Devices and methods for sensing analytes and delivering therapeutic agents

Abstract

Some examples herein provide a wearable device for sensing a concentration of an analyte and delivering a therapeutic agent. The sensor is configured to fully extend through stratum corneum, epidermis, and dermis and partially extend into subcutaneous tissue, and includes a distal end configured to be located within the subcutaneous tissue. A reservoir is configured to contact the stratum corneum and includes a polymer compounded with a drug. Control electronics coupled to a proximal end of the sensor includes a first electrode and a second electrode, and is configured to receive a signal from a distal end of the sensor corresponding to the concentration of the analyte within the subcutaneous tissue. Control electronics use the signal to determine an electrical stimulus to be applied to the first and second electrodes, and apply the electrical stimulus to deliver the therapeutic agent through the stratum corneum.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 436,476, filed on December 30, 2022, the entire content of which is incorporated herein by reference. Technical Field

[0003] This application generally relates to devices and methods for sensing one or more analytes and delivering one or more therapeutic agents. Background Art

[0004] CGM wearable devices are adhered to the skin by means of a medical - grade adhesive. Generally, CGMs are used for patients with intensive insulin therapy, and many of these patients wear patch pumps or infusion sets containing the medical - grade adhesive. In these cases, the CGM is used to notify the delivery of insulin to counter elevated glucose levels. However, this requires the user to adorn at least two devices on the body.

[0005] Several methods for delivering therapeutic agents to the skin of a recipient have been established, including microneedles, iontophoresis, electroporation, laser ablation, radiofrequency ablation, and ultrasound ablation. Such methods can overcome the barrier function of the stratum corneum to deliver a specific amount of therapeutic agent to the skin of the recipient. However, improved control over the amount of therapeutic agent delivered would be useful. Summary of the Invention

[0006] Provided herein are wearable devices for sensing one or more analytes and delivering one or more therapeutic agents and methods of using the same. The wearable device includes a sensor configured to extend completely through the stratum corneum, epidermis, and dermis of a recipient and partially into the subcutaneous tissue of the recipient. The sensor includes a proximal end and a distal end. The distal end is configured to be positioned within the subcutaneous tissue. The wearable device may include at least one reservoir configured to contact the stratum corneum and may include a polymer complexed with the therapeutic agent. The wearable device includes control electronics coupled to the proximal end of the sensor and includes a first electrode and a second electrode. The control electronics are configured to receive, via the proximal end of the sensor, a signal corresponding to the concentration of one or more analytes within the subcutaneous tissue from the distal end of the sensor. The control electronics are configured to use the signal to determine an electrical stimulation to be applied to the first electrode and the second electrode. The control electronics are configured to apply the electrical stimulation to the first electrode and the second electrode to deliver the therapeutic agent through the stratum corneum. In this way, a closed - loop control for sensing analyte concentration and delivering a therapeutic agent is provided in a single wearable device.

[0007] The device further includes a housing, and the proximal end of the sensor and the control electronics are disposed within the housing.

[0008] In some examples, in response to the electrical stimulation, an amount of the therapeutic agent is delivered from the polymer. In some examples, in response to the electrical stimulation, the amount of the therapeutic agent is delivered through the stratum corneum and into the epidermis. In some examples, in response to the electrical stimulation, the amount of the therapeutic agent is delivered through the stratum corneum and the epidermis and into the dermis.

[0009] In some examples, the electrical stimulation is applied to the first electrode and the second electrode to deliver the therapeutic agent through the stratum corneum and into the epidermis via iontophoresis. In some examples, the electrical stimulation is applied to the first electrode and the second electrode to deliver the therapeutic agent into the epidermis via electroporation. In some examples, the electrical stimulation is applied to the first electrode and the second electrode to deliver the therapeutic agent into the epidermis via magnetohydrodynamics.

[0010] In some examples, the therapeutic agent is charged. In some examples, the therapeutic agent is positively charged. In some examples, the therapeutic agent is negatively charged.

[0011] In some examples, the therapeutic agent has a neutral charge and is carried by a charged carrier. In some examples, the charged carrier is positively charged. In some examples, the charged carrier is negatively charged.

[0012] In some examples, a first reservoir of the at least one reservoir is adjacent to the first electrode. In some examples, a second reservoir of the at least one reservoir is located at a spaced distance from the first reservoir. In some examples, the second reservoir is adjacent to the second electrode. In some examples, both the first reservoir and the second reservoir include the polymer complexed with the therapeutic agent. In some examples, the electrical stimulation alternates over time to alternately deliver the therapeutic agent from the first reservoir and the second reservoir.

[0013] In some examples, the first reservoir includes the polymer complexed with the therapeutic agent, and the second reservoir includes a second polymer. In some examples, the electrical stimulation alternates over time to alternately deliver the therapeutic agent from the first reservoir and deliver counterions into the second reservoir.

[0014] In some examples, the electrical stimulation is substantially constant to deliver the therapeutic agent from the first reservoir and deliver counterions into the second reservoir.

[0015] In some examples, the electrical stimulation substantially does not interfere with the signal corresponding to the concentration of the analyte within the subcutaneous tissue.

[0016] In some examples, the control electronics receives the signal during a time when the electrical stimulation is not applied.

[0017] In some examples, the sensor is located between the first electrode and the second electrode.

[0018] In some examples, the second electrode is located between the sensor and the first electrode.

[0019] In some examples, the sensor is located in a hole within the first electrode.

[0020] In some examples, the first electrode is located in a hole within the second electrode.

[0021] In some examples, the proximal end of the sensor is less than about 1 cm from at least one of the first electrode and the second electrode.

[0022] In some examples, the control electronics is configured to determine the electrical stimulation based on a duration that the at least one reservoir has been coupled to the stratum corneum. In some examples, the control electronics is configured to increase a duration of the electrical stimulation as the duration that the at least one reservoir has been coupled to the stratum corneum increases. In some examples, the control electronics is configured to increase a magnitude of the electrical stimulation as the duration that the at least one reservoir has been coupled to the stratum corneum increases.

[0023] In some examples, the control electronics is configured to determine the electrical stimulation in response to the signal differing from a predetermined value by more than a predetermined amount.

[0024] In some examples, the analyte includes a metabolite of the therapeutic agent. In some examples, the analyte includes a metabolite of insulin, levodopa, metformin, glucagon, a GLP-1 antagonist, an SGLT-2 inhibitor, vancomycin, gentamicin, epinephrine, or naloxone.

[0025] In some examples, the therapeutic agent includes insulin, levodopa, metformin, glucagon, a GLP-1 antagonist, an SGLT-2 inhibitor, vancomycin, gentamicin, epinephrine, or naloxone.

[0026] In some examples, the device further includes an adhesive configured to adhere the sensor and the control electronics to the epidermis. In some examples, the at least one reservoir is located within the adhesive.

[0027] Some examples of the present disclosure provide a method for delivering a therapeutic agent. The method may include: receiving, by control electronics of a wearable device that adheres to the stratum corneum of a recipient, a signal from a distal end of a sensor of the wearable device via a proximal end of the sensor that is coupled to the control electronics. In one example, the distal end of the sensor is located within the subcutaneous tissue of the recipient, and the signal may correspond to the concentration of an analyte within the subcutaneous tissue. The method may include: determining, by the control electronics, an electrical stimulation to be applied between a first electrode and a second electrode of the wearable device using the signal. The method may include: applying, by the control electronics, the electrical stimulation to the first electrode and the second electrode to deliver a quantity of the therapeutic agent from at least one reservoir of the wearable device, through the stratum corneum and epidermis, and into the dermis for ingestion of the therapeutic agent by capillaries within the dermis. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figures 1A to 1E Schematically illustrates an exemplary configuration of a wearable device consistent with a particular implementation of the present disclosure and operations performed by the wearable device.

[0029] Figure 2A Schematically illustrates consistent with a particular implementation of the present disclosure Figure 1E bottom view of an exemplary configuration of the wearable device.

[0030] Figure 2B Schematically illustrates consistent with a particular implementation of the present disclosure Figure 1E example of the electric field between electrodes of the wearable device.

[0031] Figures 3 to 6 Schematically illustrates an alternative exemplary configuration of a wearable device and operations performed by the wearable device.

[0032] Figures 7A to 7B Schematically illustrates additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent and operations performed by the wearable device.

[0033] Figures 8A to 8B and Figures 9A to 9B Schematically illustrates additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent and operations performed by the wearable device.

[0034] Figures 9A to 9B Schematically illustrates additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent and operations performed by the wearable device.

[0035] Figure 10 Illustrates the operation flow in an exemplary method for delivering a therapeutic agent using a wearable device. Detailed implementation manners

[0036] The present disclosure provides a wearable device for sensing one or more analytes and delivering one or more therapeutic agents, and methods of using the same. For example, the wearable device includes a sensor for measuring the concentration of an analyte, a reservoir for storing the therapeutic agent, and control electronics for determining the analyte concentration and administering the therapeutic agent from the reservoir and into the skin of a recipient. It should be understood that as part of a single wearable device, a single sensor may include multiple working electrodes for measuring the concentrations of multiple analytes, or multiple sensors each measure the analyte concentration. The control electronics measures the analyte concentration in order to determine the amount of therapeutic agent to be administered, such as by determining the time and / or magnitude of an electrical stimulation applied to the reservoir that releases that amount of therapeutic agent and / or the rate of therapeutic agent release. In this way, the wearable device can more effectively titrate the dose to achieve maximum therapeutic effect in a manner that may be too burdensome for the user to actively manage. Additionally, by integrating both analyte measurement and therapeutic agent delivery into a single wearable device, an accurate amount and / or rate of the therapeutic agent can be rapidly and directly delivered into the skin as needed, without the involvement or intervention of the recipient. In fact, the recipient may not even necessarily know when the therapeutic agent is being delivered. In contrast, some previously known methods of administering therapeutic agents involve the recipient measuring the analyte concentration, using that information to separately determine the dose of therapeutic agent to be administered, and then separately administering that dose. Such previously known methods pose a significant burden on the recipient, and the amount and / or rate of therapeutic agent administered by the recipient may be inaccurate due to calculation errors or due to a delay between making the measurement and finally administering the therapeutic agent. Also in comparison to previously known systems, two devices must be worn on the recipient at a sufficient distance apart to separately sense the analyte and the dose of therapeutic agent without interference. For example, an insulin pump is spaced apart from a continuous glucose monitor such that an insulin preservative, which is an electroactive substance, does not interfere with the glucose concentration signal. Such previously known systems pose a significant burden on the recipient and require the purchase and maintenance of two separate wearable devices. Thus, it should be understood that in one example, the present wearable device and method continuously monitor the concentration of any suitable analyte in a user's physiological fluid (e.g., blood, interstitial fluid) from anywhere (e.g., at home, at work, traveling, or other location), and automatically administer an appropriate amount and / or rate of the therapeutic agent using the same device, without the intervention (or optionally, the knowledge) of the recipient, which provides improved outcomes and / or a reduced burden of managing a disease or health condition for the recipient.

[0037] First, some example terms used in this application will be explained. Then, an exemplary wearable device for delivering a drug to a recipient and methods of using such a device will be provided.

[0038] Terminology

[0039] To facilitate understanding of the disclosed examples, several terms are defined below.

[0040] As used herein, the term "about" is a broad term and will give its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customized meaning), and means (but is not limited to) a degree of variability of an allowable value or range, for example, within 10%, within 5%, or within 1% of the value or the range limit, and includes the exact value or range. As used herein, the term "substantially" means most or the majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the phrase "substantially free of" may mean having none or having a trace amount such that the amount of the material present does not affect the material properties of the composition containing the material, such that the material accounts for from about 0 wt% to about 5 wt%, or from about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than or equal to about 4.5 wt%, 4 wt%, 3.5 wt%, 3 wt%, 2.5 wt%, 2 wt%, 1.5 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt%, 0.1 wt%, 0.01 wt%, or about 0.001 wt% or less, or about 0 wt%.

[0041] As used herein, the terms "adhere" and "attach" are broad terms and will give their ordinary and customary meaning to those of ordinary skill in the art (and are not limited to a special or customized meaning), and mean but are not limited to, for example, holding, binding, or sticking by adhesion, bonding, gripping, interpenetration, or fusion.

[0042] As used herein, the term "analyte" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a substance or chemical component that can be analyzed in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, urine, sweat, saliva, etc.). Analytes can include naturally occurring substances, man-made substances, metabolites, and / or reaction products. In some examples, the analyte measured by the sensing region, sensing device, and sensing method is glucose. However, other analytes are also contemplated, including but not limited to carboxyprothrombin; acylcarnitine; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); androstenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bilirubin, biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-beta-hydroxy-cholic acid; cortisol; creatine; creatine kinase; creatine kinase MM isoenzyme; creatinine; cyclosporin A; d-penicillamine; deethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylase polymorphism, alcohol dehydrogenase, alpha1-antitrypsin, cystic fibrosis, Duchenne muscular dystrophy / Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diphtheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acid / acylglycine; free beta-human chorionic gonadotropin; free erythrocyte protoporphyrin; free thyroxine (FT4); free triiodothyronine (FT3); fumarylacetoacetase; galactose / gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycerol; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; beta-hydroxybutyrate; ketones; lactate; lead; lipoproteins ((a), B / A-1, beta); lysozyme; mefloquine; netilmicin; oxygen; phenobarbital; phenytoin; phytanic acid / pristanic acid; potassium, sodium, and / or other blood electrolytes; progesterone; prolactin; prolinase; purine nucleoside phosphorylase; quinine; reverse triiodothyronine (rT3); selenium; serum pancreatic lipase; sisomicin;Somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Guinea worm, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leptospira, measles / mumps / rubella, Mycobacterium leprae, Mycoplasma pneumoniae, myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, polio virus, Pseudomonas aeruginosa, Respiratory syncytial virus, Rickettsia (tsutsugamushi), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / T. lamblia, Vesicular stoma virus, Wuchereria bancrofti, Yellow fever virus); specific antigens (Hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyroid stimulating hormone (TSH); thyroxine (T4); thyroxine binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uric acid; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. In some examples, salts, sugars, proteins, fats, vitamins, and hormones naturally present in blood or interstitial fluids may also constitute analytes. Analytes may be naturally present in biological fluids or may be endogenous, such as metabolites, hormones, antigens, antibodies, etc. Alternatively, the analyte may be introduced into the body or be exogenous, such as contrast agents for imaging, radioisotopes, chemical agents, fluorocarbon-based synthetic blood, or drugs or drug compositions, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorinated hydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamine, methamphetamine, ); sedatives (barbiturates, methaqualone, tranquilizers such as ); Hallucinogens (phencyclidine, lysergic acid, mescaline, pyodate, psilocybin); Anesthetics (heroin, codeine, morphine, opium, pethidine, Fentanyl, TALWIN, ); designer drugs (fentanyl, pethidine, amphetamine, methamphetamine, and analogs of phencyclidine, e.g., ecstasy); anabolic steroids; and nicotine. Metabolites of the foregoing drugs and pharmaceutical compositions are also contemplated analytes. Analytes produced in the body such as neurochemicals and other chemicals, e.g., ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA), and histamine may also be analyzed.

[0043] As used herein, the phrases "analyte measurement device", "analyte monitoring device", "analyte sensing device", "continuous analyte sensing device", "continuous analyte sensor device", and / or "multianalyte sensor device" are broad phrases and will give their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) devices and / or systems responsible for detecting or transducing signals associated with a particular analyte or analyte combination. For example, these phrases refer to, but are not limited to, instruments responsible for detecting a particular analyte or analyte combination. In one example, the instrument includes a sensor coupled to circuitry disposed within a housing and configured to process a signal associated with an analyte concentration into information. In one example, such devices and / or systems are capable of using biorecognition elements in combination with transduction and / or detection elements to provide specific quantitative, semi-quantitative, qualitative, and / or semi-qualitative analytical information.

[0044] The phrases "biological interface membrane" and "biological interface layer", which may be used interchangeably herein, are broad phrases and will give their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) a permeable membrane (which may include multiple domains) or layer that acts as a bioprotective interface between recipient tissue and an implantable device. The terms "biological interface" and "bioprotective" may be used interchangeably herein.

[0045] As used herein, the phrase "barrier cell layer" is a broad phrase and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to special or customized meanings), and refers to (but is not limited to) a part of the foreign body reaction that forms a monolayer of adhering cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances to the implantable device.

[0046] As used herein, the terms "baseline" and "background" are broad terms and will give their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customized meanings), and refer to, but are not limited to, the amount of a signal (e.g., in the form of current and / or voltage) generated by a sensor that is independent of the concentration of the analyte being measured or is otherwise generated in the absence of the analyte.

[0047] As used herein, the terms “biosensor” and / or “sensor” are broad terms and will give their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to a special or customized meaning), and refer to (but are not limited to) a part of an analyte measurement device, an analyte monitoring device, an analyte sensing device, a continuous analyte sensing device, a continuous analyte sensor device, and / or a multi-analyte sensor device that is responsible for detecting or transducing a signal associated with a particular analyte or analyte combination. In an example, a biosensor or sensor typically includes a body, a working electrode, a reference electrode, and / or a counter electrode that are coupled to the body and form a surface configured to provide a signal during an electrochemical reaction. One or more membranes may be fixed to the body and cover the electrochemical reaction surface. In an example, such biosensors and / or sensors are capable of providing a specific quantitative, semi-quantitative, qualitative, semi-qualitative analysis signal using a biorecognition element in combination with a detection and / or transduction element.

[0048] Examples of various sensor architectures can be found in the pending U.S. application Ser. No. 63 / 321,538, filed Mar. 17, 2022, entitled “CONTINUOUS ANALYTE SENSOR SYSTEMS” (which U.S. application is incorporated herein by reference in its entirety) and U.S. Pat. No. 8,133,178, issued to Brauker et al. (which U.S. patent is incorporated herein by reference in its entirety) and U.S. Pat. Nos. 8,828,201, Simpson et al.; 9,131,885, Simpson et al.; 9,237,864, Simpson et al.; and 9,763,608, Simpson et al. (each of which U.S. patents is incorporated herein by reference in its entirety). Examples of methods for forming sensors (sensor electrode layouts and membranes) and sensor systems discussed herein can be found in the currently pending U.S. Patent Publication No. 2019 / 0307371, issued to Boock et al., which U.S. patent publication is incorporated herein by reference in its entirety.

[0049] As used herein, the term “biostable” is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a material that is relatively resistant to degradation by processes encountered in the body.

[0050] As used herein, the term “coaxial” should be broadly interpreted to include sensor architectures having elements aligned around a core along a shared axis, where the core can be configured to have a circular, elliptical, triangular, polygonal, or other cross-section, and such elements can include electrodes, insulating layers, or other elements that can be circumferentially positioned around the core layer, such as a core electrode or a core polymer wire.

[0051] As used herein, the term "continuous" is a broad term and will give its ordinary and customary meaning to a person of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) an uninterrupted or continuous portion, domain, coating, or layer of a sensor system as discussed herein.

[0052] As used herein, the term "discontinuous" is a broad term and will give its ordinary and customary meaning to a person of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a disjointed, intermittent, or separated portion, layer, coating, or domain of a sensor system as discussed herein.

[0053] As used herein, the term "semicontinuous" is a broad term and will give its ordinary and customary meaning to a person of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a portion, coating, domain, or layer that includes one or more continuous and discontinuous portions, coatings, domains, or layers. For example, a coating disposed around rather than with respect to a sensing region is "semicontinuous".

[0054] As used herein, the phrase "continuous analyte sensing" is a broad term and will give its ordinary and customary meaning to a person of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a period of time during which monitoring of analyte concentration is performed continuously, continuously, or intermittently (but regularly) (e.g., about once every 5 seconds or less to about 10 minutes or more). In additional examples, monitoring of analyte concentration is performed about once every 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, or 60 seconds to about 1.25 minutes, 1.50 minutes, 1.75 minutes, 2.00 minutes, 2.25 minutes, 2.50 minutes, 2.75 minutes, 3.00 minutes, 3.25 minutes, 3.50 minutes, 3.75 minutes, 4.00 minutes, 4.25 minutes, 4.50 minutes, 4.75 minutes, 5.00 minutes, 5.25 minutes, 5.50 minutes, 5.75 minutes, 6.00 minutes, 6.25 minutes, 6.50 minutes, 6.75 minutes, 7.00 minutes, 7.25 minutes, 7.50 minutes, 7.75 minutes, 8.00 minutes, 8.25 minutes, 8.50 minutes, 8.75 minutes, 9.00 minutes, 9.25 minutes, 9.50 minutes, or 9.75 minutes. In some examples, monitoring of analyte concentration is performed about once every 15 minutes, or about once every 30 minutes, or about once every 60 minutes. Additionally or alternatively, in some examples, monitoring of analyte concentration is performed about once every 1.5 hours, about once every 2 hours, about once every 4 hours, about once every 6 hours, or about once every 8 hours.

[0055] As used herein, the term "composite" is a broad term and will give its ordinary and accustomed meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, two or more system elements or components configured to be mechanically, covalently, ionically, or otherwise chemically bonded in at least one of the ways. In some examples, the therapeutic agent is chemically bonded in the polymer. In some examples, the therapeutic agent is mechanically bonded in the polymer.

[0056] As used herein, the term "coupled" is a broad term and will give its ordinary and accustomed meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) two or more system elements or components configured to be electrically attached, mechanically attached, thermally attached, operatively attached, chemically attached, or otherwise attached in at least one of the ways. Similarly, as used herein, the phrases "operatively connected", "operatively linked", and "operatively coupled" may refer to one or more components linked to another component in a way that facilitates the transmission of at least one signal between the components. In some examples, the components are part of the same structure and / or integrated with each other (i.e., "directly coupled"). In other examples, the components are connected via a remote device. For example, one or more electrodes can be used to detect an analyte in a sample and convert the information into a signal; then the signal can be sent to a circuit. In this example, the electrode is "operatively linked" to the electronic circuit. As used herein, the phrase "removably coupled" refers to two or more system elements or components configured to be or configured to have been electrically, mechanically, thermally, operatively, chemically, or otherwise attached and separated without damaging any of the coupled elements or components. As used herein, the phrase "permanently coupled" refers to two or more system elements or components configured to be or configured to have been electrically, mechanically, thermally, operatively, chemically, or otherwise attached, but cannot be decoupled without damaging at least one of the coupled elements or components.

[0057] As used herein, the term "distant" is a broad term and will give its ordinary and accustomed meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) an area that is relatively far from a reference point (such as a starting point or an attachment point).

[0058] As used herein, the term "domain" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a region of a membrane system, which can be a layer, a uniform or non-uniform gradient (e.g., an anisotropic region of a membrane), or a portion of a membrane capable of sensing one, two, or more analytes. The domains discussed herein can be formed as a single layer, two or more layers, bilayer pairs, or combinations thereof.

[0059] As used herein, the term "electrochemical reaction surface" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) the surface of an electrode at which an electrochemical reaction occurs. In various examples, the reaction by-products of the analyte being detected include at least one measurable substance. The at least one measurable substance can react with an electrochemically active surface (such as a working electrode).

[0060] As used herein, the term "ex vivo" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and includes (but is not limited to) a portion of a device (e.g., a sensor) adapted to be retained and / or exist outside the living body of a recipient.

[0061] As used herein, the term "recipient" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a mammal, such as a human.

[0062] As used herein, the terms "indwelling", "implanted", or "implantable" are broad terms and will give their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to a special or customized meaning), and refer to (but are not limited to) an object including a sensor that is inserted or configured to be inserted in the following ways: subcutaneous insertion (i.e., in the fatty layer between the skin and muscle), intradermal insertion (i.e., penetrating the stratum corneum and located within the epidermis or dermis of the skin), or percutaneous insertion (i.e., penetrating, entering, or passing through intact skin), which can result in the sensor having an in vivo portion and an ex vivo portion. The term "indwelling" also encompasses an object configured for subcutaneous, intradermal, or percutaneous insertion, whether or not it has been so inserted.

[0063] As used herein, the phrase "insertable volume" is a broad phrase and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) the volume in front of and beside the insertion path of the insertable portion of the analyte sensor as described herein, and the incision made in the skin for inserting the insertable portion of the analyte sensor. The insertable volume also includes up to 5 mm radially or perpendicular to the volume in front of and beside the insertion path.

[0064] As used herein, the terms "interferent" and "interfering substance" are broad terms and will give their ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refer to (but are not limited to) effects and / or substances that interfere with the measurement of an analyte of interest in a sensor to produce a signal that inaccurately represents the analyte measurement, including ions, electroactive substances, endogenous circulating substances, exogenous circulating substances, pharmacological agents, and / or electromagnetic waves (such as from a magnetic resonance imaging (MRI) system or a medical device).

[0065] As used herein, the term "in vivo" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and includes (but is not limited to) portions of a device (e.g., a sensor) adapted to be inserted into and / or present within a recipient's living body.

[0066] As used herein, the term "membrane" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a structure configured to perform functions including but not limited to: protecting the exposed electrode surface from the biological environment, diffusion resistance (limitation) of an analyte, serving as a matrix for enabling an enzymatic reaction to occur, restricting or blocking interfering substances, providing hydrophilicity at the electrochemically reactive surface of the sensor interface, serving as an interface between the recipient tissue and an implantable device, regulating the recipient tissue response via drug (or other substance) release, and combinations thereof. When used herein, the terms "membrane" and "matrix" are intended to be used interchangeably.

[0067] As used herein, the phrase "membrane system" is a broad phrase and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to but is not limited to a permeable or semi-permeable membrane made of a material several micrometers thick or thicker that can consist of two or more domains, two or more layers, or two or more layers within one domain, and is at least permeable to the analyte whose concentration is to be measured.

[0068] As used herein, the term "micro" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to, but is not limited to, small objects or scales of about 10 -6 m to 10 -3 m of small objects or scales. The term "micro" is the opposite of the term "macro", which refers to large objects that are visible without magnification. Similarly, the term "nano" refers to small objects or scales of about 10 -9 m to 10 -6 m.

[0069] As used herein, the term "optional" or "optionally" is a broad term and will give their ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) the subsequent described event or situation that may or may not occur, and this description includes the case where the event or situation occurs and the case where the event or situation does not occur.

[0070] As used herein, the term "planar" is broadly interpreted to describe a sensor architecture having a substrate including a first side and a second side and a plurality of elements disposed on one or more sides of the substrate, and these elements may or may not be electrically coupled or otherwise coupled, and these elements may include conductive or insulating layers or elements configured to operate as a circuit.

[0071] As used herein, the term "proximate" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) the spatial relationship between various elements compared to a specific reference point.

[0072] As used herein, the phrases and terms "processor module" and "microprocessor" are each broad phrases and terms and will give their ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a computer system, state machine, processor, etc. designed to perform arithmetic or logical operations using logic circuits, and the logic circuits respond to and process the basic instructions that drive the computer.

[0073] As used herein, the phrase "sensing membrane" is a broad phrase and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a permeable or semi-permeable membrane, which may include one or more domains, one or more layers or one or more layers within a plurality of domains and is composed of a material having a thickness of several micrometers or more, and which is permeable to reactants and / or co-reactants for determining an analyte of interest.

[0074] As used herein, the phrases "sensing portion", "sensing membrane", "sensing region", "sensing domain", and / or "sensing mechanism" are broad phrases and will give their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) a part of a biosensor and / or sensor that is responsible for detecting or transducing a signal associated with a specific analyte or analyte combination. In an example, the sensing portion, sensing membrane, and / or sensing mechanism generally includes an electrode that is configured to provide a signal during an electrochemical reaction with one or more membranes covering an electrochemically reactive surface. In an example, such sensing portion, sensing membrane, and / or sensing mechanism is capable of providing a specific quantitative, semi-quantitative, qualitative, semi-qualitative analysis signal using a biorecognition element combined with a detection and / or transduction element.

[0075] In one example, the sensing region determines the selectivity between one or more analytes such that only the analyte(s) that must be measured produce(s) (transduce) a detectable signal. In one example, the selection is based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte is not altered, or where the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0076] The sensing region transduces the recognition of the analyte into a semi-quantitative or quantitative signal. Thus, "transduction" as used herein and their grammatical equivalents encompass electrochemical techniques and methods. Electrochemical properties include current and / or voltage, capacitance, resistance, impedance, charge, and potential.

[0077] As used herein, the term "sensitivity" is a broad term and will give its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to special or customized meanings), and refers to (but is not limited to) the amount of signal (e.g., in the form of current and / or voltage) produced by a predetermined amount (unit) of the measured analyte. For example, for every 1 mg / dL of analyte, an amperometric sensor has a sensitivity (or slope) of about 1 picoampere to about 100 picoamperes of current.

[0078] As used herein, the phrases and terms "small diameter sensor", "small structure sensor", and "micro sensor" are broad phrases and terms and will give their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to a special or customized meaning), and refer to (but are not limited to) a sensing mechanism that is less than about 2 mm in at least one dimension. In additional examples, the sensing mechanism is less than about 1 mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95 mm, 0.9 mm, 0.85 mm, 0.8 mm, 0.75 mm, 0.7 mm, 0.65 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some examples, the largest dimension of the independently measured length, width, diameter, thickness, or perimeter of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a coaxial or wire-type sensor, where the diameter is less than about 1 mm, see, for example, U.S. Patent 6,613,379 to Ward et al. and U.S. Patent 7,497,827 to Brister et al., both of which are incorporated herein by reference in their entirety. In some alternative examples, the sensing mechanism includes electrodes deposited on a planar or substantially planar substrate, where the thickness of the implantable portion is less than about 1 mm, see, for example, U.S. Patent 6,175,752 to Say et al. and U.S. Patent 5,779,665 to Mastrototaro et al., both of which are incorporated herein by reference in their entirety. Examples of methods of forming the sensors (sensor electrode layouts and membranes) and sensor systems that can be used to prepare the present sensors can be found in U.S. Patent Publication 2019 / 0307371 to Boock et al., which is incorporated herein by reference in its entirety.

[0079] As used herein, the terms and phrases "zwitterion" and "zwitterionic compound" are each broad terms and phrases and will give their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to a special or customized meaning), and refer to (but are not limited to) a compound in which the neutral molecule of the compound has a unit positive charge and a unit negative charge at different positions within the molecule. Such compounds are a class of dipolar compounds and are sometimes also referred to as "inner salts".

[0080] Wearable Device for Delivering Therapeutic Agent and Method of Using the Same

[0081] Now reference will be made to Figures 1A to 1E 、 Figures 2A to 2B 、 Figures 3 to 6 、 Figures 7A to 7B 、 Figures 8A to 8B 、 Figures 9A to 9B and Figure 10 describe non-limiting examples of devices and methods for measuring physiological signals and / or concentrations of target analytes in vivo.Figures 1A to 1E and Figures 2A to 2B schematically illustrate an exemplary configuration of a wearable device for sensing an analyte and delivering a therapeutic agent and operations performed by the wearable device. Turning first to Figure 1A , wearable device 100 includes a housing 110, control electronics 120, a sensor 130, and at least one reservoir (e.g., a first reservoir 151 and a second reservoir 152). In one example, wearable device 100 also includes a battery 170 that is coupled to control electronics 120 and configured to provide power thereto. In one example, wearable device 100 is configured to be coupled or adhered to the stratum corneum 10 (which is part of the epidermis 20) using, for example, a suitable biocompatible adhesive pad 32 as illustrated in Figure 1A or by other coupling means such as an elastic band or an adjustable wristband. For example, a base plate 150 or an elastic band or an adjustable wristband is configured to secure wearable device 100, which includes sensor 130 and control electronics 120, to the epidermis 20. In one example, base plate 150 includes one or both of first reservoir 151 and second reservoir 152.

[0082] Figure 2A illustrates a partial plan view of wearable device 100. In the non-limiting examples illustrated in Figure 1A and Figure 2A , sensor 130 is located between a first electrode 141 and a second electrode 142. In the example illustrated in Figure 1A , first reservoir 151 is adjacent to first electrode 141, second reservoir 152 is located at a distance spaced apart from first reservoir 151, and second reservoir 152 is adjacent to second electrode 142. However, in other examples, such as further described below with reference to Figures 7A to 7B , Figures 8A to 8B , Figures 9A to 9B , sensor 130, first electrode 141, and second electrode 142, and first reservoir 151 and second reservoir 152 are arranged in other configurations and spatial relationships relative to each other. In one example, as depicted in Figure 2A , housing 110 is generally circular, and adhesive pad 32 has a circular diameter that is the same as or slightly larger than that of the housing.

[0083] The sensor 130 is configured to extend completely through the recipient's stratum corneum 10, epidermis 20, and dermis 30, and partially into the recipient's subcutaneous tissue 40. For example, the sensor 130 includes a proximal end 131 and a distal end 132. The distal end 132 is configured to be located within the recipient's subcutaneous tissue 40, and the proximal end 131 is coupled to control electronics 120 within the housing 110. The distal end 132 includes a first working electrode 133, and optionally a second working electrode 134, and optionally additional working electrodes (not shown). At least one reservoir optionally includes a polymer complexed with a therapeutic agent. In Figure 1A In the non-limiting example illustrated in, at least one of the first reservoir 151 and the second reservoir 152 (which may also be represented as R1 and R2 respectively) includes a polymer complexed with a therapeutic agent. In some other examples, as further described below, both the first reservoir 151 and the second reservoir 152 optionally store a therapeutic agent. In one example, the control electronics 120 is coupled to the proximal end 131 of the sensor 130 and includes a first electrode 141 and a second electrode 142 (which may also be represented as E1 and E2 respectively). The control electronics 120 is configured to receive, via the proximal end 131 of the sensor 130, a signal corresponding to the concentration of an analyte within the subcutaneous tissue 40 from the distal end 132 of the sensor 130.

[0084] In one example, the control electronics 120 is further configured to use the signal to determine an electrical stimulation to be applied to the first electrode 141 and the second electrode 142; and apply the electrical stimulation to the first electrode 141 and the second electrode 142. Thus, the control electronics 120 is configured and operative to automatically control the delivery of a therapeutic agent from at least one reservoir (e.g., from the first reservoir 151 and / or the second reservoir 152) to the dermis in response to the concentration of the analyte measured by the distal end 132 of the sensor 130 within the subcutaneous tissue 40. For example, at Figure 1B and Figure 2B at a specific time illustrated in, the control electronics 120 applies a voltage and a current between the first electrode 141 and the second electrode 142, which generates electric field lines 153 that penetrate the stratum corneum 10 and also completely or partially penetrate the remainder of the epidermis 20. In response to the electrical stimulation, an amount of the therapeutic agent is delivered from the polymer of the first reservoir 151 and / or the second reservoir 152. For example, the electric field generated by applying the electrical stimulation causes the therapeutic agent to be released from the first reservoir 151 and / or the second reservoir 152. At Figure 1C at a specific time illustrated in, the electrical stimulation causes the therapeutic agent 160 to move out of the reservoir 151 and through the stratum corneum 10. In one example, the therapeutic agent is positively charged, for example, as Figure 1CAs illustrated, or the therapeutic agent is uncharged (i.e., it is neutral) and carried by a positively charged carrier. Alternatively, the therapeutic agent is negatively charged, or the therapeutic agent is uncharged (i.e., it is neutral) and carried by a negatively charged carrier. In such examples, the carrier includes a charged substance complexed with the therapeutic agent, or includes a charged encapsulant in which the therapeutic agent is disposed. Electrical stimulation causes delivery of the therapeutic agent 160 into the epidermis 20 and dermis 30; alternatively, the therapeutic agent 160 is delivered into the epidermis 20 and dermis 30 via diffusion or circulation. For example, at Figure 1D the specific time illustrated, the therapeutic agent 160 is delivered into the epidermis 20 and dermis 30. At Figure 1E the specific time illustrated, the therapeutic agent 160 is delivered into the dermis 30, where capillaries 31 take up the therapeutic agent for systemic distribution. By administering and sensing in different layers of the skin and tissue, i.e., administering the therapeutic agent 160 into the epidermis 20 and dermis 30 and sensing an analyte in the subcutaneous tissue, potential interference due to sensing the therapeutic agent 160 and / or its components is avoided.

[0085] Using the wearable device 100, any suitable analyte can be measured and any suitable therapeutic agent can be delivered. Non-limiting examples of analytes are provided elsewhere herein. In some examples, the analyte measured by the wearable device 100 is selected from the group consisting of glucose, lactate, ketone bodies (such as acetoacetate, acetone or β-hydroxybutyrate), ions (such as sodium, potassium, calcium, magnesium or chloride), or hormones (such as insulin or cortisol). In some examples, the analyte measured using the wearable device 100 includes metabolites of a therapeutic agent, such as metabolites of insulin, levodopa, metformin, glucagon, GLP-1 antagonists, SGLT-2 inhibitors, vancomycin, gentamicin, epinephrine or naloxone. Non-limiting examples of therapeutic agents that can be delivered using the wearable device 100 include insulin, levodopa, metformin, glucagon, GLP-1 antagonists, SGLT-2 inhibitors, vancomycin, gentamicin, epinephrine or naloxone.

[0086] It should be understood that the control electronics 120 is configured to control the delivery of the therapeutic agent 160 via different methods. In some examples, the control electronics 120 applies an electrical stimulation to the first electrode 141 and the second electrode 142 to deliver the therapeutic agent 160 into the dermis 30 via electroporation. In other examples, the control electronics 120 applies an electrical stimulation to the first electrode 141 and the second electrode 142 to deliver the therapeutic agent 160 into the dermis 30 via iontophoresis. For further details regarding electroporation and iontophoresis, see Zhang et al., “Advances in transdermal insulin delivery”, Adv. Drug. Deliv. Rev. 139: 51-70 (2019), the entire content of which is incorporated herein by reference. In some examples, the control electronics 120 applies an electrical stimulation to the first electrode 141 and the second electrode 142 to deliver the therapeutic agent into the epidermis 20 via magnetohydrodynamics.For further details regarding magnetohydrodynamics, see the following references, the entire contents of each of which are incorporated herein by reference: Hakala et al., “Sampling of fluid through skin with magnetohydrodynamics for noninvasive glucose monitoring”, Scientific Reports 11:7609, page 9 (2021); Park et al., “Soft, smart contact lenses with integrations of wireless circuits, glucose sensors, and displays”, Sci. Adv. 4:eeap9841 (2018); Lemoff et al., “AC magnetohydrodynamic micropump”, Sensors Actuators B Chem 63:178 - 185 (2000); Jang et al., “Theoretical and experimental study of MHD (magnetohydrodynamic) micropump”, Sens. Actuators A Phys 80:84 - 89 (2000); Das et al., “Some practical applications of magnetohydrodynamic pumping”, Sens. Actuators A Phys 201:43 - 48 (2013); and Chang et al., “A needle - free technique for interstitial fluid sample acquisition using a Lorentz - force actuated jet injector”, J. Control. Release 211:37 - 43 (2015).

[0087] In one example, the analyte measured by the wearable device 100 is glucose, and the therapeutic agent delivered using the wearable device 100 is insulin. Insulin typically includes phenolic preservatives, namely phenol and / or m - cresol, which are electroactive substances that can interfere with the signals detected by the sensor. Delivery of insulin to the dermis 30 via iontophoresis and sensing of the glucose concentration in the subcutaneous tissue 40 avoids the interference of the phenolic preservatives.

[0088] As further noted above, at least one reservoir of the wearable device 100 optionally includes a polymer complexed with a therapeutic agent. For example, in Figure 1A in the non-limiting configuration illustrated, at least one of the first reservoir 151 and the second reservoir 152 (which may also be represented as R1 and R2, respectively) includes a polymer complexed with a therapeutic agent. Such polymers are particularly useful in examples where the therapeutic agent is delivered via electroporation or by iontophoresis. Figure 3 An alternative exemplary configuration of a wearable device for delivering a therapeutic agent 160 and operations performed by the wearable device are schematically illustrated. In Figure 3 in the non-limiting example 101 illustrated, iontophoresis is used, a first reservoir 151 including a first polymer complexed with a therapeutic agent, and a second reservoir 152 including a second polymer that does not store a therapeutic agent, to deliver the therapeutic agent 160. In one example, the therapeutic agent 160 is positively charged, as Figure 3 is intended to be represented by "D + ". For example, the molecules of the therapeutic agent 160 are themselves charged, or the therapeutic agent is disposed within a positively charged encapsulant. In one example, the electrical stimulation includes applying a positive charge to the first electrode 141 (which acts as an anode) and applying a negative charge to the second electrode 142 (which acts as a cathode). The positive charge applied to the first electrode 141 repels the positively charged therapeutic agent, and the negative charge applied to the second electrode 142 attracts the positively charged biocounterion 161. In response to the electrical stimulation, the therapeutic agent 160 is transported out of the first reservoir 151 in a manner such as Figures 1B to 1E described, through the stratum corneum 10, and into the epidermis 20, and into the dermis 30. Additionally, as Figure 3 illustrated, in response to the electrical stimulation, the biocounterion 161 is transported out of the epidermis 20 and / or the dermis 30, through the stratum corneum 10, and into the polymer of the second reservoir 152. In one example, the biocounterion 161 is positively charged, as Figure 3 is intended to be represented by "A + ". In some examples, the electrical stimulation is substantially constant (direct current, DC) to transport the therapeutic agent 160 out of the first reservoir 151 and transport the counterion 161 into the second reservoir 152. In other examples, the electrical stimulation alternates over time (alternating current, AC) to alternately transport the therapeutic agent 160 out of the first reservoir 151 and transport the counterion 161 into the second reservoir 152.

[0089] Figure 4 Another alternative exemplary configuration of the wearable device 100 for delivering the therapeutic agent 160 and operations performed by the wearable device are schematically illustrated. In Figure 4In the non-limiting example 102 illustrated therein, a therapeutic agent is also delivered via iontophoresis through a first reservoir 151 that includes a first polymer complexed with a therapeutic agent 160 and a second reservoir 152 that includes a second polymer that does not store the therapeutic agent. In this example, the therapeutic agent 160 has no charge (i.e., it is neutral), as Figure 4 is intended to be represented by "D" therein, and in another example, it is mixed with a positively charged carrier 162 intended to be represented by Figure 4 "C" in + . A positive charge applied to the first electrode 141 repels the positively charged therapeutic agent 160, and a negative charge applied to the second electrode 142 attracts the positively charged biocounterion 161. In response to the electrical stimulation, the therapeutic agent 160 is delivered out of the first reservoir 151 in a manner such as Figures 1B to 1E described, carried by the charged carrier 162, through the stratum corneum 10, and into the epidermis 20 and into the dermis 30. Additionally, as Figure 4 illustrated therein, in response to the electrical stimulation, the biocounterion 161 is delivered out of the epidermis 20 and / or the dermis 30, through the stratum corneum 10, and into the polymer of the second reservoir 152. In one example, the biocounterion 161 is positively charged, as Figure 4 is intended to be represented by "A" in + .

[0090] Figure 5 An alternative exemplary configuration of the wearable device 100 for delivering the therapeutic agent 160 and the operations performed by the wearable device are schematically illustrated. In Figure 5 the non-limiting example 103 illustrated therein, electroporation, a first reservoir 151 that includes a first polymer complexed with a therapeutic agent, and a second reservoir 152 that includes a second polymer that does not store the therapeutic agent 160 are used to deliver the therapeutic agent 160. In one example, the therapeutic agent 160 has no charge (i.e., it is neutral), as Figure 5 is indicated by "D" therein. In response to the electrical stimulation, the therapeutic agent 160 is delivered out of the first reservoir 151 in a manner such as Figures 1B to 1E described, through the stratum corneum 10, and into the epidermis 20 and into the dermis 30. In some examples, the electrical stimulation alternates in polarity over time (i.e., alternating current) to alternately deliver the therapeutic agent out of the first reservoir 151. The first polymer and the second polymer can be polymers such as hydrogels, which provide improved ohmic conductivity (reduced resistance) between the electrodes / reservoirs and the stratum corneum 10. For example, the polymer provides enhanced resistance matching; otherwise, most of the voltage drop may occur between the electrode and the stratum corneum, which may cause erythema and may cause burns.

[0091] Figure 6 Another exemplary configuration of the wearable device 100 for delivering the therapeutic agent 160 and the operations performed by the wearable device are schematically illustrated. In Figure 6 the non-limiting example 104 illustrated in, where electroporation, a first reservoir 151 including a first polymer complexed with the therapeutic agent 160, and a second reservoir 152 including the same polymer that also stores the therapeutic agent 160 are used to deliver the therapeutic agent 160. In one example, the therapeutic agent 160 has no charge (i.e., it is neutral), as Figure 6 intended to be shown by "D" in. In response to an electrical stimulus, the therapeutic agent 160 is delivered out of the reservoir 151 and the reservoir 152 in a manner such as Figures 1B to 1E described, through the stratum corneum 10, and into the epidermis 20 and into the dermis 30. In some examples, the electrical stimulus alternates in polarity over time (i.e., alternating current) to alternately deliver the therapeutic agent from the first reservoir 151 and the second reservoir 152.

[0092] Regardless of the specific form of the electrical stimulus and the specific mode by which the therapeutic agent 160 is delivered to the dermis 30, in at least one example, the control electronics 120 are suitably configured to determine the electrical stimulus based on the measured concentration of an analyte within the subcutaneous tissue 40. Illustratively, for example, the control electronics 120 are configured to determine the electrical stimulus in response to the signal differing from a predetermined value by more than a predetermined amount. For example, the control electronics 120 include a memory storing a predetermined value corresponding to the "normal" or "target" value of the analyte and are configured to compare the signal with the predetermined value (e.g., by calculating the difference between the signal and the predetermined value). In one example, the control electronics 120 are configured to determine the timing and / or magnitude of the electrical stimulus based on such comparison. For example, the control electronics increase the duration of the applied electrical stimulus in proportion to the magnitude of the difference between the signal and the predetermined value. Alternatively, for example, the control electronics increase the magnitude of the electrical stimulus in proportion to the magnitude of the difference between the signal and the predetermined value.

[0093] Additionally, regardless of the specific form of the electrical stimulation and the specific mode by which the therapeutic agent 160 is delivered to the dermis 30, in one example, the control electronics 120 are suitably configured to determine the electrical stimulation based on not only the measured concentration of the analyte within the subcutaneous tissue 40, but also on one or more other factors. For example, the control electronics 120 are configured to determine the electrical stimulation based on the duration for which at least one reservoir (i.e., the first reservoir 151 and / or the second reservoir 152) has been coupled to the stratum corneum 10. Illustratively, when the therapeutic agent 160 is delivered to the recipient, the concentration of the therapeutic agent 160 within at least one reservoir decreases over time. In one example, the control electronics 120 are configured to adjust the electrical stimulation so as to compensate for this depletion of the therapeutic agent 160, thereby providing a consistent and accurate delivery of the therapeutic agent 160. For example, the control electronics 120 are configured to increase the duration of the electrical stimulation as the duration for which at least one reservoir has been coupled to the epidermis increases. Additionally or alternatively, the control electronics 120 are configured to increase the magnitude of the electrical stimulation as the duration for which at least one reservoir has been coupled to the epidermis increases.

[0094] Note that in examples such as those described in reference Figures 1A to 1E 、 Figures 2A to 2B and Figures 3 to 6 the electrical stimulation and the dose of the therapeutic agent 160 substantially do not interfere with the signal corresponding to the concentration of the analyte within the subcutaneous tissue 40. For example, again referring to Figure 1B , the electric field lines 153 are generated at a position sufficiently spaced apart from the distal end 132 of the sensor 130 such that the field line intensity is negligible at the distal end and substantially does not affect the measurements made using the distal end 132. Additionally or alternatively, in some examples, the control electronics 120 receive a signal from the distal end 132 at times when no electrical stimulation is applied. Thus, when the signal is generated, the electric field lines 153 are absent and thus do not interfere with the signal. In some examples, the proximal end 131 of the sensor 130 is less than about 1 cm from at least one of the first electrode 141 and the second electrode 142.

[0095] Although Figures 1A to 1E 、 Figures 2A to 2B and Figures 3 to 6 illustrate non-limiting examples in which the sensor is located between the first electrode 141 and the second electrode 142, it should be understood that a portion of the sensor 130 and the first electrode 141 and the second electrode 142 can have any suitable arrangement relative to each other. For example, Figures 7A to 7B 、 Figures 8A to 8B and Figures 9A to 9B schematically illustrate additional alternative exemplary configurations of the wearable device 100 for delivering the therapeutic agent 160 and the operations performed by the wearable device.

[0096] A side view depicting the wearable device 102 Figure 7A and a bottom view depicting the Figure 7A device Figure 7B illustrate an example in which the second electrode 142 (E2) is located between a portion of the sensor 130 and the first electrode 141 (E1). In one example, the wearable device 102 includes a base plate 150 and a housing 110 centrally located on the base plate 150. In one example, the base plate 150 includes a medical-grade adhesive surface configured to be fixed to the epidermis. In one example, the base plate 150 includes one or more adhesive pads 32 having an adhesive surface applied to the bottom of the base plate 150 such that during operation, when the wearable device 100 is in use, the pads 32 adhere to the patient's skin, thereby helping to fix the housing 110 to the patient's skin to prevent the wearable device 100 from shifting on the skin during use. The size and shape of the pads 32 can be determined relative to the size and / or weight of the wearable device 102 and / or the body part to which the wearable device 102 is applied. The size of the pads can also be determined relative to the type of adhesive used on the pads. In one example, the one or more adhesive pads 32 have a rectangular or strip shape protruding from the opposite side away from the housing 110. In one example, the one or more adhesive pads 32 include a release liner for protecting the adhesive until the wearable device 100 is deployed.

[0097] In one example, the force released from the patient's skin by the one or more pads 32 is greater than the compressive force applied by the sensor 130 on the puncture site. A typical temporary medical adhesive can be used such that when the lifespan of the sensor 130 is reached, the wearable device 100 can be easily removed. Optionally, at least one reservoir (e.g., reservoirs 151 and 152) is located within or surrounded by the adhesive pad 32, as Figure 7B shown.

[0098] A side view depicting the wearable device 103 Figure 8A and a bottom view depicting the Figure 8A device Figure 8B illustrate an example in which the sensor 130 is located in a hole within the first electrode 141 (E1). Optionally, as Figures 8A to 8B illustrated, the first electrode 141 is located in a hole within the second electrode 142 (E2).

[0099] A side view depicting the wearable device 104 Figure 9A and a bottom view depicting the Figure 9A device Figure 9BIllustrates another example in which the second electrode 142 (E2) is located between a portion of the sensor 130 and the first electrode 141 (E1). In this example, a portion of the sensor 130 is located external to both the first electrode 141 and the second electrode 142, and the first electrode 141 is located in a hole within the second electrode 142.

[0100] As should be understood from this disclosure, the wearable device can have any of a variety of suitable configurations and can be used to implement any suitable operation. For example, Figure 10 Illustrates the operation flow in an exemplary method for delivering a therapeutic agent using a wearable device. Figure 10 The method 1000 illustrated therein includes: receiving, by control electronics of a wearable device coupled to the recipient's stratum corneum, a signal from a distal end of a sensor coupled to the control electronics via a proximal end of the sensor, the distal end of the sensor being located within the recipient's subcutaneous tissue, the signal corresponding to the concentration of an analyte within the subcutaneous tissue (operation 1010). Refer to Figures 1A to 1E 、 Figures 2A to 2B 、 Figures 3 to 6 and Figures 7A to 9B for non-limiting examples of such a device, sensor, and adhesive. Figure 10 The method 1000 illustrated therein includes: using the signal received by the control electronics to determine an electrical stimulation to be applied between a first electrode and a second electrode of the wearable device (operation 1020). Non-limiting examples of ways in which the control electronics uses a signal to determine an electrical stimulation are provided elsewhere herein. Figure 10 The method 1000 illustrated therein includes: applying the electrical stimulation determined by the control electronics to the first electrode and the second electrode (operation 1030). Figure 10 The method 1000 illustrated therein includes: delivering an amount of the therapeutic agent from at least one reservoir of the wearable device, through the stratum corneum, and into the dermis to be ingested by capillaries in the dermis (operation 1040). Non-limiting examples of electrical stimulations and ways of using such electrical stimulations to deliver a therapeutic agent from a reservoir through the epidermis and into the dermis are described elsewhere herein.

[0101] The sensor 130 is optionally configured in a manner that enhances its biocompatibility. For example, the biocompatibility of the sensor 130 is optionally enhanced by providing a biointerface film (not specifically illustrated) on one or more components of the sensor 130. In some examples, the biointerface film is configured to inhibit biofouling of the sensor 130. Non-limiting examples of materials included in the biointerface film include hard segments and / or soft segments. Examples of hard segments and soft segments for the biointerface film include aromatic polyurethane hard segments having Si groups, aliphatic hard segments, polycarbonate soft segments, or any combination thereof. In some examples of the biointerface film, polyvinylpyrrolidone (PVP) is not included. In this example where PVP is not included, the biointerface film includes polyurethane and poly(dimethylsiloxane) (PDMS). In some examples in combination with other examples herein, the biointerface films discussed herein include one or more zwitterionic compounds.

[0102] Additionally or alternatively, the biointerface film is configured to release a therapeutic compound into the biological fluid. In one example, therapeutic compounds suitable for release using the biointerface films or other films discussed herein include one or more anti-inflammatory agents, anti-infective agents, necrotizing agents, and anesthetics. Generally, anti-inflammatory agents reduce acute and / or chronic inflammation adjacent to the implant in order to reduce the formation of the FBC capsule, thereby reducing or preventing the formation of the barrier cell layer. Suitable anti-inflammatory agents include, but are not limited to, for example, non-steroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutant proteins, anti-IL-6 iNOS inhibitors (e.g., L-NAME or L-NMDA), interferons, ketoprofen, ketorolac, leflunomide, mefenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone acetonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, dexamethasone, and dexamethasone acetate.

[0103] Typically, immunosuppressants and / or immunomodulators directly interfere with several key mechanisms necessary for different cellular components involved in the inflammatory response. Suitable immunosuppressants and / or immunomodulators include anti-proliferative cell cycle inhibitors (e.g., taxanes (e.g., sirolimus), cytochalasin D, infliximab), taxanes, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiotensin, vincristine, mitomycin, statins, C MYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, PCNA ribozyme, batimastat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-protease inhibitors, probucol, BCP671, EPC antibodies, catechins, glycating agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), Escherichia coli (E.coli) heat-labile enterotoxin, NLRP3 inflammasome inhibitors, and advanced coatings.

[0104] Typically, anti-infective agents are substances that can act anti-infectively by inhibiting the spread of the infectious agent or by completely killing the infectious agent, and can be used to reduce the immune response without an inflammatory reaction at the implantation site. Anti-infective agents include, but are not limited to, antihelminthics (mebendazole); antibiotics, including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin B, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, miconazole, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), β-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (sodium penicillin G, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; polymyxin E methanesulfonate; polymyxin B sulfate; vancomycin; antiviral agents, including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamide crystalline for sterilization; gatifloxacin; and sulfamethoxazole / trimethoprim.

[0105] Generally, a necrotizing agent is any drug that causes tissue necrosis or cell death. Necrotizing agents include cisplatin, BCNU, paclitaxel, or paclitaxel derivatives, etc.

[0106] Generally, an angiogenesis agent includes a substance having direct or indirect angiogenic properties. In some cases, the angiogenesis agent additionally affects the formation of barrier cells in the body. Indirect angiogenesis means that angiogenesis can be mediated through an inflammatory pathway or an immune-stimulatory pathway. It is not fully understood how agents that induce local angiogenesis indirectly inhibit barrier cell formation; however, it is believed that some of the barrier-cell effects can be caused indirectly by the action of angiogenesis agents.

[0107] Angiogenesis agents include mechanisms that promote neovascularization around a membrane and / or reduce or minimize ischemic periods by increasing angiogenesis near the device-tissue interface. Sphingosine-1-phosphate (S1P) is incorporated into a non-limiting example of a biointerface membrane as a phospholipid with potent angiogenic activity. Monobutyrin is incorporated into another non-limiting example of a biointerface membrane as a potent vasodilator and angiogenic lipid product of adipocytes. In another non-limiting example, an antisense molecule that increases angiogenesis (e.g., thrombospondin 2 antisense) is incorporated into the biointerface membrane.

[0108] Angiogenesis agents can include mechanisms that promote inflammation, which is thought to cause accelerated neovascularization in the body. In one non-limiting example, a xenogeneic carrier (e.g., bovine collagen) that elicits an immune response through its foreign nature stimulates neovascularization and is incorporated into the biointerface membranes of the present disclosure. In another non-limiting example, lipopolysaccharide is incorporated into the biointerface membrane as an effective immune stimulant. In another non-limiting example, a protein known to regulate bone healing in tissue (e.g., bone morphogenetic protein (BMP)) is incorporated into the biointerface membrane.

[0109] Generally, angiogenic agents are substances capable of stimulating the formation of new blood vessels, which can accelerate and maintain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, copper ions, iron ions, dodecylmethylammonium chloride, basic fibroblast growth factor (bFGF) (also known as heparin-binding growth factor II and fibroblast growth factor II), acidic fibroblast growth factor (aFGF) (also known as heparin-binding growth factor I and fibroblast growth factor I), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor β (TGF-β), transforming growth factor α (TGF-α), hepatocyte growth factor, tumor necrosis factor-α (TNF-α), placental growth factor (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia-inducible factor-I (HIF-1), the angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, peptide KGHK, hypoxic tension, lactic acid, insulin, copper sulfate, estradiol, prostaglandins, cox inhibitors, endothelial cell binders (e.g., decorin or vimentin), genipin, hydrogen peroxide, nicotine, and growth hormone.

[0110] Generally, pro-inflammatory agents are substances capable of stimulating an immune response in the recipient tissue, which can accelerate or maintain the formation of a mature vascularized tissue bed. For example, pro-inflammatory agents are typically stimulants or other substances that induce chronic inflammation and a chronic granulomatous response at the implantation site. Without wishing to be bound by theory, it is believed that the formation of high tissue granulation induces blood vessels to provide an adequate or abundant supply of analytes to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, xenogeneic carriers, lipopolysaccharides, Staphylococcus aureus (S. aureus) peptidoglycan, and proteins.

[0111] Other substances that can be incorporated into one or more membranes of the present disclosure include various pharmacological agents, excipients, and other substances well known in the field of pharmaceutical formulations.

[0112] Additionally or alternatively, in some examples, the biointerface film includes a biocompatible polymer. In some examples, the biocompatible polymer is selected from the group consisting of polyvinyl butyral (PVB) or polyurethane. In certain examples, the biocompatible polymer can be a segmented block copolymer. In one example, the segmented block copolymer includes a hard segment and a soft segment. In this example, the hard segment includes an aromatic or aliphatic diisocyanate for preparing the hard segment of the segmented block copolymer. In one example, the aliphatic or aromatic diisocyanate for providing the hard segment of the polymer includes one or more of the following: norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0113] In one example, the hard segment content is from about 5 wt% to about 90 wt% of the segmented block copolymer of the biointerface film. In another example, the hard segment is from about 15 wt% to about 75 wt%. In yet another example, the hard segment is from about 25 wt% to about 55 wt%.

[0114] It should be understood that the biointerface film can include multiple layers.

[0115] It should also be understood that the sensor 130 can have any suitable configuration. In Figure 1A the non-limiting example illustrated, the sensor 130 is substantially coaxially shaped and is referred to as a "wire". The sensor 130 can alternatively be substantially planar in shape and is referred to as a "flat sensor".

[0116] Further details regarding an exemplary configuration of the control electronics 120 will now be provided. In one example, the control electronics 120 includes circuitry such as non-volatile computer-readable memory configured to store measurements such as raw signal values in volts, amperes, or ohms (which correspond to the measured analyte concentration) and a time series data set of electrical stimuli to be applied, the electrical stimuli delivering a dose of a therapeutic agent appropriate based on the measured analyte concentration. However, note that the control electronics 120 need not be configured to determine the actual concentration of the analyte within the subcutaneous tissue and similarly need not be configured to determine the actual dose of the therapeutic agent to be delivered. Instead, in one example, the control electronics 120 is configured to apply an electrical stimulus based on a signal having a particular value.

[0117] Optionally, in addition to applying the electrical stimulus, the control electronics 120 is configured to generate an output corresponding to the concentration of the analyte within the subcutaneous tissue based on the signal. Such an output can be used in any suitable manner. In some examples, the control electronics 120 includes non-volatile computer-readable memory configured to store the output or a microprocessor or digital signal processor configured to run a signal processing algorithm. Additionally or alternatively, in some examples, the control electronics 120 includes a transmitter configured to wirelessly send the output and receive an input, e.g., a near field communication (NFC), Bluetooth, WiFi, or cellular transmitter. The output can be used in any suitable manner, e.g., to continuously monitor one or more metrics of the recipient's health. In one example, the control electronics 120 receives an input from an algorithm running on a remote processor (e.g., cloud computing) via the transmitter and converts the input into a signal for delivering the therapeutic agent.

[0118] The processor module includes a central control unit that controls the processing of the control electronics. In some examples, the processor module includes a microprocessor; however, computer systems other than microprocessors may also be used to process data as described herein, such as application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), central processing units (CPUs), or graphics processing units (GPUs) may be used for some or all of the sensor central processing. In one example, the processor is coupled to a computer-readable memory, and the processor is configured via the computer-readable memory to provide semi-permanent storage of data, e.g., store data such as sensor identifiers (IDs) and programmed to process data streams (e.g., programming similar to that described in U.S. Pat. No. 8,201,74 to Goode et al., which is incorporated herein by reference in its entirety) for data smoothing and / or replacement of signal artifacts. The processor may additionally be used for the system's cache memory, e.g., for temporarily storing recent sensor data. In some examples, the processor module is coupled to one or more computer-readable memory storage components such as ROM, RAM, dynamic RAM, static RAM, non-static RAM, EEPROM, rewritable ROM, OCM, OTP memory, flash memory, etc.

[0119] In some examples, the processor module includes an analog-to-digital (A / D) converter configured to convert an analog signal received from the distal tip or end 132 into a digital signal for analysis. In one example, the processor module further includes a digital filter (e.g., an IIR or FIR filter) configured to smooth the raw data stream from the A / D converter. In some examples, the digital filter is programmed to filter data sampled at a predetermined time interval (also referred to as the sampling rate). In some examples, where the control electronics are configured to measure the analyte using the distal end 132 at discrete time intervals, these time intervals determine the sampling rate of the digital filter. In some alternative examples, where the control electronics are configured to continuously measure the analyte using the distal end 132, the processor module may be programmed to request digital values from the A / D converter at a predetermined time interval (also referred to as the acquisition time). In these alternative examples, due to the continuity of the measurement, the values obtained by the processor are advantageously averaged over the acquisition time. Thus, the acquisition time determines the sampling rate of the digital filter. In one example, the processor module is configured with a programmable acquisition time, i.e., the predetermined time interval for requesting digital values from the A / D converter can be programmed by the user within the digital circuitry of the processor module. Acquisition times of from about 2 seconds to about 512 seconds are used in some examples; however, any acquisition time may be programmed into the processor module. The programmable acquisition time is advantageous in optimizing noise filtering, time lag, and processing / battery power.

[0120] In one example, the battery 170 is operably connected to the control electronics and provides power for the wearable device. In one example, the battery is a lithium manganese dioxide battery; however, any battery of appropriate size and power may be used (e.g., AAA, coin cell, nickel cadmium battery, zinc carbon battery, alkaline battery, lithium battery, nickel metal hydride battery, lithium ion battery, zinc air battery, mercury oxide zinc battery, silver oxide battery, silver zinc battery, and / or hermetically sealed battery). In some examples, the battery is rechargeable and / or multiple batteries may be used to power the system. In some examples, the wearable device may be powered, for example, via inductive coupling. In some examples, a quartz crystal and / or a real-time clock (RTC) is operably connected to the processor and maintains the system time for the overall computer system, e.g., for the programmable acquisition time within the processor module.

[0121] In some examples, the output signal (from the control electronics) is transmitted to a receiver (e.g., a computer or other communication station). In some examples, the output signal may include a raw data stream for providing an available value of the measured analyte concentration to, for example, a patient or a doctor. In some examples, the raw data stream may be continuously or periodically algorithmically smoothed or otherwise modified, as described, for example, in US 8,10,174 to Goode et al., which is incorporated herein by reference in its entirety, to reduce deviant points that inaccurately represent the analyte concentration, for example, due to signal noise or other signal artifacts.

[0122] When the sensor is first implanted into the recipient tissue, the sensor and the receiver are initialized. This may be referred to as the startup mode and includes optionally resetting the sensor data and calibrating the sensor. In selected examples, mating the electronic unit to the mounting unit triggers the startup mode. In other examples, the startup mode is triggered by the receiver.

[0123] In some examples, the control electronics is wirelessly connected to the receiver via unidirectional or bidirectional RF transmission, etc. However, a wired connection is also contemplated. The receiver provides much of the processing and display of the sensor data and may be selectively worn and / or removed when convenient for the recipient. Thus, the sensor system may be discreetly worn and the receiver, which provides much of the processing and display of the sensor data, may be selectively worn and / or removed when convenient for the recipient. In particular, the receiver includes programming for retrospectively and / or prospectively initiating calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating the calibration of the analyte sensor in a manner such as that described in US 7,778,680, which is incorporated herein by reference in its entirety.

[0124] In some examples, the control electronics 120 can be attached to a printed circuit board (PCB) or the like and can take various forms. For example, the control electronics can be in the form of an integrated circuit (IC), such as an application specific integrated circuit (ASIC), a microcontroller, and / or a processor. Examples of systems and methods for processing sensor analyte data are described in more detail herein and in U.S. Patent Nos. 7,310,544 and 6,931,327 and U.S. Patent Publications 2005 / 0043598, 2007 / 0032706, 2007 / 0016381, 2008 / 0033254, 2005 / 0203360, 2005 / 0154271, 2005 / 0192557, 2006 / 0222566, 2007 / 0203966, and 2007 / 0208245, each of which is incorporated herein by reference in its entirety for all purposes.

[0125] In some examples, the control electronics 120 includes an adjustable current source (e.g., in an example of delivering a therapeutic agent using iontophoresis), or includes a waveform generator (e.g., in an example of delivering a therapeutic agent using electroporation). In one example, the current source is voltage controlled and compliance limits are established to limit the voltage and / or current and thereby limit harm to the recipient. In one example, the waveform generator is a direct digital synthesis variant and is also adjusted to limit the current and / or voltage. Alternatively, the waveform generator is a simple sine wave implementation, such as a voltage controlled oscillator.

[0126] Additional Comments

[0127] All references cited herein (including but not limited to published and unpublished applications, patents, and literature citations) are incorporated herein by reference in their entirety and hereby made a part of this specification. To the extent that any incorporated publication, patent, or patent application contradicts the disclosure contained herein, the specification is intended to supersede and / or take precedence over any such conflicting material.

[0128] As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0129] All numbers expressing quantities of ingredients, reaction conditions, and the like used in this specification are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. In any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant figures and the ordinary rounding method, rather than by trying to limit the application of the doctrine of equivalents to the scope of any claim.

[0130] The foregoing description has disclosed several methods and materials of the present disclosure. The present disclosure is susceptible to modifications in methods and materials and changes in the methods of manufacture and equipment. Such modifications will become apparent to those skilled in the art by considering this disclosure or the practice of the present disclosure as disclosed herein. Accordingly, the present disclosure is not intended to be limited to the specific examples disclosed herein, but rather covers all modifications and alternatives falling within the true scope and spirit of the present disclosure.

[0131] Although certain examples of the present disclosure have been illustrated with reference to specific combinations of elements, various other combinations can also be provided without departing from the teachings of the present disclosure. Accordingly, the present disclosure should not be construed as limited to the specific examples described and illustrated in the figures herein, but rather can also cover combinations of elements of the various illustrated examples and aspects thereof.

Claims

1. A wearable device for sensing the concentration of an analyte and delivering a therapeutic agent, the wearable device comprising: a sensor configured to extend completely through a recipient's stratum corneum, epidermis, and dermis and partially into the recipient's subcutaneous tissue, the sensor including a proximal end and a distal end, the distal end configured to be located within the subcutaneous tissue; at least one reservoir configured to contact the stratum corneum and include the therapeutic agent; and control electronics coupled to the proximal end of the sensor and including a first electrode and a second electrode, the control electronics configured to: receive, via the proximal end of the sensor, a signal corresponding to the concentration of the analyte within the subcutaneous tissue from the distal end of the sensor, use the signal to determine an electrical stimulation to be applied to the first electrode and the second electrode, and apply the electrical stimulation to the first electrode and the second electrode to deliver the therapeutic agent through the stratum corneum and into the recipient's dermis.

2. The wearable device according to claim 1, wherein the electrical stimulation: delivers a quantity of the therapeutic agent out of a polymer; increases the permeability of the stratum corneum to deliver the quantity of the therapeutic agent into the dermis; systemically distributes the quantity of the therapeutic agent delivered through the stratum corneum into the dermis; delivers the therapeutic agent through the stratum corneum and into the dermis via iontophoresis; delivers the therapeutic agent into the dermis via magnetohydrodynamics.

3. The wearable device according to any one of the preceding claims, wherein the therapeutic agent is uncharged, positively charged, negatively charged, or the charged carrier includes the therapeutic agent, and wherein the charged carrier is positively charged or negatively charged.

4. The wearable device according to any one of the preceding claims, wherein the at least one reservoir includes a first reservoir adjacent to the first electrode, or wherein the at least one reservoir further includes a second reservoir adjacent to the second electrode.

5. The wearable device according to any one of the preceding claims, wherein both the first reservoir and the second reservoir include a polymer complexed with the therapeutic agent.

6. The wearable device according to claim 5, wherein the electrical stimulation: alternately delivers the therapeutic agent out of the first reservoir and the second reservoir according to time-alternating polarities; delivers the therapeutic agent out of the first reservoir and delivers counterions into the second reservoir according to time-alternating polarities; substantially does not interfere with the signal corresponding to the concentration of the analyte within the subcutaneous tissue.

7. The wearable device according to any one of the preceding claims, wherein the control electronics receives the signal from the sensor at a time when the electrical stimulation is not applied.

8. The wearable device according to any one of the preceding claims, wherein the control electronics is configured to: Determine the parameters of the electrical stimulation based on the duration for which the at least one reservoir has been coupled to the stratum corneum; Increase the duration of applying the electrical stimulation as the duration for which the at least one reservoir has been coupled to the stratum corneum increases; Increase the magnitude of the electrical stimulation as the duration for which the at least one reservoir has been coupled to the stratum corneum increases; Determine the electrical stimulation in response to the signal corresponding to the concentration of the analyte differing from a predetermined value by more than a predetermined amount.

9. The wearable device according to any one of the preceding claims, wherein the analyte comprises at least one of insulin, levodopa, metformin, glucagon, GLP-1 antagonist, SGLT-2 inhibitor, vancomycin, gentamicin, adrenaline or naloxone or their metabolites.

10. The wearable device according to any one of claims 1 to 9, wherein the adhesive is configured to adhere the wearable device to the stratum corneum, and wherein the at least one reservoir is located within the adhesive.

11. A method for sensing the concentration of an analyte and delivering a therapeutic agent, the method comprising: Receiving, by control electronics of a wearable device coupled to a recipient's stratum corneum, a signal from a distal end of a sensor coupled to the control electronics via a proximal end of the sensor, the distal end of the sensor being within the recipient's subcutaneous tissue, the signal corresponding to the concentration of the analyte within the subcutaneous tissue; Using the signal received by the control electronics to determine an electrical stimulation to be applied between a first electrode and a second electrode of the wearable device; Applying the electrical stimulation determined by the control electronics to the first electrode and the second electrode; And Delivering a quantity of the therapeutic agent from at least one reservoir of the wearable device, through the stratum corneum, and into the dermis for ingestion of the therapeutic agent by capillaries in the dermis.

12. The method according to claim 11, wherein delivering a quantity of the therapeutic agent from the at least one reservoir of the wearable device comprises: Deliver the therapeutic agent out of the polymer.

13. The method according to any one of claims 11 or 12, wherein applying the electrical stimulation determined by the control electronics to the first electrode and the second electrode comprises: Increase the permeability of the stratum corneum.

14. The method according to any one of claims 11 to 13, wherein the quantity of the therapeutic agent is delivered via iontophoresis, electroporation or magnetohydrodynamics.

15. The method according to any one of claims 11 to 14, wherein applying the electrical stimulation determined by the control electronics to the first electrode and the second electrode comprises: Alternately deliver the therapeutic agent from a first reservoir or a second reservoir according to time-alternating polarities.

16. The method according to any one of claims 11 to 15, wherein applying the electrical stimulation comprises: Alternate polarities according to time or at a substantially constant polarity so as to deliver the therapeutic agent from the at least one reservoir.

17. The method according to any one of claims 11 to 16, wherein the electrical stimulation substantially does not interfere with the signal corresponding to the concentration of the analyte within the subcutaneous tissue.

18. The method according to any one of claims 11 to 17, wherein receiving the signal by the control electronics and applying the electrical stimulation determined by the control electronics occur at different times.

19. The method according to any one of claims 11 to 18, the method further comprising: The control electronics determine the parameters of the electrical stimulation based on the duration for which the at least one reservoir has been coupled to the stratum corneum.

20. The method according to any one of claims 11 to 19, wherein determining an electrical stimulation to be applied between a first electrode and a second electrode of the wearable device using the signal received by the control electronics comprises: Compare the concentration of the analyte with a predetermined value.

Images