Patent Application
20250064360
The disclosed technology relates to methods and devices that pertain to solid state sensor for touch-based rapid physiological and chemical sensing.
Recent fingertip touch-based sensors enable sweat collection from the fingertip without the need for exercise or active extraction using hygroscopic porous hydrogel for analyte collection and the electrolyte that covers the electrode surfaces to enable rapid non-invasive sensing. However, such sensors still require the use of hydrogel that is prone to drying, and also contain additional problems on the sensing process due to analyte dilution and accumulation. The use of hydrogel is also difficult in its execution and storage, making the device and operation less practical and accessible for users.
The disclosed technology can be implemented in some embodiments to provide methods, materials and devices that pertain to solid-state gel-free sensor for touch-based rapid physiological and chemical sensing.
In some implementations of the disclosed technology, a sensor device includes a substrate, a plurality of first electrodes formed over the substrate and extending in a first direction, a plurality of second electrodes formed over the substrate and extending in the first direction, a first current collector formed over the substrate and coupled to the plurality of first electrodes at one end of each first electrode, and a second current collector formed over the substrate and coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged in a second direction, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
In some implementations of the disclosed technology, a sensor device includes a plurality of first electrodes and a plurality of second electrodes; a first current collector coupled to the plurality of first electrodes at one end of each first electrode; and a second current collector formed over the substrate and coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
In some implementations of the disclosed technology, a sensor device comprising a plurality of electrode arrays for simultaneous or sequential sensing of multiple biomarkers of physiological parameters, wherein each of the electrode arrays comprises: a plurality of first electrodes and a plurality of second electrodes; a first current collector coupled to the plurality of first electrodes at one end of each first electrode; and a second current collector formed over the substrate and coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
In some implementations of the disclosed technology, an array of sensors including a plurality of sensor devices, wherein the plurality of sensor devices is formed onto a substrate for sensing multiple biomarkers in a biofluid from different locations of a body simultaneously or sequentially.
In some implementations, a method includes placing a sensor device in contact with a skin of a subject, and measuring a biomarker in a biofluid from the skin of the subject using the sensor device. In some implementations, the sensor device may include a plurality of first electrodes and a plurality of second electrodes; a first current collector coupled to the plurality of first electrodes at one end of each first electrode; and a second current collector coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
The above and other aspects and implementations of the disclosed technology are described in more detail in the drawings, the description and the claims.
Disclosed are methods, materials and devices that pertain to solid-state gel-free sensor for touch-based rapid physiological and chemical sensing. The disclosed technology can be implemented in some embodiments to provide a new class of non-invasive, pain-free sensors for the direct sampling and frequent measurement of the biomarker in sweat and the related physiological states, such as sweat rates. The sensor can operate with the user's direct contact using a fingertip or any other skin surfaces that emit passive, natural, thermoregulatory eccrine sweat, and measure the concentration of various ions and biomolecules in the sweat (e.g., sodium, potassium, chloride, glucose, lactate, urea, uric acid, bilirubin, hydroxybutyrate, vitamins, alcohol, levodopa, caffeine, cortisol, insulin, explosives, narcotics, nerve agents, fluoride, calcium, zinc, lead, cadmium, mercury) via electrical (e.g, conductivity, piezoresistive, thermoresistive, piezocapacitive, thermoelectric, piezoelectric), chemical (e.g., non-specific adsorption, specific binding, intercalation, insertion), or electrochemical (e.g., catalysis, redox reaction) transduction methods. The sensor uses a closely spaced or interdigitated electrode design that ensures a small inter-electrode distance (<1 mm), which enables the ionic pathway between two or more electrodes for signal transduction when in contact with the fingertip. Some embodiments of the disclosed technology can obviate the need for external analyte collection mechanisms, such as the use of hydrogels, hydrocolloids, porous materials, microfluidic channels, microneedles, iontophoresis, reverse iontophoresis, transdermal cholinergic agent delivery etc., and allows rapid, maintenance-free user-friendly near real-time biochemical and physiological sensing via direct skin contact. For this reason, the device also grants reusability and extended operation time, allowing the same sensor to be used repeatedly and frequently for users after a simple cleaning (wipe with a tissue or rinse with water).
Diabetes patients that need constant glucose monitoring use finger-pricking blood glucose meters which are highly invasive and painful. Alternative continuous glucose monitoring systems were developed, yet still requires the insertion of needles into the body for continuous sensing, which is invasive and requires maintenance. For the sensing of glucose and many other biomarkers important to human health, new wearable sensors were proposed featuring non-invasive sensing from more accessible biofluids such as sweat or interstitial fluids. The use of such epidermal sensors often requires arduous analyte extraction processes such as exercises, heat, or iontophoresis, and rely on complicated device structure, such as microfluidic devices, microneedles, iontophoretic patch etc. Such processes are intrusive, complex, and high maintenance for self-monitoring. Moreover, these devices require either a large quantity of analyte, or require special analyte uptake mechanism, such as microfluidic channels, or hydrogels, to ensure coverage of the electrode surfaces.
Recently, fingertip touch-based sensors were proposed that can enable sweat collection from the fingertip without the need for exercise nor active extraction using hygroscopic porous hydrogel for analyte collection and the electrolyte that covers the electrode surfaces to enable rapid non-invasive sensing and has been demonstrated for the sensing of various chemicals. However, this process still requires the use of hydrogel that is prone to drying, and also contain additional problems on the sensing process due to analyte dilution and accumulation. The use of hydrogel is also difficult in its execution and storage, making the device and operation less practical and accessible for users.
The disclosed technology can be implemented in some embodiments to provide a new approach for epidermal sweat sensing that obviates the need for any arduous sweat collection process such as exercises, heat, chemical stimulation or iontophoretic extraction. By using closely spaced electrodes functionalized with transducers for biomarkers, the user can perform sensing non-invasively, painless, and maintenance-free in a rapid fashion. The closely spaced or interdigitated electrode design obviates the use of hydrogel, which make the device more accessible, simple, stable, and for frequent repetitive measurements.
In some embodiments of the disclosed technology, a sensor device includes a plurality of first electrodes extending in a first direction, a plurality of second electrodes extending in the first direction, a first current collector coupled to the plurality of first electrodes at one end of each first electrode, and a second current collector coupled to the plurality of second electrodes at one end of each second electrode.
In some embodiments of the disclosed technology, the first electrodes and the second electrodes are arranged very close to each other (e.g., the distance between adjacent first and second electrodes can be smaller than 1 mm). As shown in
Referring to
Referring to
In one implementation, as shown in
Referring to
In some implementations, a sensor device includes a plurality of electrode arrays, each of which includes the first electrodes and the second electrodes discussed in this patent document. In one example, as shown in
In some implementations, as shown in
The device is a sensor composed of at least two electrodes, of which at least two of them are in a closely spaced or interdigitated configuration with a minimum distance of <1 mm from the other. The sensor includes a substrate made of glasses, silicon, paper, textile, or polymeric plastics or elastomers. The electrode can be fabricated via thin-film deposition processes such as ink-jet printing, sputtering, chemical/physical vapor deposition, thick-film deposition processes such as screen-printing, spray-coating, flexography, hydro or other additive or subtractive manufacturing processes such as computer numerical controlled milling, laser ablation, 3D printing, electrospinning. The sensor should contain a conductive electrode that can be composed of metal (e.g., Cu, Ag, Au, Pt), doped metal oxide (e.g., ITO, FTO), carbonaceous materials (e.g., graphite, graphene, reduced graphene oxide, activated carbon, carbon nanotubes, diamond), conductive polymer (e.g., PEDOT:PSS, polypyrrole, polyaniline, poly p-phenylene, polythiophene), or 2D materials (e.g., MoS2, WSe2, VO2). The electrode can be functionalized with various chemical/electrochemical transducers, such as enzymes (e.g., lactate oxidase, lactate dehydrogenase, glucose oxidase, glucose dehydrogenase, bilirubin oxidase, uricase, urea oxidase, alcohol oxidase, alcohol dehydrogenase, tyrosinase, catalase), catalysts (e.g., platinum, ruthenium, palladium, rhodium, silver), redox mediators (Prussian blue, Meldola's blue, methylene blue, indigo carmine, 2,2′-bipyridine, 1,4-naphthoquinone, tetrathiafulvalene, tetracyanoquinodimethane, ferrocene) antibodies, ion-selective membranes, silver/silver chloride mixture, molecularly imprinted membranes, or aptamers, for the sensing of biomarkers. The sensor may include additional closely spaced or interdigitated electrodes for physiological sensing, with physical transducers such as thermoresistive, thermoelectric, piezoresistive, piezocapacitive, piezoelectric, photovoltaic, physisorption, or chemisorption materials that sense physical properties such as temperature, skin moisture level, or pressure. The sensor may also include a protection layer composed of polymeric materials such as Nafion, chitosan, ethylcellulose, polyvinyl chloride. The sensor may also include an insulation layer composed of dielectric materials. The electrode layer composition can be a singular material as listed above, or a mixture or composite of the above materials.
The fabricated sensor may be used for non-invasive chemical sensing with optional complementary physiological sensing. In one example, the user can use the closely spaced or interdigitated sensor functionalized with glucose oxidase for the rapid and simple sensing of glucose in sweat, in order to establish a correlation to blood glucose level. The user can directly press the sensor for ca. 30-60 s where a potential step is applied chronoamperometric signal will be read to obtain the signal. In another example, the user can use closely spaced or interdigitated sensors made with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and lactate oxidase, along with a closely spaced or interdigitated sensor made with silver to sense the sweat lactate level and the skin moisture level simultaneously, and the skin moisture data can be used to calibrate the sweat lactate signal. In another example, the user can use a closely spaced or interdigitated 3-electrode sensor functionalized in which one of the electrodes is functionalized with a pH-sensitive polyaniline polymer, and another electrode functionalized with alcohol oxidase enzyme. The user can directly press on the sensor for 30-60 s where a potential step for chronoamperometry is applied to the enzyme electrode and the open-circuit potential is monitored on the pH-sensitive electrode, and the sweat pH data and sweat alcohol signal can be obtained simultaneously, and the sweat pH data can be used to calibrate the sweat alcohol signal for improved accuracy. In these examples, the sensors may be simply reused multiple times after rapid and simple cleaning of the electrode surface via rinsing with water or wiping with tissues. For nearly real-time measurement over an extended period, the obtained data can be validated with other measurement methods such as glucometer, blood test, breathalyzer etc. and establish personal calibration to associate the thermoregulatory sweat biomarker level with biomarker level in the blood or other environment of interest.
Referring to
In some implementations, the first electrodes 110 may be used as working electrodes, and the second electrodes 120 may be used as reference/counter electrodes. In some implementations, the first electrodes 110 may include PEDOT:PSS-Prussian blue (PB) cathode, and the second electrodes 120 may include poly(3,4-ethylene dioxythiophene) polystyrene sulfonate (PEDOT:PSS) anode. In some implementations, the first electrodes 110 and the second electrodes 120 are solid-state interdigitated electrodes (IDEs) printed on a styrene-isoprene-styrene block copolymer (SIS) substrate. In some implementations, the solid-state interdigitated electrodes (IDEs) are decorated with the glucose oxidase (GOx) enzyme that reacts selectively with the glucose in the fingertip sweat for subsequent detection. In some implementations, the first electrodes 110 and the second electrodes 120 extend in the same direction (e.g., the second direction) and alternately arranged at a predetermined distance. In one example, the predetermined distance between adjacent first electrodes 110 and second electrodes 120 provides ionic pathways. In some implementations, the predetermined distance is smaller than 1 mm.
In some implementations, the gel-free sensor 100 may further include a substrate structured to support the first and second electrodes 110, 120 and the first and second current collectors 130, 132. In one example, the substrate includes at least one of glass, silicon, paper, textile, polymeric plastic or elastomer. In some implementations, the gel-free sensor 100 may further include a glucose oxidase (GOx) enzyme layer formed over the first and second electrodes and the first and second current collectors to react selectively with a glucose in a body fluid for detection. In one example, the body fluid includes a fingertip sweat.
The disclosed technology can be implemented in some embodiments to provide a solid-state touch sensor that enables a frequent, accurate, non-invasive glucose monitoring.
Type 1 diabetes is a chronic disease that requires frequent blood glucose testing for preventing acute and long-term complications. Common glucose monitoring methods, including finger-pricking capillary blood tests and subdermal continuous glucose monitors, are painful and invasive, respectively, whereas recent non-invasive epidermal sensors are limited in practicality and reliability. The disclosed technology can be implemented in some embodiments to provide a convenient, rapid, and accurate approach using interdigitated electrode transducer for frequent touch-based sweat glucose biosensing that leverages the passive perspiration from the fingertip. The interdigitated design establishes a solid-state interface and eliminates the need for sweat-collecting hydrogels, which greatly simplifies the sensing workflow and grants stability and reusability. The sensor can be used repeatedly for day-long glucose self-monitoring and delivers reliable glucose data with the low mean-absolute relative difference of 8.69%, comparable to that of commercial fingerstick and continuous glucose monitors. The new protocol based on some embodiments provides convenient, practical, and pain-free glucose sensing, promoting frequent self-testing and improved diabetic self-care.
Diabetes is a global health concern, ranking among the leading causes of death. Frequent monitoring of blood glucose levels is critical for understanding the disease progression and optimizing its control. While diabetes patients have relied over the past 3 decades on performing finger-pricking self-monitoring of blood glucose (SMBG) multiple times daily, the painful, inconvenient, and invasive nature of such finger-pricking step compromises patient compliance and greatly decreases the testing frequency. Continuous glucose monitoring (CGM) addresses these limitations of SMBG and offers significant improvements in the management of diabetes. While removing the need for finger pricking and providing more insights from continuous data, CGMs still use invasive (e.g., ˜10 mm long) costly needles, require daily SMBG calibration, and are challenged by biofouling, long stabilization time, glucose time delay, and limited lifetime. While alternatives, such as non-invasive sweat and interstitial fluid (ISF) glucose sensors, have been proposed recently, their practicality is largely impeded by complex biofluid extraction mechanisms (e.g., exercise, sweat-inducing drug, reverse iontophoresis), which may induce unnatural metabolic activities or dilutions that affect the correlation with blood glucose concentrations. Indeed, it was demonstrated that sweat glucose can accurately reflect blood glucose levels upon proper harvesting of sweat. Recent advances cleverly leveraged the direct sampling of the passive, thermoregulatory sweat from the high-sweat-rate fingertip for chemical sensing, leading to the monitoring of cortisol, levodopa, glucose, caffeine, lactate, and ascorbic acid concentrations. However, such touch-based sensing has relied on hydrogel as a sweat collection interface (made of agarose or polyvinyl alcohol), mounted on the sensor, which leads to major challenges and errors due to analyte carry-over, dilution, and solvent evaporation. The use of the hydrogel interface thus suffers from inconsistent sensing results and requires inconvenient lengthy gel replacement, hence greatly impeding the reliability, repeatability, durability, simplicity, and overall practicality of such technology.
The disclosed technology can be implemented to address the above issues by providing a reusable solid-state touch-based electrochemical sensing protocol for reliable, frequent extended glucose monitoring. To eliminate the need for hydrogels, the sensor relies on a solid-state interdigitated electrode (IDE) design, which consists of a poly(3,4-ethylene dioxythiophene) polystyrene sulfonate (PEDOT:PSS) anode and PEDOT:PSS-Prussian blue (PB) cathode, printed on a styrene-isoprene-styrene block copolymer (SIS) substrate. These printed IDE electrodes are decorated with the glucose oxidase (GOx) enzyme that reacts selectively with the glucose in the fingertip sweat for subsequent detection (
To fully utilize the low volume of sweat on the fingertip, the sweat distribution on the surface of the fingertip was examined closely by using the color-changing bromocresol green dye that turns blue upon contact with the sweat. As shown in
The performance of the gel-free touch-based sensor for glucose monitoring was characterized first in-vitro using glucose in phosphate buffer solutions (PBS) at pH 7. The optimal potential was optimized at −0.1V between cathode and anode, which results in the highest CA response. Similarly, the sensor was evaluated in artificial sweat (with a lower pH of 6), showing that the optimal potential and response are unaffected by the lower pH (
The IDE design thus allows the solid-state contact-based fingertip sensing, offering significant advantages over common hydrogel-based sweat collection mechanisms in terms of simplicity, reusability, testing frequency, and data reproducibility. As a comparison, the same finger was tested repeatedly on the same sensor with and without the hydrogel with steady and falling glucose levels (before and 30 min after a meal, respectively). As shown in
Following the systematic optimization and characterization, the accuracy of the touch sensor was assessed with five healthy, non-diabetic male and female subjects between the ages of 22-36. Due to the individual differences (e.g., sweat rate, fingertip size), each subject was tested initially before and 20 min after meals to construct a personalized calibration between the CA signal of the gel-free touch-based glucose sensor and the CBG level obtained from fingerstick SMBG (
The ability to use the touch-based gel-free glucose sensor for replacing fingerstick SMBG toward frequent non-invasive and rapid glucose sensing was evaluated first over a 3 h period, during which all subjects consumed a high-calorie meal followed by a sugar-rich juice, while performing the touch-based sensing (with the same sensor) every 5 min and fingerstick CBG reference measurements at 10 min intervals (
The mean absolute relative difference (MARD) and the Clarke's error grid analysis (CEGA) are common methods to evaluate the accuracy and reliability of the glucose-sensing technologies. Commercial CGM systems commonly feature MARD values between 9-14%. The gel-free touch-based sensor is characterized with a MARD of 8.69% (with data size n=160), which reflects its high accuracy, comparable to that of commercial glucose monitoring devices. With additional calibrations (vs blood; over initial 3-5 days, instead of the first one) has shown no significant improvement in MARD, whereas when accounting for the time delay, the MARD of the sensor can be further reduced to 4.76% (Table 1). The CEGA assesses the reliability of the glucose monitoring technology, by separating the grid into separate zones, A through E, with zone A corresponding to the values within 20% of the reference and means no effect on clinical action. As shown in
The disclosed technology can be implemented in some embodiments to provide a highly accurate, simple, and rapid glucose-sensing protocol using an interdigitated, solid-state PEDOT:PSS-based electrode, which leverages the passive perspiration of the fingertips to enable reliable near real-time non-invasive monitoring of glucose levels. Eliminating the need for the sweat collecting hydrogel interface greatly simplified the operation to allow frequent repetitive measurements over the entire day while offering superior analytical performance compared to traditional hydrogel-based SPE sensors. Compatible with diverse subjects, the sensor can rapidly establish personalized calibration (from merely initial 2 fingerstick measurements), showing considerable promise towards substituting painful, frequent finger pricking SMBG and invasive CGM technologies for extended day-long continuous glucose monitoring. The new protocol offers high accuracy with low MARD and good CEGA metrics, which are comparable to those of commercial glucose sensing technologies, along with painless (blood- and needle-free), rapid operation. The same low-cost sensor can be used without any re-stabilization, performing over 50 measurements throughout the day. Such convenient touch-based sensing greatly increases the frequency of self-testing compared to traditional SMBG, to offer enhanced diabetes control. The disclosed technology may also be implemented in some embodiments to enable large-scale validation using diverse subjects, and to increase further the speed and simplicity develop an advanced blood-free calibration process and prediction algorithm, along with improved understanding of the fingertip passive perspiration phenomenon and of the role of the electrode geometry at the hydrogel-free IDE setup. Translating such contact-based sensing into wearable devices towards passive, continuous monitoring of glucose day and night would further promote its practical usage as a true CGM alternative. Combined with engineering efforts for creating a user-friendly sensor prototype, these developments may lead to highly reliable pain-free rapid, and frequent self-testing of glucose for home and other decentralized settings towards improved management of diabetes, as well as for simplified and accurate non-invasive monitoring of other key sweat biomarkers.
In some implementations, graphite, toluene, acetone, ethanol, glutaraldehyde, D-(+)-glucose, glucose oxidase (GOx), Ag flake, potassium chloride (KCl), sodium chloride (NaCl), sodium phosphate anhydrous, Prussian blue, and sodium dodecylbenzene sulfonate (DBSS) may be used for fabrication of the interdigitated electrode based on some embodiments of the disclosed technology. In some implementations, Styrene-ethylene-butylene-styrene (e.g., SEBS G1645) triblock copolymer may be used for fabrication of the interdigitated electrode based on some embodiments of the disclosed technology. In some implementations, the screen printable PEDOT:PSS paste may be used for fabrication of the interdigitated electrode based on some embodiments of the disclosed technology.
In some implementations, the IDE sensor may be fabricated using layer-by-layer screen-printing with customized four kinds of inks: the electrochromic poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) ink, the silver ink for interconnection, and an insulating resin composed of SEBS. The PEDOT:PSS ink may be formed using a mixture of ink prepared using 1 g of PEDOT:PSS paste, 0.2 mL of toluene, 0.15 mL DBSS (75 mg/ml in DI water), and 0.0135 mL of fluorosurfactant FS-65. To make the PEDOT:PSS-PB ink, similar components may be used, with additional 20 mg of PB powder that is added per 1 g of mixture. The stretchable silver ink may be synthesized. In some implementations, silver flakes, toluene, and SEBS may be mixed in a weight ratio of 4:2.37:0.63. All the inks may be homogenized by mixing them in a dual asymmetric centrifugal mixer, e.g., with a speed of 1900 RPM for 5 min. The insulating resin is prepared by dissolving SEBS a toluene solution (4:10 weight ratio). The solution is then mixed at 1900 RPM for 20 min or until the SEBS is completely dissolved in the solution.
After ink preparation, the flexible substrate for printing the fingerprint sensor is fabricated. With the assistance of a stainless-steel rod, a SIS layer of 1000 μm is formed on top of a plastic sheet of PET. The thin layer is dried at 60° C. for 30 min. The printed electrode patterns (Area of electrodes 0.02 cm2) are designed in software and are transferred to stainless steel plates (12×12 in2) etched to fabricate metallic stencils. The electrochemical system, composed of a working and reference electrodes, was screen printed using an MPM-SPM semi-automatic screen printer. The printing process consisted of printing first the reference electrode using the PEDOT:PSS ink on the SIS substrate followed by a curing step of 30 min at 120° C. Next, the working electrode was printed using the PEDOT:PSS-PB ink, similar drying conditions are applied after printing the electrode. Subsequently, the silver interconnection pattern was printed on top of the electrode system followed by a curing step of 15 min at 90° C. The interconnections are insulated using the SEBS resin. Finally, the insulator is allowed to dry for 10 min at 90° C. to obtain the printed IDE electrode.
The IDE electrodes are modified by drop-casting a mixture 6 μL of glucose oxidase (20 mg/mL in PBS 0.1 M pH 7.3) and 3 μL of glutaraldehyde (1% in DI water) on top of the exposed electrodes surfaces. After modification, the electrodes are stored overnight at 4° C. inside a refrigerator.
The in-vitro characterization of the touch-based glucose sensor was conducted using both 0.1 M PBS (pH 7.3) and artificial sweat (AS, pH 6.0). Two-electrode cyclic voltammetry between −0.35 V and 0.55V was performed to observe a redox peak of PB molecules at 0.02 V and −0.08 V in PBS and 0.12 V and −0.04 V in AS. The optimization of the applying potential was studied at different potential decreasing from 0 V to −0.3 V with 50 mV steps. From the current response at different potential, −0.1 V was selected and used in subsequential in-vitro and on-body experiments (
Fingerprint sensing was performed on healthy consenting individuals and in strict compliance with the protocol approved by the Institutional review board at the University of California, San Diego. Volunteers were asked to place their index fingers on top of the sensor for all on-body evaluations. The glucose levels were validated using a commercial blood glucose meter. Before using the sensor, volunteers were asked to clean their hands with water and soap. The on-body results were acquired using a benchtop Autolab potentiostat/galvanostat 204 from Metrohm. Chronoamperometric potential steps of −0.1 V of 30 s were used during all experiments. To collect blood glucose levels, the finger of each individual was pricked, and a small droplet of blood was analyzed. Afterward, fingertip glucose signals were measured by touching the sensor for 60 s. Next, two chronoamperometric steps were performed to quantify the current signal. The last current value from the second scan was taken as the corresponding sweat glucose level. After each sensing session, the sensor was firstly wetted with deionized water then gently wiped with paper tissue to dry for the next measurement.
Blood and fingertip glucose signals were acquired from five volunteers during 5 consecutive days in fasting state and 20 min after consuming sugar-rich food. The current and blood glucose values were plotted together and using a linear fitting, with a slope b and intercept a were acquired for each subject using data obtained from a given number of days. To obtain the predicted glucose concentration for each subject, the following formula is used:
where “i” represents the current value obtained after the second chronoamperometric scan.
Three subjects were recruited to perform 3-hour monitoring experiments. The fasting state glucose levels were recorded for 20 min, followed by meal consumption. After 90 min, a high-sugar content drink was provided to each subject. Simultaneously, blood and fingertip glucose were monitored every 10 and 5 min, respectively. Two subjects were recruited to perform 12-hour experiments. Experiments started by monitoring both blood and fingertip glucose every hour. The periodic monitoring of both parameters was changed only after meal consumption at 1, 5, and 10 h. of starting the experiment. At these times slots, blood, and fingertip glucose were monitored every 10 and 5 min, respectively.
Achieving strict glycemic control towards effective management of diabetes requires frequent or continuous measurements of glucose. Non-invasive glucose monitoring has always been regarded as the “holy grail” of next-generation biosensing technology owing to its tremendous impact on a large population and huge commercial market. Yet, after decades of development, diabetes patients, who rely on multiple blood glucose self-monitoring daily to prevent life-threatening complications, are still dependent on painful inconvenient finger-pricking glucometers and costly and invasive continuous glucose monitors (CGMs). Although sweat and interstitial fluid-based non-invasive glucose sensing technologies have been proposed, their practical implementation is yet limited due to their lengthy and complex biofluid extraction processes. Addressing these challenges, our group has recently explored the use of passive perspiration from the fingertip for chemical sensing due to its high natural sweat rate. This fingertip-based contact sensing uses hydrogel to extract sweat from the fingertip and enable chemical monitoring, and faces various limitations, such as analyte carry-over and dilution, solvent evaporation, and inconvenient gel placement and storage, that hinder its practical utility for tracking dynamically changing concentrations.
Addressing the above issues, the disclosed technology can be implemented in some embodiments to provide a reusable solid-state touch-based electrochemical sensing protocol for reliable, convenient frequent extended glucose monitoring. In addition, the disclosed technology can be implemented in some embodiments to provide a unique solid-state interdigitated electrode transducer for direct touch-based glucose monitoring without the need for any sweat-extraction mechanisms. When touched by the fingertip, the solid-state interface is rapidly covered by a sweat layer across the interdigitated electrode, which rapidly records the glucose level without any preconditioning or incubation. Such painless biosensor features reusability and speed, and therefore can greatly increase the testing frequency, compared to traditional finger pricking, towards extended tracking of dynamic glucose variations over the entire day. Unlike early studies based on stimulated sweating via exercise or iontophoresis, which reported a low correlation to blood glucose, the present use of natural perspiration offers high accuracy in predicting blood glucose levels in connection to a single first-day personalized calibration. Conducted over 160 trials on subjects with diverse backgrounds through multiple day-long glucose monitoring sessions, the sensor closely matches blood glucose temporal profiles, delivering highly accurate blood glucose concentration data, as indicated from a low mean absolute relative difference (MARD) of 8.15%, which compares favorably with the accuracy of commercial blood glucose strips and CGMs (typically 9-14%). With the attractive features of the new user-friendly non-invasive biosensing method and its high-quality data, the disclosed technology can be implemented in some embodiments to enable non-invasive glucose monitoring that can become an important component of diabetic self-care.
In some implementations, the method 1400 includes, at 1402, placing a sensor device in contact with a skin of a subject, and at 1404, measuring a biomarker in a biofluid from the skin of the subject using the sensor device. The sensor device may include a plurality of first electrodes and a plurality of second electrodes; a first current collector coupled to the plurality of first electrodes at one end of each first electrode; and a second current collector coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
Therefore, various implementations of features of the disclosed technology can be made based on the above disclosure, including the examples listed below.
Example 1. A sensor device, comprising: a substrate; a plurality of first electrodes and a plurality of second electrodes formed over the substrate; a first current collector formed over the substrate and coupled to the plurality of first electrodes at one end of each first electrode; and a second current collector formed over the substrate and coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
Example 2. The sensor device of example 1, wherein the plurality of first electrodes includes working electrodes, and the plurality of second electrodes includes reference or counter electrodes.
Example 3. The sensor device of example 1, wherein the plurality of first and second electrodes includes at least one of a metal, a carbonaceous material, a doped conductive metal oxide, a conductive polymer, or a metal salt.
Example 4. The sensor device of example 3, wherein the metal includes at least one of silver, gold, platinum, copper, titanium, or brass.
Example 5. The sensor device of example 3, wherein the carbonaceous material includes at least one of graphite, carbon-nanotubes, graphene, laser-induced graphene, glassy carbon, or reduced graphene oxide.
Example 6. The sensor device of example 3, wherein the doped conductive metal oxide includes indium-tin oxide (ITO).
Example 7. The sensor device of example 3, wherein the conductive polymer includes at least one of polyaniline, polypyrrole, polythiophene, or poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS).
Example 8. The sensor device of example 3, wherein the metal salt includes silver chloride.
Example 9. The sensor device of example 3, wherein the plurality of first and second electrodes includes an electroactive redox mediator that includes at least one of a quinone, a Prussian blue, an osmium-containing redox mediator, a ruthenium-containing mediator, an organic dye, tetrathiafulvalene, tetrathiafulvalene-tetracyanoquinodimethane, or ferrocene.
Example 10. The sensor device of example 9, wherein the quinone includes at least one of benzoquinone, naphthoquinone (NQ), anthraquinone, hydroquinone, or chlorohydroquinone.
Example 11. The sensor device of example 9, wherein the osmium-containing redox mediator includes the osmium-containing redox mediator includes osmium bipyridine.
Example 12. The sensor device of example 9, wherein the ruthenium-containing mediator includes ruthenium bipyridine.
Example 13. The sensor device of example 9, wherein the organic dye includes at least one of methylene blue, toluidine blue O, methylene green, azure A and B, or thionine.
Example 14. The sensor device of example 1, wherein the substrate includes a polymer substrate, and wherein the plurality of first and second electrodes includes one or more solid-state interdigitated electrodes (IDEs) deposited on the polymer substrate. In some implementations, the deposition can be performed using a planer deposition method. In some implementations, the first electrodes and the second electrodes include materials that are deposited onto the substrate using at least one of screen printing, inkjet printing, flexography, sputtering, lithography, electrodeposition, or direct ink writing.
Example 15. The sensor device of example 1, wherein the substrate includes at least one of glass, silicon, paper, textile, polymeric plastic or elastomer.
Example 16. The sensor device of example 15, wherein the substrate includes the polymeric plastic or the elastomer and comprises one or more polymer layers, wherein the one or more polymer layers includes at least one of polyethylene, polypropylene, polyethylene terephthalate, polyvinyl chloride, polystyrene, polysaccharide-based polymer, polystyrene-based block copolymer, polysaccharide, polyvinyl alcohol, or polyethylene vinyl acetate.
Example 17. The sensor device of example 16, wherein the polystyrene-based block copolymer includes at least one of polystyrene-polyethylene-polybutylene-polystyrene (SEBS), poly styrene-polyisoprene-polystyrene (SIS), or poly styrene-polybutylene-polystyrene (SBS)).
Example 18. The sensor device of example 16, wherein the polysaccharide includes at least one of starch polymer, cellulose, nitrocellulose, chitosan, ethylcellulose, or methylcellulose.
Example 19. The sensor device of claim 1, wherein the substrate includes at least one of fluorinated polymer, co-polymer of the fluorinated polymer, poly (vinyl difluoroethylene), tetrafluoro propylene, or hexafluoro propylene.
Example 20. The sensor device of claim 19, wherein the co-polymer of the fluorinated polymer includes poly (tetrafluoro ethylene).
Example 21. The sensor device of example 1, wherein the sensor device is structured to be placed directly onto skin surfaces to interact with a natural perspiration directly without a biofluid collection mechanism including microfluidics or hydrogels.
Example 22. The sensor device of example 21, wherein the biofluid includes a fingertip sweat.
Example 23. The sensor device of example 1, wherein the predetermined distance between the adjacent first and second electrodes includes ionic pathways for signal transduction when in contact with a skin surface of a user by natural perspiration, and wherein the ionic pathway is only constructed upon contact with the skin is eliminated upon removing the sensor from the skin surface.
Example 24. The sensor device of example 1, wherein the predetermined distance is smaller than 1 mm.
Example 25. The sensor device of example 1, wherein the plurality of first electrodes and the plurality of second electrodes are interdigitated with one another, and wherein the interdigitated electrodes arranged parallelly, radially, or concentrically.
Example 26. The sensor device of example 1, further comprising at least one of an enzymatic transduction layer or a non-enzymatic transduction layer formed over the first and second electrodes and the first and second current collectors to react selectively with a biomarker in a body fluid for detection.
Example 27. The sensor device of example 26, wherein the enzymatic transduction layer includes an enzymatic material that includes at least one of glucose oxidase, glucose dehydrogenase, lactate oxidase, lactate dehydrogenase, alcohol oxide, alcohol dehydrogenase, tyrosinase, ascorbate oxidase, urease, uricase, xanthine oxidase, tyrosinase, glutamate oxidase, laccase, hydroxybutyrate dehydrogenase, catalase, or bilirubin oxidase.
Example 28. The sensor device of example 26, wherein the non-enzymatic transduction layer includes an electroactive non-enzymatic material that includes at least one of a metal nanoparticle, a metal, a nanozyme, or an ion-selective material.
Example 29. The sensor device of example 28, wherein the metal nanoparticle includes at least one of gold nanoparticle, platinum nanoparticle, or silver nanoparticle.
Example 30. The sensor device of example 28, wherein the metal includes at least one of copper or nickel.
Example 31. The sensor device of example 28, wherein the ion-selective material includes at least one of hydrogen ionophores, sodium ionophores, potassium ionophores.
Example 32. The sensor devices of example 26, wherein the at least one of an enzymatic transduction layer or a non-enzymatic transduction layer includes at least one of an enzyme co-factor, or a cross-linking chemical deposited below, with, or above the at least one of an enzymatic transduction layer or a non-enzymatic transduction layer.
Example 33. The sensor device of example 32, wherein the enzyme co-factor includes at least one of nicotinamide adenine dinucleotide, flavin adenine dinucleotide, flavin mononucleotide, heme, or ascorbic acid.
Example 34. The sensor device of example 32, wherein the cross-linking chemical includes at least one of glutaraldehyde, epoxy, dihydrazide, bisacrylamide, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS)), stabilizer, polymer, or surfactant.
Example 35. The sensor device of example 34, wherein the stabilizer includes at least one of bovine serum albumin, human serum albumin, glycerol, or poly phenylenediamine.
Example 36. The sensor device of example 34, wherein the polymer includes at least one of polyethyleneimine, polyurethane, polyvinyl alcohol, polyvinyl pyrrolidone, chitosan, or Nafion.
Example 37. The sensor device of example 34, wherein the surfactant includes at least one of sodium dodecyl sulfate, sodium dodecyl styrene sulfonate, Triton X-100, Triton X-114, or Tween 80.
Example 38. The sensor device of example 1, further comprising: a signal transduction layer disposed over the first and second electrodes to functionalize the first and second electrodes for biomarkers; and a protection layer on the signal transduction layer to protect the signal transduction layer.
Example 39. The sensor device of example 38, wherein the protection layer includes at least one of Nafion, chitosan, polyethyleneimine, polyurethane, polyvinyl alcohol, polyvinyl chloride, poly (vinyl difluoroethylene), poly (tetrafluoro ethylene), tetrafluoro propylene, hexafluoro propylene, starch polymer, cellulose, nitrocellulose, chitosan, ethylcellulose, or methylcellulose.
Example 40. The sensor device of example 1, wherein the sensor device is configured to react selectively with a biomarker in a body fluid for detection, wherein the biomarker includes at least one of glucose, lactate, alcohol, levodopa, creatinine, urea, uric acid, bilirubin, hydroxybutyrate, vitamin, oxygen, ion, hormone, opioid, or cannabinoid.
Example 41. The sensor device of example 40, wherein the vitamin includes ascorbic acid.
Example 42. The sensor device of example 40, wherein the ion includes at least one of proton, sodium, potassium, chloride, fluoride, calcium, zinc, lead, cadmium, or mercury.
Example 43. The sensor device of example 40, wherein the hormone includes at least one of cortisol, adrenaline, or insulin.
Example 44. The sensor device of example 1, wherein the sensor device is integrated with an additional sensor for measuring physical parameters when in contact with a skin, wherein the physical parameters include at least one of temperature, moisture, or pressure.
Example 45. The sensor device of example 1, wherein the sensor device is integrated with an additional sensor for measuring physiological parameters when in contact with a skin, wherein the physiological parameters include blood oxygen levels, heart rate, fingerprint patterns, or blood pressure.
Example 46. A sensor device comprising a plurality of electrode arrays for simultaneous or sequential sensing of multiple biomarkers of physiological parameters, wherein each of the electrode arrays comprises: a plurality of first electrodes and a plurality of second electrodes; a first current collector coupled to the plurality of first electrodes at one end of each first electrode; and a second current collector coupled to the plurality of second electrodes at one end of each second electrode, wherein the first electrodes and the second electrodes are alternately arranged, and adjacent first and second electrodes are spaced apart from each other by a predetermined distance.
Example 47. An array of sensors including a plurality of sensor devices according to any of examples 1-46, wherein the plurality of sensor devices is formed onto a substrate for sensing multiple biomarkers in a biofluid from different locations of a body simultaneously or sequentially.
Example 48. A method, comprising: placing a sensor device according to any of claims 1-47 in contact with a skin of a subject; and measuring a biomarker in a biofluid from the skin of the subject using the sensor device.
Example 49. The method of example 48, wherein the biomarker includes at least one of glucose, lactate, alcohol, levodopa, creatinine, urea, uric acid, bilirubin, hydroxybutyrate, vitamin, oxygen, ion, hormone, opioid, or cannabinoid.
Example 50. The method of example 48, further comprising measuring at least one of a physical parameter or a physiological parameter together with the biomarker, wherein the physical parameter includes at least one of temperature, moisture, or pressure, and the physiological parameter includes at least one of skin resistance, temperature, blood oxygen levels, heart rate, fingerprint patterns, or blood pressure.
Implementations of the subject matter and the functional operations described in this patent document can be implemented in various systems, digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. Implementations of the subject matter described in this specification can be implemented as one or more computer program products, i.e., one or more modules of computer program instructions encoded on a tangible and non-transitory computer readable medium for execution by, or to control the operation of, data processing apparatus. The computer readable medium can be a machine-readable storage device, a machine-readable storage substrate, a memory device, a composition of matter effecting a machine-readable propagated signal, or a combination of one or more of them. The term “data processing unit” or “data processing apparatus” encompasses all apparatus, devices, and machines for processing data, including by way of example a programmable processor, a computer, or multiple processors or computers. The apparatus can include, in addition to hardware, code that creates an execution environment for the computer program in question, e.g., code that constitutes processor firmware, a protocol stack, a database management system, an operating system, or a combination of one or more of them.
A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program does not necessarily correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network.
The processes and logic flows described in this specification can be performed by one or more programmable processors executing one or more computer programs to perform functions by operating on input data and generating output. The processes and logic flows can also be performed by, and apparatus can also be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit).
Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read only memory or a random access memory or both. The essential elements of a computer are a processor for performing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto optical disks, or optical disks. However, a computer need not have such devices. Computer readable media suitable for storing computer program instructions and data include all forms of nonvolatile memory, media and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.
It is intended that the specification, together with the drawings, be considered exemplary only, where exemplary means an example. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Additionally, the use of “or” is intended to include “and/or”, unless the context clearly indicates otherwise.
While this patent document contains many specifics, these should not be construed as limitations on the scope of any invention or of what may be claimed, but rather as descriptions of features that may be specific to particular embodiments of particular inventions. Certain features that are described in this patent document in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination.
Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. Moreover, the separation of various system components in the embodiments described in this patent document should not be understood as requiring such separation in all embodiments.
Only a few implementations and examples are described and other implementations, enhancements and variations can be made based on what is described and illustrated in this patent document.
This patent document claims priority to and benefits of U.S. Provisional Appl. No. 63/266,513, entitled “GEL-FREE SENSOR FOR TOUCH-BASED RAPID PHYSIOLOGICAL AND CHEMICAL SENSING” and filed on Jan. 6, 2022. The entire contents of the before-mentioned patent application are incorporated by reference as part of the disclosure of this document.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/060264 | 1/6/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63266513 | Jan 2022 | US |
