NOVEL METHOD FOR TRANSDERMAL MEASUREMENT OF VOLATILE ANESTHETICS

Abstract

Devices and methods of making and using the device for the non-invasive detection of volatile anesthetics are provided. The devices are capable of measuring the concentration of volatile anesthetics transdermally and in a non-invasive manner. The devices and methods can be applied in detection of volatile anesthetics in samples collected from human skin perspiration.

Claims

1. A fuel-cell based sensing device for continuously detecting a concentration of a volatile anesthetic in a sample, the sensing device comprising: a sensor unit comprising a working electrode as an anode, a counter electrode as a cathode, a reference electrode, and an electrolyte; circuitry configured to control a potential applied to the sensor unit; and circuitry configured to measure a current output between the working electrode and the counter electrode and a potential between the working electrode and the reference electrode through the electrolyte, the anode and the cathode being separated by, and in electrical contact with, the electrolyte, the working electrode being disposed on an anode side of the electrolyte, the counter electrode being disposed on a cathode side of the electrolyte opposite to the anode side of the electrolyte such that the counter electrode faces the working electrode, the reference electrode being disposed on the cathode side of the electrolyte, the reference electrode being in electrical contact with the electrolyte and disposed adjacent to, though separated from, the counter electrode, the sample being a product of a human transdermal diffusion process, a thickness of the electrolyte being in a range of from 0.01 cm to 0.03 cm such that H.sup.+ ions exchange between the working electrode and the reference electrode, a first part of the anode side of the electrolyte corresponding to the counter electrode being uncovered by the working electrode and a second part of the anode side of the electrolyte corresponding to the reference electrode being uncovered by the working electrode, the working electrode having an extended portion physically separated from the electrolyte and extending away from the electrolyte in a first direction, and the counter electrode having an extended portion physically separated from the electrolyte and extending away from the electrolyte in a second direction opposite to the first direction.

2. The device according to claim 1, the electrolyte being a proton exchange membrane (PEM).

3. The device according to claim 1, an active surface area of the working electrode being smaller than an active surface area of the counter electrode.

4. The device according to claim 1, the sample comprising human skin perspiration.

5. The device according to claim 1, the working electrode, the counter electrode, and the reference electrode comprising a material selected from stainless steel and nickel.

6. The device according to claim 5, the stainless steel being micro-perforated and the nickel being porous.

7. The device according to claim 5, the working electrode, the counter electrode, and the reference electrode each being coated with a catalytic material comprising nickel, gold, iron, platinum, carbon, or a combination thereof, the catalytic material acting as a reaction mediator.

8. The device according to claim 7, the electrodes being coated with nickel.

9. The device according to claim 1, the volatile anesthetic being a hydrogenated ether selected from isoflurane, sevoflurane, enflurane, and desflurane.

10. A method of continuously detecting a concentration of a volatile anesthetic in a skin perspiration sample collected from a human subject, the method comprising: contacting a sample of human skin perspiration with a fuel-cell based sensing device, the sensing device comprising: a sensor unit comprising a working electrode as an anode, a counter electrode as a cathode, a reference electrode, and an electrolyte; circuitry configured to control a potential applied to the sensor unit; and circuitry configured to measure a current output between the working electrode and the counter electrode and a potential between the working electrode and the reference electrode through the electrolyte; obtaining open-circuit potential (OCP) of the sensor unit by scanning a range of voltage; comparing the OCP to a threshold value characteristic to a material employed in the working electrode; applying the OCP across the working electrode and the reference electrode while conducting a series of amperometric measurements; and determining the concentration of the volatile anesthetic based on the amperometric measurements, the anode and the cathode being separated by, and in electrical contact with, the electrolyte, the working electrode being disposed on an anode side of the electrolyte, the counter electrode being disposed on a cathode side of the electrolyte opposite to the anode side of the electrolyte such that the counter electrode faces the working electrode, the reference electrode being disposed on the cathode side of the electrolyte, the reference electrode being in electrical contact with the electrolyte and disposed adjacent to, though separated from, the counter electrode, the working electrode, the counter electrode, and the reference electrode each comprising a thin coating of a material comprising nickel, iron, gold, platinum, carbon, or a combination thereof, as a catalyst, the sample of human skin perspiration being collected from a subject treated with anesthetics, a thickness of the electrolyte being in a range of from 0.01 cm to 0.03 cm such that H.sup.+ ions exchange between the working electrode and the reference electrode, a first part of the anode side of the electrolyte corresponding to the counter electrode being uncovered by the working electrode and a second part of the anode side of the electrolyte corresponding to the reference electrode being uncovered by the working electrode, the working electrode having an extended portion physically separated from the electrolyte and extending away from the electrolyte in a first direction, and the counter electrode having an extended portion physically separated from the electrolyte and extending away from the electrolyte in a second direction opposite to the first direction.

11. The method according to claim 10, the electrolyte being a proton exchange membrane (PEM).

12. The method according to claim 10, the working electrode, the counter electrode, and the reference electrode comprising a material selected from stainless steel and nickel.

13. The method according to claim 12, the working electrode comprising porous nickel or stainless steel coated with a thin layer of nickel.

14. The method according to claim 10, the device being placed in direct contact with a skin surface from which the sample is collected.

15. A device for measuring a concentration of a volatile anesthetic in a skin perspiration sample collected from a human subject, the device comprising: a fuel cell based sensing device; a means of displaying a concentration measured with the sensing device; and circuitry configured to process and analyze concentration data output by the sensing device, the sensing device comprising: a sensor unit comprising a working electrode as an anode, a counter electrode as a cathode, a reference electrode, and an electrolyte; circuitry configured to control a potential applied to the sensor unit; and circuitry configured to measure a current output between the working electrode and the counter electrode and a potential between the working electrode and the reference electrode through the electrolyte, the anode and the cathode being separated by, and in electrical contact with, the electrolyte, the working electrode being disposed on an anode side of the electrolyte, the counter electrode being disposed on a cathode side of the electrolyte opposite to the anode side of the electrolyte such that the counter electrode faces the working electrode, the reference electrode being disposed on the cathode side of the electrolyte, the reference electrode being in electrical contact with the electrolyte and disposed adjacent to, though separated from, the counter electrode, the working electrode, the counter electrode, and the reference electrode each comprising a thin coating of a material comprising iron, gold, platinum, carbon, or a combination thereof, as a catalyst, a thickness of the electrolyte being in a range of from 0.01 cm to 0.03 cm such that H.sup.+ ions exchange between the working electrode and the reference electrode, a first part of the anode side of the electrolyte corresponding to the counter electrode being uncovered by the working electrode and a second part of the anode side of the electrolyte corresponding to the reference electrode being uncovered by the working electrode, the working electrode having an extended portion physically separated from the electrolyte and extending away from the electrolyte in a first direction, and the counter electrode having an extended portion physically separated from the electrolyte and extending away from the electrolyte in a second direction opposite to the first direction.

16. The device according to claim 15, further comprising an electronic platform coupled to the sensing device for receiving user input.

17. The device according to claim 15, further comprising a casing for enclosing the sensing device, the casing being adapted to a format selected from wearable accessories, apparels, shoes, and vehicular accessories.

18. The device according to claim 15, further comprising a power supply.

19. The device according to claim 15, the working electrode comprising stainless steel coated with a thin layer of nickel.

20. The device according to claim 15, the electrolyte being a proton exchange membrane (PEM).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1A is a top view of a preferred embodiment of the fuel-cell based sensor.

[0014] FIG. 1B is a lateral view of a preferred embodiment of the sensor.

[0015] FIG. 1C is a dorsal view of a preferred embodiment of the sensor.

[0016] FIG. 2 shows the results of an open circuit potential study of the fuel-cell based sensor in the presence of isoflurane, an exemplary flurane composition.

[0017] FIG. 3 shows the amperometric/current signals of the sensor in the presence (Exposed) and absence (Shielded) of isoflurane.

[0018] FIG. 4 shows changes in amperometric/current signals of the sensor when exposed to isoflurane and shielded from isoflurane.

[0019] FIG. 5 shows the effect of isoflurane on the current measured by the sensor. The experiments were carried out with and without isoflurane (concentration range between 5 ppm and 200 ppm). Linear response with respect to the concentration occurred between 5 ppm and 40 ppm.

[0020] FIG. 6 shows the linear calibration fit obtained from the isoflurane amperometric studies. The linear response was from 5 ppm to 40 ppm with a slope of 77.5 pA.

DETAILED DISCLOSURE

[0021] Embodiments of the subject invention provide devices, and methods of making and using the same, for the non-invasive detection of volatile anesthetics. In some embodiments, a fuel-cell based electrochemical detector of the subject invention is capable of measuring the concentration of volatile anesthetics transdermally and in a non-invasive manner.

[0022] In preferred embodiments, devices and methods provided herein can be applied in detection of volatile anesthetics in samples collected from human skin perspiration.

[0023] In an embodiment, a fuel cell based device can continuously detecting the concentration of volatile anesthetics in a sample, and the device can comprise: [0024] a sensor unit comprising a working electrode as an anode, a counter electrode as a cathode, a reference electrode, and a polymer electrolyte membrane, the anode and the cathode being separated by, and in electrical contact with, the electrolyte, the reference electrode being in electrical contact with the electrolyte and disposed adjacent to, though separated from, the counter electrode; [0025] circuitry capable of controlling the potential applied to the sensor unit; and [0026] circuitry capable of measuring the current output of the sensor unit.

[0027] In some embodiments, the electrolyte material can be a proton exchange membrane (PEM). In a preferred embodiment, the electrolyte is NAFION (DuPont), a class of perfluorinated PEM. In an exemplary embodiment, the NAFION membrane was a 424 reinforced with PTFE fiber measuring approximately 0.03 cm in thickness.

[0028] A PEM-based fuel cell operates with gaseous hydrogen as the fuel and oxygen from ambient air as the oxidant. In conventional PEM-based fuel cells, the PEM comprises one or more fluorinated polymers. It is desirable to employ PEMs with high proton conductivity at low relative humidity and long-term chemical, electrochemical, and thermal stability, as well as low gas permeability under normal operating conditions. In addition to NAFION, other organic polymer membranes can also be used in the fuel cell based sensor as the electrolyte. Non-limiting examples include GORE-SELECT reinforced membranes (W. L. Gore), ACIPLEX (Asahi Chemicals), FLEMION (Asahi Glass), and BAM (Ballard Power) for cell operation temperature not exceeding 90 C.; other art-recognized sulfonated or phosphonated polymers can be used in high-temperature applications.

[0029] In some embodiments, the electrodes comprise stainless steel. In specific embodiments, the electrodes comprise micro-perforated stainless steel. At least one of the stainless steel electrodes (preferably, the anode) can be deposited with a thin, flexible coating of a material acting as a catalyst and a reaction mediator. In some embodiments, the coating material can include nickel, iron, gold, platinum, carbon, and combinations thereof. Those skilled in the art would recognize that other electrically conductive and semiconductive coating materials (or electrode materials) can also serve as catalyst for the redox reaction and accommodate electron transfer to generate electrochemical signals. In preferred embodiments, the coating comprises nickel. Advantageously, the fuel-cell based sensor constructed from stainless steel and nickel not only demonstrates efficacy in providing selective sensing capability for volatile anesthetics but also lowers the overall cost of the device.

[0030] A volatile anesthetic as used herein can be a pharmaceutical composition comprising, as the main component(s), at least one of the following compounds: isoflurane, sevoflurane, enflurane, and desflurane. In some embodiments, the volatile aesthetic can also be a gas such as, for example, nitrous oxide or xenon. In addition to volatile anesthetics, embodiments of the subject invention provide that the fuel-cell based sensor can be used to detect other volatile pharmaceutical compositions.

[0031] In certain embodiments, the volatile anesthetics that can be detected by the device provided herein have been previously administered to a human subject (e.g., a patient in need of anesthetic treatment) and transdermally diffused through the skin of the subject.

[0032] In some embodiments, the working electrode is located on the anode side of the membrane, and the counter and reference electrodes are placed on the cathode side of the membrane (FIGS. 1A-1C). In an embodiment, the thickness of the micro-perforated stainless steel electrodes can be between about 0.01 cm and about 0.03 cm, and preferably about 0.02 cm. The active surface area of the working electrode is preferably slightly less than that of the counter electrode for the purpose of maximizing the extent of oxygen reduction at the counter electrode and providing sufficient oxygen supply to consume the fuel at the working electrode/PEM interface. In an exemplary embodiment, the active surface area of the working electrode can be about 1.2 cm.sup.2 (e.g., 1.5 cm0.8 cm), while that of the counter electrode and the reference electrode can be approximately 1.5 cm.sup.2 (e.g., 1.5 cm1.0 cm) and 0.3 cm.sup.2 (e.g., 1.5 cm0.2 cm), respectively.

[0033] In contrast to traditional fuel cells, which employ a two-electrode system (i.e., an anode and a cathode), an exemplary embodiment of the subject invention employs a three-electrode system. The three-electrode system is advantageous because, in a two-electrode system, the electrochemical potential measurement reflects the full-cell reaction potential, whereas in the three-electrode system the half-cell potential can be measured independently. In a three-electrode system, the current between the working electrode and the counter electrode is measured as a function of the applied potential between the two electrodes.

[0034] In the three-electrode system provided herein, the cathodic reaction can be represented by the following equations:

O.sub.2+e.sup.O.sub.2*.sup.(1)

O.sub.2*.sup.+RX.fwdarw.RO.sub.2*+X.sup.(2)

RO.sub.2*+e.sup..fwdarw.RO.sub.2.sup.(3)

where R is the volatile anesthetic compound, and X is a halogen molecule in the anesthetic compound. Subsequent to the reaction in Equation (3), oxygen is reduced at the cathode and the electrons are consumed in this process. Further, nickel deposited on the anode oxidizes in the presence of atmospheric oxygen, humidity, and applied potential, generating a current that flows towards the cathode. The current can then be detected using an amperometric method and quantified to delineate the concentration of the volatile anesthetics.

[0035] In some embodiments, the three-electrode system can be constructed in such a way that the working electrode and the reference electrode are located in close proximity to each other, albeit on opposite sides of the PEM electrolyte, enabling easy exchange of H.sup.+ ions (FIGS. 1A and 1B). This design facilitates the monitoring of the anodic reaction of the fuel-cell based sensor.

[0036] One advantage of the three-electrode system is that it monitors only the anodic half-cell reaction as given in Equation (1). This can be achieved by measuring the potential between the anode and the reference electrode, and letting the current pass between the anode and the cathode. This mechanism yields a more stable signal of the concentration of the anesthetics at the anode than the traditional two-electrode system. Additional advantages of the three-electrode system includes, for example, a stable reference voltage provided by abundant atmospheric oxygen reduction occurring across the reference and working electrode, avoidance of short circuit voltage between the working and the reference electrode, and elimination of limited electron flow due to limited surface area of the counter electrode.

[0037] In some embodiments, the sample is a product of human transdermal diffusion process. Exemplary embodiments provide that the sample is obtained from human skin perspiration of a subject who has received anesthetics treatment.

[0038] In an embodiment, a method of continuously detecting the concentration of volatile anesthetics in skin perspiration collected from a human subject can comprise: [0039] contacting a sample with the sensing device provided herein; [0040] obtaining open-circuit potential (OCP) of the sensor unit by scanning a range of voltage; [0041] comparing the OCP to a threshold value characteristic to the material employed in the working electrode; [0042] applying the OCP across the working and the reference electrode while conducting a series of amperometric measurements; and [0043] determining the concentration of the volatile anesthetic based on the amperometric measurements.

[0044] In some embodiments, the sensing device can be placed in direct contact with human skin. Human skin comprises epidermis and dermis as the outermost two layers. Volatile anesthetics diffused out of the epidermis interact with the anode of an exemplary fuel-cell based sensor when the sensor is disposed in close proximity to the skin surface.

[0045] In another embodiment, a device for determining the amount of volatile anesthetics in a skin perspiration sample collected from a human subject can comprise: [0046] the fuel-cell based sensing device provided herein; [0047] a means of displaying the concentration of the anesthetics measured with the sensing device; [0048] circuitry capable of processing and analyzing the concentration data output by the sensing device; and [0049] optionally a casing that encloses the sensing device.

[0050] The anesthetics sensing device provided herein can be integrated with additional components for various applications. Embodiments of the integrated device include, but are not limited to, wrist watches, bracelets, and arm bands; apparel such as shirts, jackets, and pants; accessories such as gloves, glasses, goggles, necklaces, and lanyards; headsets and headbands; shoes; vehicle accessories such as a steering wheel and its cover, a transmission stick and its cover, ignition button, and keys.

[0051] In some embodiments, the measured anesthetics can be shown via a display capable of portraying data in the form of visual text and/or images. Non-limiting examples of the display include devices comprising liquid crystal materials, electrophoretic material, and/or electrochromic materials that are commonly found in applications such as electronic paper, computer monitors, handheld devices and the like.

[0052] In some embodiments, the fuel-cell based sensor provided herein can be incorporated (e.g., retrofitted) into devices manufactured by third parties.

[0053] Embodiments of the integrated devices comprise casings for the sensors provided herein and can help prevent circuitry damage and hold the sensor components together. The materials that can be used to develop the casings include, but are not limited to, polymers, fabrics, and metals.

[0054] In further embodiments, the integrated sensing device comprises an electronic platform for receiving user input.

[0055] In addition to monitoring the concentration of volatile anesthetics, technologies provided herein can also be used for sensors aimed to detect other chemical species capable of diffusing through the skin including, but not limited to, oxygen, carbon dioxide, carbon monoxide, acetone, glucose, salts, esters, aldehydes, and oxides of nitrogen.

[0056] Further, in some embodiments, the fuel-cell based sensor can be combined with other techniques including, but not limited to, ultrasound, electrotransport, and electroporation that facilitate the transport of volatile anesthetics through the skin, leading to minimal or no delay in estimating the concentration of the anesthetics based on the transdermal reading.

[0057] Advantageously, the fuel-cell based sensor provided herein can monitor the concentration of volatile anesthetics from skin perspiration and transdermal diffusion even in the presence of high humidity. This is accomplished by, in accordance with embodiments of the subject invention, taking advantage of low-cost materials such as stainless steel and nickel for the electrodes and the catalyst, respectively. This combination of devices and techniques allows selectivity in detecting transdermal content of volatile anesthetics and can be adapted in a variety of applications such as, for example, wearable devices.

[0058] The methods and processes described herein can be embodied as code and/or data. The software code and data described herein can be stored on one or more machine-readable media (e.g., computer-readable media), which may include any device or medium that can store code and/or data for use by a computer system. When a computer system and/or processer reads and executes the code and/or data stored on a computer-readable medium, the computer system and/or processer performs the methods and processes embodied as data structures and code stored within the computer-readable storage medium.

[0059] It should be appreciated by those skilled in the art that computer-readable media include removable and non-removable structures/devices that can be used for storage of information, such as computer-readable instructions, data structures, program modules, and other data used by a computing system/environment. A computer-readable medium includes, but is not limited to, volatile memory such as random access memories (RAM, DRAM, SRAM); and non-volatile memory such as flash memory, various read-only-memories (ROM, PROM, EPROM, EEPROM), magnetic and ferromagnetic/ferroelectric memories (MRAM, FeRAM), and magnetic and optical storage devices (hard drives, magnetic tape, CDs, DVDs); network devices; or other media now known or later developed that is capable of storing computer-readable information/data. Computer-readable media should not be construed or interpreted to include any propagating signals. A computer-readable medium of the subject invention can be, for example, a compact disc (CD), digital video disc (DVD), flash memory device, volatile memory, or a hard disk drive (HDD), such as an external HDD or the HDD of a computing device, though embodiments are not limited thereto. A computing device can be, for example, a laptop computer, desktop computer, server, cell phone, or tablet, though embodiments are not limited thereto.

EXAMPLES

[0060] The following are examples that illustrate the aforementioned embodiments and should not be construed as limiting. All of the chemical supplies provided herein, unless otherwise noted, were obtained via commercial sources and are readily available for procurement.

Example 1Coating an Electrode with a Catalyst for the Fuel-Cell Based Sensor

[0061] The coating of a catalyst (i.e., nickel) on the micro-perforated stainless steel sheet electrodes was achieved by a five-step process. The steps comprise: (i) anodically electrocleaning the stainless sheet for 5 mins with 25% H.sub.2SO.sub.4 below room temperature by applying a current density of 13.94 A/m.sup.2. During electrocleaning, the stainless steel served as the anode and the lead sheet served as the cathode; (ii) acid-cleaning the stainless sheets at room temperature with 1:10:1000 solution of HCl, H.sub.2SO.sub.4, and DI water; (iii) Wood's nickel strike using 1.5M HCl and 1.009 M anhydrous nickel chloride solution and applying current densities of 4.65 A/m.sup.2 and 1.4 A/m.sup.2 for 2 mins each. In the Wood's nickel strike setup, a pure nickel sheet was used as the anode and the target electrode as the cathode; (iv) galvanostatically electroplating the sheets with nickel by Watt's deposition method at 50 C. at 0.2 A in a mixture of 0.93 M nickel sulfamate, 0.025 M nickel chloride, and 0.48 M boric acid solution; (v) baking and drying the sheets at 190 C. for 2 hrs. The voltage was maintained at below 3 V during the electroplating process. In some embodiments, a porous nickel sheet can be used as an electrode material in lieu of a nickel-coated micro-perforated stainless steel sheet.

Example 2Measuring the Effect of Volatile Anesthetics on the OCP of the Sensor

[0062] The open circuit potential (OCP) of the fuel-cell based sensor in the presence of isoflurane was examined and the results are as shown in FIG. 2. An isoflurane cloud was introduced to the sensor system after 500 s of OCP scanning. Amperometric studies were completed with the sensor exposed and shielded to isoflurane vapor (FIG. 3). The effect of isoflurane vapor concentration on the current measured by the senor was also investigated.

[0063] As shown in FIG. 2, the OCP deviated 40 mV from the point of introducing the isoflurane cloud, indicating a potential difference was resulted due to the redox chemical reactions described herein. After removing the volatile cloud, the OCP signal of the sensor gradually reached a steady state (see also FIG. 4).

[0064] The effect of concentration of isoflurane on the current measured by the sensor can be seen in FIG. 5. A linear response was observed when the concentration of the isoflurane was between 5 ppm and 40 ppm. This linear response was further analyzed using a calibration fit as shown in FIG. 6.

[0065] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.

[0066] All patents, patent applications, provisional applications, and publications referred to or cited herein (including those in the References section) are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

REFERENCES

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