WO2018138158A1

WO2018138158A1 - Re-generable wearable filter for long-term use

Info

Publication number: WO2018138158A1
Application number: PCT/EP2018/051741
Authority: WO
Inventors: Hendrik Roelof Stapert; Mark Thomas Johnson; Lutz Christian GERHARDT; Pippinus Maarten Robertus Wortelboer
Original assignee: Koninklijke Philips N.V.
Priority date: 2017-01-30
Filing date: 2018-01-24
Publication date: 2018-08-02

Abstract

Wearable or insertable device (100, 300) and methods of monitoring a physiological condition of a patient (200) are described herein. Wearable or insertable devices (100, 300) may include a substrate (102, 302) affixable to a patient. The device may also have a re-generable filter with a sampling unit (103) that obtains one or more fluid samples from the patient and a re-generation unit (130) that applies fluid back- flow to the sampling unit (103). In some embodiments, the sampling unit (103) may include a plurality of microneedles (106). The device may also have a detection module (170) and/or an assay module (180) fluidly coupled with the sampling unit (103). The detection module (170) may determine the presence of at least one biomarker (122) contained in the fluid sample(s), and the assay module (180) may determine a measurement of at least one biomarker (122) contained in the fluid sample(s).

Description

RE-GENERABLE WEARABLE FILTER FOR LONG-TERM USE

FIELD OF THE INVENTION

The present disclosure is directed generally to the use of a wearable or insertable device for the measurement of biomarkers. More particularly, but not exclusively, the various apparatuses, methods, and systems disclosed herein relate to a re-generable filter that includes a re-generation unit.

BACKGROUND OF THE INVENTION

Ultrafiltration is a commonly used clinical technique where large molecules responsible for poor sensor performance are excluded from a sample matrix. Conventional ultrafiltration is typically accomplished through the use of commercial filter membranes. These filter membranes are often similar to those filters used for hemodialysis and hemofiltration and those that are used ex vivo. Commercially available filter membranes are designed for short-term hemodialysis, hemo-filtration, and/or ultra-filtration, and these commercially available filters have a relatively heterogeneous porous structure. For example a wide variety of membranes (e.g. polysulfone, polyacrylonitrile, polymethacrylates and poly(ethylene) glycol co(polymers), polyamide, cellulose, teflon membranes, and polymer fibres that are spun or weaved into an interconnecting mat-like structures) have been developed to facilitate a rapid rate of water flow and the passage of small and large molecules for short-term hemodialysis, hemo-filtration, and ultra-filtration. These membranes may perform well for short periods of time, but may develop an obstructive pathway due to adhesion of proteins, cells, platelets and thrombi formation, making these membranes undesirable for long-term monitoring of targeted biomarkers.

Generally, biomarkers are substances, structures, or processes or its products that can be measured in the body and influence, diagnose, or predict the incidence of outcome or disease. Biomarkers may be categorized into various different categories: 1) screening biomarkers - those that identify the risk of developing a disease; 2) diagnostic biomarkers - those that identify (or rule out) a disease; 3) prognostic biomarkers - those that predict disease progression; 4) pharmacodynamics biomarkers - those that examine pharmacological response; 5) biomarkers that monitor disease activity and clinical response to an intervention; and 6) severity biomarkers - which may act as a surrogate endpoint in clinical trials. Some non-limiting examples of biomarkers include cytokines and interleukins, electrolytes, ketones, triglycerides, insulin, glucose, cholesterol, Cortisol, vitamins, antioxidants, reactive oxygen species, markers for cancer and anti-cancer therapy, circulating tumor cells, markers of specific medications, micro-ribonucleic acid (miRNA), and the like. Long-term monitoring of biomarkers may be particularly relevant for diagnostic or prognostic biomarkers (e.g. long-term monitoring of insulin levels in diabetic patients).

Implantable porous catheters have been proposed for long-term monitoring and may overcome some of the problems associated with traditional filter membranes. For example, these proposals include the use of an implantable micropump, thus eliminating the need for a sample collection device (that may clog) entirely. However, the nature of being an implanted device renders these proposed devices as invasive. Wearable devices have increased in use and have become more accepted in both the clinical environment and for home monitoring. Readings from wearable or insertable devices may be monitored and then may be used to adjust one's lifestyle and/or medication. There exists a need in the art for a minimally invasive, on-skin, wearable apparatus and methods for long-term filtration of large molecules from the sample matrix and monitoring of target biomarkers.

SUMMARY OF THE INVENTION

The present disclosure is directed to inventive methods and apparatuses for a wearable or insertable device that allows for long-term (continuous or periodic) sampling and analysis of biomarkers using a re-generable filter. Generally, in one aspect a wearable or insertable device is disclosed, where the wearable or insertable device contains: a substrate that is affixable to tissue of a patient; a re-generable filter, where the re-generable filter includes a sampling unit coupled to the substrate, the sampling unit adapted to obtain one or more fluid samples from the tissue of the patient, and a re-generation unit adapted to apply fluid back- flow to the sampling unit; a module, fluidly coupled with the sampling unit, where the module is adapted to determine a presence or measure of at least one biomarker contained in the one or more fluid samples; and, a power unit operably coupled with the re-generation unit.

In some aspects the sampling unit further comprises a plurality of microneedles, in fluid communication with at least one reservoir, the reservoir adapted to provide a sample to the detection or assay modules. In other aspects, the plurality of microneedles each have an inner diameter of about 1.5μηι to about 2 μηι and an inner-lumen with surface chemical gradient coatings, wherein the surface chemical gradient is switched by a signal from the detection module or power unit. In still other aspects, the plurality of microneedles each have an inner-lumen coated in a biocompatible material known for anti- fouling.

In some aspects, the re-generation unit actively applies fluid back-flow to the sampling unit. In other aspects, the re-generation unit further contains a piezo-electric unit adapted to reversibly empty and clean the sampling unit by ultrasound pressure waves generated by the piezo-electrical unit. In still other aspects, the re-generation unit is further arranged to apply a switchable electric field across an insulating layer to an inner lumen of each microneedle of a plurality of microneedles. In still other aspects, the re-generation unit further contains light elements adapted to produce shock waves in fluid back- flow through the sampling unit. In still other aspects, the re- generation unit further contains a rotating element arranged to induce up-flow and back- flow of non-Newtonian body fluid through the sampling unit.

Generally, in another aspect, a method of monitoring a physiological condition of a patient is disclosed, where the method includes: placing a wearable or insertable device on a patient; collecting one or more fluid samples with the wearable or insertable device, where the one or more fluid samples are collected through a sampling unit; preventing clogging of the sampling unit, where the prevention includes introducing fluid back-flow through the sampling unit; determining a measure or presence of at least one biomarker based on the collected one or more fluid samples; and, inferring the physiological condition of the patient based on the determined measure or presence of the at least one biomarker. In some aspects of the method, the sampling unit further contains a plurality of microneedles and the preventing clogging of the sampling unit includes each microneedle having an inner-lumen coated in a biocompatible material known for anti-fouling.

In some aspects of the method, preventing clogging of the sampling unit includes applying a reversed fluid flow through under-pressure initiated by a plurality of ultrasound pressure waves generated by a piezo-electrical unit. In other aspects of the method, preventing clogging of the sampling unit includes applying an electric field across an insulating layer to an inner lumen of each of a plurality of microneedles. In still other aspects of the method, preventing clogging of the sampling unit includes applying an external force to the wearable or insertable device. In still other aspects of the method, preventing clogging of the sampling unit includes switching surface chemistry inside the plurality of

microneedles, each of the plurality of microneedles having an inner lumen with gradient coatings and an inner diameter of about 1.5μηι to about 2 μηι. In still other aspects of the method, preventing clogging of the sampling unit includes using shock waves to apply fluid back- flow through the sampling unit. In still other aspects of the method, preventing clogging of the sampling unit includes interrupting rotation of a spinning rod inside each of a plurality of microneedles. In still other aspects of the method, the method further includes exchanging data regarding the physiological condition of the patient with one or more remote computing devices.

Generally, in another aspect a method of monitoring a physiological condition of a patient is disclosed, the method including: placing a wearable or insertable device on the patient, where the wearable or insertable device contains a substrate that is affixable to tissue of a patient, a re-generable filter, where the re-generable filter contains a sampling unit coupled to the substrate that is adapted to obtain one or more fluid samples from the tissue of the patient and a re-generation unit adapted to apply fluid back- flow to the sampling unit, a module, fluidly coupled with the sampling unit, where the module is adapted to determine a presence or measure of at least one biomarker contained in the one or more fluid samples, and a power unit operably coupled with the logic or the re-generation unit; collecting one or more fluid samples with the wearable or insertable device, where the fluid sample is collected through a sampling unit; preventing clogging of the sampling unit, where the prevention includes introducing fluid back- flow; determining a measure or presence of at least one biomarker based on the collected one or more fluid samples; and, inferring the physiological condition of the patient based on the determined measure or presence of the at least one biomarker.

In some aspects of the method, preventing clogging of the sampling unit includes each microneedle having an inner-lumen coated in a biocompatible material known for anti-fouling.

Where used herein the term "affixed" or "affixable" may include the removable attachment of a device to tissue, for example with an adhesive material to the outer surface of skin. Additionally, or alternatively, the term "affixed" or "affixable" may also include the insertion and placement of a device into internal tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally, but not exclusively, refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the disclosure.

Fig. 1 illustrates a cross-section of human skin with an embodiment of a wearable device.

Fig. 2 depicts an example method for determining a physiological condition of a patient.

Fig. 3 depicts an embodiment of an apparatus configured with selected aspects of the present disclosure that is inserted into tissue of a patient.

Figs. 4A-C depict an example of how a microneedle may be cleared of obstructions and/or adhesions.

Fig. 5 depicts an example of a microneedle with electrowetting elements.

DETAILED DESCRIPTION OF EMBODIMENTS

A challenge in taking blood samples (either periodic or continuous) by a wearable or insertable device is separating various component cells from plasma proteins and other molecular biomarkers of interest. This may be challenging due to the adhesion of proteins, cells, platelets, etc. that may create an obstruction in the sampling pores or filter; thus, it is desirable to prevent this clogging. It may also be desirable to separate blood cells, platelets, and target biomarkers (e.g. plasma proteins, small molecules like cholesterol and glucose). By filtering out various molecules and preventing clogging of the sampling pore, accurate long-term (either periodic or continuous) readings of biomarkers in order to track health of an individual patient may be achieved through the use of wearable or insertable devices.

A wearable or insertable device described herein may include a re-generable filter, an assay module for performing a biochemical test, a detection module for detecting the presence of targeted biomolecules, a user interface, a power unit, and/or a logic. In various embodiments, the re-generable filter may also include a sampling unit for the collection of samples and a re-generation unit that prevents long term obstruction of the filter. The sampling unit may be configured to collect samples from the patient, and may further include pores of defined sizes, charged surfaces, microneedles of a particular size to filter out undesirable molecules, etc. While examples described herein refer to the use of

"microneedles", this is not intended to be limiting. For example, electrospun fibers may also be used in order to filter out undesired molecules, and the apparatuses and methods described herein may also be used in conjunction with electrospun fibers or other filtering mechanisms known in the art.

In some embodiments the sampling unit is comprised of an array of microneedles capable of reaching anatomical structures such as small blood vessels and/or capillaries or interstitial fluid. In some embodiments, the inner diameter of the microneedles may be large enough to accommodate the passage of blood plasma, but small enough to prevent the passage of red blood cells (RBCs), white blood cells (WBCs), and platelets into the microneedle. There are a variety of types of WBCs, for example neutrophils, basophils, eosinophils, lymphocytes, monocytes, macrophages, etc., and as such there is a wide range in the size of WBCs. Typically, the diameter of WBCs range from about 6.8 μηι to about 30 μηι. RBCs are typically disc shaped, and have diameters that range from about 6.2 μηι to about 8.2 μηι and thicknesses of about 2μηι to about 2.5 μηι. Platelets typically range from about 2μηι to about 3μηι. Therefore, a microneedle with an inner diameter of about 1.5μηι to about 2μηι may prevent the passage of these types of cells into the microneedle, and thus into the wearable or insertable device.

Referring to Fig. 1 (which is not drawn to scale), an embodiment of a wearable device 100 disclosed herein is illustrated. In the illustrated embodiment, the wearable device 100 is in the form of a thin patch or tattoo-like structure with a user interface 150, a power unit 160, and logic 140. In various embodiments, the wearable device 100 is affixed to a patient by means of a substrate 102 (which may be flexible or rigid depending on the application). For example, microneedles 106 disposed on one side of substrate 102 (e.g., a bottom side in Fig. 1) may be inserted (e.g., pierced) through tissue 107, which in some cases may be the surface of the patient's skin. Assuming that is the case, tissue 107 may include an epidermis 1 14 separated from a dermis 1 16 by an epidermal-dermal junction ("EDJ") 1 18. The tips 108 of microneedles 106 may reach one or more capillaries 120 (which may carry arterial or venous blood). Assuming the biomarkers 122 sought to be assayed are contained in the capillaries 120, a fluid sample may be collected via one or more microneedles 106, such that the RBCs, WBCs, and platelets are not collected due to the size constraints of the inner diameter of the microneedle. Although described primarily in terms of blood samples, that is not to be understood as limiting, in alternate embodiments the biomarkers sought to be analyzed may be in, and samples may be collected from other sample types including, but not limited to saliva, sweat, lymph fluid, urine, interstitial fluid, feces, exhaled breath

concentrated, and the like. In these and other embodiments, the size of the inner diameter of the microneedle may vary based on the intended use and targeted biomarker. For example, the inner diameter of the microneedle may be larger than 1.5μηι to about 2μηι where the targeted biomarker is larger than these constraints.

The wearable device 100 of Fig. 1 also includes a re-generable filter. The re- generable filter may include a sampling unit 103 and a re-generation unit 130. The sampling unit 103 may include of a collection of components, such as microneedles 106 described previously and, in some embodiments, at least one reservoir 104 for storing the collected sample (though not necessarily all together from the individual microneedles). In other embodiments, the device may be inserted beneath the tissue surface, as is described below with respect to Fig. 3.

Over time, the components of the sampling unit 103, for example microneedles 106, may become obstructed due to the aggregation and/or adhesion of proteins, cells, platelets, etc. With conventional approaches the pores of sampling units 103 (e.g. the inner lumens of the microneedles) may clog within hours of continuous or periodic sampling. Accordingly, in various embodiments, the inner-lumen of the microneedles 106 may be coated with a biocompatible coating known to enhance anti-fouling, for example albumin or poly(ethylene)glycol based coatings. These biocompatible coatings may slow the obstruction of the openings of the microneedles by minimizing adhesion of proteins, cells, etc. to the inner lumen of the microneedle. However, in some instances these coatings may be not sufficient to prevent obstructions during long-term use. Other methods of avoiding obstructing the microneedles 106 of the sampling unit 103 include, but are not limited to, rinsing or purging the microneedles with an anticoagulant, for example heparin, a coating on the inner lumen of microneedle that entraps air in order to prevent the clogging of the tip of the microneedle, and/or the use of actuation or vibration to prevent and break up obstructions. This rinsing or purging of the microneedles may be driven by various techniques, including, but not limited to, the use of an electric field (e.g. electrowetting, the use of surface gradients, etc.).

Obstructions may develop in the sampling unit 103 despite use of conventional methods of prevention. This may be especially true in long-term monitoring, where there may be, as time progresses, a time dependent deterioration of the ability of the sampling unit 103 to effectively collect a sample. Thus, the ability of the wearable device 100 to be used for long-term monitoring depends, in part, on the ability to prevent and/or clear these obstructions. The re-generation unit 130 may prevent long-term obstruction of the sampling unit 103 by introducing the back- flow of fluid through the sampling unit 103 which may dislodge and force out any proteins, cells, etc. that have adhered to the inner lumen(s) of the microneedle(s). In some embodiments, this fluid may be fluid that was able to pass through the sampling unit 103 (e.g., the microneedles 106) and may have already been analyzed by the wearable device 100. Alternatively, or additionally, the fluid may be recently collected and sourced from a small reservoir (e.g., 104). Such a reservoir, where present, may also contain additional elements (e.g. other chemicals for aiding in combatting obstructions, such as anti-coagulants). Additionally, the back-flow of fluid may create conditions that are unfavorable for the formation of these adhesions and obstructions in the sampling unit 103. Various mechanisms for generating and applying back-flow and/or under-pressure by the regeneration unit 130 are described herein.

In some embodiments, the re-generation unit 130 may include a piezo-electric unit that may use electricity to generate pressure to actively re-generate the filter (e.g., the sampling unit 103, which as noted above includes the microneedles 106), including inner- lumen^) of the microneedle(s) 106, by applying reverse fluid flow. In some embodiments the piezo-electric unit may include one or more vibrating piezo crystals and/or one or more capacitive micromachined ultrasonic transducers (CMUT) affixed to or positioned within a close proximity to the microneedles. The piezo-electric unit may produce needle wall vibrations and vacuum bubbles within the fluid contained within the inner-lumen of the microneedle, including the target analyte(s). These bubbles may grow, oscillate, and collapse/implode with enough intensity to clear the inner-lumen from adsorbed or adhering biomolecules. In other words, the ultrasound waves produced by the piezo-electric unit may create short, intense fluid flows through cavitation techniques, which act to dislodge and force out any proteins, cells, etc. that may have adhered to the inner lumen of the

microneedle.

In some embodiments, a continuous flow of fluid into a patient's tissue or collection reservoir may be achieved in additional to and/or simultaneously with regenerating the filter, for example by using a piezo-electric unit. In some embodiments, this continuous fluid flow into a patient's tissue or collection reservoir may be facilitated by use of geometrically tapered microneedles and/or geometrically tapered inner-lumens of microneedles, using coatings and/or other techniques to generate switching between hydrophobic and hydrophilic stated within the inner-lumen of the microneedle, and/or use of electric charges within or near the microneedles, including, but not limited to the use of electrowetting as described herein. In some embodiments the fluid flow may be directed into the device, for example into a reservoir. In other embodiments, the fluid flow may be directed into a patient's tissue. In still other embodiments, the directionality of the fluid flow may be determined by the placement of the piezo-electric unit relative to the microneedle. As an illustrative, non-limiting example, where a piezo-electric crystal(s) is placed at the base of the microneedle (e.g. by the substrate; as illustrated in Figs. 4A-4C) the fluid flow may be directed into a patient's tissue. Alternatively, where a piezo-electric crystal(s) is placed at the microneedle tip (not shown in Fig 4 A-4C) the fluid flow may be directed into the device.

Further embodiments may include an accelerometer, which may provide a device information regarding a gravity direction, which may allow a device to identify the most suitable actuation segments for use in filter re-generation.

Figs. 4A-4C illustrate a technique for preventing clogging of the sampling unit, as well as an apparatus that embodies the use of a cavitation technique with a piezoelectric unit for such prevention. Fig. 4A illustrates a stage 420 of a technique of cleaning a microneedle and clearing its inner lumen 409 of obstruction. In stage 420 a microneedle 406, or a plurality thereof, has adhesions/obstructions to be cleaned. The apparatus of Fig. 4A contains at least one microneedle 406 with various blood cells and/or bodily liquids 402 and the like adhered to a surface of an inner lumen 409 of the microneedle 406, a piezo-electric unit 408, and a power input 412. In some embodiments, including that depicted in Figs. 4A- C, the piezo-electric unit 408 may contain its own power source 412 (e.g. a battery).

However in other embodiments, the piezo-electric unit 408 may draw power from the power source 160 of the wearable device 100. In Fig. 4B, which demonstrates a stage 440 of the aforementioned technique, microneedle 406 is actively being cleared of obstruction, e.g., by way of producing bubbles 422 through acoustic cavitation generated by the piezo-electric unit 408 in the form of bubbles 422. Consequently, these bubbles 422 act to dislodge and force out any proteins, cells, etc. (e.g. adhesions 402 of varying compositions) that may have adhered to the inner lumen of the microneedle 404.

Fig. 4C illustrates a final stage 460 of cleaning a microneedle 406 in which it is cleared of obstruction. The collapse/implosion of bubbles 422 produced at stage 440 generates a fluid back-flow which clears the microneedle 406 of any dislodged debris.

Although only a single microneedle 406 is illustrated in Fig. 4A-4C, this is not to be understood as limiting as the method and apparatuses illustrated therein may be used with a single microneedle or a plurality of microneedles.

In still other embodiments, the re-generation unit 130 may function by adjusting the capillary forces within the microneedles. For example, adjusting the capillary forces within the microneedles may be achieved through the process of electrowetting, during which an electric field is applied across a layer insulating the inner surface of the microneedle, causing the surface tension to be altered from hydrophilic, where the fluid is drawn to the interior of the microneedle (for example, for use during sample collections) to hydrophobic, where the fluid is repelled from the interior of the needle (for example, for use in releasing the collected sample from the microneedle) However, in some embodiments it may be that the repelling from the inner surface is not immediate. Furthermore, the electric field, which induces the change in the surface tension from hydrophilic to hydrophobic, can be repeatedly applied and removed. This repeated application, and corresponding switching of the surface tension back and forth between hydrophilic and hydrophobic, may flush fluid through the microneedle and clear any adhesions or obstructions present. In some embodiments, the switching of the surface tension back and forth between hydrophilic and hydrophobic, in combination with the fluid flow generated thereby, may be also used for breaking apart obstructing substances and/or adhesions from the interior surfaces of a microneedle.

The surface chemistry of the inner-lumen of the microneedles may also be altered using other techniques. For example, the inner-lumen of the microneedles may be coated such that the coating is a hydrophobic to hydrophilic gradient (or vice versa) from the tip of the microneedle to the opposing end of the microneedle. Such a gradient may induce back-flow through the inner-lumen of the microneedle and may dislodge and force out any proteins, cells, etc. that have adhered to surfaces of the inner lumen of the microneedle. These gradient coatings may be present in the inner-lumen of the microneedle at all times, or they may be selectively applied as desired. For example, the surface chemistry of the inner lumen of the microneedles may be altered through the use of light, such that an interruption in the supply of the target analyte (e.g. biomarker) to the assay and/or detection unit signals a light to cause the surface chemistry to be adjusted to form a gradient.

Although described herein in terms of using electro wetting or gradients, the use of surface chemistry to induce back- flow and thus prevent the formation of obstructions in the microneedles is not so limited. Any method of adjusting capillary forces known in the art capable of alternating surface tension and adhesive forces in order to apply back- flow and induce the dislodge any proteins, cells, etc. that have adhered to the inner lumen of the microneedle may be used.

In other embodiments, the re-generation unit 130 may use electrowetting to activate electrode elements and dynamically change the droplets of fluid inside the inner- lumen of the microneedle, as illustrated in Fig. 5. This electrowetting may occur at liquid- liquid or liquid-air interfaces inherent in the inner-lumen of the microneedle. As illustrated in Fig. 5, one or more electrowetting electrodes 501 1 - 50 In may be circumferentially integrated into the microneedle 506 itself, including, but not limited to, integration into the inner-lumen 509 of the microneedle 506. The electrodes, as illustrated in Fig. 5, may be connected to one or more switches (5021 - 502n) powered by a battery 503. The sequential activation and multiplexing of the electrode elements 501 1 - 50 In (for example, by the one or more switches) may result in the fluid contained in the inner-lumen 509 of the microneedle 506, including, but not limited to, any target analyte(s) 522 (e.g. biomarker(s)) present, to dynamically change, thus changing the angle of contact between the inner-lumen 509 of the microneedle 506 and the bioanalyte 522. In some embodiments, this may result in the angle of the fluid (bioanalyte/biomarker 522), including any target analyte(s) present in the inner- lumen 509, to be reduced. This sequential activation and multiplexing may induce a gradient and/or a pumping action, which may lead to fluid flow. In some embodiments, fluid may flow from the inner-lumen 509 of the microneedle 506 into tissue of the patient. In other embodiments, fluid may flow from the inner-lumen 509 of the microneedle 506 into a container within the device, such as a reservoir or a waste container (not illustrated in Fig. 5).

In still other embodiments, the re-generation unit 130 utilizes external force to create fluid flow out of the microneedles. External pressure may be applied to a chamber inside the wearable or insertable device 100 which generates fluid flow through and then out of the inner-lumen of the microneedle (i.e. back-flow). This back-flow may dislodge and force out any proteins, cells, etc. that have adhered to the inner lumen of the microneedle, thus removing any obstructions and allowing sampling and monitoring to continue. In some embodiments, the fluid creating the fluid back- flow may be fluid that was able to pass through the filter and may have been previously analyzed by the wearable or insertable device. Alternatively, or additionally, the fluid may be recently collected and sourced from a small reservoir (e.g., 104). Such a reservoir, where present may also contain additional elements (e.g. other chemicals for aiding in combatting obstructions). In some embodiments the external pressure may be from a wearer pressing with, for example, a finger on a designated area of the device. In other embodiments, the external pressure may be from an alternate mechanical source. When the external pressure is removed, both the chamber and the wearable or insertable device may be returned to their original state due to the elasticity of the device and/or chamber. Once retuned to the original state, sample collection and monitoring may continue as usual.

In other embodiments, shock waves may be used to generate and apply back- flow and/or under-pressure. Generally, shock waves may propagate through any obstruction present in the sampling unit (e.g., inner-lumens of the microneedles) and this may cause a change in pressure, temperature, density, etc. in the obstruction(s). These changes may cause any obstructions present, such as adhesions of proteins, cells, etc. to be dislodged and forced out of the inner-lumen of the microneedle. Any method of producing shock waves known in the art may be used; however, it may be that light or lased-induced liquid jet production is used. Generally, the process of laser-induced liquid jet production involves inserting an optical fiber into a capillary tube filled with water. A laser beam is then transmitted via the optical fiber and produces water vapor bubbles toward the capillary exit. The water is then expelled from the capillary exit by the expanding bubbles. The collapse and rebound of microbubbles and water flow generated by the emanation of water creates shock waves. With respect to a wearable or insertable device, an optical fiber may be inserted into the inner-lumen of the microneedles as necessary to prevent or clear any obstructions.

Alternatively, the optical fiber may remain in place, e.g., within the inner-lumen of the microneedle, and may be activated as necessary. The transmission of a laser beam via the optical fiber in the fluid-filled inner-lumen of the microneedle may create bubbles, which may then dislodge any obstructions or adhesions to the inner-lumen. The bubbles may also cause the fluid and/or any dislodged obstructions or adhesions to be expelled from the inner- lumen of the microneedle.

In other embodiments, the Weissenberg effect may be used to induce back- flow of fluid through the microneedle. The Weissenberg effect is a physical phenomenon where a spinning rod, or other rotating element, is inserted into a non-Newtonian solution of liquid. The liquid, rather than being cast outward by the spinning rod, is drawn towards the rod and rises up around it. In some embodiments, the wearable or insertable device may further contain a spinning rod inside of the microneedle such that the spinning rod and Weissenberg effect aid in the collection of a sample and pulling of fluid through the inner- lumen of the microneedle. The spinning of the rod within the microneedle may be powered by the power unit of the wearable or insertable device. When the rotation of the rod is interrupted, the fluid that was rising up around the rod will flow back (towards, and ultimately through, the tip of the microneedle) without further intervention due to inertia. This back- flow of fluid upon the cessation of the rod spinning dislodges and forces out any obstructions or adhesions of proteins, cells, etc. that may be present attached to or within the inner-lumen of the microneedle.

Again referring to Fig. 1, the illustrated embodiment of the wearable or insertable device 100 further includes a detection module 170 which detects the presence of targeted biomolecules. For example, the detection module 170 may be used to detect the presence of glucose or cholesterol in a sample. Where the desired information is

presence/absence data for a target biomolecule this may be the conclusion of the analysis. However, where quantitative measurement may be desired, an assay module 180 may perform a biochemical assay on the sample. The assay module 180 may perform

biochemical assays using chemical, electrical, optical, or other energy-based approaches, and/or any other conventional assay technique. In some embodiments, the detection module 170 and assay module 180 may be incorporated into the same physical space and/or into a single module with both functions. In some embodiments, the assay module 180 may use chemical or enzymatic techniques and optical measuring device. For example, a chemical reaction may result in a gradient of color change to indicate a measurement. This color change may then be read and interpreted by an optical reader. In other embodiments, the assay module 180 may be configured to use techniques such as, or similar to, the following: enzyme-linked immunosorbent assay ("ELISA"), which uses antibodies and color change or fluorescence to identify a biomarker; western blotting (or "protein immunoblot"); eastern blotting; Southern blotting; northern blotting; southwestern blotting, electrophoresis, mass spectroscopy, gene or protein arrays, flow cytometry, etc. In other embodiments

measurement may include transcriptome assay using e.g. micro-array technique for gene expression studies or quantitative polymerase chain reaction (PCR). In still other

embodiments measurement may include epigenetic markers, such as DNA methylation, histone acetylation and miRNA.

The wearable or insertable device 100 may further contain a user interface 150, as illustrated in Fig. 1. The user interface 150 may include data input and/or output components and may also be both attached and integrated directly with the device or may be separated therefrom for ease of use and access. For example, a user may input data through the user interface 150 via a touchscreen incorporated on the wearable or insertable device 100, audio input systems such as voice recognition systems, microphones, etc. In other embodiments, a user may interface with the wearable device 100 utilizing a remote computing device (e.g. computer, smart phone, smart watch, etc.) wirelessly coupled with the wearable or insertable device 100 via the logic 140. For example, in some embodiments, a user may input a selection of the type of biochemical analysis to perform. Data may be output to a user via a visual display, such as a liquid crystal display (LCD) on the wearable device and/or through non- visual outputs such as audio and tactile output. In other embodiments, a user may receive notifications or output information from the wearable device 100 through a secondary device (e.g. computer, smart phone, etc.) wirelessly coupled with the wearable or insertable device 100 via the logic 140. For example, in some embodiments, the user interface 150 may output information to the user indicating the results of a biochemical analysis and/or may indicate that it is desirable for the re-generation unit to activate back- flow to cleanse the sampling unit 103.

The power unit 160 may take various forms, such as one or more batteries, which may or may not be rechargeable, e.g., using one or more integrated solar cells (not depicted) or by periodically being connected to a power source. Furthermore, the power unit 160 may be various power harvesting techniques wherein electrical power is generated from the heat of the wearer of the device, electrochemical harvesting techniques from ions within the human body and/or biological fuel cells, etc. Alternatively, power harvesting may occur as a result of generation of electrical potential from kinetic energy. In still further embodiments, power may be generated from solar or other devices to power the logic and other modules while also charging batteries for later use. Even further embodiments may allow for power to be generated through inductive coupling with an external inductive field source. Of course, in some embodiments, one or more of the power units may be omitted in favor of external power and/or computing resources, such as a computing device that may be operably coupled, for instance, with the logic 140.

The logic 140 may take various forms, such one or more microprocessors that execute instructions stored in memory (not depicted) which may be functionally connected with the logic or other supporting circuitry. Other forms of logic may include a field- programmable gate array ("FPGA"), an application-specific integrated circuit ("ASIC"), or other types of controllers and/or signal processors. In various embodiments, the logic 140 may control various aspects of operation of apparatus 100 described herein. In some embodiments, the logic 140 may include one or more wired or wireless communication interfaces (not depicted) that may be used to exchange data with one or more remote computing devices using various technologies, such as Bluetooth, Wi-Fi, USB, etc. In various embodiments, the logic 140 may be operably coupled with one or more re-generation units 130, e.g., via one or more busses (not depicted), and may be configured to operate one or more re-generation units 130 to induce back- flow of fluid through the sampling unit.

Referring now to Fig. 2, an example method 200 for determining a physiological condition of a patient that may be practiced, for instance, using the apparatus (100) described herein is depicted. While operations of method 200 are depicted in a particular order, this is not meant to be limiting. In various embodiments, one or more operations may be added, omitted, and/or reordered.

At block 202, a wearable or insertable device configured with selected aspects of the present disclosure may be placed onto, or inserted into, tissue of a patient, such as the patient's skin. In some embodiments, this may include inserting at least one microneedle into the tissue. The wearable device may be adhered to the patient's tissue in various ways. In some embodiments in which multiple microneedles are employed, insertion of the microneedles into the tissue may itself affix the wearable device to the patient's tissue. In other embodiments, the microneedles may remain in a recessed position and are deployed or launched at a later time point after insertion into the tissue. Additionally or alternatively, various biocompatible adhesives may be applied to the wearable or insertable device to affix the wearable device to the patient's tissue. In some embodiments, an adhesive bandage or other suitable component may be used to "tape" the wearable or insertable device to the patient's tissue. In other embodiments, the device may be inserted beneath the tissue surface, as is described below with respect to Fig 3. In some embodiments, the adhesive may serve multiple purposes. For example, in some embodiments the adhesive may also be used to seal blood vessel following surgical procedures and the like (e.g. fibring glue, cyanoacrylate, electrocuring glue, etc.). In other embodiments, the adhesive may be a gel patch or a silicone rubber patch for use in coupling acoustic (ultrasounds) waves generated by a piezo-electric unit to patient tissue.

At block 204, the wearable or insertable device collects one or more fluid samples through a sampling unit. In some embodiments the sampling unit contains microneedles with an inner diameter of about 1.5μηι to about 2μηι, so as to filter out RBCs, WBCs, and platelets from fluid passing through the microneedle(s), and thus into the wearable or insertable device. In some embodiments the collection of fluid samples may be continuous for a defined time period or until a fixed activity is complete. In other

embodiments, the samples are collected at various time points. In some embodiments, the period of time in which samples are collected may be defined by the user, third-party, necessity of the biomarker being monitored, etc. In other embodiments, the period of time in which samples are collected may remain indefinite.

At block 206, the wearable or insertable device uses fluid back-flow through the sampling unit to prevent the clogging of the sampling unit and filter. In other words, the re-generation unit prevents long-term obstruction of the sampling unit (e.g. microneedles) by introducing fluid back flow into the sampling unit which may dislodge and force out any proteins, cells, etc. that have adhered to the inner lumen of the microneedle. As described above, there are multiple embodiments for generating fluid back-flow by the regeneration unit, these include, but are not limited to: the regeneration unit further comprising a piezoelectric unit; adjusting the capillary force/surface chemistry through electrowetting and/or light; applying external pressure; using shock waves; using the conditions created during after the Weissenberg effect, and combinations thereof. Furthermore, in some embodiments, the back- flow material may be recycled or may be reabsorbed by surrounding tissue following clearing of sampling unit and filter.

At block 208, the wearable or insertable device detects and/or measures at least one biomarker. In some embodiments, the wearable device contains a detection module that detects the presence of targeted biomolecules, in order to determine the presence or absence of the targeted biomolecule. In other embodiments, where a quantitative

measurement may be desirable, an assay module may perform a biochemical assay on the sample. The assay module may perform biochemical assays using chemical, electrical, optical, or other energy-based approaches, and/or any other conventional assay technique. It is to be understood that the use of a detection module and an assay module are not mutually exclusive, and in some embodiments both may be present in the wearable or insertable device.

At block 210, the wearable or insertable device, based on the results of the measurements from block 208, infers information about the physiological condition of the patient. For example, memory (not depicted) of the wearable or insertable device may be preprogrammed with a lookup table or other similar data that enables the logic to determine information regarding a physiological condition based on the measurement of the one or more biomarkers in the sample collected by the sampling unit.

In some embodiments, a wearable or insertable device configured with selected aspects of the present disclosure may be communicatively coupled with various remote computing devices in order to exchange data. For example, the coupling may include one or more wired or wireless communication interfaces that may be used to exchange data with one or more remote computing devices using various technologies, such as Bluetooth, Wi-Fi, ultra- wide band (UWB), etc. In some embodiments, this coupling allows for display (video, audio, or any other known means) of data.

While embodiments described herein are directed primarily to wearable apparatuses that patients affix to outer surfaces of their skin, this is not meant to be limiting. Various techniques and mechanisms described herein are equally applicable to devices that may be inserted beneath a patient's skin. Fig. 3 depicts an insertable apparatus 300 that has been inserted subcutaneously in the dermis 316 of a patient's tissue 307. Many of the components depicted in Fig. 1 are also depicted in Fig. 3, such as the sampling unit 103, regeneration unit 130, detection module 170, assay module 180, power unit 160, and logic 140, and therefore are numbered similarly. Unlike other embodiments described above, insertable apparatus 300 includes microneedles 306 protruding from both first side 304 and second side 305. And while not depicted in Fig. 3, in some embodiments, microneedles 306 may protrude from other surfaces of base 302, such as the sides (i.e., transversely to the outer surface of the patient's skin). Moreover, while base 302 and other bases depicted herein have been generally cuboid, this is not meant to be limiting. In various embodiments, base 302 and other bases described herein may have other shapes, such as cylindrical, spherical, pyramidal, or any other two or three dimensional shape or volume. While the insertable device 300 of Fig. 3 is shown inserted into the tissue 307 intradermally, this is not meant to be limiting. In various embodiments, insertable device 300 may be inserted into other depths, depending on what sensing and/or dilating/ablating purposes it is meant to achieve. For example, in some embodiments, insertable apparatus 300 may be inserted into tissue 307 in deeper layers of tissue, e.g., into the hypodermis (a.k.a. the subcutaneous fat layer, adipose tissue) of tissue 307. It should be understood that in various embodiments, one or more features described with respect to each embodiment depicted in each figure may be incorporated, alone or in combination with other disclosed features, into any other embodiment described herein, as well into other embodiments not explicitly described herein

In another aspect of the invention a method of monitoring a physiological condition of the patient may comprise: placing 202 a wearable or insertable device on the patient, wherein the wearable or insertable device comprises; a substrate that is affixable to tissue of a patient, a re-generable filter, wherein the re-generable filter comprises a sampling unit coupled to the substrate, wherein the sampling unit obtains one or more fluid samples from the tissue of the patient, and a re-generation unit adapted to apply fluid back- flow to the sampling unit; and a module 170, 180, fluidly coupled with the sampling unit 103, wherein said module is adapted to determine a presence or measure of at least one biomarker 122, wherein at least one biomarker is contained in the one or more fluid samples; collecting 204 one or more fluid samples with the wearable or insertable device, wherein the fluid sample is collected through the sampling unit; preventing 206 clogging of the sampling unit, wherein the prevention includes introducing fluid back- flow; determining 208 a measure or presence of at least one biomarker based on collected one or more fluid samples; and inferring 210 the physiological condition of the patient based on the determined measure or presence of the at least one biomarker. In this method one or more microneedles of a plurality of microneedles forming part of the sampling unit has an inner-lumen coated in a biocompatible material known for anti-fouling.The wearable or insertable device and methods described herein may be utilized for long term continuous or periodic monitoring, by providing a regeneration unit that prevents long term clogging or obstruction of the sampling unit by introducing fluid back-flow. The method of inducing back- flow may vary and the biomarkers monitored may vary depending on the diagnostic, therapeutic, and management goals of the individual patient.

While several inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, (bio)materials, enzymes, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

Although described separately, it is to be understood that any of the embodiments described herein may be used alone or in combination with any other embodiment(s) described herein.

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms. The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases.

Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e. "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 21 1 1.03. It should be understood that certain expressions and reference signs used in the claims pursuant to Rule 6.2(b) of the Patent Cooperation Treaty ("PCT") do not limit the scope.

Claims

CLAIMS:

1. A wearable or insertable device (100, 300) comprising:

a substrate (102, 302) that is affixable to tissue (107, 307) of a patient;

a re-generable filter, wherein the re-generable filter comprises: a sampling unit (103) fluidly coupled to the substrate (102, 302), wherein the sampling unit is adapted to obtain one or more fluid samples from the tissue of the patient, and

a re-generation unit (130) adapted to apply fluid back- flow to the sampling unit (103); and a module (170, 180), fluidly coupled with the sampling unit (103), wherein said module is adapted to determine a presence or measure of at least one biomarker (122), wherein at least one biomarker is contained in the one or more fluid samples.

2. The wearable or insertable device (100, 300) of claim 1, wherein the sampling unit further comprises a plurality of microneedles (106, 306, 406), in fluid communication with at least one reservoir (104, 304), the reservoir adapted to provide a sample to the module (170, 180).

3. The wearable or insertable device (100, 300) of claim 2, wherein one or more microneedles of the plurality of microneedles includes an inner-lumen (409) with a surface chemical gradient coating, wherein the surface chemical gradient is arranged to be switched by a signal from the module (170, 180).

4. The wearable or insertable device (100, 300) of claim 2, wherein one or more of the plurality of microneedles (106, 306, 406) has an inner-lumen (409) coated in a biocompatible material known for anti-fouling.

5. The wearable or insertable device (100, 300) of claim 1, wherein the regeneration unit (130) further comprises a piezo-electric unit (404) adapted to reversibly empty and clean the sampling unit by ultrasound pressure waves generated by the piezo- electrical unit.

6. The wearable or insertable device (100, 300) of claim 1, wherein the regeneration unit (103) is further arranged to apply a switchable electric field across an insulating layer to an inner lumen (409) of one or more microneedles (106, 306, 406) of a plurality of microneedles.

7. The wearable or insertable device (100, 300) of claim 2, wherein each microneedle of the plurality of microneedles (106, 306, 406) has an inner diameter of about 1.5 μηι to about 2 μηι.

8. The wearable or insertable device (100, 300) of claim 1, wherein the regeneration unit (130) further comprises light elements adapted to produce shock waves in fluid back-flow through the sampling unit (103).

9. The wearable or insertable device (100, 300) of claim 1, wherein the re- generation unit (130) further comprises a rotating element arranged to induce up-flow and back-flow of non-Newtonian body fluid through the sampling unit (103).

10. A method of monitoring a physiological condition of a patient (200), the method comprising:

placing (202) a wearable or insertable device on the patient;

collecting (204) one or more fluid samples with the wearable or insertable device, wherein the one or more fluid samples are collected through a sampling unit;

preventing (206) clogging of the sampling unit, wherein the preventing includes introducing fluid back- flow through the sampling unit;

determining (208) a measure or presence of at least one biomarker based on collected one or more fluid samples; and

inferring (210) the physiological condition of the patient based on the determined measure or presence of the at least one biomarker.

1 1. The method of claim 10, wherein the sampling unit further comprises a plurality of microneedles and one or more microneedles has an inner-lumen coated in a biocompatible material known for anti-fouling.

12. The method of claim 10, wherein preventing (206) clogging of the sampling unit includes applying a reversed fluid flow through under-pressure initiated by a plurality of ultrasound pressure waves generated by a piezo-electrical device.

13. The method of claim 10, wherein preventing (206) clogging of the sampling unit includes applying an electric field across an insulating layer to an inner lumen of one or more of a plurality of microneedles.

14. The method of claim 10, wherein preventing (206) clogging of the sampling unit includes one of: applying an external force to the wearable or insertable device;

switching surface chemistry inside the plurality of microneedles; using shock waves to apply fluid back- flow through the sampling unit; and interrupting rotation of a spinning rod inside each of a plurality of microneedles.

15. The method of claim 10, wherein the method further comprises exchanging data regarding the physiological condition of the patient with one or more remote computing devices.