference in its entirety.

FIELD OF EMBODIMENTS

The present embodiments relate generally to non-invasive or minimally invasive transdermal measurement systems. More specifically, the embodiments relate to microfluidic transdermal glucose measurement systems in which a thin electrode is contained within a fluid-transmitted capillary, and processes for their production and use.

BACKGROUND

Minimally invasive transdermal systems are described in, for example, co-owned U.S. Pat. Nos. 6,887,202 and 7,931,592, both entitled “Systems and Methods for Monitoring Health and Delivering Drugs Transdermally,” as well as co-owned U.S. application Ser. No. 13/459,392, each of which is incorporated herein by reference in its entirety. These systems, like the embodiments described herein, provide for a minimally invasive sampling technique and device suitable for rapid, inexpensive, unobtrusive, and pain-free monitoring of important biomedical markers, such as glucose.
Existing systems remain open to improvement in various aspects, including consistency in sampling and measurement.

SUMMARY

A sensing device, designed to be used in contact with the skin, is provided. The device contains a plurality of individually controllable sites for electrochemically monitoring an analyte, such as glucose, in interstitial fluid of a user. The device includes:
a hydrophobic layer, designed to contact the skin; an overlaying first structural layer;
an overlaying metal electrode layer;
an overlaying second structural layer;
for each such detection site, a capillary channel traversing these layers, thus providing an opening adjacent the skin;
wherein said metal electrode layer is discontinuous at the circumference of said capillary channel, such that two non-contiguous edge portions of electrode are present within the circumference of said channel;
applied to one such edge portion of the metal electrode layer, such that it is exposed to the interior of said capillary channel, a sensing layer effective to measure said analyte; and
surrounding the lower end of said capillary channel, adjacent said hydrophobic layer, an electronic element (microheater) effective to produce heat when a sufficient voltage is applied thereto.
Also provided are electrical conduits and contacts such that a voltage can be applied to the microheater, and an additional voltage can be applied between the two edge portions of the electrode layer, and an electrochemical response from the sensing material/electrode layer, indicative of the concentration of analyte in the sample fluid, can be detected.
In selected embodiments, the hydrophobic layer is hydrophobic silicone. The first structural layer may be a glass or ceramic-like material. The metal electrode layer is preferably gold or platinum, and the sensing layer, for use in detecting glucose, is preferably a conducting polymer, such as polypyrrole (PPy), modified with glucose oxidase (GOx), and preferably further containing an effective amount of a mediator such as ferricyanide. The second structural layer is preferably non-absorbent and/or hydrophobic, and may also be a layer of hydrophobic silicone.
The diameter of the capillary channel, in one embodiment, is about 50 μm.
The thickness of the metal electrode layer is generally in the range of 100 nm to 1 micron range, e.g. 100-500 nm, 500-1000 nm, 500-800 nm, 250-750 nm, 300-500 nm, etc. An exemplary thickness is about 500 nm. The structural layers generally have thicknesses such that the overall thickness of the device is about 1 mm or less.
The thickness of the applied sensing layer, measured in a direction perpendicular to the capillary channel length, may be 200 nm or less, 100 nm or less, or 50 nm or less, in selected embodiments.
In use, a voltage is applied to the microheater sufficient to ablate the stratum corneum of the underlying skin, e.g. a voltage of about 3 V, typically for about 30 msec. This ablation allows interstitial fluid to enter the capillary channel, where it rises via both capillary action and the body's hydrostatic pressure and contacts the sensing material (e.g. PPy/GOx) within the capillary. A second voltage, typically 0.2-0.4 V, is applied to the electrode layer, i.e. between the two above-described edge portions of the electrode layer, and the level of analyte (e.g. glucose) contacting the sensing material is electrochemically detected, in accordance with known methods.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates an embodiment of a sensing device as disclosed herein.

DETAILED DESCRIPTION

A section of an exemplary sensing device, designed to be used in contact with the skin, is shown in FIG. 1. The device typically contains a plurality of individually controllable sites, of which one is illustrated in the FIGURE, for electrochemically monitoring an analyte, such as glucose, in interstitial fluid of a user. The device, in a preferred embodiment, includes:
a hydrophobic layer 12, designed to contact the skin;
an overlaying first structural layer 14;
an overlaying metal electrode layer 16;
an overlaying second structural layer 18;
a capillary channel 20 traversing these layers, thus providing an opening adjacent the skin;
wherein said metal electrode layer is discontinuous at the circumference of said capillary channel, such that two non-contiguous edge portions of electrode are present within the circumference of said channel;
applied to one such edge portion of the metal electrode layer, such that it is exposed to the interior of said capillary channel, a sensing layer 22 effective to measure said analyte; and
surrounding the lower end of said capillary channel, adjacent to said hydrophobic layer, an electronic element (microheater) 24, effective to produce heat when a sufficient voltage is applied thereto.
The diameter of the capillary channel, in one embodiment, is about 50 μm.
The thickness of the metal electrode layer is generally in the range of 100 nm to 1 micron range, e.g. 100-500 nm, 500-1000 nm, 500-800 nm, 250-750 nm, 300-500 nm, etc. An exemplary thickness is about 500 nm. The thickness of the structural layers is not generally critical (although layer 12 should be sufficiently thick to insulate sensing material 22 from heat produced by microheater 24), but these may also be in the general range of hundreds of nm, e.g. 100-500 nm, 500-1000 nm, 500-800 nm, 250-750 nm, 300-500 nm, etc. The overall thickness of the device is generally less than 1 mm.
The diameter of the capillary channel 20, in one embodiment, is about 50 μm. Other diameter ranges, e.g. 10-100 μm, or 25-75 μm, could also be effective.
Also provided, though not shown in the FIGURE, are electrical conduits and contacts such that a voltage can be applied to the microheater, and an additional voltage can be applied to the electrode layer (i.e. between the two above-described edge portions of the electrode layer), and an electrochemical response from the sensing material/electrode layer, indicative of the concentration of analyte in the sample fluid, can be detected. The multiple detection sites within a device are preferably individually controllable; i.e. voltages can be selectively applied to a given detection site or sites by a user of the device.
In selected embodiments, the hydrophobic layer 12 is hydrophobic silicone, though any biocompatible/non-irritating hydrophobic material can be used. The structural layer 14 may be a glass or ceramic-like material, which provides thermal insulation between the microheater 24 and sensing material 22, or other structurally stable, nonabsorbent, preferably thermally insulating material. The metal electrode layer 16 is preferably gold or platinum.
A sensing layer 22 effective to measure the analyte is present on one of the above-described edge portions of the metal electrode layer, such that it the sensing material is exposed to the interior of the capillary channel. The sensing layer 22, for use in detecting glucose, is preferably a conducting polymer, such as polypyrrole (PPy), modified with the enzyme glucose oxidase (GOx).
Preferably, in fabrication, the PPy-GOx layer is electrodeposited, in accordance with known methods (see, e.g., Liu et al., Matl. Sci. Eng. C 27(1):47-60 (January 2007); Yamada, et al., Chem. Lett. 26(3):201-202 (1997); Fortier, et al., Biosens. Bioelectronics 5:473-490 (1990)) as an extremely thin layer on an exposed face of the metal electrode, as shown in the FIGURE. Measuring in the direction perpendicular to the capillary length, the thickness of the applied layer may be, e.g. 200 nm or less, 100 nm or less, or 50 nm or less, in selected embodiments.
In one embodiment, a mediator such as ferricyanide, as known in the art, is co-deposited along with the PPy and GOx. This system allows electrochemical measurement of the analyte to be carried out at a voltage of about 0.2-0.4V. A somewhat higher voltage (e.g. 0.7 V), which can lead to interference from other molecules in the interstitial fluid, would typically be required without the mediator. Other electron-accepting mediators known in the art for use with GOx include ferrocene derivatives, conducting organic salts such as tetrathiafulvalen-tetracycloquinodimethane (TTF-TCNQ), quinone compounds, phenothiazine compounds, and phenoxazine compounds.
The multilayer structure of the device containing the capillary channels can be fabricated by known deposition and etching methods. The sensing material 22 is, in one embodiment, applied by electrodeposition to one of the exposed edges of the gold electrode within the formed capillary channel 20, as noted above. As noted above, two noncontiguous edges of electrode are present within the microchannel, to allow for electrochemical detection. These edges could be visualized as two distinct semicircles within the inner surface of the channel, one of which is treated with the sensing material.
In use, a voltage is applied to the microheater sufficient to ablate the stratum corneum of the underlying skin, e.g. a voltage of about 3 V, typically for about 30 msec. This ablation (which typically produces a temperature of about 130° C.) allows interstitial fluid to enter the capillary channel, where it rises via capillary action and hydrostatic pressure and contacts the sensing material (e.g. PPy/GOx) within the capillary. A second voltage, typically 0.2-0.4 V, is then applied between the two above-described edge portions of the electrode layer), and the level of analyte (e.g. glucose) contacting the sensing material is electronically detected, preferably amperometrically detected, in accordance with known methods.
The device design presents various advantages, including the following. The sensor electrode pair, including the metal (e.g. gold) electrode and PPy/GOx-treated electrode (i.e. the two edge regions described above, one treated with sensor material), are located within the microcapillary channel and thus separated spatially from the microheater. This configuration avoids possible heat degradation of the enzyme. Further to this aspect, structural layer 14 is preferably formed of a heat-insulting material, such as a glass or ceramic material.
The detection of glucose is typically realized using chronoamperometry (measurement of current generated versus time for a voltage step). Ideally, every glucose molecule reaching the GOx sensing electrode should immediately release its electrons to produce the measured current. To achieve this condition, the electrode should have a low surface area to sample volume ratio, to ensure that glucose is not depleted in the vicinity of the sensing electrode during analysis. Accordingly, the sensing electrode is fabricated to be extremely small; i.e. essentially the width of the metal electrode layer 16, as shown in the FIGURE. Preferred thicknesses (measured in the direction perpendicular to the channel length) of the applied sensor layer 22 may be, e.g. 200 nm or less, 100 nm or less, or 50 nm or less, in selected embodiments, in the 100 nm to 1 micron range, e.g. 500 nm. Diffusion times (i.e. the time for glucose molecules to reach the GOx enzyme) are reduced for similar reasons.
In general, the thickness of a metal layer applied via conventional metal deposition methods, e.g. electrodeposition or vapor deposition, can be precisely controlled, as compared to control of lateral dimensions of the planar surface area. Accordingly, high consistency in the effective sensor area (which is, again, the width dimension of the metal electrode layer 16), as well as roughness of the electrode layer, is achieved, giving high consistency between one sensor element and another, within a single device or between different devices. In fabrication of the multilayer device, the gold thickness can be easily reproduced with very little sidewall imperfections/roughness, and the exposed region (at the capillary wall) becomes the sensor electrode area.
Although glass/ceramic/polymeric substrate layers are exemplified, other materials, such as paper or other cellulose substrates, electrospun fibers, or other polymers, could also be used for the non-metal layers (12, 14, 18) in the device. However, surfaces contacting the skin, such as the lower surface of layer 12, should be non-absorbent and preferably hydrophobic in nature, in order to direct fluid flow from the skin into and though the capillary channel 20 to the sensing material 22. Methods of treating materials such as paper to render selected portions hydrophobic and/or non-absorbent are known in the art; see, e.g. Martinez, et al., Anal. Chem. 2010, 82, 3-10. The surface of structural layer 12 contacting the interior of the microchannel should be non-absorbent but should not repel water, so that sample fluid travels efficiently to the sensing area without volume loss.
Integrated circuitry (IC), including radio frequency (RF) communication capability, may be included peripheral to the device in order to transmit data readings to a remote location. By way of example, this transmission may employ Bluetooth devices, or it may be facilitated as part of a home area network (HAN) in a first instance, e.g., using protocols such as those described as part of the Zigbee standards. Further still, the data readings may be further transmitted outside of the HAN in accordance with a home health or telehealth communications system using existing wide area networks (WANs) such as the Internet.
One skilled in the art recognizes the other areas of application for the devices described herein. While the examples specifically described herein are directed to glucose monitoring, adaptations could be made to ascertain other information from the biomolecules and biomarkers in the interstitial fluid. For example, the individual sites could monitor for infectious disease (microbial, fungal, viral); hazardous compounds; heart or stroke indicators (troponin, C-reactive protein); chemical or biological toxins; cancer markers (PSA, estrogen); drug efficacy and dosing (metabolites): and the like. Such applications of the device as described are considered to be within the scope of the present invention.

Claims

1. A sensing device comprising a plurality of individually controllable detection sites for electrochemically monitoring an analyte in interstitial fluid of a user, each individually controllable detection site comprising:

a dual opening capillary channel traversing multiple layers and having one of the dual openings located adjacent to the skin of the user, the multiple layers including at least a hydrophobic layer, designed to contact the skin, and a metal electrode layer, wherein the metal electrode layer is discontinuous at a circumference of the capillary channel, such that two non-contiguous edge portions of the metal electrode layer are present within the circumference of said channel; and

a first non-contiguous edge portion of the metal electrode layer including a sensing layer applied thereto and being exposed to an interior of the capillary channel, wherein the sensing layer is effective to measure the analyte within interstitial fluid of the user entering the capillary channel and contacting the first non-contiguous edge portion including the sensing layer.

2. The sensing device of claim 1, further comprising: a microheater located adjacent said hydrophobic layer, the microheater being effective to produce heat when a sufficient voltage is applied thereto to ablate the stratum corneum of the underlying skin and access the interstitial fluid containing the analyte.

3. The sensing device of claim 1, wherein the hydrophobic layer is silicone.

4. The sensing device of claim 1, wherein the first structural layer is selected from the group consisting of glass and a ceramic-like material.

5. The sensing device of claim 1, wherein the metal electrode layer is selected from the group consisting of gold and platinum.

6. The sensing device of claim 5, wherein the sensing layer is a conducting polymer.

7. The sensing device of claim 6, wherein the conducting polymer is polypyrrole (PPy).

8. The sensing device of claim 7, wherein the polypyrrole (PPy) is modified with glucose oxidase (GOx).

9. The sensing device of claim 8, wherein the polypyrrole (PPy) is modified with glucose oxidase (GOx) is co-deposited on the edge of the metal electrode layer with a mediator.

10. The sensing device of claim 9, wherein the mediator is ferricyanide.

11. A method for electrochemically monitoring an analyte in interstitial fluid of a user, the method comprising:

contacting the user's skin with a monitoring device, the monitoring device including a plurality of individually controllable detection sites for electrochemically monitoring the analyte in interstitial fluid of a user;

controlling at least a first of the individually controlled detection sites to apply a first voltage to a microheater located adjacent to the user's skin at the first of the individually controlled detection sites, wherein the microheater produces heat responsive to the applied first voltage, the heat being sufficient to ablate the stratum corneum of the underlying skin and access the interstitial fluid of the user containing the analyte;

receiving the accessed interstitial fluid at a first opening of a dual opening capillary channel of the first of the individually controlled detection sites, wherein the accessed interstitial fluid rises through the capillary channel, traversing multiple material layers including at least a hydrophobic layer contacting the user's skin, first structural layer and a metal electrode layer that is discontinuous at a circumference of the capillary channel, such that two non-contiguous edge portions of the metal electrode layer are present within the circumference of said capillary channel, a first non-contiguous edge portion of the metal electrode layer including a sensing layer applied thereto and being exposed to an interior of the capillary channel;

applying a second voltage between the two non-contiguous edge portions of the metal electrode layer when the interstitial fluid passes thereby within the capillary channel; and

electronically detecting the analyte in the interstitial fluid using the sensing layer responsive to the application of the second voltage.

12. The method of claim 11, further comprising applying the first voltage for approximately 30 msec.

13. The method of claim 12, wherein the first voltage is about 3V.

14. The method of claim 11, wherein the second voltage is about 0.2 to 0.4 V.

15. The method of claim 11, wherein the hydrophobic layer is silicone.

16. The method of claim 11, wherein the first structural layer is selected from the group consisting of glass and a ceramic-like material.

17. The method of claim 11, wherein the metal electrode layer is selected from the group consisting of gold and platinum.

18. The method of claim 17, wherein the sensing layer is a conducting polymer.

19. The method of claim 18, wherein the conducting polymer is polypyrrole (PPy).

20. The method of claim 19, wherein the polypyrrole (PPy) is modified with glucose oxidase (GOx).