Health monitoring device

Abstract

Enhanced systems, media and techniques that include the actions of applying a health monitoring device to a surface of a tissue of interest, the health monitoring device includes a microneedle array including a plurality of microneedles, where the plurality of microneedles includes functionalized microspheres. The techniques also includes collecting, by one or more microneedles of the plurality of microneedles, fluid corresponding to the tissue of interest, where collecting the fluid includes: facilitating, by one or more fluidic channels within the one or more microneedles, flow of the fluid from the tissue of interest to a sensing layer including a plurality of biomarker sensors.

Description

Atorney Docket No. 43374-0857WO1HEALTH MONITORING DEVICETECHNICAL FIELD

[0001] This specification relates to health monitoring devices.BACKGROUND

[0002] Health monitoring devices and point-of-care testing (POCT) healthcare can enable rapid, on-site diagnostics and patient monitoring. These technologies include wearable devices like glucose monitors and smartw atches, which track vital signs and health metrics in real-time, providing valuable data for both patients and healthcare providers. POCT allows for testing and results at the patient’s location, reducing the barrier to diagnosis and treatment decisions. The integration of digital health technologies, such as mobile health applications and electronic medical records, can enhance patient engagement and can improve health outcomes by facilitating timely interventions and personalized care.SUMMARY

[0003] This specification describes technologies for a health monitoring device. These technologies generally involve a health monitoring device using biocompatible, microspheres of PLA functionalized with assays, and formed into microneedles. Once the microneedles penetrate the skin, the microneedles can uptake fluid through fluidic channels in the microneedles, e.g., interstitial fluid, whole blood, or components of blood, and characterize the fluid to measure the concentration of biomarkers on the same device. The measured concentration of biomarkers can be captured using a sensor, e.g., camera, arranged to capture a readout of a set of biomarker indicators corresponding to the microneedles. A health monitoring ecosystem to receive the captured readout can generate, using predictive modeling, health indicators, treatment, and outcomes for the user.

[0004] In general, one innovative aspect of the subject matter described in this specification can be embodied in methods that include the actions of applying a health monitoring device to a surface of a tissue of interest, the health monitoring device includes a microneedle array including a plurality of microneedles, w here the plurality of microneedles includes functionalized microspheres. The method also includes collecting, by one or more microneedles of the plurality of microneedles, fluid corresponding to the tissue of interest, where collecting the fluid includes: facilitating, by one or more fluidic channels within the one or more microneedles, flow of the fluid from the tissue of interest to a sensing layer including a plurality of biomarker sensors. The method also includes providing the fluid to the functionalized microspheres within the one or more microneedles to produce a reaction. The method also includes capturing, by a sensor, readout data from the pl ural i ty of biomarker sensors in the sensing layer of the health monitoring device. The method also includesAtorney Docket No. 43374-0857WO1providing, by the sensor, the readout data from the plurality of biomarker sensors sensing layer of the health monitoring device.

[0005] In general, another innovative aspect includes a sensing layer include a plurality of biomarker sensors. The health monitoring device also includes and a microneedle array in fluidic contact with the sensing layer and include a plurality of microneedles corresponding to the plurality of biomarker sensors, the plurality of microneedles include microspheres, where a portion of the microspheres are functionalized microspheres corresponding to one or more biomarkers. The device also includes fluidic channels within the plurality' of microneedles and configured to facilitate flow of fluid through the microneedles to corresponding ones of the plurality of biomarker sensors when the health monitoring device is affixed to a surface of a tissue of interest.

[0006] In general, another innovative aspect includes applying a health monitoring device to a surface of a tissue of interest, the health monitoring device including a microneedle array including a plurality of microneedles, the plurality of microneedles in fluidic contact with a reservoir configured to retain a therapeutic fluid. The method also includes injecting, by one or more microneedles of the plurality of microneedles and from the reservoir, the therapeutic fluid to the tissue of interest, where injecting the therapeutic fluid includes: facilitating, by one or more fluidic channels within the one or more microneedles, flow of the therapeutic fluid from the reservoir to the tissue of interest.

[0007] Other embodiments of any of the above aspects include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0008] Implementations can include one or more of the following features. In some implementations, the method where a first subset of microneedles of the plurality of microneedles includes a first type of functionalized microspheres and a second subset of microneedles of the plurality of microneedles includes a second type of functionalized microspheres, and where capturing readout data from the plurality of biomarker sensors includes: capturing first readout data corresponding to a first reaction of the first ty pe of functionalized microspheres with the fluid; and capturing second readout data corresponding to a second reaction of the second type of functionalized microspheres with the fluid.

[0009] In some implementations, capturing readout data includes capturing, by an image sensor, optical data from the biomarker sensors.

[0010] In some implementations, the biomarker sensors include colorimetric indicators, and where capturing readout data includes capturing, by an image sensor, colorimetric data from the colorimetric indicators.Atorney Docket No. 43374-0857WO1

[0011] In some implementations, providing the fluid to the functionalized microspheres within the one or more microneedles to produce the reaction includes: providing, to the colorimetric indicators, biomarkers within the fluid to produce a colorimetric response.

[0012] In some implementations, providing the fluid to the functionalized microspheres within the one or more microneedles to produce the reaction includes: providing, to the colorimetric indicators, enzymatic biomarkers within the fluid to produce a colorimetric response.

[0013] In some implementations, providing enzymatic biomarkers includes obtaining, through an enzyme reaction or cascade of enzyme reactions of the functionalized microspheres with the fluid, a reaction product including enzy matic biomarkers; and providing the enzymatic biomarkers.

[0014] In some implementations, capturing readout data from the plurality of biomarker sensors includes capturing readout data with a mobile device, and where providing, by the sensor, the readout data from the plurality of biomarker sensors sensing layer of the health monitoring device includes providing, by the mobile device, the readout data to a health monitoring system.

[0015] In some implementations, the method further includes receiving, from the health monitoring system and using a trained predictive health model, a predictive health outcome corresponding to the readout data.

[0016] In some implementations, collecting fluid from the tissue of interest includes collecting at least one of interstitial fluid, whole blood, and components of blood, collecting fluid from the tissue of interest can include collecting two or more of interstitial fluid, whole blood, and component of blood by two or more microneedles of the microneedle array.

[0017] In some implementations, collecting fluid from the tissue of interest includes collecting fluid from a dermal layer of skin.

[0018] In some implementations, applying the health monitoring device includes puncturing a surface of the tissue of interest by one or more microneedles of a microneedle array of the health monitoring device. Applying the health monitoring device can include applying compressive force to the health monitoring device onto a surface of the tissue of interest using one or more of a finger, hand, or a compressing member. Applying the health monitoring device can include using an adhesive to reversibly affix the health monitoring device to a surface of the tissue of interest.

[0019] In some implementations, the health monitoring device further includes: an adhesive layer configured to reversibly affix the microneedle array to the surface of the tissue of interest.

[0020] In some implementations, the health monitoring device further includes: a compressing member arranged with respect to the health monitoring device to apply’ a compressive force to cause at least a portion of the plurality of microneedles of the microneedle array to punctureAtorney Docket No. 43374-0857WO1the surface of the tissue of interest. The portion of functionalized microspheres can include enzyme-linked spheres. The enzyme-linked spheres can include one of cholesterol oxidase, cholesterol esterase, and glucose oxidase.

[0021] In some implementations, the biomarker sensors include colorimetric indicators. The colorimetric indicators can be configured to react with biomarkers present in the fluid when the health monitoring device is affixed to the surface of the tissue of interest. The colorimetric indicators can be configured to react with biomarkers or enzymatic byproducts present in the fluid when the health monitoring device is affixed to the surface of the tissue of interest.

[0022] In some implementations, the health monitoring device further includes generating enzymatic biomarkers by reacting the functionalized microspheres with the fluid when the health monitoring device is affixed to the surface of the tissue of interest. The plurality of microneedles can include a length of between 0.5 mm to 3 mm, and where at least a portion of the length of the plurality of microneedles is configured to penetrate the tissue of interest when the health monitoring device is affixed to the surface of the tissue of interest.

[0023] In some implementations, the fluidic channels within the plurality of microneedles are configured to facilitate flow of one or more of interstitial fluid, whole blood, or components of blood through the microneedles. The fluidic channels within the plurality of microneedles can be configured to facilitate the flow of a fluid volume of at least 10 microliters through the microneedles. The fluidic channels within the plurality of microneedles can be configured to facilitate the flow of the fluid volume in less than 15 minutes.

[0024] The technology described in this specification can be implemented so as to realize one or more of the follow ing advantages. The described invention can provide a low-cost, disposable solution for measuring health indicators at point-of-care or at-home use. By offering a lower-cost, disposable and simplified health monitoring device, users can measure more easily, independently, and more regularly, which can lead to improved monitoring and treatment of conditions. The data collected by the health monitoring devices can be used to build a predictive model to better understand and serve healthcare needs, e.g., improve early-detection of illness and treatment.

[0025] By providing point-of-use results, the health monitoring device can provide real-time diagnostics and remove the time-delay associated with lab-based testing. In particular, the point-of-use functionality can lower a bar of accessibility to users who may otherwise have mobility issues, users who live a prohibitive distance from a lab or clinic, or those who may require frequent testing. Healthcare providers can leverage at-home testing results at the onset of clinic visits or in the practice of remote / tele-healthcare practices, which can extend availability of healthcare services into remote regions or regions without healthcare providers. In some embodiments, the healthAtorney Docket No. 43374-0857WO1monitoring device uses passive, non-electrochemical measurements such that no onboard power system is needed, e.g., no onboard battery, which can further reduce device profile and cost, as well as increase ease of disposal.

[0026] The microneedles of the health monitoring device are fabricated using biocompatible materials, which can reduce the hazard of contamination when used in human tissue.

[0027] The details of one or more embodiments of the subject matter of this specification are set forth in the accompanying drawings and the description below. Other features, aspects, and advantages of the subject matter will become apparent from the description, the drawings, and the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 is an example operating environment for a health monitoring device.

[0029] FIGS. 2A-2B depict various views of an example health monitoring device.

[0030] FIGS. 2C-2D depict cross-sectional views of example health monitoring devices.

[0031] FIG. 3 is a flow diagram of an example process for fabricating a health monitoring device.

[0032] FIG. 4 is a flow diagram of another example process for fabncating a health monitoring device.

[0033] FIG. 5 depicts another example process for fabricating a health monitoring device.

[0034] FIGS. 6A-6E depict an example process for fabricating a health monitoring device.

[0035] FIG. 7 depicts various views of different example microneedle designs.

[0036] FIGS. 8A-8C depict applying a microneedle to a tissue sample.

[0037] FIG. 9 depicts various views of an example microneedle array of a health monitoring device.

[0038] FIG. 10 is a flow diagram of an example process for a health monitoring device.

[0039] FIGS. 11 A and 1 IB depict cross-sectional views of example health monitoring devices for drug delivery.

[0040] FIG. 11C depicts a cross-sectional view of an example health monitoring device.

[0041] FIG. 12 is a schematic of an example health monitoring device.

[0042] FIG. 13 is a schematic of an example health monitoring device.

[0043] Like reference numbers and designations in the various drawings indicate like elements.Attorney Docket No. 43374-0857WO1DETAILED DESCRIPTION

[0044] FIG. 1 is an example operating environment 100 for a health monitoring device 102. Health monitoring device 102 can be applied to a surface 104 of tissue 106, e.g., upper arm, forearm, thigh, calf, back, abdomen, or another region of interest of skin tissue.

[0045] Health monitoring device 102 includes a microneedle array 108, e.g., microneedles 108a, 108b and a sensing layer 110. Microneedles can be configured to pierce through the surface of the tissue and uptake fluid from the tissue 106, e.g., interstitial fluid, blood or blood components, or the like. A microneedle can have a length of between 0.5 mm to 3 mm, where at least a portion of the length of the microneedle is configured to penetrate the tissue when the health monitoring device is affixed to the surface of the tissue.

[0046] The microneedle array is configured to include fluidic channels within one or more of the microneedles, e.g., microneedles 108a, 108b, through which fluid extracted from the tissue 106 can flow. In some implementations, the fluidic channels are configured to facilitate the flow of a fluid volume, e.g., at least 10 microliters, at least 15 microliters, at least 20 microliters, over a period of time. The period of time to collect the fluid volume can be, for example, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less. In some implementations, the microneedle array is configured to extract a same volume of fluid through two or more microneedles of the microneedle array over a given period of time. For example, the microneedles of the microneedle array can include fluidic channels configured to extract a threshold volume of fluid into each of the microneedles within the 10-15 minute time period.

[0047] In some implementations, at least one microneedle of the microneedle array is configured to extract a different volume of fluid and / or extract fluid at a different rate than at least one other microneedle of the microneedle array. For example, one or more of the microneedles may be configured to extract more or less fluid and / or extract at a slower or faster rate than at least one other microneedle of the array. The difference in rate and / or volume can be selected, for example, based on the metabolic data of interest that is collected by the microneedle, e.g., delayed extraction or a slower extraction of fluid. In another example, a larger volume of fluid may be collected based on a requirement of a fluid volume needed for a particular indicator, e.g., to generate sufficient enzymatic byproduct for a conclusive test result.

[0048] The fluidic channels can be formed through a sintering process through which a compressed microsphere powder in a mold is sintered to form the fluidic channels, e.g., capillaries, in the porous sintered microneedle. Further details related to the microneedle array fabrication process are described below with reference to FIGS. 6A-6E.Atorney Docket No. 43374-0857WO1

[0049] The extracted fluid flows through the microneedle(s) and catalyzes one or more chemical or electrochemical reactions with the microneedle composite and / or in the sensing layer 110. Composition and fabrication of the microneedle array 108 is described in further detail with reference to FIGS. 3-7 below.

[0050] Sensing layer 110 can include, for example, a colorimetric indicator layer, a secondary metabolite sensing layer, an electrochemical sensing layer, or another type of sensing layer in fluidic and / or electrical communication with the fluidic channels of the microneedle array. Sensing layer 110 includes an array of biomarker sensors, e.g., biomarker sensor 111. Each biomarker sensor is in fluidic contact with a corresponding microneedle, e.g., microneedle 108b, configured to provide fluid through a fluidic channel to the biomarker sensor in the sensing layer 110. In some implementations, biomarker sensor 111 is formed of a same material composition as the corresponding microneedle, e.g., are formed as a unified structure where the biomarker sensor is located opposite the insertion point of the microneedle.

[0051] Sensing layer 110 can be configured to receive extracted fluid from the tissue 106 through at least one microneedle of the microneedle array 108 and / or secondary compounds, e.g., fluids, generated by reaction(s) of the extracted fluid with analytes within at least one microneedle of the microneedle array. The sensing layer 110 can include secondary chemical and / or electrochemical reactions to generate an optical response, e.g., colorimetric, fluorescent, etc., and / or electrochemical response. The colorimetric and / or electrochemical response of the sensing layer can be measurable by a sensor and / or visible to a human operator, e.g., a quantifiable and / or qualifiable measurement.

[0052] A sensor 112 can be configured to capture data characterizing the sensing layer 110. Sensor 112 can be, for example, an image sensor, e.g., camera, charge couple device (CCD), complementary metal-oxide semiconductor (CMOS) sensor, or the like. The image sensor can be configured to capture image data in a given wavelength range, e.g., corresponding to the colorimetric reaction of the sensing layer 110. For example, the image sensor can be configured to capture image data in visible wavelength, e.g., RGB sensor, infrared wavelength range. In another example, the image sensor can be configured to capture fluorescent or phosphorescent image data. Sensor 112 can be, for example, a chemical sensor, an electro-chemical sensor, electrical sensor, or another sensor configured to measure an electrical or chemical output reaction from the microneedle array. For example, sensor 112 can be configured to measure a change in resistivity of a surface of the sensing layer 110, e.g. using electrical probe measurements.

[0053] In some implementations, multiple sensors 112 can be used to capture data from the sensing layer 110. For example, two or more sensors 112 can be used to capture data from differentAtorney Docket No. 43374-0857WO1portions of the sensing layer, e.g., corresponding to different microneedles sensitized to perform different biometric measurements. At times, two or more image sensors 112 can be configured to capture different wavelength ranges, e.g., visible and infrared, corresponding to different colorimetric reactions of the sensing layer.

[0054] In some implementations, sensor 112 is positionable with respective to the health monitoring device 102 to capture, e.g., readout, sensor data by the sensor 112 of the sensing layer 110. Sensor 112 can be positionable by a human operator, e.g., a camera, electrical probe, etc. For example, the sensor 112 can be held in proximity of the sensing layer 110 such that a field of view of the sensor 112. In another example, the sensor 112 can be held in proximity of the sensing layer 110 such that the sensor 112 is in physical and / or electrical contact with the sensing layer 110.

[0055] In some implementations, sensor 112 is a component of the health monitoring device. For example, sensor 112 can be affixed to a housing (not shown) for the health monitoring device and arranged to capture sensor data of the sensing layer 110 when the health monitoring device 102 is applied to the tissue 106. In some examples, the sensor 112 can be in data communication with health monitoring system 120 through network 118 using a wireless or wired data communication link, e.g., Bluetooth, Wi-Fi, ZigBee, or the like. In some examples, the sensor 112 can be in data communication with health monitoring system 120 through client device 114, where client device 114 can receive sensor data from sensor 112 through a wireless or wired data communication link.

[0056] In some implementations, sensor 112 is a component of a client device 114. Client device 114 can be a mobile phone, tablet, or another smart device in data communication with a health monitoring system 120 over a network 118. Client device 114 can be a dedicated readout device, e.g., a handheld readout device, operable to capture sensor data by one or more sensors of the readout device. Client device 114 can include an application interface 116 through which a user may interact with a health monitoring system 120. The application interface 116 can provide guidance to a user for capturing data readout from the health monitoring device 102, e.g., aligning the sensor(s) 112 wdth the health monitoring device 102 to capture colorimetric and / or electrochemical data from the health monitoring device 102.

[0057] In some implementations, sensor 112 is in data communication over a network 118 with a health monitoring system 120. The health monitoring system 120 can be hosted on one or more cloud-based servers 122, local area servers, or a combination of both. In instances in which the sensor 112 is a component of a client device, the sensor 112 can be in data communication with the health monitoring system 120 through the client device 114.

[0058] Sensor 112 can provide sensor data captured by sensor(s) 112 to the health monitoring system 120 and stored in a data store 124, e.g., a cloud-based data store. Data store 124 can be, forAtorney Docket No. 43374-0857WO1example, an electronic medical records repository' accessible by an electronic medical records system. The sensor data and / or analysis of the sensor data can be viewable through the electronic medical records system by healthcare professionals, e.g., the patient’s care team.

[0059] In some implementations, the health monitoring system can share information with an electronic medical records system. For example, so that the collected biometric data and analysis of the biometric data can be compared directly to historical biomarker data for the user, e.g.. for the patient. The comparison of data and analysis can be used to establish health monitoring trends for the user. The collected data using health monitoring devices can be backward and / or forward compatible with data collected by the same or other methods.

[0060] Health monitoring system 120 can access the sensor data from data store 124 to train and refine predictive models related to health monitoring, detection, treatment, and the like. For example, health monitoring system 120 can perform biomarker pattern recognition using sensor data captured by sensor 112 of the sensing layer 110. Health monitoring system can be used to measure patient compliance and data consistency and delay that information to calculate its preventative power and general health improvement.

[0061] For situations in which the systems discussed here collect personal information about people, or may make use of personal information, the people may be provided with an opportunity to control whether programs or features collect personal information (e.g., information about a person’s activities, a person’s preferences, or a person’s current location), or to control whether and / or how the system operates. In addition, certain data may be anonymized in one or more ways before it is stored or used, so that personally identifiable information is removed. For example, a person’s identity may be anonymized so that no personally identifiable information can be determined for the person. Thus, the person may have control over how information is collected about them and used.

[0062] In some implementations, health monitoring system 120 receives additional biometric data for the user. The additional biometric data can be collected by one or more other health monitoring devices. For example, the additional biometric data can include heart rate, blood pressure, temperature, blood oxygenation, and the like. The additional biometric data can be collected by health monitoring devices other than the health monitoring device 102 and can be stored in data store 124. In some instances, the additional biometric data is collected within a same time frame as the biometric data from health monitoring device 120, e.g., reflective of user health conditions at the time. In some examples, the additional biometric data can be collected by the user’s smart watch, smart phone, or another smart device, and is provided through the network to data store 124 and is accessible to health monitoring system 120.Atorney Docket No. 43374-0857WO1

[0063] In some implementations, health monitoring system 120 provides health monitoring feedback responsive to the sensor data collected by sensor(s) 112 from health monitoring device 102. The health monitoring feedback can include analysis of the sensor data collected. Predictive analytics related to diagnosis, treatment, or other monitoring of one or more medical conditions. The health monitoring system can provide feedback responsive to health conditions including, for example, cardiovascular disease, neurodegenerative disease, metabolic conditions, longevity, organ disease, e.g., kidney, liver, pancreatic, etc., health, or other forms of traditional diagnostics. In some instances, the health monitoring system can provide feedback responsive to blood glucose levels, thyroid activity, or the like. In some implementations, health monitoring system 120 can provide treatment suggestions responsive to analysis of the sensor data collected, e.g., preventative actions and / or curative actions.

[0064] FIGS. 2A-2B depict various views of an example health monitoring device. As depicted in FIG. 2A, health monitoring device 200 can include an adhesive layer 202 to affix the health monitoring device to the surface of the tissue, e.g., to surface 104 of tissue 106, and hold the health monitoring device in place. In some implementations, e.g., as described with reference to FIGS. 8B-8C below, the health monitoring device includes or is configured to couple to an applicator, e.g., a compressing member. The applicator is configured to apply the health monitoring device 102 to the surface of the tissue of interest.

[0065] The adhesive can be selected to be biocompatible, e.g., to minimize allergic reaction, as well as to affix the health monitoring device to the surface of the tissue in a reversible, temporary manner. In some examples, the health monitoring device can have a profile resembling an adhesive bandage or medical dressing. As depicted in FIG. 2A, the adhesive layer 202 can be arranged with respect to a sensing layer 204 including the microneedle array to secure the microneedle array onto the tissue, e g., on opposing sides of the readout coupon.

[0066] FIG. 2B depicts a block diagram of an example sensing layer 204 of the health monitoring device, e.g., sensing layer 110. Sensing layer 204 includes biomarker sensors, e.g., biomarker sensor 206, each biomarker sensor corresponding to a microneedle of the microneedle array. Each biomarker sensor can be configured to present a diagnostic result, e.g., a colorimetric indicator, electrochemical readout, fluorescent readout, amperimetric or potentiometric readout, capacitive readout, or the like, for a respective fluid sample extracted by the corresponding microneedle for the biomarker sensor. In some implementations, biomarker sensors can include antibody capture and / or enzyme cascades to measure various biomarkers.

[0067] Sensing layer 204 can include one or more different types of biomarker sensors, each biomarker sensor corresponding to a microneedle configured to extract fluid from the tissue andAtorney Docket No. 43374-0857WO1facilitate the flow of the fluid along a fluidic channel to the biomarker sensor. For example, as depicted in FIG. 2B, sensing layer 204 includes types A. B, C. and D of biomarker sensors, each sensitized to sense a corresponding disease state. In some implementations, sensing layer 204 can include 2 or more biomarker sensors configured to detect a same disease state, e.g., for repeatability, larger sample set, etc.

[0068] In some implementations, biomarker sensors can be configured, e.g., sensitized, to detect different relative states of a same disease, e.g., are configured to detect at different sensitivity levels. For example, each of two or more biomarkers can be sensitized to detect different threshold amounts of an analyte. Further description of biomarker sensor configuration is found below with reference to FIGS. 3-7.

[0069] A health monitoring device can be configured to collect fluid, e.g., interstitial fluid, whole blood, components of blood, etc., through the microneedle array from different regions of the tissue, e.g., from an interstitial layer of the dermis, capillaries, etc. In some implementations, a health monitoring device is configured to extract fluid from a same tissue region, e.g., the papillary dermis, reticular dermis, sub-dermis regions. In some implementations, the health monitoring device is configured to extract fluid from two or more different tissue regions and / or to extract two or more different types of fluid from tissue region(s). In some instances, e.g., where whole blood is collected by the microneedle array, the health monitoring device can include a filtration layer to separate out the blood plasma between the microneedle and the sensing layer.

[0070] In some implementations, the health monitoring device is configured to extract fluid from the same tissue region. FIG. 2C depicts a cross-sectional view of an example health monitoring device 220. Health monitoring device 220 includes a microneedle array 222 including multiple microneedles. As depicted, the microneedle array 222 includes microneedles 224a, 224b, 224c, and 224d. all having a same length, e.g., a same depth of penetration into the tissue 226. The microneedles 224a-d penetrate into the tissue and facilitate the flow of fluid from the tissue through the microneedle array and into the sensing layer 228 including biomarker sensors, e.g., biomarker sensors 230a, 230b, 230c, and 230d. In such cases, the fluid extracted by the microneedle array 222 can be sourced from a same region of the tissue, e.g., a same or from proximate dermis layer(s).

[0071] In some implementations, the health monitoring device is configured to extract fluid from two or more tissue regions. FIG. 2D depicts a cross-sectional view of an example health monitoring device 240. Health monitoring device 240 includes a microneedle array 242 including multiple microneedles. As depicted, the microneedle array 242 includes microneedles 244a, 244b, 244c, and 244d. At least one of the microneedles, e.g., microneedles 244a, 244c, have a different length than at least one or more other microneedles, e.g., microneedles 244b, 244d. TheAtorney Docket No. 43374-0857WO1microneedles 224a-d penetrate into the different regions of tissue, e.g., regions 246a, 246b, and facilitate the flow of fluid from the different regions of tissue, e.g., different depths below a surface of the skin, through the microneedle array and into the sensing layer 248 including biomarker sensors, e.g., biomarker sensors 250a, 250b, 250c, and 250d. In such cases, the fluid extracted by the microneedle array 242 can be sourced from two or more different regions of the tissue, e.g., to collect different samples of fluid from the tissue.Health Monitoring Device Fabrication Process

[0072] Health monitoring device, e.g., health monitoring device 102, includes a microneedle array, a sensing layer including biomarker sensors, and a fixture, e.g., an adhesive layer, for affixing the health monitoring device to the tissue of interest. FIGS. 3. 4, 5, and 6A-6E described methods for fabricating the health monitoring device. FIG. 3 is a flow diagram of an example process 300 for fabricating a health monitoring device. As described above, components of the health monitoring device can be fabricated using biocompatible materials, e.g., biodegradable and bioactive materials.

[0073] Raw materials are obtained 302. The raw materials can include polymeric material(s), solvent(s), etc.

[0074] The polymeric materials can include water-soluble polymers and non-water-soluble polymers. In some instances, two or more polymeric materials are used as raw materials, each dissolved in a respective solvent. The raw materials can include, for example, a first organic phase solution and a second aqueous phase solution which can be emulsified to form microspheres.

[0075] The organic phase solution can include a polymer material and a solvent. The polymer material can include, for example, a biocompatible polymeric material having at least a threshold biocompatibility and / or biodegradability. In some instances, the biocompatible polymeric material is less than at a threshold regulatory requirement of harm in instances in which a portion of the polymer material is residual in the tissue after removal of the health monitoring device. The polymer material can be, for example, a thermoplastic material. In some instances, the polymer material is polylactic acid (PLA). In some instances, the polymer material is poly caprolactone. The biocompatible polymeric material can be dissolved in an organic solvent, for example, dichloromethane (DCM).

[0076] In some implementations, the polymer material is a polymeric material such as polycarbonate, polypropylene, polyethylene, high-density polyethylene, super high-density polyethylene, PTFE, or the like. In such cases, the polymer material may not include threshold requirements of biocompatibility and / or biodegradability and can be fabricated to be sufficientlyAtorney Docket No. 43374-0857WO1robust to avoid contamination of the tissue, e.g., to prevent a portion of the polymer material from remaining within the tissue after removal of the health monitoring device.

[0077] The aqueous solution can include a polymer material and water. The polymer material can include, for example, a synthetic water-soluble polymer. For example, the polymer material can be polyvinyl alcohol (PVA). The PVA can be dissolved in a solvent, e.g., water.

[0078] The raw materials are emulsified 304 to obtain microspheres dispersed in solution. In some implementations, the first organic phase solution is added to the second aqueous solution and emulsified and thermally treated to obtain microspheres. In some instances, mixtures of various molecular weights and having different mixtures ratios of two or more polymer materials can be used. For example, the aqueous solution can include a mixture of PLA and poly caprolactone, in selected ratios, e.g.. to obtain specific molecular weight and other physical properties.

[0079] FIG. 4 is a flow diagram of another example process 400 for fabricating a health monitoring device. The organic phase solution is obtained 402. In some implementations, obtaining the organic phase solution includes dissolving a biocompatible polymer material in a solvent. For example, a molecular weight of PLA can be, e.g., 80, 84, 100, 180, 191, 200, 19600, 160.000 kDaltons is dissolved in solvent. In another example, a molecular weight of 14,000, 50,000, 80,000 kDaltons is dissolved in solvent. An amount of biocompatible polymer material in solvent can be, for example, 1.5%, 2.5%, 3.5%, 4%, 7% or more weight per volume. In some examples, 2-10 g of PLA is dissolved in 150-250 mL of DCM. Dissolving the biocompatible polymer in solvent can include heating the solution, agitating the solution, or a combination of both. The solution can be stirred, shaken, homogenized, or otherwise agitated. For example, the solution can be stirred at a rate of 250 RPM, 350 RPM, 450 RPM, 550 RPM, or faster. Stirring methods can include, for example, stir Bar, overhead stirrer, homogenizer, or shaker. In some examples, the solution can be maintained between 20 to 30 °C. In some examples, the solution can be held at a fixed temperature during the agitation process. In some implementations, the parameters of the emulsification process, e.g., temperature, agitation, etc., is used to control a particle size distribution and particle size of the resulting microspheres.

[0080] The aqueous phase solution is obtained 404. In some implementations, obtaining the aqueous phase solution includes dissolving a water-soluble polymer in water. For example, a molecular weight of PVA can be, e.g., 9500, 18000, 50,000, 94000, 166000, 200000 kDaltons dissolved in water. An amount of water-soluble polymer material in water can be, for example, 1.5%, 2.5%, 3.5%, 4%, 7% or more weight per volume. For example, 2-10 g of polyvinyl alcohol (PVA) is dissolved in 150-250 mL of water. Dissolving the water-soluble polymer in water can include heating the solution, agitating the solution, or a combination of both. The solution can beAtorney Docket No. 43374-0857WO1stirred, shaken, homogenized, or otherwise agitated. For example, the solution can be stirred at a rate of 250 RPM, 350 RPM, 450 RPM. 550 RPM, or faster. Stirring methods can include, for example, stir Bar, overhead stirrer, homogenizer or shaker. In some examples, the solution can be maintained between 20 to 30 °C. In some examples, the solution can be held at a fixed temperature during the agitation process.

[0081] The organic phase solution is combined 406 with the aqueous phase solution while mixing. In some implementations, a ratio of the biocompatible polymer to the water-soluble polymer of the first solution and second solution, respectively is, for example, 1:1, 2:1, 1:2. In some implementations, a first agitation protocol is applied to the aqueous phase solution while the organic phase solution is added, and a second agitation protocol is applied to the combined solution after the addition is completed. For example, the solution can be stirred at a first rate, e.g., 250 RPM, 350 RPM, 450 RPM, 550 RPM, during the addition and at a second rate, e.g., 800 RPM, 900 RPM, 1000 RPM, 1200 RPM, after the addition of the organic phase solution to the aqueous phase solution. In some implementations, a temperature of the combined solution is maintained during the emulsification process, e.g., between 20 to 30 °C.

[0082] In some implementations, the combined solution is emulsified during a time period until the solvent of the component organic phase solution evaporates. For example, the combined solution can be mixed at a maintained temperature for a time period, e.g., 12 hours, 24 hours, 36 hours, 72 hours, until the DCM evaporates.

[0083] The combined solution is processed 408 to remove residual water-soluble polymer material. For example, the combined solution can be centrifuged and resuspended one or more times, e.g., 2 times, 3 times, 4 times, or more, to remove residual water-soluble polymer. The process 408 can include pausing the agitation of the solution during the process, e.g., halting the stirring of the solution. In some examples, the combined solution is treated to remove residual PVA to below a threshold amount within the combined solution to obtain a remaining solution. In some implementations, process 408 includes a washing and filtering process. The washing and filtering process can be performed one or more times, e.g., 2 times, 3 times, 4 times, 6 times, 8 times, to obtain a final solution.

[0084] The final solution is processed 410 to filter and dry the microspheres in the final solution. In some implementations, the process 410 includes filtering the final solution under vacuum through a filter, e.g., a 0.15 micron, 0.18 micron, 0.2 micron, 0.22 micron, 0.25 micron pore size filter. In some implementations, the process 410 includes drying the filtered final solution under vacuum for a period of time to obtain the dried microspheres. The drying process can beAtorney Docket No. 43374-0857WO1performed for 5 hours, 10 hours, 12, hours, 18 hours, 24 hours, or longer, under vacuum conditions. At times, the drying process can be performed at temperatures between 20 to 30 °C.

[0085] The dried microspheres are separated 412 into a powder. In some implementations, the separation process includes a mechanical separation, e.g., using a grinder, mortar and pestle, or other mechanical agitation to separate out the microspheres. The microspheres include a distribution of sizes, e.g., 100 nanometers to 50 microns.

[0086] Referring back to FIG. 3, the obtained microspheres are functionalized 306. In some implementations, the microspheres are functionalized with enzymes, e.g., functionalized with amines, where the selected enzymes depend in part on an analyte of interest to characterize with the health monitoring device. In some instances, a portion of the microspheres used in forming the microneedle array are functionalized, e.g., less than the entire microsphere quantity. The functionalized microspheres can be blended with non-functionalized microspheres prior to molding the microneedle.

[0087] FIG. 5 depicts an example process 500 for a health monitoring device. The process described with reference to FIG. 5 is an example process for producing a reaction related to cholesterol. In general, the overarching concept of amine functionalization to produce enzyme-linked microspheres for reacting with selected metabolites and measuring by-products or secondary by-products of the reaction chain may be applied to characterize various different metabolic functions.

[0088] In step A. microspheres are obtained, e.g., microspheres are obtained as described with reference to FIG. 4.

[0089] In step B, microspheres are reacted in a first solution to produce amine-functionalized microspheres, e.g., -NH2 amino group. In one example, PLA microspheres are immersed in a solution of Ethylenediaminetetraacetic acid (EtDA) in methanol (MeOH). A concentration of the microspheres in solution can be, for example, 25-100 mg / mL. A concentration of EtDA in methanol can be, for example, 0.25-10% (v / v). In some implementations, the reaction is heated, e.g., 30 °C, 40 °C, 50 °C, 60 °C. The reaction can be performed for a period of time, for example, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes.

[0090] In step C, amine functionalized microspheres are reacted in a second solution to produce enzyme-linked microspheres. A concentration of aminated microspheres can be, for example, 25 to 100 mg / mL in the second solution. In one example, the aminated microspheres obtained in step B are reacted with a second solution of Bis-N-succinimidyl- (pentaethylene glycol) ester linker (Bis(NHS)PEG 5). For example. 2.5 mM Bis(NHS)PEG 5 in 10 mM phosphate buffer (PBS) containing 1% v / v dimethylsulfoxide (DMSO). The reaction can be performed at aAtorney Docket No. 43374-0857WO1maintained temperature, for example, 20 °C to 30 °C, for a period of time, e.g., 30 minutes, 45 minutes, 60 minutes, 90 minutes. The microspheres may be rinsed in PBS to remove unbound linker. The PEG-coated microspheres can be reactivated in a third solution. For example, a mixture of N-Hydroxy succinimide (NHS) (0.1 M in Milli-Q water) and l-ethyl-3-(3-dime-thylaminopropyl) carbodiimide (EDC) (0.4 M in Milli- Q water). The mixture(v:v) can be, for example 25:75, 50:50, 75:25. The reactivation can proceed for a period of time, e.g., 10 minutes. 15 minutes, 20 minutes, 30 minutes, at a maintained temperature, for example. 20 °C to 30 °C. After rinsing, the microspheres can be reacted in an enzyme solution. The enzyme solution can be, for example, cholesterol oxidase, cholesterol esterase, glucose oxidase. Cholesterol oxidase solution, e.g., Cholesterol oxidase in PBS, and rinsed with PBS. For example, 1000 microliters of microsphere solution is mixed with 500 microliters of Cholesterol oxidase solution. The concentration of Cholesterol oxidase in PBS to form the solution can be, for example, 50 nM, 100 nM, 150 nM, 200 nM. The reaction can be performed for a period of time, for example, 30 minutes, 60 minutes, 90 minutes, 120 minutes, at a maintained temperature, for example, 20 °C to 30 °C.

[0091] In some implementations, different volumes of the microspheres used in forming the microneedle array are functionalized with different enzymes, e.g., to characterize different analytes. An enzy me or enzyme cascade can be used to react specifically with biomarkers and measure the reaction product colorimetrically. Different enzy me classes can include, for example, oxidases, oxidases and esterases, phosphatases, and kinases. Secondary metabolites can include, for example, acids / bases. hydrogen peroxide, and phosphates.

[0092] In some implementations, different volumes of the microspheres are functionalized to have different levels of sensitivity' to a given analyte, e.g., more or less of the fraction of microspheres forming a given microneedle of a microneedle array are functionalized with the enzyme to adjust a sensitivity level to the analyte. For example, a concentration of enzyme-linked microspheres can be 0.5-10 mg / mL in a concentration of the metabolite, e.g., cholesterol, of 0.005 -0.5% in a solution, e.g., 0.1 % Triton X.

[0093] The pathway to reacting the enzyme-activated microspheres can include, at step D, providing the metabolite, e.g., cholesterol, to cause the reaction between the enzyme-activated microsphere with the metabolite, e.g., react cholesterol with the cholesterol oxidase. The reaction produces, at step E, a reacted metabolite, e.g., oxidized cholesterol, with by-products that can be measured, e.g., by a colorimetric indicator. For example, a colorimetric indicator can include a peroxide indicator, e.g., o-Dianisidine Solution, Amplex Red Solution, or the like. At step F, the peroxide by-product of the reaction generates a colorimetric reaction at a biomarker sensor 111 of a health monitoring device 102 which can be captured by a sensor 112.Atorney Docket No. 43374-0857WO1

[0094] In some implementations, a volume of microspheres can include a blend of two or more quantities of functionalized microspheres which are each sensitized to a different analyte.

[0095] Referring back to FIG. 3, the activated microspheres are provided 308 to a mold to form one or more microneedles of a microneedle array for biomarker detection. One of more of the microneedles of the microneedle array can be formed from a given quantity of the functionalized microspheres or a blend of functionalized microspheres with non-functionalized microspheres.

[0096] FIGS. 6A-6E depict an example process for fabricating a health monitoring device. FIG. 6A depicts an example mold 600 for receiving the activated microspheres. The mold 600 can be fabricated from various materials, for example, stainless steel, aluminum, or another metal. In some instances, the mold 600 can be fabricated from ceramic, high-temperature plastic or polymers, or another material compatible with a fabrication process for forming the inverse shape of the microneedle array. A fabrication process to form the mold 600 can include subtractive manufacturing, e.g., computer numerical control (CNC) manufacturing, laser cutting, or another form of high-resolution machining. A fabrication process to form the mold 600 can include additive manufacturing, e.g., stereolithography (SLA), digital light processing (DLP), two-photo polymerization (2PP), selective laser sintering (SLS), or another form of high-resolution additive manufacturing.

[0097] The mold 600 is fabricated to retain at least one inverse form of the microneedle array. In some instances, multiple inverse forms of the same or different microneedle arrays can be fabricated in the mold 600 to allow for multi-device fabrication. The fabricated mold 600 may be cleaned and / or baked to remove any residual dust and water contaminants.

[0098] The mold 600 is overfilled with microsphere powder 602, as depicted in FIG. 6B. As noted above, the mold can be filled with two or more different microsphere powder volumes. For example, at least one microneedle volume 604a defined in the mold 600 can be filled with a different microsphere powder than at least one other microneedle volume 604b defined in the mold 600. The different microsphere powders can be activated with different enzymes, e.g., to characterize different metabolites, or be activated with different sensitivities of the same enzyme, e.g., to characterize different levels of the same metabolite.

[0099] The microspheres in the mold are compressed with a pneumatic press 606, as depicted in FIG. 6C. In some implementations, two or more compression steps are implemented to press the microsphere powder. A first compression step is used to press a first volume of powder, e.g., 20 mg, 30 mg, 40 mg, into the microneedle volumes of the mold 600. The first compression step can include using a similarly shaped form to press the microsphere power into the tips of the microneedle volumes, e.g., a hypodermic needle. A second compression step includes a packingAtorney Docket No. 43374-0857WO1fixture having similar dimensions, e.g., within a threshold tolerance, as the microneedle array sensing layer, e.g., sensing layer 110. that is pressed into the mold to pack the microsphere powder. A compression force can be applied using a pneumatic press in the second compression step, for example, 70, 90, 100, 120, 150, 200, 220, 250, 275, 3001bs of force.

[0100] In some implementations, an iterative packing and compression process is implemented following the second compression step, where the mold 600 is packed and subsequently reloaded with powder cyclically to obtain a packed mold 620. Excess material can be removed with a straight edge from a top portion of the packed mold 620.

[0101] FIG. 6D depicts a sintering and annealing process for the packed mold 620. In some implementations, the packed mold 620 is sintered in a convection oven using a sintering profile selected to sinter and densify the microspheres while avoiding mechanical stress on the microneedle array and disassociation / degradation of the enzymes on the enzyme-activated microspheres. For example, a sintering profile can include ramped heating to a first peak temperature, e.g., 90 °C, 100 °C, 120 °C, 110 °C, 130 °C, 140 °C, 150 °C, 170 °C, 200 °C, ahold at the first peak temperature for a first period of time, e.g., 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, and a ramped cooling to room temperature. In some examples, a secondary annealing profile is additionally implemented including a ramped heating to a second peak temperature, e.g., 80 °C, 100 °C, 120 °C, a hold at the second peak temperature for a second period of time, e.g., 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, and a ramped cooling to room temperature.

[0102] The sintering and annealing processes form fluidic channels through the sintered and densified microspheres in the microneedles. The fluidic channels can provide pathways to flow fluid from an exterior surface of a corresponding microneedle including the fluidic channel and to a biomarker sensor.

[0103] After the sintering and annealing process, the microneedle array 640 is removed from the mold 600 and may be inspected for quality. FIG. 7 depicts various views of different example microneedle designs 702, 704, 706, 708, 710, 712, 714.

[0104] In some implementations, parameters of the fabrication process, e.g., microsphere size distribution, compression force, sintering process, and annealing process, are selected in part to yield a target range of densification of the microspheres. For example, parameters of the fabrication process are selected in part to yield a target set of characteristics of the fluidic channels, e.g., to yield a target range of fluid extraction and volumetric extraction.

[0105] Referring back to FIG. 3, the formed microneedle array is provided 310 for biomarker detection. The formed microneedle array can be affixed to an adhesion layer, e.g., adhesion layer 202, to form a health monitoring device. Optionally, the health monitoring device can include anAtorney Docket No. 43374-0857WO1installation apparatus for affixing or for reversible affixing and removing the health monitoring device from the tissue.

[0106] In some implementations, a target region of tissue is a dermis layer of the skin tissue, e.g., approximately 0.5 to 4 mm depth from a surface of the skin. Target region accessibility can depend in part, for example, on age, fat percentage, muscle percentage, body area of target region of tissue, and the like. For example, the target region accessibility can differ between users due to variation, for example, in skin elasticity, layer compression, skin surface tension, etc. As a result, an additional needle stroke can be used to penetrate into the dermis layer and counteract skin tenting, as depicted in FIG. 8A.

[0107] In some implementations, as depicted in FIG. 8B, an adhesive layer 802, e.g.. adhesive layer 202 of the health monitoring system can be used to hold the local surface of the tissue. The adhesive layer 802 can minimize the tented area, e.g., reducing the tenting shape and depth. Adhesive layer 802 can include a 3M™ pressure-sensitive adhesive, e.g., LSE300, 9472, etc., a Scarpa™ skin adhesive, a cyanoacrylate, or another adhesive having biocompatibility.

[0108] In some implementations, as depicted in FIG. 8C, applied force 804, e.g., applied to a surface opposing the tip of the microneedle 806, can result in denser and more stable supporting layers of tissue. The applied force 804 can reduce the ability of the tissue to tent and compress further. Applied force 804 can be applied manually, e.g., using a user’s finger or hand, or can be applied with a compressing member 808. Compressing member can have an inner diameter (ID) of 0.075”, 0.08”. 0.085”, 0.09”, and an outer diameter (OD) of A”, ‘A”. 1”.

[0109] In some implementations, an arrangement of the microneedles in the microneedle array can be selected such that at least a threshold of the microneedles of the microneedle array make incisions in the tissue into the target region when the health monitoring device is applied to the surface of the tissue. FIG. 9 depicts various views 900, 902, 904 of an example microneedle array of a health monitoring device. As depicted in FIG. 9, the microneedles 906a, 906b, 906c, 906d are arranged in a circular pattern such that the lines of tension about the circular microarray are even.Health Monitoring Device Operation Process

[0110] FIG. 10 is a flow diagram of an example process 1000 for a health monitoring device. Applying 1002 a health monitoring device to a surface of a tissue of interest. For example, a health monitoring device 102 is applied to the surface of tissue 106, e.g., surface of the skin. Applying 1002 includes puncturing the tissue of interest by one or more microneedles of a microneedle array of the health monitoring device. Applying the health monitoring device can include applyingAtorney Docket No. 43374-0857WO1compressive force to the health monitoring device onto the surface of the skin tissue. A compressive force can be applied manually, e.g.. using a finger, hand. A compressive force can be applied using a tool or an applicator, e.g., a compressing member. Applying the health monitoring device can include using an adhesive to reversibly affix the health monitoring device to the surface of the skin tissue.

[0111] Collecting 1004, by one or more microneedles of a microneedle array of the health monitoring device, fluid corresponding to the tissue of interest. Collecting 1004 includes facilitating the flow of the fluid from the tissue of interest through the one or more microneedles of the microneedle array and into the sensing layer of the health monitoring device, e.g., by a capillary effect. The flow of fluid can be facilitated by fluidic channels formed within the sintered microspheres of the microneedle from an exterior surface of the microneedle through to a portion of the microneedle in fluidic contact with the sensing layer. As the fluid flows through the one or more microneedles, the fluid reacts with the enzy me-linked microspheres within the microneedle to produce a reaction, e.g., as described with reference to FIG. 5.

[0112] Capturing 1006, by a sensor, a readout from a sensing layer of the health monitoring device. For example, sensor 112 captures a readout of a biomarker sensor 111 in the sensing layer 110. The readout includes a reaction of the biomarker indicator with the biomarker or a secondary metabolic sensing result in the fluid flowing through the one or more microneedles. For example, colorimetric or secondary metabolite sensing results from the sensing layer 110. In some examples, a colorimetric indicator reacts with the biomarker to produce a color or reacts with enzymatic biomarkers to produce a color. Examples of biomarkers include, for example, electrolytes and total non-specific proteins. Examples of enzyme classes include, for example, aminotransferases and phosphatases. In some examples, secondary metabolite sensing uses enzymes or an enzyme cascade to react with biomarkers and measure the reaction product colorimetrically. Examples of enzyme classes include, for example, oxidases, oxidases + esterases, phosphatases, and kinases. Examples of secondary metabolites include, for example, acids / bases, hydrogen peroxide, and phosphate.

[0113] Providing 1008, by the sensor, the readout from the sensing layer of the health monitoring device. In some implementations, the sensor 112 provides a readout, e.g., colorimetric readout, from multiple biomarker sensors in the sensing layer to a health monitoring system 120.Additional Health Monitoring Device Embodiments

[0114] In some implementations, a health monitoring device is configured for delivery of one or more fluids when the health monitoring device is applied to the surface of the tissue of interest.Attorney Docket No. 43374-0857WO1FIGS. 11 A and 1 IB depict cross-sectional views of example health monitoring devices 1100, 1102 for drug delivery. As depicted, health monitoring device 1102 includes a microneedle array 1106. Microneedles, e.g., microneedle 1108, of the microneedle array is in fluidic communication with a reservoir 1110 of the health monitoring device 1102. Reservoir 1110 can be configured to retain a fluid of interest, e.g., a drug or another therapeutic component. The fluid retained by the reservoir 1110 can flow through the microneedle of the microneedle array and disperse into the tissue 1112 when the health monitoring device 1102 is affixed to the tissue 1112. In some examples, the health monitoring device 1102 includes two or more reservoir regions, which can be fluidically separated. In such examples, at least one microneedle of the microneedle array can be configured to deliver a first fluid from a first reservoir from at least one other microneedle configured to deliver a second, different fluid from a second reservoir.

[0115] In some implementations, microneedles of the microneedle array 1106 are functionalized with therapeutic material, e.g., enzymes, using processes similar to those described with reference to FIGS. 3-5. The functionalized microspheres within the microneedles can intermingle with the fluid extracted from the tissue of interest and generate a therapeutic reaction, e.g., release of a drug or fluid of interest into the tissue of interest.

[0116] In some implementations, for example, as depicted in FIG. 1 IB, at least a first portion of the microneedles of the microneedle array 1120 of health monitoring device 1104 are a different length than a second portion of microneedles. In such cases, the health monitoring device 1104 can be configured to penetrate different regions of the tissue of interest, e.g., different dermal layers, to deliver a same or different fluid to the different regions. For example, a first set of microneedles 1122a, 1122b are configured to penetrate a first region 1114a and a second set of microneedles 1122c, 1122d are configured to penetrate a second region 1114b of the tissue of interest.

[0117] In some implementations, a health monitoring device is configured to extract fluid from the tissue of interest, e.g., as described with reference to FIGS. 2A-2D, and additionally configured to provide, e.g., inject, fluid into the tissue of interest, e.g., as described with reference to FIGS. 11A-1 IB. FIG. 11C depicts a cross-sectional view of an example health monitoring device 1140. Health monitoring device 1140 includes a microneedle array 1142, where a first portion of microneedles, e.g., microneedle 1144a, is configured to extract fluid from the tissue of interest 1146, and a second portion of microneedles, e.g., microneedle 1144b, is configured to provide fluid to the tissue of interest. Microneedle 1144a can be configured to extract fluid and provide the fluid through respective fluidic channels within the microneedle to a biomarker sensor 1148, e.g., a colorimetric indicator or another sensor as described above. Microneedle 1144b canAtorney Docket No. 43374-0857WO1be configured to provide fluid from a reservoir 1150 to the tissue of interest through respective fluidic channels within the microneedle 1144b.

[0118] In some implementations, a health monitoring device configured to perform extraction of fluid from the tissue as well as injection of fluid into the tissue of interest includes a feedback control loop to control one or more operations of the health monitoring device. As depicted in FIG. 11C, a controller 1152 can be configured to receive feedback from one or more biomarker sensors 1148 and generate control signals to control operation, e.g., delivers’, of the fluid from one or more reservoirs 1150 of the health monitoring device. Controller 1152 can be, for example, a microcontroller, active or passive sw itch, or another analog or digital component. Controller 1152 can be configurable to receive an input from the biomarker sensor and provide a control to update an operation of at least one microneedle to provide fluid, e.g., a drug, through a microneedle into the tissue.

[0119] In some implementations the health monitoring device includes a passive control operation. Controller 1152 can include fluidic channels to facilitate flow of fluid from one or more microneedles 1144a configured to extract fluid from tissue of interest 1146 and provide the extract fluid and / or a reactant byproduct to one or more microneedles 1144b, where the one or more microneedles 1144b provide the extracted fluid, reactant byproduct, or another fluid retained by reservoir 1150 into the tissue of interest 1146. For example, controller 1152 can be a passive device including a hydrophilic material to absorb fluid, e.g., interstitial fluid, extracted from the tissue of interest and / or enzymatic byproduct between the extracted fluid and functionalized microsphere. The absorbed fluid can optionally be reacted with a reactant embedded within the hydrophilic material and the reacted product and / or absorbed fluid can be provide to the microneedles 1144b to be injected into the tissue of interest.

[0120] In some implementations, the health monitoring device can include a microneedle array where the microneedles of the microneedle array are formed using non-functionalized microspheres. For example, the microspheres can be formed, e.g., using a process as described with reference to FIG. 4, and formed into the mold, e.g., using a process as described with reference to FIGS. 6A-6E, but without an intervening step of functionalizing at least a portion of the microspheres with an enzyme. Instead, the microneedle array can be arranged in fluidic contact with a secondary material to perform assay(s) with the extracted fluid.

[0121] FIG. 12 is a schematic of an example health monitoring device. As depicted, health monitoring device 1200 includes a microneedle array 1202 in fluidic contact with a secondary material 1204. The secondary material can be a material having at least a threshold absorption, e.g., an absorbent piece of paper. For example, the secondary material can be cellulose paper orAtorney Docket No. 43374-0857WO1another wicking material. The secondary' material can have hydrophilic properties, where fluid extracted from the tissue of interest 1206 through the fluidic channels within the microneedle array 1202 reach the secondary material and are extracted onto the secondary material. The secondary' material can include assays agents, e.g., can be embedded with, coated with, incorporate assay agents, etc. The extracted fluid can be laterally flowed across a length of the secondary' material, e g., as in a lateral flow test, where the fluid is then reacted with the assay agents. In some instances, the secondary material can increase a time to equalization, thereby smoothing any local variation of the reactions between the extracted fluid and the assay agents.

[0122] In some implementations, the health monitoring device includes or is fluidically coupled to a vacuum source. FIG. 13 is a schematic of an example health monitoring device 1300. A vacuum source 1302 can be configured to perform vacuum extraction of the fluid collected by the microneedle array 1304. A vacuum source 1302 can be, for example, a peristaltic or vacuum pump. In such cases, a microneedle array 1304 where the microneedles of the microneedle array are formed using non-functionalized microspheres. For example, the microspheres can be formed, e g., using a process as described with reference to FIG. 4, and formed into the mold, e.g., using a process as described with reference to FIGS. 6A-6E, but without an intervening step of functionalizing at least a portion of the microspheres with an enzyme. Once the microneedle array is saturated, e.g., after extracting a threshold volume of fluid from the tissue of interest 1306, a vacuum source 1302 is interfaced with the microneedle array 1304 using a seal 1308, e.g., an O-ring, and a vacuum is drawn to extract the collected fluid.

[0123] In some implementations, the health monitoring device is removed and processed after a threshold volume of fluid is extracted from the tissue of interest. In such cases the microneedle array can include both functionalized and unfunctionalized microspheres. Once the microneedle array is saturated, e.g., after a selected amount of time, after at least a threshold volume of fluid is extracted, the health monitoring device is removed, and the microneedle array is crushed to release the microspheres and capillary pathways from one another. The resulting crushed microspheres are presented to a solution mimicking interstitial fluid or serum, thus the output of the assay on the spheres are released into the solution and testing for the assay output can be conducted on the solution. This solution can subsequently be presented to a lateral flow test, e.g., similar to a rapid covid test, pregnancy test, or the like, that has been functionalized with multiple assays. The solution can subsequently be presented to a test strip or other test apparatus that would detect the output of the assays on the microspheres.

[0124] In some implementations, the health monitoring device includes a microneedle array that is formed around a solid sharp structure, like a traditional hypodermic needle. For example, aAtorney Docket No. 43374-0857WO134 gauge or higher needle. In this case, the health monitoring device can be formed as discussed above, with the addition of the hard needle. The hard needle can be used to pierce the skin, removing the need for the microneedles having a sharp tip. Then the fluid can flow into the capillaries in the formed microsphere structures around the hard needle. In some instances, the solid sharp structure and one or more microneedles of the microneedle array are configured to penetrate the tissue of interest and extract fluid.

[0125] In some implementations, the health monitoring device includes a microneedle array formed using metallic micro or nanoparticles. For example, titanium dioxide, alumina, silver, nickel, or the like, in nanoparticle and / or microparticle form can be used to form the microneedles of the microneedle array.

[0126] In some implementations, the fluid extracted using the health monitoring device can be transferred to a separate device and / or location to perform analytics on the extracted fluid, e.g., metabolic testing. In such cases, colorimetric readouts can be performed with a separate device that could also look at fluorescence for different types of indicators.

[0127] The subject matter and the actions and operations described in this specification can be implemented in digital electronic circuitry, in tangibly-embodied computer software or firmware, in computer hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. The subject matter and the actions and operations described in this specification can be implemented as or in one or more computer programs, e.g., one or more modules of computer program instructions, encoded on a computer program carrier, for execution by, or to control the operation of, data processing apparatus. The carrier can be a tangible non-transitory computer storage medium. Alternatively, or in addition, the carrier can be an artificially-generated propagated signal, e.g., a machinegenerated electrical, optical, or electromagnetic signal, that is generated to encode information for transmission to suitable receiver apparatus for execution by a data processing apparatus. The computer storage medium can be or be part of a machine-readable storage device, a machine-readable storage substrate, a random or serial access memory device, or a combination of one or more of them. A computer storage medium is not a propagated signal.

[0128] The term "data processing apparatus7’ encompasses all kinds of apparatus, devices, and machines for processing data, including by way of example a programmable processor, a computer, or multiple processors or computers. Data processing apparatus can include specialpurpose logic circuitry, e.g., an FPGA (field programmable gate array), an ASIC (applicationspecific integrated circuit), or a GPU (graphics processing unit). The apparatus can also include, in addition to hardware, code that creates an execution environment for computer programs, e.g.,Atorney Docket No. 43374-0857WO1code that constitutes processor firmware, a protocol stack, a database management system, an operating system, or a combination of one or more of them.

[0129] A computer program can be written in any form of programming language, including compiled or interpreted languages, or declarative or procedural languages; and it can be deployed in any form, including as a stand-alone program, e.g., as an app, or as a software module, component, engine, subroutine, or other unit suitable for executing in a computing environment, which environment may include one or more computers interconnected by a data communication network in one or more locations.

[0130] A computer program may, but need not, correspond to a file in a file system. A computer program can be stored in a portion of a file that holds other programs or data, e.g., one or more scripts stored in a markup language document, in a single file dedicated to the program in question, or in multiple coordinated files, e.g., files that store one or more modules, sub-programs, or portions of code.

[0131] The processes and logic flows described in this specification can be performed by one or more computers executing one or more computer programs to perform operations by operating on input data and generating output. The processes and logic flows can also be performed by special-purpose logic circuitry, e.g., an FPGA, an ASIC, or a GPU, or by a combination of specialpurpose logic circuitry' and one or more programmed computers.

[0132] Computers suitable for the execution of a computer program can be based on general or special-purpose microprocessors or microcontrollers or a combination of them, or any other kind of central processing unit. Generally, a central processing unit will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of a computer are a central processing unit for executing instructions and one or more memory devices for storing instructions and data. The central processing unit and the memory can be supplemented by, or incorporated in, special-purpose logic circuitry.

[0133] Generally, a computer will also include, or be operatively coupled to, one or more mass storage devices, and be configured to receive data from or transfer data to the mass storage devices. However, a computer need not have such devices. Moreover, a computer can be embedded in another device, e.g., a mobile telephone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a Global Positioning System (GPS) receiver, or a portable storage device, e.g., a universal serial bus (USB) flash drive, to name just a few.

[0134] To provide for interaction with a user, the subject matter described in this specification can be implemented on one or more computers having, or configured to communicate with, a display device, e.g., a LCD (liquid crystal display) monitor, or a virtual -reality (VR) orAtorney Docket No. 43374-0857WO1augmented-reality (AR) display, for displaying information to the user, and an input device by which the user can provide input to the computer, e.g., a keyboard and a pointing device, e.g., a mouse, a trackball or touchpad. Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback and responses provided to the user can be any form of sensory feedback, e.g., visual, auditory', speech, or tactile feedback or responses; and input from the user can be received in any form, including acoustic, speech, tactile, or eye tracking input, including touch motion or gestures, or kinetic motion or gestures or orientation motion or gestures. In addition, a computer can interact with a user by sending documents to and receiving documents from a device that is used by the user; for example, by sending web pages to a web browser on a user’s device in response to requests received from the web browser, or by interacting with an app running on a user device, e.g., on a smartphone or electronic tablet. Also, a computer can interact with a user by sending text messages or other forms of message to a personal device, e.g., a smartphone that is running a messaging application, and receiving responsive messages from the user in return.

[0135] This specification uses the term "‘configured to” in connection with systems, apparatus, and computer program components. That a system of one or more computers is configured to perform particular operations or actions means that the system has installed on it software, firmware, hardware, or a combination of them that in operation cause the system to perform the operations or actions. That one or more computer programs is configured to perform particular operations or actions means that the one or more programs include instructions that, when executed by data processing apparatus, cause the apparatus to perform the operations or actions. That special-purpose logic circuitry' is configured to perform particular operations or actions means that the circuitry' has electronic logic that performs the operations or actions.

[0136] The subject matter described in this specification can be implemented in a computing system that includes a back-end component, e.g., as a data server, or that includes a middleware component, e.g., an application server, or that includes a front-end component, e.g., a client computer having a graphical user interface, a web browser, or an app through which a user can interact with an implementation of the subject matter described in this specification, or any combination of one or more such back-end, middleware, or front-end components. The components of the system can be interconnected by any form or medium of digital data communication, e.g., a communication network. Examples of communication networks include a local area network (LAN) and a wide area network (WAN), e.g., the Internet.

[0137] The computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. TheAtorney Docket No. 43374-0857WO1relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other. In some implementations, a server transmits data, e.g., an HTML page, to a user device, e.g., for purposes of displaying data to and receiving user input from a user interacting with the device, which acts as a client. Data generated at the user device, e.g., a result of the user interaction, can be received at the server from the device.

[0138] While this specification contains many specific implementation details, these should not be construed as limitations on the scope of what is being claimed, which is defined by the claims themselves, but rather as descriptions of features that may be specific to particular implementations of particular inventions. Certain features that are described in this specification in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple implementations separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially be claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claim may be directed to a subcombination or variation of a subcombination.

[0139] Similarly, while operations are depicted in the drawings and recited in the claims in a particular order, this by itself should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be advantageous. Moreover, the separation of various system modules and components in the implementations described above should not be understood as requiring such separation in all implementations, and it should be understood that the described program components and systems can generally be integrated together in a single software product or packaged into multiple software products.

[0140] Particular implementations of the subject matter have been described. Other implementations are within the scope of the following claims. For example, the actions recited in the claims can be performed in a different order and still achieve desirable results. As one example, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In some cases, multitasking and parallel processing may be advantageous.

Claims

Atorney Docket No. 43374-0857WO1CLAIMSWhat is claimed is:

1. A method comprising:applying a health monitoring device to a surface of a tissue of interest, the health monitoring device comprising a microneedle array including a plurality of microneedles, wherein the plurality of microneedles comprise functionalized microspheres;collecting, by one or more microneedles of the plurality of microneedles, fluid corresponding to the tissue of interest, wherein collecting the fluid comprises:facilitating, by one or more fluidic channels within the one or more microneedles, flow of the fluid from the tissue of interest to a sensing layer comprising a plurality of biomarker sensors; andproviding the fluid to the functionalized microspheres within the one or more microneedles to produce a reaction;capturing, by a sensor, readout data from the plurality of biomarker sensors in the sensing layer of the health monitoring device; andproviding, by the sensor, the readout data from the plurality of biomarker sensors sensing layer of the health monitoring device.

2. The method of claim 1, wherein a first subset of microneedles of the plurality of microneedles comprise a first type of functionalized microspheres and a second subset of microneedles of the plurality' of microneedles comprise a second type of functionalized microspheres, andwherein capturing readout data from the plurality of biomarker sensors comprises:capturing first readout data corresponding to a first reaction of the first type of functionalized microspheres with the fluid; andcapturing second readout data corresponding to a second reaction of the second type of functionalized microspheres with the fluid.

3. The method of claim 1 , wherein capturing readout data comprises:capturing, by an image sensor, optical data from the biomarker sensors.

4. The method of claim 3, wherein the biomarker sensors comprise colorimetric indicators, and wherein capturing readout data comprises:Atorney Docket No. 43374-0857WO1capturing, by an image sensor, colorimetric data from the colorimetric indicators.

5. The method of claim 4, wherein providing the fluid to the functionalized microspheres within the one or more microneedles to produce the reaction comprises:providing, to the colorimetric indicators, biomarkers within the fluid to produce a colorimetric response.

6. The method of claim 4, wherein providing the fluid to the functionalized microspheres within the one or more microneedles to produce the reaction comprises:providing, to the colorimetric indicators, enzymatic biomarkers within the fluid to produce a colorimetric response.

7. The method of claim 6, wherein providing enzymatic biomarkers comprises:obtaining, through an enzyme reaction or cascade of enzyme reactions of the functionalized microspheres with the fluid, a reaction product including enzymatic biomarkers; andproviding the enzymatic biomarkers.

8. The method of claim 1, wherein capturing readout data from the plurality' of biomarker sensors comprises capturing readout data with a mobile device, andwherein providing, by the sensor, the readout data from the plurality of biomarker sensors sensing layer of the health monitoring device comprises providing, by the mobile device, the readout data to a health monitoring system.

9. The method of claim 8, further comprising:receiving from the health monitoring system and using a trained predictive health model, a predictive health outcome corresponding to the readout data.

10. The method of claim 1, wherein collecting fluid from the tissue of interest comprises:collecting at least one of interstitial fluid, whole blood, and components of blood.

11. The method of claim 10, wherein collecting fluid from the tissue of interest comprises collecting two or more of interstitial fluid, whole blood, and component of blood by two or more microneedles of the microneedle array.Atorney Docket No. 43374-0857WO112. The method of claim 1, wherein collecting fluid from the tissue of interest comprises collecting fluid from a dermal layer of skin.

13. The method of claim 1 , wherein applying the health monitoring device comprises puncturing a surface of the tissue of interest by one or more microneedles of a microneedle array of the health monitoring device.

14. The method of claim 1, wherein applying the health monitoring device comprises applying compressive force to the health monitoring device onto a surface of the tissue of interest using one or more of a finger, hand, or a compressing member.

15. The method of claim 1 , wherein applying the health monitoring device comprises using an adhesive to reversibly affix the health monitoring device to a surface of the tissue of interest.

16. A health monitoring device comprising:a sensing layer comprising a plurality of biomarker sensors; anda microneedle array in fluidic contact with the sensing layer and comprising a plurality of microneedles corresponding to the plurality7of biomarker sensors, the plurality7of microneedles comprising:microspheres, wherein a portion of the microspheres are functionalized microspheres corresponding to one or more biomarkers; andfluidic channels within the plurality of microneedles and configured to facilitate flow of fluid through the microneedles to corresponding ones of the plurality of biomarker sensors when the health monitoring device is affixed to a surface of a tissue of interest.

17. The health monitoring device of claim 16, further comprising:an adhesive layer configured to reversibly affix the microneedle array to the surface of the tissue of interest.

18. The health monitoring device of claim 16, further comprising:a compressing member arranged with respect to the health monitoring device to apply a compressive force to cause at least a portion of the plurality of microneedles of the microneedle array to puncture the surface of the tissue of interest.

19. The health monitoring device of claim 16, wherein the portion of functionalized microspheresAtorney Docket No. 43374-0857WO1comprise enzyme-linked spheres.

20. The health monitoring device of claim 19, wherein the enzyme-linked spheres comprise one of cholesterol oxidase, cholesterol esterase, and glucose oxidase.

21. The health monitoring device of claim 16, wherein the biomarker sensors comprise colorimetric indicators.

22. The health monitoring device of claim 21, wherein the colorimetric indicators are configured to react with biomarkers present in the fluid when the health monitoring device is affixed to the surface of the tissue of interest.

23. The health monitoring device of claim 21, wherein the colorimetric indicators are configured to react with biomarkers or enzymatic byproducts present in the fluid when the health monitoring device is affixed to the surface of the tissue of interest.

24. The health monitoring device of claim 23, further comprising:generating enzymatic biomarkers by reacting the functionalized microspheres with the fluid when the health monitoring device is affixed to the surface of the tissue of interest.

25. The health monitoring device of claim 1 , wherein the plurality of microneedles comprise a length of betw een 0.5 mm to 3 mm, and w herein at least a portion of the length of the plurality of microneedles is configured to penetrate the tissue of interest when the health monitoring device is affixed to the surface of the tissue of interest.

26. The health monitoring device of claim 16, wherein the fluidic channels w ithin the plurality of microneedles are configured to facilitate flow of one or more of interstitial fluid, whole blood, or components of blood through the microneedles.

27. The health monitoring device of claim 26, w herein the fluidic channels w ithin the plurality of microneedles and configured to facilitate the flow7of a fluid volume of at least 10 microliters through the microneedles.

28. The health monitoring device of claim 27, w herein the fluidic channels w ithin the plurality ofAtorney Docket No. 43374-0857WO1microneedles and configured to facilitate the flow of the fluid volume in less than 15 minutes.

29. A method comprising:applying a health monitoring device to a surface of a tissue of interest, the health monitoring device comprising a microneedle array including a plurality of microneedles, the plurality of microneedles in fluidic contact with a reservoir configured to retain a therapeutic fluid; and injecting, by one or more microneedles of the plurality of microneedles and from the reservoir, the therapeutic fluid to the tissue of interest, wherein injecting the therapeutic fluid comprises:facilitating, by one or more fluidic channels within the one or more microneedles, flow of the therapeutic fluid from the reservoir to the tissue of interest.

30. A method comprising:applying a health monitoring device to a surface of a tissue of interest, the health monitoring device comprising a microneedle array including a first plurality of microneedles, wherein the first plurality of microneedles comprise functionalized microspheres;collecting, by one or more microneedles of the first plurality of microneedles, fluid corresponding to the tissue of interest, wherein collecting the fluid comprises:facilitating, by one or more fluidic channels within the one or more microneedles, flow of the fluid from the tissue of interest to a sensing layer comprising a plurality of biomarker sensors; andproviding the fluid to the functionalized microspheres within the one or more microneedles to produce a reaction;capturing, by a sensor, readout data from the plurality of biomarker sensors in the sensing layer of the health monitoring device;determining, from the readout data, a control signal to cause an injection of a therapeutic fluid from a reservoir in fluidic contact with a second plurality of microneedles into the tissue of interest; andproviding, to the control signal to cause the injection of the therapeutic fluid into the tissue of interest.

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