Patent Application
20200330016
The present disclosure is directed generally to the use of a wearable or insertable device for the measurement of biomarkers and/or administration of medicine. More particularly, but not exclusively, the various apparatuses, methods, and systems disclosed herein relate to microneedles with mechanically-responsive material that is reactive to stimuli to purge fluid from, or draw fluid into, microneedles.
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 products of processes 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, anti-oxidants, 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 micro-pump, 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.
Insertables and/or patches (e.g., e-tattoos) used for the detection and analysis of biomarkers need to be designed in such a way that the body fluids to be analyzed are transported appropriately throughout the analysis process. This includes, for instance, the need of drawing the body fluid (e.g. via a microneedle), washing detection surfaces/chambers, and emptying an analysis circuit (e.g. emptying microneedle as preparation for the next analysis phase). Fluid transport inside such devices is typically realized by using micro-pumps inside the devices or by taking advantage of capillary forces. However, the use of micro-pumps inside devices typically brings the disadvantage that, in general, all microneedles are activated at the same time. And although these pumps are not large, there is limited space in wearable (and especially insertable) devices which makes use of a multiplicity of such pumps prohibitive.
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. Generally, in one aspect a wearable or insertable device is disclosed, where the wearable or insertable device contains: a substrate (or base) 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 1.5 μm to about 2 μm 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 1.5 μm to about 2 μm. 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.
In another aspect, a medical device may include: a base defining at least one reservoir; at least one microneedle extending from the base, wherein the at least one microneedle is insertable into tissue and defines an inner lumen that fluidly couples the at least one reservoir with the tissue; and a mechanically responsive material disposed on an inner surface of the at least one microneedle, wherein the inner surface of the at least one microneedle defines the inner lumen of the at least one microneedle, and the mechanically responsive material is reactive to a stimulus to undergo one or more mechanical responses.
In various embodiments, the medical device may further include one or more stimulation components that may be selectively activated to provide the stimulus to the mechanically responsive material. In various embodiments, at least one mechanical response of the one or more mechanical responses of the mechanically responsive material purges fluid from the inner lumen of the at least one microneedle. In various embodiments, the medical device may further include a valve positioned between the mechanically responsive material and the at least one reservoir. In various embodiments, the valve may be closable such that the at least one mechanical response of the mechanically responsive material purges fluid from the inner lumen into the tissue. In various embodiments, the valve may be openable such that the at least one mechanical response of the mechanically responsive material purges fluid from the inner lumen into the at least one reservoir.
In various embodiments, at least one of the one or more mechanical responses of the mechanically responsive material draws fluid into the inner lumen of the at least one microneedle. In various embodiments, a first mechanical response of the one or more mechanical responses may include expansion of the mechanically-responsive material and a second mechanical response of the one or more mechanical responses may include contraction of the mechanically-responsive material.
In various embodiments, the mechanically responsive material may be divided into a plurality of individually-reactive segments that are arranged along a length of the at least one microneedle, wherein stimulation of the plurality of individually-reactive segments in a predetermined sequence may cause the individually-reactive segments to expand in accordance with the predetermined sequence to purge fluid from, or draw fluid into, the inner lumen.
In various embodiments, the mechanically-responsive material may include one or more paddles that extend from the inner surface into the inner lumen, wherein the one or more paddles are operable to purge fluid from, or draw fluid into, the inner lumen. In various embodiments, the one or more paddles may include a plurality of individually-operably paddles that are operably in a predetermined sequence to purge fluid from, or draw fluid into, the inner lumen. In various embodiments, one or more of the paddles may be operable as a valve to selectively open and close the inner lumen. In various embodiments, at least one given paddle of the one or more paddles may include a folding actuator that is operable to fold the given paddle upon itself.
In various embodiments, the mechanically-responsive material may be transitionable between a hydrophilic state in which the mechanically-responsive material attracts fluid, and a hydrophobic state in which the mechanically-responsive material repels fluid. In various embodiments, the mechanically-responsive material is constructed with electroactive polymer (“EAP”) or magnetorheological elastomer (“MRE”). In various embodiments, the mechanically-responsive material may be constructed with shape-memory polymer or with light-activated liquid crystal networks.
In various embodiments, the stimulus may include heat, electricity, electromagnetic radiation (i.e. visible or invisible light), one or more acoustic waves, a magnetic field, or any combination thereof.
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.
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.
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 μm to about 30 μm. RBCs are typically disc shaped, and have diameters that range from about 6.2 μm to about 8.2 μm and thicknesses of about 2 μm to about 2.5 μm. Platelets typically range from about 2 μm to about 3 μm. Therefore, a microneedle with an inner diameter of about 1.5 μm to about 2 μm may prevent the passage of these types of cells into the microneedle, and thus into the wearable or insertable device.
Referring to
The wearable device 100 of
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 re-generation 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(s) 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 re-generating 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
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 electrowetting 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
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 returned 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
The wearable or insertable device 100 may further contain a user interface 150, as illustrated in
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
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
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 1.5 μm to about 2 μm, 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 piezo-electric 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.
While the insertable device 300 of
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.
In various embodiments, these stimuli may be applied by one or more stimulation components 671, such as light sources (e.g., light-emitting diodes, alone or in combination with various optical component such as collimators, light guides, lenses, etc.), piezoelectric components, speakers, chemical injectors, magnets, electrically conductive contacts, thermally-conductive contacts, and so forth. One or more stimulation components 671 may be arranged at various positions relative to microneedle 606, such as at its base, along its length, near its tip, or elsewhere in a base/substrate (e.g., 102, 302). In various embodiments, one or more stimulation components 671 may be operated to provide one or more of the aforementioned stimuli based on user input (e.g., the user presses a button or speaks a command), periodically (e.g., according to a schedule), or otherwise automatically (e.g., in response to various events, such as reservoir 104 being filled or emptied, or failing to fill or empty). For the sakes of brevity and clarity, only a single stimulation component 671 is depicted in
In some embodiments, mechanically-responsive material 670 may take the form of an electroactive polymer (“EAP”) that reacts mechanically, for instance, to electricity. Additionally or alternatively, in various embodiments, mechanically-responsive material 670 may take the form of magnetorheological elastomer (“MRE”) that reacts mechanically, for instance, to application of a magnetic field. MRE's may be a class of solids that include a polymeric matrix with embedded micro- or nano-sized ferromagnetic particles. In some embodiments, these particles may include carbonyl iron. Additionally or alternatively, in various embodiments, mechanically-responsive material 670 may take the form of shape-memory material such as shape-memory polymer that reacts mechanically, for instance, to a change of temperature. Additionally or alternatively, in various embodiments, mechanically-responsive material 670 may take the form of light-activated liquid crystal networks that react mechanically, for instance, to various forms of light (electromagnetic radiation).
In some embodiments, mechanically-responsive material 670 may include material (e.g., a coating) that is transitionable between a hydrophilic state in which it attracts fluid, and a hydrophobic state in which it repels fluid, similar to the embodiment depicted in
In
In
In
The sequences of expansions/contractions depicted in
In some embodiments, after the filling phase (
In some embodiments, microneedle (e.g., 106, 306, 406, 506, 606, 706) may be constructed so that there is a gradual change in the dimensions of the microneedle and/or the thickness of the mechanically-responsive material. When there is a thickness gradient over the microneedle's length—and the mechanically-responsive material expands—the fluid may be purged from of the inner lumen, either towards surrounding tissue or into a reservoir, depending on the gradient direction.
In
In various embodiments, paddles 878 may extend completely around the inner surface that defines inner lumen 809, such that each paddle would appear as a ring if removed. Additionally or alternatively, in some embodiments, each paddle may extend less than completely around the inner surface that defines inner lumen 878, and each paddle 878 may have various shapes, such as an oar shape, a polygon, etc. In some embodiments, a cyclic motion may be established amongst paddles 878, e.g., between paddles 878 at opposite positions along the longitudinal axis of microneedle 806, to create a net drag around the paddles 878 in one direction or another. In some embodiments, only the paddles 878 may be constructed with mechanically-responsive material 870, and the paddles 878 may be secured to an inner surface of lumen 809 that is constructed with different, e.g., non-mechanically-responsive material, such as thermally conductive material in which a heat gradient may be induced.
In
In some embodiments, a flexible substrate may be added to a paddle such as paddles 878 in
In some embodiments, bending actuator 984 may be constructed at least in part with one or more of the aforementioned mechanically-responsive materials. Consequently, bending actuator 984 may be operable (e.g., mechanically induced) to bend paddle 978 up or down (e.g., upstream/downstream) within inner lumen 909, as was depicted in
Folding actuator 982 may be constructed with a mechanically responsive material that, when exposed to the various stimuli described herein, folds upon itself, which consequently causes a blade portion of the paddle 978 to fold. This folding is best seen at bottom of
As noted above, in some embodiments, mechanically-responsive material may be constructed at least in part with activate-able liquid crystal networks, such as light-activated liquid crystal networks. Light-switchable surface topographies such as light-activated liquid crystal networks can be used to create various types of peristaltic fluid movement and/or, instead of merely expanding or contracting, may be used to create desired fluid channels to control fluid flow and/or fluid flow rates. When light-activated liquid crystal networks are suitably arranged and correctly designed, they can be selectively activated to, for instance, create fluid flow channels that modify the fluid flow inside the microneedle. Additionally or alternatively, such surfaces could be designed and used to move fluid faster through the needles as volume can be periodically displaced by switching on/off the topography.
At block 1004, one or more fluid samples may be collected with the wearable or insertable device. In various embodiments, this collection may include applying stimulation to, or withdrawing stimulation from, mechanically responsive material (e.g., 670, 770, 870) within an inner lumen of one or more microneedles (e.g., 106, 306, 406, 506, 606, 706, 806, 906) of the wearable or insertable device to induce a first mechanical response (e.g., contraction, swinging of paddles 878, creation of microchannels) in the mechanically-responsive material.
At block 1006, a presence or measure of at least one biomarker may be determined from the collected one or more fluid samples, e.g., by detection module 170 and/or assay module 180 in
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 2111.03. 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.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2018/084686 | 12/13/2018 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62599323 | Dec 2017 | US |
