WO2026020101A1 - Wearable systems for lactate detection and system for drug delivery based upon lactate detection - Google Patents

Abstract

A system includes a wearable device including a base adapted to be connected to skin of a patient. An electrochemical sensor is connected to the base. The electrochemical sensor includes a sensor medium responsive to lactate. The electrochemical sensor is in fluid connection with one or more transdermal fluid paths in connection with the base. The one or more transdermal fluid paths are configured to be placed in fluid connection with the subdermal fluid of the patient. The system further includes electronic circuitry including at least one measurement system in operative connection with the electrochemical sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the subdermal fluid.

Description

WEARABLE SYSTEMS FOR LACTATE DETECTION AND SYSTEM FOR

DRUG DELIVERY BASED UPON LACTATE DETECTION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Patent Application Serial No.

63/673,233, filed July 19, 2024, the disclosure of which is incorporated herein by reference.

BACKGROUND ART

[0002] The following information is provided to assist the reader in understanding technologies disclosed below and the environment in which such technologies may typically be used. The terms used herein are not intended to be limited to any particular narrow interpretation unless clearly stated otherwise in this document. References set forth herein may facilitate understanding of the technologies or the background thereof. The disclosure of all references cited herein are incorporated by reference.

[0003] As a part of the opioid epidemic, opioid overdose deaths are a significant health problem in the US. Millions of adults are exposed to opioids, which increases their risk of serious injury and hospitalization. There were 100,306 drug overdose deaths in the United

States during the 12 months ending in April 2021, an increase of 28.5% from the 78,056 deaths during the same period the year before. The data also reveals that the pediatric population is significantly affected by opioid overdose, with a two-fold increase in pediatric opioid-induced deaths from 1999 to 2016. Patients who experienced an opioid overdose accounted for $1.94 billion in annual hospital costs, besides billions of dollars lost in productivity from premature death due to overdose. Opioids overdoses may, for example, arise from one or more of an accidental overuse, an unintended drug interaction, or intentional misuses.

[0004] Opioid overdose deaths continue to rise in the United States. Opioid overdose entails physical and mental symptoms such as disorientation, confusion and respiratory depression, which can be fatal. The reasons behind this are multifactorial, but include a lack of resources to treat the earliest signs of opioid overdose in the field prior to emergency responder involvement. Naloxone, a drug used to reverse opioid overdose, faces challenges associated with its delivery. Outside of the hospital setting, naloxone is widely available as an inhaler. In case of an opioid overdose event, naloxone is usually administered by a second person as the patient may be incapacitated. [0005] Naloxone faces challenges associated with its delivery. Using a naloxone inhaler during an opioid-overdose event may be challenging for patients living alone or pediatric patients. Using an inhaler depends on the immediate availability of the inhaler device in the field, the proper identification of the patient's opioid overdose diagnosis, a second person for administration, and the proper education on device use.

[0006] Further, determining respiratory distress arising from opioid overdose or other causes presents significant challenges. Although number of methodologies have been attempted to determine or sense respiratory depression, there has been limited success.

Many such systems or methodologies incorporate biomechanical sensors (for example, measuring electrical impedance wall or excursion of the chest). However, such systems and methodologies do not provide acceptable accuracy. Indeed, even in a highly controlled setting such as an operating room, detection of respiratory distress presents difficulties.

[0007] It is desirable to develop improved technologies for determining an opioid overdose as well as treating such an overdose.

SUMMARY OF THE INVENTION

[0008]

[0009] A system includes a wearable device including a base adapted to be connected to skin of a patient. An electrochemical sensor is connected to the base. The electrochemical sensor includes a sensor medium responsive to lactate. The electrochemical sensor is in fluid connection with one or more transdermal fluid paths in connection with the base. The one or more transdermal fluid paths are configured to be placed in fluid connection with the subdermal fluid of the patient. The system further includes electronic circuitry including at least one measurement system in operative connection with the electrochemical sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the subdermal fluid.

[0010] In a number of embodiments, the one or more transdermal fluid paths include at least one of (i) one or more catheters via which the subdermal fluid is transportable and (ii) one or more transdermal needles via which the subdermal fluid is transportable. The wearable device may, for example, include a plurality of transdermal needles. Such transdermal needles may, for example, be a porous transdermal microneedles.

[0011] The base may include an adhesive patch. The subdermal fluid may, for example, be dermal interstitial fluid. In a number of embodiments, the sensor medium includes at least one nanostructure. The at least one measurement system may, for example, be configured to determine the concentration of lactate based upon a measured value of the variable. [0012] The electrochemical sensor may be an amperometric electrochemical sensor. The electrochemical sensor may include a working electrode including the sensor medium, which includes at least one nanostructure, a counter electrode, and (optionally) a reference electrode.

[0013] In a number of embodiments, the electrochemical sensor further comprises a first conductive terminal in electrical connection with the sensor medium and a second conductive terminal in electrical connection with the sensor medium, which comprises at least one nanostructure, wherein the second conductive terminal is spaced from the first conductive terminal. The electrochemical sensor may, for example, operate as a chemiresistor or a field effect transistor.

[0014] A nanostructure or nanostructures hereof may, for example, be selected from the group consisting of single-walled nanotubes, multiple-wall nanotubes, nanowires, nanofibers, nanorods, nanospheres, and nanoribbons. In a number of embodiments, the sensor medium includes carbon nanostructures. The carbon nanostructures may include single-walled carbon nanotubes, and optionally semiconductor enriched single-walled carbon nanotubes.

[0015] In a number of embodiments, the sensor medium further includes an enzymatic material for which lactate is a substrate or a non-enzymatic material interactive with lactate.

The enzymatic material may, for example, include lactate oxidase or lactate dehydrogenase.

The sensor medium may further include an entity that interacts with hydrogen peroxide. The entity that interacts with hydrogen peroxide may, for example, be Prussian blue.

[0016] In a number of embodiments, the system further includes a delivery system in operative connection with the electronic circuitry. The delivery system is configured for delivery of a drug, which is an opioid overdose reversal medication. Delivery of the drug may occur upon the electronic circuitry measuring a change in at least one property of the sensor medium associated with a predetermined threshold concentration of lactate in the subdermal fluid. The delivery system may include a source of the drug and a fluid path in fluid connection with the source of the drug via which the drug is transportable. The fluid path is configured to be transdermally connected to the patient. The drug may, for example, be selected from the group of naloxone, nalmefene, and buprenorphine. The delivery system may further include a pumping mechanism in connection with the electronic circuitry and with the source of the drug.

[0017] A method of detecting lactate concentration in a person or patient includes providing a wearable device including a base adapted to be connected to skin of a patient. An electrochemical sensor is connected to the base and includes a sensor medium responsive to lactate. The electrochemical sensor is in fluid connection with one or more transdermal fluid paths in connection with the base. The one or more transdermal fluid paths are configured to be placed in fluid connection with the subdermal fluid of the patient.

The electrochemical sensor further includes electronic circuitry including at least one measurement system in operative connection with the electrochemical sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the subdermal fluid.

[0018] A method of treating respiratory distress resulting from opioid overdose includes (i) providing a wearable device including a base adapted to be connected to skin of a patient, an electrochemical sensor connected to the base and including a sensor medium responsive to lactate, the electrochemical sensor being in fluid connection with one or more transdermal fluid paths in connection with the base, the one or more transdermal fluid paths being configured to be placed in fluid connection with the subdermal fluid of the patient, and electronic circuitry including at least one measurement system in operative connection with the electrochemical sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the subdermal fluid; and (ii) providing a delivery system in operative connection with the electronic circuitry, the delivery system being configured for delivery of a drug which is an opioid overdose reversal medication upon the electronic circuitry measuring the change in at least one property of the sensor medium associated with a predetermined threshold concentration of lactate in the subdermal fluid.

[0019] The present devices, systems, and methods, along with the attributes and attendant advantages thereof, will best be appreciated and understood in view of the following detailed description taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF DRAWINGS

[0020] FIG. 1A illustrates schematically the interaction of an embodiment of a porous microneedle patch device hereof with human skin.

[0021] FIG. IB illustrates schematically an embodiment of an integrated system hereof including a lactate sensor and an opioid overdose reversal medication into a single transdermal device or patch.

[0022] FIG. 1C illustrates schematically an embodiment of a system hereof including a transdermal device or patch including a lactate sensor and a separate transdermal device or patch including a delivery system for an opioid overdose reversal medication. [0023] FIG. 2A illustrates schematically the metabolization of glucose to lactate.

[0024] FIG. 2B illustrates schematically the enzymatic conversion of lactate to pyruvate via

Lactate oxidase (LOx) enzyme.

[0025] FIG. 2C illustrates schematically an embodiment of the geometry of a lactate sensor hereof.

[0026] FIG. 3A illustrates a photograph of a transparent or translucent microneedle patch placed over the electrode assembly of a commercially available screen printed carbon electrode (SPCE) available from Zensor R&D Co., Ltd. of Taichung City, Taiwan, which was used in forming representative electrodes for studies hereof.

[0027] FIG. 3B illustrates schematically the SPCE of FIG. 3A without the microneedle patch.

[0028] FIG. 3C illustrates schematically the SPCE of FIG. 3A including the microneedle patch over the electrode assembly.

[0029] FIG. 4 illustrates results of a representative studies of amperometry volume effects of an embodiment of a sensor hereof.

[0030] FIG. 5 illustrates results of a representative amperometry studies of an embodiment of a sensor hereof modified with Prussian blue over a range of lactate concentrations in phosphate buffer saline (PBS).

[0031] FIG. 6 illustrates results of a calibration curve of representative amperometry studies in PBS of an embodiment of a sensor hereof modified with Prussian blue.

DESCRIPTION

[0032] It will be readily understood that the components of the embodiments, as generally described and illustrated in the figures herein, may be arranged and designed in a wide variety of different configurations in addition to the described representative embodiments.

Thus, the following more detailed description of the representative embodiments, as illustrated in the figures, is not intended to limit the scope of the embodiments, as claimed, but is merely illustrative of representative embodiments.

[0033] Reference throughout this specification to "one embodiment" or "an embodiment"

(or the like) means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearance of the phrases "in one embodiment" or "in an embodiment" or the like in various places throughout this specification are not necessarily all referring to the same embodiment. [0034] Furthermore, described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided to give a thorough understanding of embodiments. One skilled in the relevant art will recognize, however, that the various embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, et cetera. In other instances, well known structures, materials, or operations are not shown or described in detail to avoid obfuscation.

[0035] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a needle" includes a plurality of such needles and equivalents thereof known to those skilled in the art, and so forth, and reference to "the needle" is a reference to one or more such needles and equivalents thereof known to those skilled in the art, and so forth.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value, as well as intermediate ranges, are incorporated into the specification as if individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contraindicated by the text.

[0036] The terms "electronic circuitry," "circuitry" or "circuit," as used herein include, but is not limited to, hardware, firmware, software, or combinations of each to perform a function(s) or an action(s). For example, based on a desired feature or need, a circuit may include a software-controlled microprocessor, discrete logic such as an application specific integrated circuit (ASIC), or other programmed logic device. A circuit may also be fully embodied as software. As used herein, "circuit" is considered synonymous with "logic." The term "logic," as used herein includes, but is not limited to, hardware, firmware, software, or combinations of each to perform a function(s) or an action(s), or to cause a function or action from another component. For example, based on a desired application or need, logic may include a software-controlled microprocessor, discrete logic such as an application specific integrated circuit (ASIC), or other programmed logic device. Logic may also be fully embodied as software.

[0037] The term "processor," as used herein includes, but is not limited to, one or more of virtually any number of processor systems or stand-alone processors, such as microprocessors, microcontrollers, central processing units (CPUs), and digital signal processors (DSPs), in any combination. The processor may be associated with various other circuits that support operation of the processor, such as random-access memory (RAM), read-only memory (ROM), programmable read-only memory (PROM), erasable programmable read only memory (EPROM), clocks, decoders, memory controllers, or interrupt controllers, etc. These support circuits may be internal or external to the processor or its associated electronic packaging. The support circuits are in operative communication with the processor. The support circuits are not necessarily shown separate from the processor in block diagrams or other drawings.

[0038] The term "controller," as used herein includes, but is not limited to, any circuit or device that coordinates and controls the operation of one or more input and/or output devices. A controller may, for example, include a device having one or more processors, microprocessors, or central processing units capable of being programmed to perform functions.

[0039] The term "memory system" refers to one or more electronic components that store data and instructions. In computerized systems, a processor system can quickly access information stored in a memory system. Memory of memory systems allows storage and retrieval of information and may, for example, include primary memory and secondary memory. Primary memory includes, for example, RAM, cache memory, etc. Secondary memory includes, for example, hard drives, hard disk drives etc.

[0040] The term "software," as used herein includes, but is not limited to, one or more computer readable or executable instructions that cause a computer or other electronic device to perform functions, actions, or behave in a desired manner. The instructions may be embodied in various forms such as routines, algorithms, modules, or programs including separate applications or code from dynamically linked libraries. Software may also be implemented in various forms such as a stand-alone program, a function call, a servlet, an applet, instructions stored in a memory, part of an operating system or other type of executable instructions. It will be appreciated by one of ordinary skill in the art that the form of software is dependent on, for example, requirements of a desired application, the environment it runs on, or the desires of a designer/programmer or the like.

[0041] As used herein, and unless otherwise stated or otherwise clear from the context, terms such as generally or approximately when used in connection with, for example, a value, refer to a range of values with 10%, within 5%, or desirably with 1% of the associated value. As used herein in the term "and/or" means one of or both of an entity. Thus, A and/or means A or B, or both A and B. [0042] In general, nanostructures are structures of intermediate size between microscopic and molecular structures. Nanostructures may, for example, have at least one dimension in the range of 0.1 to hundreds of nanometers. Many nanostructures have at least one dimension in the range of 1 to 100 nm. Nanotubes are, for example, considered two- dimensional nanostructures and may have a diameter in the range of, for example, 0.1 nm to hundreds of nm and a length that may be significantly greater than the diameter.

Microstructures, for example, typically have a size in the range of 1 mm to 1 mm.

[0043] As described below in connection with, for example, FIGS. 1A through 1C, in a number of embodiments, the devices, systems and methods hereof include a sensor such as a nanostructure-based sensor for detection of lactate (as a biomarker for oxygen deprivation/respiratory distress). Such a sensor may, for example, be combined with a delivery system for an opioid overdose reversal medication (for example, naloxone) which are effective for opioids including prescription painkillers such as oxycodone (often know by the brand name OxyContin*), fentanyl, methadone, and Vicodin (including a combination hydrocodone and acetaminophen), as well as for street drugs like heroin. In that regard, a biofeedback-enabled system hereof may dispense an opioid overdose reversal medication such as naloxone transdermally into the body upon detecting the earliest signs of an opioid overdose event. Currently, there is no FDA-approved, commercially available transdermal technology to detect opioid overdose or an automated delivery system to dispense an opioid overdose reversal medication such as naloxone in the hour of need.

[0044] The systems hereof may, for example, be formed as or include a transdermal patch.

The opioid overdose reversal medication may, for example, be delivered via iontophoresis (a process of transdermal drug delivery in which a voltage gradient is used on the skin) in response to measurement of a threshold concentration of lactate by a sensor hereof which measures lactate levels over time. Pumping systems, as for example, currently used in delivering insulin, may also be used to deliver the opioid overdose reversal medication.

[0045] As described above, lactate is a biomarker of oxygen deprivation and is elevated during cardiorespiratory distress resulting from an opioid overdose. In general, glucose is converted to lactate in the body primarily through a process called glycolysis, particularly under anaerobic conditions as summarized in FIG. 2A. Lactate is metabolized by the liver, heart and the kidneys. The liver is the primary pathway for metabolism of lactate. However, the removal of lactate is reduced by various factors including, hypoxia, acidosis, low oxygen supply, and hypoperfusion. Opioid overdose can lead to death as a result of the effects of opioids upon the part of the brain which regulated breathing, which may trigger hypoxia. [0046] During an overdose event, as the lactate level rises from the baseline values, a lactate sensor hereof may be used to detect the increase in lactate concentration and trigger release of a drug such as naloxone, reversing the effects of the opioid. Both patients experiencing overdose arising from use of a prescribed opioid and overdose arising from intentional misuse of an opioid can benefit from such technology. In that regard, even patients intentionally misusing opioids are looking for safety measures to prevent comorbidities.

[0047] A typical dose of naloxone for opioid overdoses is in the range of approximately 0.4 to 4 mg. Such a dose is less than a cubic centimeter or cc (typically in the range of 0.2 to 0.3 cc). Rates of transdermal delivery of a drug such as naloxone via, for example, anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients. Polymeric microneedle-mediated transdermal delivery also holds potential for rapid and sustained delivery of drugs for opioid overdose treatment. The pharmacokinetic properties of drug delivery systems hereof may be comparable to that seen with the commercially available products such as naloxone, while reducing or eliminating the limitations associated therewith as discussed above. A mechanistic model of drug release may be employed with drug delivery systems hereof (such as, transdermal patches), which may be integrated with pharmacokinetic modeling to optimize the design of the drug delivery systems to reproduce in-vivo pharmacokinetics of opioid overdose reversal medications obtained through commercial intramuscular and intranasal devices.

[0048] FIGS. 1A through 1C illustrate embodiments of integrated systems hereof including a transdermal delivery system and a sensor system providing a lactate biofeedback mechanism. In a number of embodiments, carbon nanomaterial-based sensors (such as amperometric sensors, field-effect transistors (FETs) or chemiresistors), which have shown to have remarkable sensitivity and low detection limits for a variety of biological analytes, are used in systems hereof to sense lactate levels. In a number of embodiments hereof, a functionalized carbon nanomaterial-based biosensor is integrated on the transdermal patch for the real-time detection of serum lactate.

[0049] FIG. 1A illustrates the transdermal interaction of a fluid pathway including porous microneedles 22 of a representative embodiment of a transdermal patch 20. Microneedles are drug delivery systems that can deliver both small molecules and macromolecules, as well as micro particles. A sensing component of a lactate sensor hereof may be placed in fluid connection with subdermal fluid via microneedles 22. Such a sensing component may, for example, be functionalized with an enzymatic receptor (for example., lactate oxidase, lactate dehydrogenase) or with a non-enzymatic receptor (for example, 5-nitrophenyl boronic acid, aptamers etc.) for the specific recognition of lactate. The specific interaction between lactate and its receptor will induce changes in one or more measured characteristics of variables of the sensor (for example, an electrical property thereof). The measured change(s) can be directly relatable to lactate concentration.

[0050] FIG. IB illustrate a system 10 hereof in which a lactate sensing system or sensor system 100, electronic circuitry 200 (which may function as a measurement system, an analysis system, and a control system for sensing and drug delivery operations), and a drug delivery system 300, are integrated into common transdermal patch system 20. Sensor system 100 may, for example, be a two- or three-electrode amperometric sensor system including a working electrode 110, a counter electrode 120 and, optionally, a reference electrode 130 as discussed further below.

[0051] Electronic circuity 200 hereof may, for example, include a processor system 210 in communicative connection with a memory system 220 as illustrated in FIG. IB. Memory system 220 may, for example, have stored therein one or more algorithms executable by processor system 210 to achieve measurement of lactate concentration via sensor system

100, analysis of data, and/or control of sensor system 100 and drug delivery system 300.

Electronic circuitry may, for example, further include a communication system 230 (for wired and/or wireless communication - for example, via BLUETOOTH etc.), and a power system 240 (for example, a battery system) in operative connection with powered components of system 10.

[0052] Drug delivery system 300 may, for example, include a pressurizing or transport mechanism 310 in operative connection with a source, container or repository 320 of an opioid overdose reversal medication or drug such as naloxone. Source 320 may, for example, be in fluid connection with one or more of microneedles 22 via a conduit 330 for delivery of the opioid overdose reversal medication.

[0053] As described above, transdermal patch 20 (for example, an adhesive transdermal patch) includes fluid path including a plurality of microneedles 22 in the illustrated embodiment of FIG. IB, which may be placed in fluid connection with subdermal fluid.

Microneedles 22 may, for example, include a plurality or abundance of interconnected pores

24 that can, for example, produce capillary action. In that regard, microneedles 22 pierce the epidermal layer and create micro-channels in the skin, which allow therapeutic agents to, for example, diffuse into the dermal layer. Various pore sizes and porosities of porous microneedles can be achieved via use of different materials and preparation processes as known in the art. Microneedles may, for example, be manufactured from metals, silicone, ceramic and synthetic polymers. Depending upon the manufacture and materials, microneedles can be classified as solid, hollow, porous, dissolving, coated etc. Application of porous microneedles can be adapted to various scenarios or uses herein. A porous microneedle patch hereof may, for example, be fabricated from a biocompatible and non- dissolvable polymer to have interconnected porosity as described above (that is, in situ porous microstructure). The porous microneedles breach the subcutaneous layer to access subdermal fluid such as dermal interstitial fluid. In the illustrated embodiment of FIG. IB, the porous microneedles facilitate the collection and sampling of fluid at a backing layer 26 of transdermal patch system 20, which is in direct contact or fluid connection with lactate sensor 100. Realtime, and generally continuous, measurement of lactate concentrations in the fluid can thereby be achieved.

[0054] FIG. 1C illustrates another embodiment of a system 10a hereof in which a sensor system 100a is on a separate transdermal patch 20a than delivery system 300a. In the embodiment of FIG. 1C, the fluid path placing sensor system 100a in fluid connection with subdermal fluid include a short extending transdermal catheter or conduit 28a (for example, a polymeric catheter). Electronic circuitry 200a of sensor system 100a may, for example, be placed in communicative connection with delivery system 300a in a manner similar to the manner in which insulin pumps are placed in connection with continuous glucose monitor.

As described in connection with drug delivery system 300, drug delivery system 300a may, for example, include a pressurizing or transport mechanism 310a in operative connection with a source, container or repository 320a of an opioid overdose reversal medication or drug such as naloxone. Source 320a may, for example, be in fluid connection with the patient via a short polymeric catheter or conduit 330a.

[0055] Referring, for example, to FIGS. 2B through 3C, in a number of studied embodiments, a sensor system 100b was formed using a Zensor SE101 SPCE (see FIGS. 3A through 3C) including a base 102b having an electrode assembly formed thereof. The electrode assembly included a carbon-based working electrode 110b, a carbon-based counter electrodes 120b and a silver-based reference electrode 130b. Electrically conductive lines 112b, 122b, and 132b extend between working electrode 110b, counter electrode

120b, and reference electrode 130b to electrical contacts 114b, 124b, and 134b, respectively. A connector 150b, as known in the electrical and computer arts may be used to place electrical contacts 114b, 124b, and 134b (and, thereby, working electrode 110b, counter electrode 120b, and reference electrode 130b) in communicative connection with electronic circuitry 200b (for example, via connector 150b as illustrated in FIG. 3C). In the illustrated embodiment, an insulating layer 140b is positioned over electrically conductive lines 112b, 122b, and 132b. In FIGS. 3A and 3C, a transdermal patch 20b is illustrated over the electrode assembly to be in fluid connection with the electrode assembly via porous microneedles 22b thereof (as, for example, described above for sensor system 100).

Transdermal patch 20b is illustrated to be transparent or translucent in FIGS. 3A and 3C.

[0056] In a number of studied embodiments, working electrode 110b included a sensing medium including single walled carbon nanotubes (SWCNT). Lactate oxidase (LOX) enzyme was incubated on the SWCNT. As illustrated in FIG. 28, in a number of embodiments, lactate is oxidized by the enzyme, forming, H2O2, which is detected. The lactate oxidase was covered with a protective layer in a number of studied embodiments. For example, a polymer (such as chitosan crosslinked via glutaraldehyde) may be used to form a protective layer. The enzymes remained active and functioned to oxidize lactate. In a number of embodiments, a molecule responsive to H2O2 such as Prussian blue was deposited on the surface of the SPCE for the detection of H2O2 (see, for example, FIG. 2C). In a number of embodiments, an electrolyte solution including potassium ferricyanide (K3[Fe(CN)₆] was used together with iron(lll) chloride (FeCI3) for electrodeposition of Prussian Blue on the electrodes.

[0057] The lactate sensors or sensor systems hereof exhibit improved accuracy as compared to many currently available lactate sensor system. Such accuracy may be particularly important in systems in which a lactate sensor is used to measure lactate concentration as a biomarker for respiratory distress brought on by an opioid rejections. In that regard, it is very desirable to minimize or eliminate false positives in such systems.

Delivering a dose of an opioid overdose reversal medication can put the patient into withdrawal which is associated with extreme discomfort.

[0058] As described above, lactate is produced in the human body when cells break down glucose and other carbohydrates for energy. Lactate is typically 1-2 mmol/L at rest but can increase to greater than 15 to 20 mmol/L during intense exertion. Blood lactate levels may serve as an indirect marker for biochemical events such as fatigue within exercising muscle.

Thresholds of lactate concentration determined to trigger delivery of a dose of a drug such as naloxone may thus be set to at least 15 or 20 mmol/L in a number of embodiments of sensing systems hereof to prevent delivery to a patient exhibiting an elevated lactate level resulting from physical exertion. Physiological lactate levels are typically less than 2 mmol/L in blood and interstitial fluid for healthy adults, with a range extending to as high as 15 mmol/L during intense anaerobic exercise. As described above, lactate sensors hereof may, for example, be formulated to be sensitive to a range of lactate concentration in excess of 15 or 20 mmol/L in a number of embodiments (see, for example, FIGS. 4 through 6).

[0059] FIG. 4 illustrates results of a representative studies of amperometry volume effects of an embodiment of a lactated sensor hereof (as described in connection with FIGS. 3A through 3C), while FIG. 5 illustrates results of a representative amperometry studies of an embodiment of a lactate sensor hereof modified with Prussian blue over a range of lactate concentrations in PBS. FIG. 6 illustrates results of a calibration curve of representative amperometry studies of an embodiment of a sensor hereof modified with Prussian blue. In addition to studies in PBS, sensors hereof were demonstrated to detect lactate in interstitial fluid and synthetic urine.

[0060] As described above, lactate sensors hereof were formulated to be sensitive to a range of lactate concentration in excess of 15 mmol/L. The detection limit of lactate sensor hereof can be readily lowered or otherwise improved via the variation/optimization of sensor variables. In sensors hereof in which the sensor medium includes an enzyme (such as lactate oxidase), one may for example, improve detection of the enzymatically catalyzed product (hydrogen peroxide in the case of lactate oxidase) and/or improve conversion of lactate. For example, the composition and/or structure of the electrode (such as the ratio of nanostructures to Prussian blue (an electron transfer mediator) and/or the ratio of nanostructures to enzyme) may be modified. Further, the manner in which the enzyme or other lactate receptor is attached to the nanostructures may be modified to improve electron transfer between the nanostructures and enzyme or other receptor. Moreover, to overcome non-specific absorption, a blocking layer as known in the sensor arts (for example, including bovine serum albumin (BSA) and/or polyethylene glycol) may be used in the case of sample fluids such as blood fluids. Still further, higher activity enzymes and/or receptors may be used and/or or more enzyme and/or receptors may be loaded upon the nanostructures to, for example, avoid lactose saturation.

[0061] Additional sensors may be used to assist in determining or confirming that an elevated lactate level is associated with opioid overdose. FIG. 1C, for example, illustrates additional sensors 400 and 400a, which may, for example, be a pH sensor, an opioid sensor, an opioid metabolite sensor, etc. Nanostructure-based opioid/opioid metabolite sensors are, for example, descried in U.S. Patent Application Publication No. 2022/0365078 and U.S. Patent Application Serial No. 18/631,488, the disclosures of which are incorporated herein by reference. A nanostructure-based pH sensor is described in PCT International Patent Publication No. WO 2013/009875, the disclosure of which is incorporated herein by reference. All such sensors may, for example, be incorporated into a single transdermal patch in a number of embodiments hereof.

[0062] Although lactate sensors hereof are discussed in connection with systems for automated delivery of an opioid overdose reversal medication, the lactate sensors hereof may be used in any situation in which it is desirable to measure lactate levels of a person/patient. For example, lactate sensors hereof may be used in connection with athletic training, in connection with surgeries in operating rooms, in connection with intensive care unit patients, etc.

[0063] As described above, nanostructure-based sensors (wherein the sensor medium of the sensing electrode includes one or more nanostructures) are desirable for use in the lactate sensor systems hereof. Amperometric sensors are discussed above. Additionally, chemically sensitive solid-state resistors (chemiresistors) and field-effect transistors (FETs) may, for example, exhibit room temperature sensitivity to lactate in, for example, a clinical sample such as a subdermal interstitial fluid, serum/plasma, etc. In a nanostructure-based

FET device, one, for example, measures electrical current through nanostructures such as semiconductor-enriched- or sc-SWCNT under an applied gate voltage. In chemiresistor devices, a gate voltage is not applied. In both types of devices, an electrical property (for example, conductance or resistance) of nanostructures such as nanotubes changes upon exposure to an analyte such as lactate, thereby providing a sensor signal. Depending on the semiconducting nature of the nanostructures, application of a gate voltage can provide amplification of the sensor signal.

[0064] Nanostructure-based electrochemical sensors, including FET and chemiresistor sensors/devices, are, for example, discussed in PCT International Publication Number WO

2025/042890, and U. 5. Patent Application Publication Nos 2024/0345074, 2022/0365078,

2023/0309920, and 2020/0093429, the disclosures of which are incorporate herein by reference. The use of nanostructures such as SWCNT in connection with various sensors and other applications is also described, for example, in International Patent Application

Publication Number WO 2008/088789, U.S. Patent Application Publication Nos.

2011/0127446, and 2024/0345074, and U.S. Patent Nos. 8,920,764, 9,482,638, 10,436,745,

10,801,982, 10,244,964, 11,685,657, 11,712,200, 12,203,830, 12,213,800, the disclosures of which are incorporated herein by reference.

[0065] Nanotubes such as single-walled carbon nanotubes or SWCNTs and semiconductor- enriched (sc-)-SWCNTs provide suitable candidate for incorporation into small and low power devices lactate sensors hereof because they demonstrate extreme environmental sensitivity, high electrical conductivity, and inherent compatibility with existing microelectronic fabrication techniques.

[0066] Single-walled carbon nanotubes are classified based on their electrical properties.

Nanotubes may, for example, be considered to be either semiconducting or metallic. The nanotube synthesis process typically yields a mix of both metallic and semiconducting nanotubes. Purification steps are required to enrich the samples to be either mostly metallic or mostly semiconducting. Either mixed or purified nanostructures may be used in the sensor systems hereof. However, purified semiconducting nanostructures may provide improved, lower levels of detection and a wider dynamic range in devices, systems, and methods hereof. As used herein, the term "semiconductor enriched" (in reference to nanostructures such as sc-SWCNTs) indicates that there is a semiconducting content of at least 66%. In a number of embodiments, the semiconducting content is at least 90%, at least

95%, at least 99%, or at least 99.9%. In general, a greater semiconducting content will result in a better output signal.

[0067] In single-walled carbon nanotubes, all carbon atoms are located on the surface where current flows, making a stable conduction channel that is extremely sensitive to a surrounding chemical environment. Nanotubes and other nanostructures (including single- walled nanotubes (SWNTs) such as SWCNT's) have the ability to change conductance in response to interaction with analytes.

[0068] Various nanostructures other than SWCNTs are suitable for use in the present invention. Such nanostructures include, but are not limited to, multi-walled carbon nanotubes, graphene nanosheets and their derivatives (for example, reduced graphene oxide and holey graphene), nanowires, nanofibers, nanorods, nanospheres, nanoribbons (for example, interconnected nanoribbons of holey reduced graphene oxide) or the like, or mixtures of such nanostructures. Moreover, in addition to carbon, those skilled in the art will appreciate that the nanostructures of the present invention can be formed of boron, boron nitride, and carbon boron nitride, silicon, germanium, gallium nitride, zinc oxide, indium phosphide, molybdenum disulfide, silver, and/or other suitable materials. The formation and/or function of reduced graphene oxide and holey graphene compositions are, for example, discussed in U.S. Patent Nos. 8,920,764, 9,482,638, and 10,801,982, and U.S.

Patent Application Publication No. 2021/0122638, the disclosures of which are incorporated herein by reference. [0069] Experimental

[0070] Fabrication of Lactate Sensor. A commercial screen-printed carbon electrode (SPCE,

SE101, 3mm, Zensor) was used for the fabrication of a representative lactate sensor. The working and counter electrode were made of carbon. An Ag/AgCI paste was used for the fabrication of reference electrode. Single-walled carbon nanotubes (SWCNT, IsoSol-SlOO, Nanolntegris) were applied as sensing materials. Firstly, 5 pL of SWCNT (0.05 g ml"¹, dispersed in toluene) was cast onto the working electrode. After the evaporation of organic solvent, the same step was repeated by adding another 5 pL of SWCNT. Subsequently, the working electrode was incubated with 10 pL of chitosan (0.6% wt in acetic acid) for 2 h.

Finally, the working electrode was incubated with 10 pg of lactate oxidase (20 pl, produced from Aerococcus viridans, Sigma-Aldrich) overnight at room temperature. The lactate sensor was then stored at 4 °C before use.

[0071] Electrodeposition of Prussian Blue. Initially, an electrolyte solution is prepared.

Potassium ferricyanide (K₃[Fe(CN)6]) was dissolved in deionized water to prepare a 1.0 x 10 ³ mol L^-1 solution. KCI was then added to reach a final concentration of 0.1 mol L^-1 as the supporting electrolyte. The electrochemical cell was then assembled. 20 ml of the prepared ferricyanide/KCI solution was poured into the electrochemical cell. The working electrode (carbon paste or CNT), platinum wire counter electrode, and Ag/AgCI reference electrode were then immersed into the solution. Scan parameters can be set before initiation of a cyclic voltammetry process as follows: -0.3 V to +1.2 V (vs. Ag/AgCI) for the potential range, 50 mV s^-1 for the scan rate, and 300 for the number of cycles. Electrochemical cycling then promotes the formation of Prussian Blue on the electrode surface. See, for example, Nossol,

E. and Zarbin, A, A Simple and Innovative Route to Prepare a Novel Carbon Nanotube/Prussian Blue Electrode and Its Utilization as a Highly Sensitive H₂O₂

Amperometric Sensor, Advanced Functional Materials, 19, no. 24, 3980-86 (2009), https://doi.org/10.1002/adfm.200901478.

[0072] Alternative method for deposition of Prussian blue. A Prussian blue precursor solution is prepared by dissolving 2.5 mM iron (III) chloride (FeCl₃) and 2.5 mM potassium ferricyanide (K₃[Fe(CN)₆]) in nanopure water. Additionally, 0.1 M KCI and 0.1 M HCI are added to the solution as the supporting electrolyte and to maintain acidity. The solution is deoxygenated by bubbling nitrogen gas through the solution for 5 minutes to remove dissolved oxygen. In the electrodeposition of Prussian blue, the precursor solution is first poured into the cell. The working electrode, the platinum counter electrode, and the Ag/AgCI reference electrode are immersed in the solution. Scan parameters can be set as follows: -0.5 V to +0.65 V (vs. Ag/AgCI) for the potential range, 50 mV s^-1 for the scan rate, and 15 for the number of cycles. Subsequently, the electrode is removed and rinsed thoroughly with double-distilled water to eliminate any loosely bound reactants or byproducts. For electrochemical activation, a fresh supporting electrolyte solution including

0.1 M KCI + 0.1 M HCI may be used. The washed electrode is immersed in the activation solution. Cyclic voltammetry is applied with the following parameters: +350 mV to -50 mV (vs. Ag/AgCI) for the potential range, 50 mV s^-1 for the scan rate, and 25 for the number of cycles. In a final wash step, the electrode is removed and rinsed gently with double-distilled water. The electrode may be stored or used immediately in an electrochemical measurement. See, for example, Li, N. B., et al., Characterization and Electrocatalytic Properties of Prussian Blue Electrochemically Deposited on Nano-Au/PAMAM Dendrimer-

Modified Gold Electrode, Biosensors and Bioelectronics, 23, no. 10: 1519-26 (May 15, 2008), https://doi.Org/10.1016/j.bios.2008.01.009.

[0073] LOX functionalization and surface modification with glutaraldehyde and chitosan.

5 pL of 40 mg/mL of LOx was drop-cast on the modified working electrode and let dry in ambient conditions. Further 3.5 pl of 1% (w/v) glutaraldehyde(GA) solution (prepared in deionized water) was applied to the dried a Prussian-blue-modified electrode surface. The electrode was allowed to dry completely under ambient conditions (room temperature, ~25 °C). A 3.5 pl of 1% (w/v) chitosan solution (prepared in 0.1 M acetic acid) was pipetted onto the same surface. The electrode was allowed to dry completely under the same ambient conditions. The chitosan application was applied two more times, for a total of three layers. Each time, 3.5 pL of the chitosan solution was applied and allowed to dry completely before the next layer. After adding the final chitosan layer, the modified electrode was placed in a refrigerator at ~4 °C and allow it to dry overnight until ready for use. See, for example, De la Paz, E., et al., Non-lnvasive Monitoring of Interstitial Fluid

Lactate through an Epidermal lontophoretic Device, Taianta 254, 124122 (March 1, 2023), https://doi.Org/10.1016/j.talanta.2022.124122.

[0074] As an alternative, a single layer of 5 pL of 1% (w/v) chitosan solution (prepared in

0.1 M acetic acid) is drop-cast onto the dried Prussian-blue-modified electrode surface. The electrode is then placed in a sealed chamber containing glutaraldehyde vapors (for example, a bottle cap with ~50% GA solution) and kept at ~4 °C overnight. The GA vapors crosslink the chitosan film uniformly, creating a stable, functionalized surface without direct liquid glutaraldehyde contact. See, for example, Schiffman, J.D. and Schauer, C.L, Cross-Linking Chitosan Nanofibers, Biomacromolecules 8, no. 2, 594-601 (February 1, 2007): https://doi.org/10.1021/bm060804s.

[0075] Amperometry. In a number of representative studies hereof, the electrochemical detection of lactate was achieved by amperometry. Lactate solutions at different concentrations were prepared in, for example, phosphate buffer saline (PBS). For each test, the lactate sensor was first incubated with 100 pL of PBS for two minutes, and current was measured by amperometry as the blank (high voltage: -0.55 V; low voltage: -0.6 V, time length: 80 seconds). Then, 1 pL of lactate solution at different concentrations (from 10^-4 to 10"² g ml"¹, result in 10"⁶ to IO*⁴ g ml"¹ on the sensor) was added onto the lactate sensor, and current was measured by amperometry after incubation for two minutes. The current value at 60 s was chosen for calibration plotting. Each sample was tested three times, and the last test result was used for data processing. The real-time monitoring of lactate was also achieved by amperometry. The time length was set as 1000 s, and 1 pl of lactate solution at different concentrations was added onto the sensor every 60 s.

[0076] The foregoing description and accompanying drawings set forth a number of representative embodiments at the present time. Various modifications, additions and alternative designs will, of course, become apparent to those skilled in the art in light of the foregoing teachings without departing from the scope hereof, which is indicated by the following claims rather than by the foregoing description. All changes and variations that fall within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

Claims

1. A system, comprising: a wearable device comprising a base adapted to be connected to skin of a patient, an electrochemical sensor connected to the base and comprising a sensor medium responsive to lactate, the electrochemical sensor being in fluid connection with one or more transdermal fluid paths in connection with the base, the one or more transdermal fluid paths being configured to be placed in fluid connection with the subdermal fluid of the patient, and electronic circuitry comprising at least one measurement system in operative connection with the electrochemical sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the subdermal fluid.

2. The system of claim 1 wherein the one or more transdermal fluid paths comprise one or more catheters via which the subdermal fluid is transportable or comprise one or more transdermal needles via which the subdermal fluid is transportable.

3. The system of claim 2 wherein the wearable device comprises a plurality of transdermal needles.

4. The system of claim 2 wherein the wearable device comprises a plurality of porous transdermal microneedles.

5. The system of any one of claims 1 through 4 wherein the base comprises an adhesive patch.

6. The system of any one of claims 1 through 4 wherein the subdermal fluid is dermal interstitial fluid.

7. The system of any one of claims 1 through 4 wherein the sensor medium comprises at least one nanostructure.

8. The system of any one of claims 1 through 4 wherein the at least one measurement system is configured to determine the concentration of lactate based upon a measured value of the variable.

9. The system of claim 1 wherein the electrochemical sensor is an amperometric electrochemical sensor.

10. The system of claim 9 wherein the electrochemical sensor comprises a (i) working electrode comprising the sensor medium which comprises at least one nanostructure, (ii) a counter electrode, and (iii) a reference electrode.

11. The system of claim 1 wherein the electrochemical sensor further comprises a first conductive terminal in electrical connection with the sensor medium and a second conductive terminal in electrical connection with the sensor medium, which comprises at least one nanostructure, the second conductive terminal being spaced from the first conductive terminal.

12. The system of claim 11 wherein the electrochemical sensor operates as a chemiresistor or a field effect transistor.

13. The system of claim 12 wherein the at least one nanostructure is selected from the group consisting of single-walled nanotubes, multiple-wall nanotubes, nanowires, nanofibers, nanorods, nanospheres, and nanoribbons.

14. The system of claim 13 wherein the sensor medium comprises carbon nanostructures.

15. The system of claim 14 wherein the carbon nanostructures comprise single-walled carbon nanotubes, and optionally semiconductor enriched single-walled carbon nanotubes.

16. The system of any one of claims 1 through 4 wherein the sensor medium further comprises an enzymatic material for which lactate is a substrate or a non-enzymatic material interactive with lactate.

17. The system of claim 16 wherein the enzymatic material is lactate oxidase or lactate dehydrogenase.

18. The system of claim 17 wherein the sensor medium further comprises an entity that interacts with hydrogen peroxide.

19. The system of claim 18 wherein the entity that interacts with hydrogen peroxide comprises Prussian blue.

20. The system of any one of claims 1 through 4 further comprising a delivery system in operative connection with the electronic circuitry, the delivery system being configured for delivery of a drug which is an opioid overdose reversal medication upon electronic circuitry measuring the change in at least one property of the sensor medium associated with a predetermined threshold concentration of lactate in the subdermal fluid.

21. The system of claim 20 wherein the delivery system comprises a source of the drug and a fluid path in fluid connection with the source of the drug which is configured to be transdermally connected to the patient via which the drug is transportable.

22. The system of claim 20 wherein the drug is selected from the group of naloxone, nalmefene, and buprenorphine.

23. The system of claim 20 wherein the delivery system further comprises a pumping mechanism in connection with the electronic circuitry and with the source of the drug.

24. A method of detecting lactate concentration in a person, comprising: providing a wearable device comprising a base adapted to be connected to skin of the person, an electrochemical sensor connected to the base and comprising an electrochemical sensor comprising a sensor medium responsive to lactate, the electrochemical sensor being in fluid connection with one or more transdermal fluid paths in connection with the base, the one or more transdermal fluid paths being configured to be placed in fluid connection with the subdermal fluid of the person, and electronic circuitry comprising at least one measurement system in operative connection with the electrochemical sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the fluid.

25. The method of claim 24 wherein the one or more transdermal fluid paths comprise at least one of one or more catheters via which the subdermal fluid is transportable and one or more transdermal needles via which subdermal fluid is transportable.

26. The method of claim 25 wherein the wearable device comprises a plurality of transdermal needles.

27. The method of claim 25 wherein the wearable device comprises a plurality of porous transdermal microneedles.

28. The method of any one of claims 24 through 27 wherein the base comprises an adhesive patch.

29. The method of any one of claims 24 through 27 wherein the subdermal fluid is dermal interstitial fluid.

30. The method of any one of claims 24 through 27 wherein the sensor medium comprises at least one nanostructure.

31. The method of any one of claims 24 through 27 wherein the at least one measurement system is configured to determine the concentration of lactate based upon a measured value of the variable.

32. The method of any one of claim 24 through 27 wherein the electrochemical sensor is an amperometric electrochemical sensor.

33. The method of claim 32 wherein the electrochemical sensor comprises (i) a working electrode comprising the sensor medium which comprises at least one nanostructure, (ii) a counter electrode, and a (iii) reference electrode.

34. The method of any one of claims 24 through 27 wherein the sensor further comprises a first conductive terminal in electrical connection with the sensor medium and a second conductive terminal in electrical connection with the sensor medium, which comprises at least one nanostructure, the second conductive terminal being spaced from the first conductive terminal.

35. The method of claim 34 wherein the electrochemical sensor operates as a chemiresistor or a field effect transistor.

36. The method of claim 35 wherein the at least one nanostructure is selected from the group consisting of single-walled nanotubes, multiple-wall nanotubes, nanowires, nanofibers, nanorods, nanospheres, and nanoribbons.

37. The method of claim 36 wherein the sensor medium comprises carbon nanostructures.

38. The method of claim 37 wherein the carbon nanostructures comprise single-walled carbon nanotubes, and optionally semiconductor enriched single-walled carbon nanotubes.

39. The method of any one of claim 24 through 27 wherein the sensor medium further comprises an enzymatic material for which lactate is a substrate or a non-enzymatic material interactive with lactate.

40. The method of claim 39 wherein the enzymatic material is lactate oxidase or lactate dehydrogenase.

41. The method of claim 40 wherein the sensor medium further comprises an entity that interacts with hydrogen peroxide.

42. The method of claim 41 wherein the entity that interacts with hydrogen peroxide comprises Prussian blue.

43. A method of treating respiratory distress resulting from opioid overdose, comprising: providing a wearable device comprising a base adapted to be connected to skin of the patient, an electrochemical sensor connected to the base and comprising a sensor medium responsive to lactate, the electrochemical sensor being in fluid connection with one or more transdermal fluid paths in connection with the base, the one or more transdermal fluid paths being configured to be placed in fluid connection with the subdermal fluid of the patient, and electronic circuitry comprising at least one measurement system in operative connection with the sensor to measure a variable providing a measure of change in at least one property of the sensor medium which is dependent upon the presence of lactate in the fluid; and providing a delivery system in operative connection with the electronic circuitry, the delivery system being configured for delivery of a drug which is an opioid overdose reversal medication upon the electronic circuitry measuring the change in at least one property of the sensor medium associated with a predetermined threshold concentration of lactate in the subdermal fluid.

44. The method of claim 43 wherein the wearable device comprises at least one of one or more catheters via which the subdermal fluid is transportable and one or more transdermal needles via which subdermal fluid is transportable.

45. The method of claim 44 wherein the wearable device comprises a plurality of transdermal needles.

46. The method of claim 45 wherein the wearable device comprises a plurality of porous transdermal microneedles.

47. The method of any one of claims 43 through 46 wherein the base comprises an adhesive patch.

48. The method of any one of claims 43 through 46 wherein the subdermal fluid is dermal interstitial fluid.

49. The method of any one of claims 43 through 46 wherein the sensor medium comprises at least one nanostructure.

50. The method of any one of claims 43 through 46 wherein the at least one measurement system is configured to determine the concentration of lactate based upon a measured value of the variable.

51. The method of claim 43 wherein the electrochemical sensor is an amperometric electrochemical sensor.

52. The method of claim 51 wherein the electrochemical sensor comprises (i) a working electrode comprising the sensor medium which comprises at least one nanostructure, (ii) a counter electrode, and (iii) a reference electrode.

53. The method of claim 43 wherein the electrochemical sensor further comprises a first conductive terminal in electrical connection with the sensor medium and a second conductive terminal in electrical connection with the sensor medium, which comprises at least one nanostructure, the second conductive terminal being spaced from the first conductive terminal.

54. The method of claim 53 wherein the electrochemical sensor operates as a chemiresistor or a field effect transistor.

55. The method of claim 54 wherein the at least one nanostructure is selected from the group consisting of single-walled nanotubes, multiple-wall nanotubes, nanowires, nanofibers, nanorods, nanospheres, and nanoribbons.

56. The method of claim 55 wherein the sensor medium comprises carbon nanostructures.

57. The method of claim 56 wherein the carbon nanostructures comprise single-walled carbon nanotubes, and optionally semiconductor enriched single-walled carbon nanotubes.

58. The method of any one of claim 43 through 46 wherein the sensor medium further comprises an enzymatic material for which lactate is a substrate or a non-enzymatic material interactive with lactate.

59. The method of claim 58 wherein the enzymatic material is lactate oxidase or lactate dehydrogenase.

60. The method of claim 59 wherein the sensor medium further comprises an entity that interacts with hydrogen peroxide.

61. The method of claim 60 wherein the entity that interacts with hydrogen peroxide comprises Prussian blue.

62. The method of claim 43 wherein the delivery system comprises a source of the drug system and a fluid path in fluid connection with the source of the drug which is configured to be transdermally connected to the patient via which the drug is transportable.

63. The method of claim 62 wherein the drug is selected from the group of naloxone, nalmefene, and buprenorphine.

64. The method of any one of claims 62 and 63 wherein the delivery system further comprises a pumping mechanism in connection with the electronic circuitry and with the source of the drug.