Devices and methods for sensing analytes and delivering therapeutic agents - Patents.com

Abstract

Some examples herein provide a wearable device for sensing an analyte concentration and delivering a therapeutic agent. The sensor is configured to fully penetrate the stratum corneum, epidermis, and dermis and extend partially into the subcutaneous tissue, and includes a distal end configured to be positioned within the subcutaneous tissue. The reservoir is configured to contact the stratum corneum and includes a polymer complexed with a drug. Control electronics coupled to the proximal end of the sensor include first and second electrodes and are configured to receive a signal from the distal end of the sensor corresponding to the analyte concentration in the subcutaneous tissue. The control electronics uses the signal to determine an electrical stimulus to apply to the first and second electrodes and applies the electrical stimulus to deliver the therapeutic agent across the stratum corneum.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 436,476, filed December 30, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION This application relates generally to devices and methods for sensing one or more analytes and delivering one or more therapeutic agents. [Background technology]

[0003] CGM wearables are adhered to the skin with a medical-grade adhesive. CGMs are often used by patients undergoing intensive insulin therapy, many of whom wear patch pumps or infusion sets that contain the medical-grade adhesive. In these situations, CGMs are used to signal insulin delivery to offset elevated glucose levels. However, this requires users to wear at least two devices on their body.

[0004] Several methods have been established for delivering therapeutic agents to host skin, including microneedles, iontophoresis, electroporation, laser ablation, radiofrequency ablation, and ultrasonic ablation.These methods can overcome the barrier function of the stratum corneum to deliver a specific amount of therapeutic agent to host skin.However, it is useful to improve the control of the amount of therapeutic agent delivered. Summary of the Invention

[0005] 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 fully penetrate the stratum corneum, epidermis, and dermis of a host and extend partially into the subcutaneous tissue of the host. 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 a therapeutic agent. The wearable device includes control electronics coupled to the proximal end of the sensor, the control electronics including a first electrode and a second electrode. The control electronics is configured to receive, via the proximal end of the sensor, a signal corresponding to the concentration of one or more analytes in the subcutaneous tissue from the distal end of the sensor. The control electronics is configured to use the signal to determine an electrical stimulus to be applied to the first electrode and the second electrode. The control electronics is configured to apply the electrical stimulus to the first and second electrodes to deliver the therapeutic agent across the stratum corneum. In this way, closed-loop control for sensing analyte concentration(s) and delivering therapeutic agent(s) is provided in a single wearable device.

[0006] The device further includes a housing within which the proximal end of the sensor and control electronics are disposed.

[0007] In some instances, in response to the electrical stimulus, an amount of the therapeutic agent is transported from the polymer. In some instances, in response to the electrical stimulus, an amount of the therapeutic agent is transported through the stratum corneum into the epidermis. In some instances, in response to the electrical stimulus, an amount of the therapeutic agent is transported through the stratum corneum and the epidermis into the dermis.

[0008] In some examples, applying the electrical stimulus to the first and second electrodes delivers the therapeutic agent through the stratum corneum into the epidermis by iontophoresis. In some examples, applying the electrical stimulus to the first and second electrodes delivers the therapeutic agent into the epidermis by electroporation. In some examples, applying the electrical stimulus to the first and second electrodes delivers the therapeutic agent into the epidermis by magnetohydrodynamics.

[0009] In some instances, the therapeutic agent is electrically charged. In some instances, the therapeutic agent is positively charged. In some instances, the therapeutic agent is negatively charged.

[0010] In some instances, the therapeutic agent has a neutral charge and is carried by a charged carrier. In some instances, the charged carrier is positively charged. In some instances, the charged carrier is negatively charged.

[0011] 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 a distance away 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 a polymer complexed with a therapeutic agent. In some examples, the electrical stimulation alternates as a function of time to alternately deliver the therapeutic agent from the first reservoir and the second reservoir.

[0012] In some examples, the first reservoir includes a polymer complexed with a therapeutic agent and the second reservoir includes a second polymer, and in some examples, the electrical stimulation alternates as a function of time, alternating between transporting the therapeutic agent from the first reservoir and transporting counterions into the second reservoir.

[0013] In some instances, the electrical stimulus is substantially constant to transport the therapeutic agent from the first reservoir and the counterion into the second reservoir.

[0014] In some instances, the electrical stimulation does not substantially interfere with the signal corresponding to the concentration of the analyte in the subcutaneous tissue.

[0015] In some examples, the control electronics receives the signal during times when no electrical stimulation is being applied.

[0016] In some examples, the sensor is located between the first electrode and the second electrode.

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

[0018] In some examples, the sensor is located within an opening in the first electrode.

[0019] In some examples, the first electrode is located within an opening in the second electrode.

[0020] In some examples, the proximal end of the sensor is less than about 1 cm from at least one of the first and second electrodes.

[0021] In some examples, the control electronic circuitry is configured to determine the electrical stimulation based on the duration that the at least one reservoir is coupled to the stratum corneum. In some examples, the control electronic circuitry is configured to increase the duration of the electrical stimulation as the duration that the at least one reservoir is coupled to the stratum corneum increases. In some examples, the control electronic circuitry is configured to increase the magnitude of the electrical stimulation as the duration that the at least one reservoir is coupled to the stratum corneum increases.

[0022] In some examples, the control electronics is configured to determine the electrical stimulation in response to the signal differing by more than a predetermined amount from a predetermined value.

[0023] In some examples, the analyte comprises a metabolite of a therapeutic drug, ie, a metabolite of insulin, levodopa, metformin, glucagon, a GLP-1 antagonist, an SGLT-2 inhibitor, vancomycin, gentamicin, epinephrine, or naloxone.

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

[0025] In some examples, the device further includes an adhesive configured to adhere the sensor and control electronics to the epidermis, hi some examples, the at least one reservoir is located within the adhesive.

[0026] Some examples herein provide a method for delivering a therapeutic agent. The method may include receiving, by a control electronic circuit of a wearable device adhered to the stratum corneum of a host, a signal from a distal end of a sensor of the wearable device via a proximal end of the sensor coupled to the control electronic circuit. In one example, the distal end of the sensor is located in subcutaneous tissue of the host, and the signal may correspond to a concentration of an analyte in the subcutaneous tissue. The method may include determining, by the control electronic circuit, an electrical stimulus 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 electronic circuit, the electrical stimulus to the first and second electrodes to transport a quantity of the therapeutic agent from at least one reservoir of the wearable device through the stratum corneum and the epidermis into the dermis for uptake of the therapeutic agent by capillaries in the dermis. [Brief explanation of the drawings]

[0027] [Figure 1A] 1A-1C schematically illustrate example configurations of a wearable device and operations performed by the wearable device consistent with embodiments of the present disclosure. [Figure 1B]1A-1C schematically illustrate example configurations of a wearable device and operations performed by the wearable device consistent with embodiments of the present disclosure. [Figure 1C] 1A-1C schematically illustrate example configurations of a wearable device and operations performed by the wearable device consistent with embodiments of the present disclosure. [Figure 1D] 1A-1C schematically illustrate example configurations of a wearable device and operations performed by the wearable device consistent with embodiments of the present disclosure. [Figure 1E] 1A-1C schematically illustrate example configurations of a wearable device and operations performed by the wearable device consistent with embodiments of the present disclosure. [Figure 2A] 1C schematically illustrates a bottom view of an exemplary configuration of the wearable device of FIG. 1E, consistent with an embodiment of the present disclosure. [Figure 2B] 1C illustrates a schematic diagram of an example of an electric field between electrodes of the wearable device of FIG. 1E, consistent with an embodiment of the present disclosure. [Figure 3] 10A and 10B illustrate schematically alternative exemplary configurations of a wearable device and operations performed by the wearable device. [Figure 4] 10A and 10B illustrate schematically alternative exemplary configurations of a wearable device and operations performed by the wearable device. [Figure 5] 10A and 10B illustrate schematically alternative exemplary configurations of a wearable device and operations performed by the wearable device. [Figure 6] 10A and 10B illustrate schematically alternative exemplary configurations of a wearable device and operations performed by the wearable device. [Figure 7A] 10A-10C schematically illustrate additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent, and operations performed by the wearable device. [Figure 7B] 10A-10C schematically illustrate additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent, and operations performed by the wearable device. [Figure 8A]10A-10C schematically illustrate additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent, and operations performed by the wearable device. [Figure 8B] 10A-10C schematically illustrate additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent, and operations performed by the wearable device. [Figure 9A] 10A-10C schematically illustrate additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent, and operations performed by the wearable device. [Figure 9B] 10A-10C schematically illustrate additional alternative exemplary configurations of a wearable device for delivering a therapeutic agent, and operations performed by the wearable device. [Figure 10] 1 illustrates a flow of operations in an exemplary method for delivering a therapeutic agent using a wearable device. DETAILED DESCRIPTION OF THE INVENTION

[0028] Provided herein are wearable devices 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 an analyte concentration, a reservoir for storing a therapeutic agent, and control electronics for determining the analyte concentration and administering the therapeutic agent from the reservoir into the host's skin. It is understood that a single sensor may include multiple working electrodes for measuring multiple analyte concentrations, or multiple sensors each measuring an analyte concentration, as part of a single wearable device. The control electronics measures the analyte concentration to determine the amount of therapeutic agent to be administered, for example, by determining the duration and / or magnitude of electrical stimulation to apply to the reservoir that releases that amount of therapeutic agent, and / or the rate at which the therapeutic agent is released. In this manner, the wearable device can more effectively titrate administration for maximum therapeutic benefit in a manner that would otherwise be too burdensome for the user to manage voluntarily. Furthermore, by integrating both analyte measurement and therapeutic agent delivery into a single wearable device, precise amounts and / or rates of therapeutic agent can be delivered directly into the skin rapidly and as needed, without the need for host involvement or intervention. In fact, the host may not even necessarily know when the therapeutic agent is being delivered. In contrast, some previously known therapeutic agent delivery methods involve the host measuring an analyte concentration, using that information to separately determine the dose of therapeutic agent to administer, and then separately administering that dose. Such previously known methods impose a significant burden on the host, and the amount and / or rate of therapeutic agent administered by the host may be inaccurate due to miscalculation or a delay between when the measurement is made and when the therapeutic agent is ultimately administered. Also, compared to conventional systems, two devices must be worn on the host, separated by a sufficient distance, to separately sense the analyte and administer the therapeutic agent without interference. For example, an insulin pump is separated from a continuous glucose monitor so that insulin preservatives, which are electroactive species, do not interfere with the glucose concentration signal. Such conventional systems impose a significant burden on the host and require the purchase and maintenance of two separate wearable devices.It will thus be appreciated that the present wearable devices and methods, in one example, 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, while traveling, or elsewhere) and, using the same device, automatically administer an appropriate amount and / or rate of therapeutic agent without the need for host intervention (or, optionally, knowledge), thereby providing the host with improved outcomes and / or reduced burden of disease or condition management.

[0029] First, some exemplary terms used in this application are explained. Then, exemplary wearable devices for delivering drugs to a host and methods of using such devices are provided.

[0030] term To facilitate understanding of the disclosed embodiments, several terms are defined below.

[0031] As used herein, the term "about" is a broad term and is to be given its ordinary and accustomed meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to allowing for a degree of variability in values ​​or ranges, for example, within 10%, within 5%, or within 1% of the stated limits of a stated value or range, including, but not limited to, the exactly stated value or range. As used herein, the term "substantially" refers to a majority or 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" can mean having no or an insignificant amount of material present such that the amount of material present does not affect the material properties of the composition including the material, such as about 0% to about 5% by weight of the composition being the material, or about 0% to about 1%, or about 5% by weight or less, or about 4.5% by weight or less, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001% by weight or less, or about 0% by weight.

[0032] As used herein, the terms "stick" and "adhere" are broad terms and are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, holding, joining, or fastening, for example, by adhering, bonding, grasping, interpenetrating, or fusing.

[0033] As used herein, the term "analyte" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, a substance or chemical constituent in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymphatic fluid, urine, sweat, saliva, etc.) that can be analyzed. Analytes can include naturally occurring substances, man-made substances, metabolites, and / or reaction products. In some examples, the analyte measured by the sensing region, devices, and methods is glucose. However, other analytes are contemplated as well, including acarboxyprothrombin; acylcarnitines; adenine phosphoribosyltransferase; adenosine deaminase; albumin; α-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bilirubin; biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-β-hydroxycholic acid; cortisol; creatine; creatine kinase; creatinine Enzyme MM isoenzymes; creatinine; cyclosporine A; d-penicillamine; deethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylation polymorphisms, alcohol dehydrogenase, alpha-1-antitrypsin, cystic fibrosis, Duchenne / 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's hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diphtheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;Fatty acids / acylglycines; free beta-human chorionic gonadotropin; free erythrocyte porphyrins; free thyroxine (FT4); free triiodothyronine (FT3); fumarylacetoacetase; galactose / gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione peroxidase; glycerol; glycocholate; 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, β); lysozyme; mefloquine; netilmicin; oxygen; phenobarbitone; phenytoin; phytanic acid / pristanic acid; potassium, sodium, and / or other blood electrolytes; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse triiodothyronine tri-iodothyronine, rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-zeta antibody, arbovirus, pseudorabies virus, dengue virus, guinea worm, Echinococcus granulosus, Entamoeba histolytica, enterovirus, giardiasis, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leptospirosis, measles / mumps / Rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, Parainfluenza virus, Plasmodium, Poliovirus, Pseudomonas aeruginosa, Respiratory syncytial virus, Rickettsia (tsutsugamushi disease), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / rangeli, Vesicular stomatitis virus, Wuchereria bancrofti, Yellow fever virus); Specific antigens (Hepatitis B virus, HIV-1); Succinylacetone; Sulfadoxine; Theophylline; Thyrotropin (TSH); Thyroxine (T4);Analytes include, but are not limited to, thyroxine-binding globulin, trace elements, transferrin, UDP-galactose-4-epimerase, urea, uric acid, uroporphyrinogen I synthase, vitamin A, leukocytes, and zinc protoporphyrin. Salts, sugars, proteins, fats, vitamins, and hormones naturally present in blood or interstitial fluid can also constitute analytes in certain embodiments. Analytes can be naturally present in biological fluids or can be endogenous, e.g., metabolites, hormones, antigens, antibodies, etc. Alternatively, the analyte can be introduced into the body or can be exogenous, such as a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including, but not limited to, insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, RITALIN®, CYLERT®, PRELUDIN®, DIDREX®, PRESTATE®, VORANIL®, SANDREX®, PLEGINE®); anti-inflammatory drugs. Antidepressants (barbiturates, methaqualone, tranquilizers such as VALIUM®, LIBRIUM®, MILTOWN®, SERAX®, EQUANIL®, and TRANXENE®); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, and psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, PERCOCET®, PERCODAN®, TUSSIONEX®, fentanyl, DARVON®, TALWIN, and LOMOTIL®); synthetic narcotics (fentanyl, meperidine, amphetamine, methamphetamine, and phencyclidine analogs, e.g., ecstasy); anabolic steroids;Analytes of interest include, but are not limited to, drugs and nicotine. Metabolites of the aforementioned drugs and pharmaceutical compositions are also contemplated. Analytes such as neurochemicals and other chemicals produced in the body, such as ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (FHIAA), and histamine, can also be analyzed.

[0034] As used herein, the phrases “analyte measuring device,” “analyte monitoring device,” “analyte sensing device,” “continuous analyte sensing device,” “continuous analyte sensor device,” and / or “multi-analyte sensor device” are broad terms and are given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, analyte apparatus and / or systems responsible for detecting specific analytes or combinations of analytes or transducing signals associated therewith. For example, these terms refer to, but are not limited to, instruments responsible for detecting specific analytes or combinations of analytes. In one example, the instrument includes a sensor coupled to a circuit arranged within a housing and configured to process the signal associated with the analyte concentration into information. In one example, such an apparatus and / or system is capable of providing specific quantitative, semi-quantitative, qualitative, and / or semi-qualitative analytical information using a biorecognition element combined with a transduction and / or detection element.

[0035] As used interchangeably herein, the phrases "biointerface membrane" and "biointerface layer" are broad terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning), 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 the host tissue and the implantable device. The terms "biointerface" and "bioprotective" are used interchangeably herein.

[0036] As used herein, the phrase "barrier cell layer" is a broad phrase that is to be given its ordinary and customary meaning to those skilled in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to the portion of the foreign body response that forms a cohesive monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances into the implantable device.

[0037] As used herein, the terms "baseline" and "background" are broad terms and are to be given their ordinary and customary meaning to those of skill in the art (and are not limited to any special or customized meaning), and refer, without limitation, to a signal (e.g., in the form of current and / or voltage) produced by a sensor that is independent of the concentration of the analyte being measured, or otherwise the amount of signal produced in the absence of the analyte.

[0038] As used herein, the terms "biosensor" and / or "sensor" are broad terms and are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, a portion of an analyte measuring device, analyte monitoring device, analyte sensing device, continuous analyte sensing device, sequential analyte sensing device, and / or multi-analyte sensing device responsible for detecting a specific analyte or combination of analytes or transducing a signal associated therewith. In embodiments, a biosensor or sensor generally comprises a body and working, reference, and / or counter electrodes coupled to the body and forming a surface configured to provide a signal during an electrochemical reaction. One or more membranes may be affixed to the body and cover the electrochemically reactive surface. In embodiments, such biosensors and / or sensors are capable of providing a specific quantitative, semi-quantitative, qualitative, or semi-qualitative analytical signal using a biorecognition element combined with a detection and / or transduction element.

[0039] Various examples of sensor architectures can be found in pending U.S. Application No. 63 / 321,538, entitled "CONTINUOUS ANALYTE SENSOR SYSTEMS," filed March 17, 2022, which is incorporated herein by reference in its entirety, as well as U.S. Patent No. 8,133,178 to Brauker et al., and U.S. Patent No. 8,828,201 to Simpson et al., U.S. Patent No. 9,131,885 to Simpson et al., U.S. Patent No. 9,237,864 to Simpson et al., and U.S. Patent No. 9,763,608 to Simpson et al., which are incorporated herein by reference in their entirety. Examples of methods of forming the sensors (sensor electrode layouts and membranes) and sensor systems discussed herein can be found in currently pending U.S. Patent Application Publication No. 2019 / 0307371 to Boock et al., which is incorporated herein by reference in its entirety.

[0040] As used herein, the term "biostable" is a broad term that is to be given its ordinary and customary meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, materials that are relatively resistant to degradation by processes encountered in vivo.

[0041] As used herein, the term "coaxial" should be interpreted broadly to include sensor architectures having elements aligned along a shared axis around a core that may be configured to have a circular, elliptical, triangular, polygonal, or other cross-section, and such elements may include electrodes, insulating layers, or other elements that may be positioned circumferentially around a core layer, such as a core electrode or core polymer wire.

[0042] As used herein, the term "continuous" is a broad term and is to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an uninterrupted or unbroken portion, domain, coating, or layer of the sensor system discussed herein.

[0043] As used herein, the term "discontinuous" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, disconnected, interrupted, or separated portions, layers, coatings, or domains of the systems discussed herein.

[0044] As used herein, the term "semi-continuous" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any 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 that is disposed around but not over a sensing area is "semi-continuous."

[0045] As used herein, the phrase "continuous analyte sensing" is a broad phrase that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, continuous, continuous, and / or intermittent (but periodic) monitoring of analyte concentration over a period of time, such as, for example, every about 5 seconds or less to about 10 minutes or more. In further embodiments, monitoring of the analyte concentration is performed every about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds to about 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.25, 3.50, 3.75, 4.00, 4.25, 4.50, 4.75, 5.00, 5.25, 5.50, 5.75, 6.00, 6.25, 6.50, 6.75, 7.00, 7.25, 7.50, 7.75, 8.00, 8.25, 8.50, 8.75, 9.00, 9.25, 9.50, or 9.75 minutes. In some examples, the analyte concentration is monitored about every 15 minutes, or about every 30 minutes, or about every 60 minutes. Additionally or alternatively, in some examples, the analyte concentration is monitored about every 1.5 hours, about every 2 hours, about every 4 hours, about every 6 hours, or about every 8 hours.

[0046] As used herein, the term "conjugated" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, two or more system elements or components that are configured to be mechanically, covalently, ionically, and / or otherwise chemically bound together. In some examples, the therapeutic agent is chemically bound in the polymer. In some examples, the therapeutic agent is mechanically bound in the polymer.

[0047] As used herein, the term "coupled" is a broad term and is to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, two or more system elements or components that are configured to be electrically, mechanically, thermally, operatively, chemically, or otherwise attached to at least one other. Similarly, as used herein, the phrases "operably connected," "operably linked," and "operably coupled" refer to one or more components that are coupled to another component in a manner 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 are integrated with one another (i.e., "directly coupled"). In other examples, the components are connected via remote means. For example, one or more electrodes can be used to detect analytes in a sample and convert that information into a signal, which can then be transmitted to an electronic circuit. In this example, the electrodes are "operably coupled" to the electronic circuit. As used herein, the phrase "removably coupled" refers to two or more system elements or components that are configured or configured to be attached and detached electrically, mechanically, thermally, operatively, chemically, or otherwise, 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 that are configured or attached electrically, mechanically, thermally, operatively, chemically, or otherwise, but cannot be separated without damaging at least one of the coupled elements or components.

[0048] As used herein, the term "distal" is a broad term and is to be given its ordinary and customary meaning to those skilled in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, an area that is relatively far away from a reference point such as an origin or attachment point.

[0049] As used herein, the term "domain" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, a region of a membrane system that may be a layer, a uniform or non-uniform gradient (e.g., an anisotropic region of a membrane), or a portion of a membrane that is capable of sensing one, two, or more analytes. Domains discussed herein can be formed as a single layer, as two or more layers, as a pair of bilayers, or as combinations thereof.

[0050] As used herein, the term "electrochemically reactive surface" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the surface of an electrode on which an electrochemical reaction occurs. In various examples, the by-product of the reaction of the analyte being detected includes at least one measurable species. The at least one measurable species is capable of reacting with an electrochemically active surface, such as a working electrode.

[0051] As used herein, the term "ex vivo" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), encompassing, but not limited to, a portion of a device (e.g., a sensor) that is adapted to reside and / or exist outside the host organism.

[0052] As used herein, the term "host" is a broad term and is given its ordinary and customary meaning to those of skill in the art (and is not limited to any special or customized meaning), and refers to mammals, such as, but not limited to, humans.

[0053] As used herein, the terms "in-dwelling," "implanted," or "implantable" are broad terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not to be limited to any special or customized meaning) and refer to an object (e.g., a sensor) that is inserted or configured to be inserted subcutaneously (i.e., within the fatty layer between the skin and muscle), intradermally (i.e., penetrating the stratum corneum and located within the epidermal or dermal layer of the skin), or transcutaneously (i.e., penetrating, entering, or passing through intact skin), which may result in a sensor having an in vivo portion and an ex vivo portion. The term "in-dwelling" also encompasses an object configured to be inserted subcutaneously, intradermally, or percutaneously, whether or not it is itself inserted.

[0054] As used herein, the phrase "insertable volume" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to, but is not limited to, the volume anterior and lateral to 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 perpendicularly to the volume anterior and lateral to the insertion path.

[0055] As used herein, the terms "interfering substance" and "interfering species" are broad terms and are to be given their ordinary and customary meaning to those of skill in the art (and are not limited to any special or customized meaning), and refer to effects and / or species, including, but not limited to, ions, electroactive substances, endogenous circulating species, exogenous circulating species, pharmacological agents, and / or electromagnetic waves (such as from a magnetic resonance imaging (MRI) system or medical device), that interfere with the measurement of an analyte of interest at a sensor, producing a signal that does not accurately represent the analyte measurement.

[0056] As used herein, the term "in vivo" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), encompassing, but not limited to, portions of a device (e.g., a sensor) adapted for insertion into and / or presence within the body of a host.

[0057] As used herein, the term "membrane" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers to a structure configured to perform functions including, but not limited to, protecting exposed electrode surfaces from the biological environment, resisting (limiting) the diffusion of analytes, acting as a matrix for catalysts to enable enzymatic reactions, limiting or screening interfering species, providing hydrophilicity at electrochemically reactive surfaces of a sensor interface, acting as an interface between host tissue and an implantable device, modulating host tissue response through drug (or other substance) release, and combinations thereof. As used herein, the terms "membrane" and "matrix" are meant to be interchangeable.

[0058] As used herein, the phrase "membrane system" is a broad phrase that is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to a permeable or semi-permeable membrane that may be composed of two or more domains, layers, or layers within domains, that is composed of material that is several microns or more thick, and that is at least permeable to the analyte whose concentration is to be measured.

[0059] As used herein, the term "micro" is a broad term and is to be given its ordinary and customary meaning to those skilled in the art (and is not to be limited to any special or customized meaning), and refers to a size of approximately 10 microns that is not visible without magnification. -6 ~10-3 "Micro" refers to objects or scales that are small, but not limited to, those on the order of 10 microns. The term "micro" is in contrast to the term "macro," which refers to objects that are large enough to be seen without magnification. Similarly, the term "nano" refers to objects that are approximately 10 -9 ~10 -6 Refers to a small object or scale of m.

[0060] As used herein, the terms "optional" or "optionally" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), meaning, without limitation, that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when it does not occur.

[0061] As used herein, the term "planar" should be interpreted broadly 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, which may or may not be electrically or otherwise coupled, and which may include conductive or insulating layers or elements configured to operate as a circuit.

[0062] As used herein, the term "proximal" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not to be limited to any special or customized meaning), and refers to, but is not limited to, the spatial relationship between various elements relative to a particular reference point.

[0063] As used herein, the phrases and terms "processor module" and "microprocessor" are each broad phrases and terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning) and refer to, but are not limited to, a computer system, state machine, processor, or the like, designed to perform arithmetic or logical operations using logic circuitry that responds to and processes the basic instructions that drive a computer.

[0064] As used herein, the phrase "sensing membrane" is a broad phrase and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), and refers, without limitation, to a permeable or semi-permeable membrane that may include one or more domains, layers, or layers within domains, is composed of a material having a thickness of several microns or more, and is permeable to reactants and / or co-reactants used in determining an analyte of interest.

[0065] As used herein, the phrases "sensing moiety," "sensing membrane," "sensing region," "sensing domain," and / or "sensing mechanism" are broad terms and are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not limited to any special or customized meaning), and refer to, but are not limited to, a portion of a biosensor and / or sensor responsible for detecting or transducing a signal associated with a particular analyte or combination of analytes. In examples, the sensing moiety, sensing membrane, and / or sensing mechanism generally comprise electrodes configured to provide a signal during an electrochemical reaction with one or more membranes covering an electrochemically reactive surface. In examples, such sensing moieties, sensing membranes, and / or sensing mechanisms are capable of providing a specific quantitative, semi-quantitative, qualitative, or semi-qualitative analytical signal using a biorecognition element in combination with a detection and / or transduction element.

[0066] In one example, the sensing region determines selectivity between one or more analytes such that only the analyte that must be measured results in (transduces) a detectable signal. In one example, this selection can be based on any chemical or physical recognition of the analyte by the sensing region, where the chemical composition of the analyte does not change, or where the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.

[0067] The sensing region converts the recognition of the analyte into a semi-quantitative or quantitative signal. Thus, as used herein, "transducing" or "transduction" and their grammatical equivalents encompass electrochemical techniques and methods. Electrochemical properties include current and / or voltage, capacitance, resistance, impedance, charge, and potential.

[0068] As used herein, the term "sensitivity" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to any special or customized meaning), 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 given amount (unit) of analyte measured. For example, an amperometric sensor may have a sensitivity (or slope) of about 1 to about 100 picoamps of current per 1 mg / dL of glucose analyte.

[0069] As used herein, the phrases and terms “small diameter sensor,” “miniature structured sensor,” and “microsensor” are broad phrases and terms that are to be given their ordinary and customary meaning to those skilled in the art (and are not limited to any special or customized meaning) and refer to, but are not limited to, a sensing mechanism having at least one dimension less than about 2 mm. In further embodiments, the sensing mechanism has at least one dimension less than about 1 mm. In some examples, the sensing mechanism (sensor) is less than about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm. In some examples, the largest independently measured dimension of the length, width, diameter, thickness, or circumference of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a coaxial or needle-type sensor having a diameter less than about 1 mm. See, for example, U.S. Patent No. 6,613,379 to Ward et al. and U.S. Patent No. 7,497,827 to Brister et al., both of which are incorporated by reference in their entireties. In some alternative embodiments, the sensing mechanism includes electrodes deposited on a planar or substantially planar substrate, and the thickness of the implantable portion is less than about 1 mm. See, for example, U.S. Patent No. 6,175,752 to Say et al. and U.S. Patent No. 5,779,665 to Mastrototaro et al., both of which are incorporated by reference in their entireties. Examples of methods of forming the sensor (sensor electrode layout and films) and sensor systems that can be used to prepare the present sensors can be found in U.S. Patent Application Publication No. 2019 / 0307371 to Boock et al., which is incorporated by reference in its entirety.

[0070] As used herein, the terms "zwitterion" and "zwitterionic compound" are broad terms and phrases, respectively, that are to be given their ordinary and customary meaning to one of ordinary skill in the art (and are not to be limited to any special or customized meaning), and refer to, but are not limited to, compounds in which a neutral molecule of the compound has a unit positive charge and a unit negative charge at different locations within the molecule. Such compounds are a type of zwitterionic compound and are sometimes referred to as "inner salts."

[0071] Wearable devices for delivering therapeutic agents and methods of using same Non-limiting examples of devices and methods for measuring physiological signals and / or target analyte concentrations in vivo are now described with reference to FIGS. 1A-1E, 2A-2B, 3-6, 7A-7B, 8A-8B, 9A-9B, and 10. FIGS. 1A-1E and 2A-2B schematically illustrate exemplary configurations of wearable devices for sensing analytes and delivering therapeutic agents, and operations performed by the wearable devices. Referring initially to FIG. 1A, wearable device 100 includes housing 110, control electronics 120, sensor 130, and at least one reservoir (e.g., first reservoir 151 and second reservoir 152). In one example, wearable device 100 also includes battery 170 coupled to and configured to power control electronics 120. 1A , or by other attachment means such as an elastic strap or an adjustable wristband. For example, a foot plate 150 or an elastic strap or an adjustable wristband is configured to secure the wearable device 100, including the sensor 130 and the control electronics 120, to the epidermis 20. In one example, the foot plate 150 includes one or both of a first reservoir 151 and a second reservoir 152.

[0072] 2A shows a partial plan view of the wearable device 100. In the non-limiting example shown in FIGS. 1A and 2A, the sensor 130 is located between the first electrode 141 and the second electrode 142. As shown in FIG. 1A, the first reservoir 151 is adjacent to the first electrode 141, the second reservoir 152 is located a distance away from the first reservoir 151, and the second reservoir 152 is adjacent to the second electrode 142. However, in other examples, such as those further described below with reference to FIGS. 7A-7B, 8A-8B, and 9A-9B, the sensor 130, the first and second electrodes 141 and 142, and the first and second reservoirs 151 and 152 are arranged in other configurations and spatial relationships relative to one another. In one example, as shown in FIG. 2A, housing 110 is generally circular and adhesive pad 32 has a circular diameter that is the same as or slightly larger than the circular diameter of the housing.

[0073] The sensor 130 is configured to completely penetrate the host's stratum corneum 10, epidermis 20, and dermis 30 and extend partially into the host'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 reside within the host's subcutaneous tissue 40, and the proximal end 131 is coupled to the control electronics 120 within the housing 110. The distal end 132 includes a first working electrode 133, an optional 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 the non-limiting example shown in FIG. 1A , at least one of the first reservoir 151 and the second reservoir 152 (sometimes designated R1 and R2, respectively) includes a polymer complexed with a therapeutic agent. In certain other examples, as described further below, both first reservoir 151 and second reservoir 152 optionally store a therapeutic agent. In one example, control electronics 120 is coupled to proximal end 131 of sensor 130 and includes first electrode 141 and second electrode 142 (which may also be denoted E1 and E2, respectively). Control electronics 120 is configured to receive, via proximal end 131 of sensor 130, from distal end 132 of sensor 130, a signal corresponding to the concentration of an analyte in subcutaneous tissue 40.

[0074] In one example, control electronics 120 is also configured to use the signal to determine and apply electrical stimuli to first electrode 141 and second electrode 142. Thus, control electronics 120 is configured and used to automatically control delivery of a therapeutic agent into the dermis from at least one reservoir (e.g., from first reservoir 151 and / or second reservoir 152) in response to the concentration of an analyte measured in subcutaneous tissue 40 by distal end 132 of sensor 130. For example, at certain times shown in FIGS. 1B and 2B , control electronics 120 applies a voltage and current between first electrode 141 and second electrode 142, which generates electric field lines 153 that penetrate the stratum corneum 10 and also fully or partially penetrate the remainder of epidermis 20. In response to the electrical stimulus, a quantity of the therapeutic agent is transported from the polymer of the first reservoir 151 and / or the second reservoir 152. For example, an electric field generated by the application of the electrical stimulus causes the release of the therapeutic agent from the first reservoir 151 and / or the second reservoir 152. At a particular time, as shown in FIG. 1C, the electrical stimulus causes the migration of the therapeutic agent 160 from the reservoir 151 across the stratum corneum 10. In one example, the therapeutic agent is positively charged, as shown in FIG. 1C, or the therapeutic agent has no charge (i.e., is neutral) and is carried by a positively charged carrier. Alternatively, the therapeutic agent is negatively charged, or the therapeutic agent has no charge (i.e., is neutral) and is carried by a negatively charged carrier. In such an example, the carrier includes a charged species to which the therapeutic agent is complexed or a charged encapsulating agent in which the therapeutic agent is disposed. The electrical stimulus causes the transport of the therapeutic agent 160 into the epidermis 20 and the dermis 30. Alternatively, the therapeutic agent 160 may be transported into the epidermis 20 and dermis 30 by diffusion or circulation. For example, at a particular time shown in Figure ID, the therapeutic agent 160 is transported into the epidermis 20 and dermis 30. At a particular time shown in Figure IE, the therapeutic agent 160 is transported into the dermis 30, where the 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 the analyte in the subcutaneous tissue, potential interference with sensing the therapeutic agent 160 and / or its components is avoided.

[0075] Wearable device 100 can be used to measure any suitable analyte and deliver any suitable therapeutic agent. Non-limiting examples of analytes are provided elsewhere herein. In some examples, the analyte measured by wearable device 100 is selected from the group consisting of glucose, lactate, ketone bodies (such as acetoacetate, acetone, or beta-hydroxybutyrate), ions (such as sodium, potassium, calcium, magnesium, or chloride), or hormones (such as insulin or cortisol). In some examples, the analyte measured using wearable device 100 includes a metabolite of a therapeutic agent, such as a metabolite of insulin, levodopa, metformin, glucagon, a GLP-1 antagonist, an SGLT-2 inhibitor, 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.

[0076] It will be appreciated that the control electronics 120 is configured to control the delivery of the therapeutic agent 160 in a variety of ways. In some examples, the control electronics 120 applies electrical stimulation to the first electrode 141 and the second electrode 142 to deliver the therapeutic agent 160 into the dermis 30 by electroporation. In other examples, the control electronics 120 applies electrical stimulation to the first electrode 141 and the second electrode 142 to deliver the therapeutic agent 160 into the dermis 30 by iontophoresis. Further details regarding electroporation and iontophoresis are provided in Zhang et al., "Advances in transdermal insulin delivery," Adv. Drug. Deliv. Rev. 139:51-70 (2019), the entire contents of which are incorporated herein by reference. In some examples, the control electronics 120 applies electrical stimulation to the first electrode 141 and the second electrode 142 to deliver a therapeutic agent into the epidermis 20 by magnetohydrodynamics.For further details regarding magnetohydrodynamics, please 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, p. 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).

[0077] 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 contains phenolic preservatives, i.e., phenol and / or m-cresol, which are electroactive species that can interfere with the signal detected by the sensor. By delivering insulin to the dermis 30 by iontophoresis and sensing the glucose concentration in the subcutaneous tissue 40, interference from the phenolic preservatives is avoided.

[0078] As further described above, at least one reservoir of the wearable device 100 optionally includes a polymer complexed with a therapeutic agent. For example, in the non-limiting configuration shown in FIG. 1A , at least one of the first reservoir 151 and the second reservoir 152 (which may also be referred to as R1 and R2, respectively) includes a polymer complexed with a therapeutic agent. Such polymer(s) find particular utility in examples where the therapeutic agent is delivered by electroporation or iontophoresis. FIG. 3 schematically illustrates an alternative exemplary configuration of a wearable device for delivering a therapeutic agent 160, and operations performed by the wearable device. In the non-limiting example 101 shown in FIG. 3 , the therapeutic agent 160 is delivered using iontophoresis, with the first reservoir 151 including a first polymer complexed with a therapeutic agent and the second reservoir 152 including a second polymer that does not store a therapeutic agent. In one example, the therapeutic agent 160 is the polymer identified in FIG. 3 as "D +1B-1E , the therapeutic agent 160 is positively charged. For example, the therapeutic agent 160 molecules themselves may be charged, or the therapeutic agent may be disposed within a positively charged encapsulating agent. In one example, the electrical stimulation includes applying a positive charge to the first electrode 141 (which functions as an anode) and a negative charge to the second electrode 142 (which functions 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 biological counterions 161. In response to the electrical stimulation, the therapeutic agent 160 is transported from the first reservoir 151 across the stratum corneum 10 into the epidermis 20 and into the dermis 30 in a manner similar to that described in FIGS. 1B-1E . 3, in response to the electrical stimulus, biological counterions 161 are transported from the epidermis 20 and / or dermis 30 across the stratum corneum 10 into the polymer of the second reservoir 152. In one example, the ... + ". In some examples, the electrical stimulus is substantially constant (direct current, DC) to transport the therapeutic agent 160 from the first reservoir 151 and transport the counterions 161 into the second reservoir 152. In other examples, the electrical stimulus alternates as a function of time (alternating current, AC) to alternate between transporting the therapeutic agent 160 from the first reservoir 151 and transporting the counterions 161 into the second reservoir 152.

[0079] 4 schematically illustrates another alternative exemplary configuration of the wearable device 100 for delivering a therapeutic agent 160, and operations performed by the wearable device 100. In the non-limiting example 102 shown in FIG. 4, the therapeutic agent is also delivered by iontophoresis via a first reservoir 151 containing a first polymer complexed with the therapeutic agent 160, and a second reservoir 152 containing a second polymer that does not store a therapeutic agent. In this example, the therapeutic agent 160 has no charge (i.e., is neutral), as represented by "D" in FIG. 4, and in a further example, the therapeutic agent 160 may be ... +1B-1E , the therapeutic agent 160 is mixed with a positively charged carrier 162, as represented by "A" in FIG. 4 . The positive charge applied to the first electrode 141 repels the positively charged therapeutic agent 160, and the negative charge applied to the second electrode 142 attracts the positively charged biological counterion 161. In response to the electrical stimulus, the therapeutic agent 160 is transported from the first reservoir 151 across the stratum corneum 10 into the epidermis 20 and into the dermis 30 by being carried by the charged carrier 162 in the manner described in FIGS. 1B-1E . Furthermore, in response to the electrical stimulus, the biological counterion 161 is transported from the epidermis 20 and / or dermis 30 across the stratum corneum 10 into the polymer of the second reservoir 152, as shown in FIG. 4 . In one example, the biological counterion 161 is transported from the epidermis 20 and / or dermis 30 across the stratum corneum 10 into the polymer of the second reservoir 152, as represented by "A" in FIG. 4 . + " and is positively charged.

[0080] FIG. 5 schematically illustrates an alternative exemplary configuration of the wearable device 100 for delivering a therapeutic agent 160 and operations performed by the wearable device 100. In the non-limiting example 103 shown in FIG. 5, the therapeutic agent 160 is delivered using electroporation, with a first reservoir 151 including a first polymer complexed with the therapeutic agent and a second reservoir 152 including a second polymer that does not store the therapeutic agent 160. In one example, the therapeutic agent 160 has no charge (i.e., is neutral), as represented by "D" in FIG. 5. In response to an electrical stimulus, the therapeutic agent 160 is transported from the first reservoir 151 across the stratum corneum 10 into the epidermis 20 and into the dermis 30 in a manner similar to that described in FIGS. 1B-1E. In some examples, the electrical stimulus alternates polarity as a function of time (i.e., alternating current), alternately transporting the therapeutic agent from the first reservoir 151. The first polymer and second polymer can be polymers, such as hydrogels, that provide improved ohmic conductivity (reduced resistance) between the electrode / reservoir and the stratum corneum 10. For example, the polymer improves impedance matching, where otherwise most of the voltage drop would occur between the electrode and the stratum corneum, which could cause erythema and potentially burns.

[0081] FIG. 6 schematically illustrates an alternative exemplary configuration of, and operations performed by, the wearable device 100 for delivering a therapeutic agent 160. In the non-limiting example 104 shown in FIG. 6, the therapeutic agent 160 is delivered using electroporation, where a first reservoir 151 includes a first polymer complexed with the therapeutic agent 160 and a second reservoir 152 includes the same polymer that also stores the therapeutic agent 160. In one example, the therapeutic agent 160 has no charge (i.e., is neutral), as represented by "D" in FIG. 6. In response to an electrical stimulus, the therapeutic agent 160 is transported from reservoir 151 and from reservoir 152 across the stratum corneum 10 into the epidermis 20 and into the dermis 30 in a manner similar to that described in FIGS. 1B-1E. In some examples, the electrical stimulation alternates polarity as a function of time (ie, alternating current) to alternately deliver therapeutic agents from the first reservoir 151 and the second reservoir 152.

[0082] Regardless of the particular form of electrical stimulation and the particular mode by which the therapeutic agent 160 is delivered to the dermis 30, the control electronics 120, in at least one example, is suitably configured to determine the electrical stimulation based on the measured concentration of the analyte in the subcutaneous tissue 40. Illustratively, for example, the control electronics 120 is configured to determine the electrical stimulation in response to a signal that differs from a predetermined value by more than a predetermined amount. For example, the control electronics 120 includes a memory that stores a predetermined value corresponding to a "normal" or "target" value of the analyte (e.g., configured to compare the signal to the predetermined value by calculating the difference between the signal and the predetermined value). In one example, the control electronics 120 is configured to determine the duration and / or magnitude of the electrical stimulation based on such a comparison. For example, the control electronics increases the duration for which the electrical stimulation is applied in proportion to the magnitude of the difference between the signal and the predetermined value. Alternatively, for example, the control electronics increases the magnitude of the electrical stimulation in proportion to the magnitude of the difference between the signal and the predetermined value.

[0083] Furthermore, regardless of the particular form of electrical stimulation and the particular mode by which the therapeutic agent 160 is delivered to the dermis 30, the control electronic circuitry 120 is suitably configured, in one example, to determine the electrical stimulation based not only on the measured concentration of the analyte in the subcutaneous tissue 40, but also on one or more other factors. For example, the control electronic circuitry 120 is configured to determine the electrical stimulation based on the duration that at least one reservoir (i.e., the first reservoir 151 and / or the second reservoir 152) remains coupled to the stratum corneum 10. Illustratively, the concentration of the therapeutic agent 160 in the at least one reservoir decreases over time as the therapeutic agent 160 is delivered to the host. In one example, the control electronic circuitry 120 is configured to adjust the electrical stimulation to compensate for such depletion of the therapeutic agent 160 in order to provide a consistent and accurate administration of the therapeutic agent 160. For example, the control electronic circuitry 120 is configured to increase the duration of the electrical stimulation as the duration that the at least one reservoir remains 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 that the at least one reservoir is coupled to the epidermis increases.

[0084] 1A-1E, 2A-2B, and 3-6, it should be noted that the electrical stimulation and administration of therapeutic agent 160 do not substantially interfere with the signal corresponding to the concentration of the analyte in subcutaneous tissue 40. For example, referring again to FIG. 1B, the electric field lines 153 are generated at a location sufficiently far from the distal end 132 of sensor 130 such that their strength is negligible at the distal end and does not substantially affect measurements made using distal end 132. Additionally or alternatively, in some examples, control electronics 120 receives the signal from distal end 132 at a time when no electrical stimulation is being applied. Thus, at the time the signal is generated, electric field lines 153 are not present and therefore do not interfere with the signal. In some examples, proximal end 131 of sensor 130 is less than about 1 cm from at least one of first electrode 141 and second electrode 142.

[0085] 1A-1E, 2A-2B, and 3-6 show non-limiting examples in which the sensor 130 is located between the first electrode 141 and the second electrode 142, it will be understood that the portion of the sensor 130 and the first electrode 141 and the second electrode 142 can have any suitable arrangement relative to one another. For example, FIGS. 7A-7B, 8A-8B, and 9A-9B schematically illustrate additional alternative exemplary configurations of the wearable device 100, and operations performed by the wearable device 100, for delivering a therapeutic agent 160.

[0086] FIG. 7A , showing a side view of the wearable device 102, and FIG. 7B , showing a bottom view of the device of FIG. 7A , 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 foot plate 150 and a housing 110 centrally positioned on the foot plate 150. In one example, the foot plate 150 includes a medical-grade adhesive surface configured to secure to the epidermis. In one example, the foot plate 150 includes one or more adhesive pads 32 having adhesive surfaces applied to the bottom of the foot plate 150 to help secure the housing 110 to the patient's skin during operation, such that the pads 32 adhere to the patient's skin when the wearable device 100 is in use, thereby preventing the wearable device 100 from shifting position on the skin during use. The size and shape of the pad 32 may be determined relative to the size and / or weight of the wearable device 102 and / or the part of the body to which the wearable device 102 is applied. The size of the pad may also be determined relative to the type of adhesive used on the pad. In one example, the one or more adhesive pads 32 are rectangular or band-shaped protruding from both sides of the housing 110. In one example, the one or more adhesive pads 32 include a peel-off release layer to protect the adhesive until the wearable device 100 is deployed.

[0087] In one example, the release force from the patient's skin by one or more pads 32 is greater than the compressive force applied to the puncture site by sensor 130. A typical temporary medical adhesive may be used to allow for easy removal of wearable device 100 when the life of sensor 130 is reached. Optionally, at least one reservoir (e.g., reservoirs 151 and 152) is located within or surrounded by adhesive pad 32, as shown in FIG. 7B.

[0088] 8A, which shows a side view of the wearable device 103, and FIG. 8B, which shows a bottom view of the device of FIG. 8A, show an example in which the sensor 130 is located within an opening in the first electrode 141 (E1). Optionally, as shown in FIGS. 8A-8B, the first electrode 141 is located within an opening in the second electrode 142 (E2).

[0089] 9A, which shows a side view of the wearable device 104, and FIG. 9B, which shows a bottom view of the device of FIG. 9A, show 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, the portion of the sensor 130 is located outside both the first electrode 141 and the second electrode 142, and the first electrode 141 is located within an opening in the second electrode 142.

[0090] As will be appreciated from this disclosure, the wearable device can have any of a variety of suitable configurations and can be used to implement any suitable operations. For example, FIG. 10 illustrates a flow of operations in an exemplary method for delivering a therapeutic agent using a wearable device. Method 1000 illustrated in FIG. 10 includes receiving, by control electronics of the wearable device coupled to the stratum corneum of a host, a signal from a distal end of a sensor via a proximal end of the sensor coupled to the control electronics, the distal end of the sensor being located in subcutaneous tissue of the host, the signal corresponding to a concentration of an analyte in the subcutaneous tissue (OPERATION 1010). Non-limiting examples of such devices, sensors, and adhesives are described with reference to FIGS. 1A-1E, 2A-2B, 3-6, and 7A-9B. Method 1000 illustrated in FIG. 10 includes determining an electrical stimulus to apply between a first electrode and a second electrode of the wearable device using the signal received by the control electronics (OPERATION 1020). Non-limiting examples of how the control electronics may use the signals to determine an electrical stimulus are provided elsewhere herein. Method 1000 shown in FIG. 10 includes applying an electrical stimulus determined by the control electronics to a first electrode and a second electrode (OPERATION 1030). Method 1000 shown in FIG. 10 includes transporting a quantity of a therapeutic agent from at least one reservoir of the wearable device through the stratum corneum and into the dermis for uptake of the therapeutic agent by capillaries in the dermis (OPERATION 1040). Non-limiting examples of electrical stimuli and methods of using such electrical stimuli to transport a therapeutic agent from a reservoir through the epidermis and into the dermis are described elsewhere herein.

[0091] The sensor 130 is optionally configured in a manner to enhance its biocompatibility. For example, the biocompatibility of the sensor 130 is optionally enhanced by providing a biointerface membrane (not specifically shown) on one or more component(s) of the sensor 130. In some examples, the biointerface membrane is configured to inhibit biofouling of the sensor 130. Non-limiting examples of materials that may be included in the biointerface membrane(s) include hard segments and / or soft segments. Examples of hard segments and soft segments used for the biointerface membrane include aromatic polyurethane hard segments with Si groups, aliphatic hard segments, polycarbonate soft segments, or any combination thereof. In some examples of the biointerface membrane(s), polyvinylpyrrolidone (PVP) is not included. In this example where PVP is not included, the biointerface membrane includes polyurethane and poly(dimethylsiloxane) (PDMS). In some examples, which may be combined with other examples herein, the biointerface membranes discussed herein include one or more zwitterionic compounds.

[0092] Additionally or alternatively, the biointerface membrane(s) are configured to release a therapeutic compound into the biological fluid. In one example, therapeutic compounds suitable for release using the biointerface membrane(s) or other membranes discussed herein include one or more of an anti-inflammatory agent, an anti-infective agent, a necrotic agent, and an anesthetic agent. Generally, the anti-inflammatory agent reduces acute and / or chronic inflammation adjacent to the implant to reduce FBC capsule formation and reduce or prevent barrier cell layer formation. Suitable anti-inflammatory agents include, for example, nonsteroidal anti-inflammatory drugs such as acetomethophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 muteins, anti-IL-6 iNOS inhibitors (e.g., L-NAME or L-NMDA), interferons, ketoprofen, ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin. Drugs, NSAIDs), 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, fluocinonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol propionate, dexamethasone, and dexamethasone acetate.

[0093] Generally, immunosuppressants and / or immunomodulators directly interfere with several key mechanisms required for the involvement of different cellular elements in the inflammatory response. Suitable immunosuppressants and / or immunomodulators include antiproliferative agents, cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopeptin, vincristine, mitomycin, statins, C These include MYC antisense, sirolimus (and analogs), restenase, 2-chlorodeoxyadenosine, PCNA ribozyme, batimustat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catchin, glycation agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), E. coli scalding enterotoxin, NLRP3 inflammasome inhibitors, and advanced coatings.

[0094] Generally, anti-infective agents are substances that can act against infection by inhibiting the spread of the infectious agent or by killing the infectious agent altogether, which can act to reduce the immune response without an inflammatory reaction at the implant site. Anti-infectives include anthelmintics (mebendazole), antibiotics containing aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolide antibiotics (azithromycin, clarithromycin, erythromycin), penicillin antibiotics (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, thicacillin). antiviral medications including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolone antibiotics (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin; and sulfamethoxazole / trimethoprim.

[0095] Generally, a necrotic agent is any drug that causes tissue necrosis or cell death. Necrotic agents include cisplatin, BCNU, taxol or taxol derivatives, and the like.

[0096] Generally, angiogenic agents include substances with direct or indirect angiogenic properties. In some cases, angiogenic agents additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis may be mediated through inflammatory or immune-stimulating pathways. It is not fully known how agents that induce local angiogenesis indirectly inhibit barrier cell formation; however, it is believed that some barrier cell effects may result indirectly from the effects of angiogenic agents.

[0097] The angiogenic agent promotes neovascularization around the membrane and / or increases angiogenesis near the device-tissue interface, thereby reducing or minimizing the ischemic period. Sphingosine-1-phosphate (S1P), a phospholipid with potent angiogenic activity, is incorporated into the biointerface membrane in one non-limiting example. Monobutyrin, a potent vasodilator and angiogenic lipid product of adipocytes, is incorporated into the biointerface membrane in another non-limiting example. In another non-limiting example, an antisense molecule (e.g., thrombospondin-2 antisense) that increases angiogenesis is incorporated into the biointerface membrane.

[0098] Angiogenic agents may include mechanisms that promote inflammation, which is thought to accelerate neovascularization in vivo. In one non-limiting example, a heterologous carrier, such as bovine collagen, elicits an immune response and stimulates neovascularization due to its foreign nature and is incorporated into the biointerface membrane of the present disclosure. In another non-limiting example, lipopolysaccharide, a potent immunostimulant, is incorporated into the biointerface membrane. In another non-limiting example, a protein, such as a bone morphogenetic protein (BMP), known to regulate bone healing in tissues, is incorporated into the biointerface membrane.

[0099] Generally, angiogenic agents are substances that can stimulate neovascularization, which can accelerate and sustain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include copper ions, iron ions, tridodecylmethylammonium 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 beta (TGF-beta), transforming growth factor alpha (TGF-alpha), hepatocyte growth factor, tumor necrosis factor-alpha (TNF-alpha), placental growth factor (PGF-alpha), and erythrocyte growth factor (YGF). These include, but are not limited to, thrombolytic enzyme inhibitors (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia inducible factor-I (HIF-1), angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, peptide KGHK, hypoxic tension, lactate, insulin, copper sulfate, estradiol, prostaglandins, Cox inhibitors, endothelial cell binding agents (e.g., decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and growth hormone.

[0100] Generally, pro-inflammatory agents are substances capable of stimulating an immune response in host tissue, which can accelerate or sustain the formation of a mature vascularized tissue bed. For example, pro-inflammatory agents are generally irritants or other substances that induce chronic inflammation and a chronic granular response at the implantation site. Without wishing to be bound by theory, it is believed that the formation of advanced tissue granulation induces blood vessels, which provide an adequate or abundant supply of analytes to the device-tissue interface. Pro-inflammatory agents include, but are not limited to, heterologous carriers, lipopolysaccharides, Staphylococcus aureus peptidoglycan, and proteins.

[0101] Other substances that can be incorporated into one or more membranes of the present disclosure include various drugs, excipients, and other substances well known in the art of pharmaceutical formulation.

[0102] Additionally or alternatively, in some examples, the biointerface membrane(s) comprises 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 may be a segmented block copolymer. In one example, the segmented block copolymer comprises a hard segment and a soft segment. In this example, the hard segment comprises an aromatic or aliphatic diisocyanate used to prepare the hard segment of the segmented block copolymer.In one example, the aliphatic or aromatic diisocyanate used to provide the hard segment of the polymer is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), tolylene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), bicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (4,4'-diphenylmethane diisocyanate), or the like. 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'-biphenyldiisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or combinations thereof.

[0103] In one example, the hard segment can be about 5% to about 90% by weight of the segmented block copolymer of the biointerface membrane. In another example, the hard segment can be about 15% to about 75% by weight. In yet another example, the hard segment can be about 25% to about 55% by weight.

[0104] It will be appreciated that the biointerface membrane(s) may comprise multiple layers.

[0105] It will be further understood that the sensor 130 can have any suitable configuration. In the non-limiting example shown in Figure 1A, the sensor 130 is substantially coaxially shaped and is referred to as a "wire." The sensor 130 may alternatively be substantially flat and is referred to as a "flat sensor."

[0106] Further details regarding an exemplary configuration of control electronics 120 are now provided. In one example, control electronics 120 includes circuitry, such as a non-volatile computer-readable memory, configured to store a time series data set of raw signal values ​​in volts, amperes, or ohms, among other scales (corresponding to measured analyte concentrations), and an electrical stimulus to be applied that delivers an appropriate dose of therapeutic agent based on the measured analyte concentrations. Note, however, that control electronics 120 need not be configured to determine the actual concentration of analyte in the subcutaneous tissue, nor similarly, need it be configured to determine the actual dose of therapeutic agent to be delivered. Rather, in one example, control electronics 120 is configured to apply an electrical stimulus based on a signal having a particular value.

[0107] Optionally, in addition to applying the electrical stimulus, the control electronics 120 is configured to generate an output corresponding to the concentration of an analyte in the subcutaneous tissue based on the signal. Such output can be used in any appropriate manner. In some examples, the control electronics 120 includes a non-volatile computer-readable memory configured to store the output, or a microprocessor or digital signal processor configured to execute a signal processing algorithm. Additionally or alternatively, in some examples, the control electronics 120 includes a transmitter configured to wirelessly transmit the output, e.g., a near-field communication (NFC), Bluetooth, WiFi, or cellular transmitter. The output can be used in any appropriate manner, e.g., to continuously monitor one or more indicators of the host's health. In one example, the control electronics 120 receives input via the transmitter from an algorithm running on a remote processor (e.g., cloud computing) and converts the input into a signal that delivers a therapeutic agent.

[0108] 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, although computer systems other than microprocessors can be used to process data as described herein; for example, an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), a central processing unit (CPU), or a graphical processing unit (GPU) can be used for some or all of the sensor's central processing. In one example, the processor is coupled to computer-readable memory, through which the processor is configured to provide semi-permanent storage of data, e.g., storage of data such as sensor identifiers (IDs), and programming for processing data streams (e.g., programming for data smoothing and / or signal artifact replacement similar to that described in U.S. Patent No. 8,20174 to Goode et al., which is incorporated herein by reference in its entirety). The processor can additionally be used for system cache memory, e.g., to temporarily store 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, rewriteable ROM, OCM, OTP memory, flash memory, etc.

[0109] In some examples, the processor module includes an analog-to-digital (A / D) converter configured to convert analog signals received from the distal tip or distal end 132 to digital signals for analysis. In one example, the processor module 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 sampled data at predetermined time intervals (also referred to as the sample rate). In some examples, the control electronics is configured to measure analytes using the distal end 132 at discrete time intervals, and these time intervals determine the sample rate of the digital filter. In some alternative examples, where the control electronics is configured to continuously measure analytes using the distal end 132, the processor module can be programmed to request digital values ​​from the A / D converter at predetermined time intervals, also referred to as the acquisition time. In these alternative examples, values ​​acquired by the processor are advantageously averaged over the acquisition time due to the continuity of the measurements. Thus, the acquisition time determines the sample 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 is user-programmable within the digital circuitry of the processor module. Acquisition times of about 2 seconds to about 512 seconds are used in some examples. However, any acquisition time can be programmed into the processor module. A programmable acquisition time is advantageous for optimizing noise filtering, time lag, and processing / battery power.

[0110] In one example, a battery 170 is operably connected to the control electronics and powers the wearable device. In one example, the battery is a lithium manganese dioxide battery; however, any suitable size and power battery can be used (e.g., AAA, coin cell, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium ion, zinc-air, zinc-mercury oxide, silver-oxygen, silver-zinc, and / or sealed). In some examples, the battery is rechargeable and / or multiple batteries can be used to power the system. In some examples, the wearable device can be powered, for example, via inductive coupling. In some examples, a quartz crystal and / or real-time clock (RTC) is operably connected to the processor and maintains system time for the entire computer system, for example, during programmable acquisition times within the processor module.

[0111] In some examples, the output signal (from the control electronics) is transmitted to a receiver (e.g., a computer or other communications station). The output signal may, in some examples, include a raw data stream that is used, for example, to provide a patient or physician with a useful value of the measured analyte concentration. In some examples, the raw data stream may be algorithmically smoothed or otherwise modified, continuously or periodically, to reduce outlying points that do not accurately represent the analyte concentration due to, for example, signal noise or other signal artifacts, in a manner such as that described in U.S. Pat. No. 8,101,174 to Goode et al., which is incorporated herein by reference in its entirety.

[0112] When the sensor is first implanted in the host tissue, the sensor and receiver are initialized. This can be referred to as a wake-up mode, which optionally includes resetting sensor data and calibrating the sensor. In selected embodiments, mating the electronics unit to the mounting unit triggers the wake-up mode. In other embodiments, the wake-up mode is triggered by the receiver.

[0113] In some examples, the control electronics is wirelessly connected to the receiver, such as via one-way or two-way RF transmission. However, wired connections are also contemplated. The receiver provides much of the processing and display of the sensor data and can be selectively attached and / or removed at the host's convenience. Thus, the sensor system can be unobtrusively worn, and the receiver, which provides much of the processing and display of the sensor data, can be selectively attached and / or removed at the host's convenience. In particular, the receiver includes programming for retroactively 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 described in U.S. Pat. No. 7,778,680, the entirety of which is incorporated herein by reference.

[0114] In some examples, the control electronics 120 may be affixed to a printed circuit board (PCB) or the like and may take a variety of forms. For example, the control electronics may take 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. Pat. Nos. 7,310,544 and 6,931,327, as well as U.S. Patent Application Publication Nos. 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 by reference in its entirety for all purposes.

[0115] In some examples, the control electronics 120 includes a regulated current source (e.g., in examples where the therapeutic agent is delivered using iontophoresis) or a waveform generator (e.g., in examples where the therapeutic agent is delivered using electroporation). In one example, the current source is voltage controlled, and compliance limits are established to limit the voltage and / or current to limit harm to the host. In one example, the waveform generator is of the direct digital synthesis type and is regulated to limit the current and / or voltage. Alternatively, the waveform generator is a simple sinusoidal implementation, e.g., a voltage controlled oscillator.

[0116] Additional comments All references cited herein, including, but not limited to, published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and made a part of this specification. To the extent that the publications and patents or patent applications incorporated by reference conflict with the present disclosure contained herein, the present specification is intended to supersede and / or supersede any such conflicting material.

[0117] 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.

[0118] All numbers expressing quantities of ingredients, reaction conditions, and so forth used herein should be understood to be modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0119] The above description discloses various methods and materials of the present disclosure. The present disclosure is susceptible to modifications in the methods and materials, and to changes in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from consideration of the present disclosure or practice of the present disclosure disclosed herein. Accordingly, the present disclosure is not intended to be limited to the particular embodiments disclosed herein, but rather is intended to cover all modifications and alternatives falling within the true scope and spirit of the present disclosure.

[0120] Although particular embodiments of the present disclosure have been illustrated with reference to particular combinations of elements, various other combinations may be provided without departing from the teachings of the present disclosure. Thus, the present disclosure should not be construed as being limited to the particular exemplary embodiments described herein and illustrated in the figures, but may also encompass combinations of elements of the various illustrated embodiments and aspects thereof.

Claims

1. 1. A wearable device for sensing an analyte concentration and delivering a therapeutic agent, the wearable device comprising: a sensor configured to completely penetrate the stratum corneum, epidermis, and dermis of a host and extend partially into a subcutaneous tissue of said host, the sensor having a proximal end and a distal end; a sensor, the distal end of which is configured to be positioned within the subcutaneous tissue; at least one reservoir configured to contact the stratum corneum and containing the therapeutic agent; control electronics coupled to the proximal end of the sensor, the control electronics comprising a first electrode and a second electrode; receiving, via the proximal end of the sensor, a signal from the distal end of the sensor corresponding to the concentration of the analyte in the subcutaneous tissue; using the signal to determine an electrical stimulus to be applied to the first electrode and the second electrode; and control electronics configured to apply the electrical stimulus to the first electrode and the second electrode to deliver the therapeutic agent across the stratum corneum and into the dermis of the host.

2. The electrical stimulation delivering an amount of said therapeutic agent from the polymer; increasing the permeability of the stratum corneum to transport the amount of the therapeutic agent into the dermis; distributing the amount of the therapeutic agent transported through the stratum corneum and into the dermis systemically; delivering a therapeutic agent through the stratum corneum into the dermis by iontophoresis; The wearable device of claim 1 , wherein the therapeutic agent is delivered into the dermis by magnetohydrodynamics.

3. 3. The wearable device of claim 1 or 2, wherein the therapeutic agent is neutrally charged, positively charged, negatively charged, or a charged carrier contains the therapeutic agent, and the charged carrier is positively or negatively charged.

4. 4. The wearable device of claim 1, wherein the at least one reservoir comprises a first reservoir adjacent to the first electrode, or the at least one reservoir further comprises a second reservoir adjacent to the second electrode.

5. The wearable device of claim 1 , wherein both the first reservoir and the second reservoir comprise a polymer complexed with the therapeutic agent.

6. The electrical stimulation Alternatingly delivering the therapeutic agent from the first reservoir and the second reservoir with alternating polarity as a function of time; transporting the therapeutic agent from the first reservoir and counterions into the second reservoir with alternating polarity as a function of time; The wearable device of claim 5 , wherein the wearable device does not substantially interfere with a signal corresponding to a concentration of an analyte in the subcutaneous tissue.

7. The wearable device of claim 1 , wherein the control electronic circuit receives the signal from the sensor when the electrical stimulus is not being applied.

8. The control electronics determining parameters of the electrical stimulation based on a duration that the at least one reservoir is coupled to the stratum corneum; and increasing the duration of applying the electrical stimulus as the duration that the at least one reservoir is coupled to the stratum corneum increases; increasing the magnitude of the electrical stimulus as the duration that the at least one reservoir is coupled to the stratum corneum increases; and and determining the electrical stimulus in response to the signal corresponding to a concentration of the analyte that differs from a predetermined value by more than a predetermined amount.

9. The wearable device of any one of claims 1 to 8, wherein the analyte comprises at least one of insulin, levodopa, metformin, glucagon, a GLP-1 antagonist, an SGLT-2 inhibitor, vancomycin, gentamicin, epinephrine, or naloxone, or a metabolite thereof.

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

11. 1. A method for sensing an analyte concentration and delivering a therapeutic agent, comprising: receiving, by control electronics of a wearable device coupled to a stratum corneum of a host, a signal from a distal end of the sensor via a proximal end of the sensor coupled to the control electronics, the distal end of the sensor being located within a subcutaneous tissue of the host, the signal corresponding to the concentration of the analyte in the subcutaneous tissue; using the signal received by the control electronics to determine an electrical stimulus to apply between a first electrode and a second electrode of the wearable device; applying the electrical stimulus to the first electrode and the second electrode as determined by the control electronics; and transporting a quantity of the therapeutic agent from at least one reservoir of the wearable device through the stratum corneum and into the dermis for uptake of the therapeutic agent by capillaries in the dermis.

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

13. 13. The method of claim 11 or 12, wherein applying the electrical stimulus to the first electrode and the second electrode as determined by the control electronics comprises increasing the permeability of the stratum corneum.

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

15. 15. The method of any one of claims 11-14, wherein applying the electrical stimuli to the first electrode and the second electrode as determined by the control electronics comprises alternately delivering the therapeutic agent from a first reservoir or a second reservoir with alternating polarity as a function of time.

16. 16. The method of any one of claims 11 to 15, wherein applying the electrical stimulus comprises alternating polarity as a function of time or with a substantially constant polarity to transport the therapeutic agent from the at least one reservoir.

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

18. 18. The method of any one of claims 11 to 17, wherein receiving a signal by a control electronic circuit and applying the electrical stimulus determined by the control electronic circuit occur at different times.

19. 19. The method of any one of claims 11 to 18, further comprising determining, by control electronics, parameters of the electrical stimulation based on the duration that the at least one reservoir is bound to the stratum corneum.

20. 20. The method of any one of claims 11 to 19, wherein using the signal received by the control electronics to determine an electrical stimulus to apply between a first electrode and a second electrode of the wearable device comprises comparing the concentration of the analyte to a predetermined value.

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