Microneedle integrated interstitial fluid biomarker sensor system and method thereof

Abstract

A wearable interstitial fluid (ISF) sensing includes a first patch layer (102) and an electronics module component layer (106). The electronics module component layer (106) is laminated to the first patch layer (102) to form a patch component (112) and a plurality of microneedles (114) extending from the patch component (112). The electronics module component layer (106) includes a substrate (168) and a sensor positioned on the substrate (168). Each microneedle of the plurality of microneedles (114) includes a microneedle base (146) extending from the patch component (112), a body (148) extending from the microneedle base (146), and a tip (150) extending from the body (148). The body (148) defines a slot (160) extending through the first patch layer (102) of the body (148). The slot (160) defines a first opening (212) and a second opening (214). At least one sensor (144) is positioned above the second opening (214). The first opening (212), the slot (160), and the sensor define a channel (210) exposed to the environment. The channel (210) is configured to direct (210) the ISF to the sensor (144).

Description

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with Government support under a development agreement funded by the Air Force Research Laboratory. The Government has certain rights in this invention. Background Art

[0003] The subject matter described herein relates generally to wearable sensing systems, and more particularly to wearable systems for sensing biomolecules in a user's interstitial fluid.

[0004] Continuous or on-demand monitoring of biochemical data or biomarkers may be important for certain medical conditions. For example, monitoring biomarkers or drugs administered to the user can enable the monitored user or medical professional to perform medical intervention when the biomarkers indicate that medical intervention may be beneficial and / or is necessary for the proper management of the medical condition. Poor management of these medical conditions may cause short-term or long-term harm to the user. Similarly, biomarkers can be monitored to assess the performance of the user during sports, military or cognitive activities. The ability to detect and quantify biomarkers in real time on site enables the user or observer to implement changes in the short or long term to enhance performance or prevent performance from deteriorating (e.g., maintaining water, ensuring adequate rest, increasing or reducing training / task load, using drugs or supplements to enhance performance, etc.).

[0005] At least some known biochemical monitoring devices monitor the user's blood. These biochemical monitoring devices typically include at least one needle or microneedle that penetrates the user's skin and directs the blood to a sensing device located on the surface of the skin. The sensing device detects and reports the presence and / or concentration of biomarkers in the blood to the user or a medical professional. However, since the sensing device is located on the surface of the skin, the blood usually needs to be constantly replenished and must be disposed of after the sensing device has analyzed the blood. Typically, the core absorbs the blood and the core is discarded when the core can no longer absorb the blood. Therefore, in order to continuously monitor and analyze the blood, the core is usually replaced frequently. In addition, these biochemical monitoring devices may be difficult for users to use due to blood clots (e.g., the extracted blood may coagulate within the biochemical monitoring device). In addition, since the needle extends through the innervation layer within the skin, these biochemical monitoring devices may cause pain to the user.

[0006] At least some known biochemical monitoring devices detect and analyze the user's sweat. These biochemical monitoring devices are completely non-invasive (i.e., the biochemical monitoring device does not penetrate the user's skin), are usually applied to the user's skin, and usually include a patch fixed to the skin with an adhesive. Therefore, these biochemical monitoring devices usually do not cause pain to the user's wearing. The sensing device is attached to the patch, which detects biomarkers in the user's sweat. However, for some biomarkers, the concentration in sweat is poorly correlated with their concentration in the user's blood. Therefore, sweat detection biochemical monitoring devices may not report accurate results for certain analytes / medical conditions / performance scenarios. In addition, because the biochemical monitoring device detects body fluids outside the body, sweat may be contaminated during contact with the skin, and therefore the quality and quantity of the sample may depend on the environment. Finally, these devices rely on the presence of a sufficient volume of sweat to fill the sensor, and are therefore limited to the situation where enough sweat is produced, and the time resolution may vary as a function of the sweat rate / environment.

[0007] In contrast, for many medical conditions and performance metrics, the concentration of biomarkers in interstitial fluid (ISF) correlates with the concentration of biomarkers in the user's blood because the ISF is in continuous equilibrium with the blood via the capillary vasculature. In addition, because the ISF is not excreted, the ISF is less likely to be contaminated by the environment. In addition, the ISF, which accounts for approximately 20% of body fluids, does not coagulate, making it an excellent source for continuous and on-demand biomarker monitoring. In addition, in situ monitoring of ISF (monitoring the ISF within the user's dermis) is inherently a more temperature-controlled monitoring technology than other ISF monitoring technologies because temperature fluctuations of the user's body are minimal.

[0008] At least some known biochemical monitoring devices monitor the ISF of the user. These biochemical monitoring devices usually include at least one needle or microneedle, which penetrates the skin of the user and guides the ISF to a sensing device located on the skin surface. These sensing devices detect biomarkers in the ISF of the user. However, since the sensing device is located on the skin surface, it is necessary to constantly replenish the ISF and dispose of the ISF after the sensing device has analyzed it. Usually, the core absorbs the ISF and the core is discarded when the core can no longer absorb the ISF. Therefore, in order to continuously monitor and analyze the ISF, the core is usually replaced frequently. Due to the low hydrostatic pressure of the interstitial fluid in the tissue, a significant force is applied to extract the interstitial fluid from the tissue, as a negative ambient pressure (vacuum) at the skin surface or a positive mechanical pressure on the skin to force the ISF out. Both scenarios increase the complexity of the ISF collection device, usually require direct user intervention, and increase the discomfort felt by the user.

[0009] In addition, at least some known biochemical monitoring devices monitor the user's ISF subcutaneously. These biochemical monitoring devices typically include an applicator with at least one needle that penetrates the user's skin and deposits at least one sensing device deep in the tissue (e.g., in subcutaneous fat for continuous glucose monitoring). The sensing device is communicatively coupled to an electronic device positioned on the skin that reports the detected biomarkers to the user or a medical professional. However, because the sensing device penetrates the skin, cells adjacent to the sensing device may be stimulated by the sensing device and may therefore generate ISF near the sensing device, which may distort the concentration of certain inflammation-related biomarkers detected by the sensing device. Summary of the invention

[0010] In one aspect, a wearable interstitial fluid (ISF) sensing device is provided. The wearable ISF sensing device includes a first patch layer and an electronic device module component layer. The electronic device module component layer is laminated to the first patch layer to form a patch component and a plurality of microneedles extending from the patch component. The electronic device module component layer includes a substrate and at least one sensor positioned on the substrate. Each microneedle in the plurality of microneedles includes a microneedle base extending from the patch component, a body extending from the microneedle base, and a tip extending from the body. The body defines a slot of the first patch layer extending through the body. The slot defines a first opening and a second opening. The at least one sensor is positioned above the second opening. The first opening, the slot, and the at least one sensor define a channel exposed to the environment. The channel is configured to guide the ISF to the at least one sensor.

[0011] In another aspect, a method for detecting biomarkers in a user's interstitial fluid (ISF) is provided. The method includes adhering a wearable ISF sensing device to the user's skin. The wearable ISF sensing device includes at least one microneedle and at least one sensor positioned within the microneedle. The at least one microneedle includes a microneedle base, a body extending from the microneedle base, and a tip extending from the body. The body defines a slot extending through the body. The slot defines a first opening and a second opening. The at least one sensor is positioned above the second opening. The first opening, the slot, and the at least one sensor define a channel. The method also includes directing the ISF into the channel leading to the at least one sensor. The method also includes detecting at least one biomarker with the at least one sensor. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] These and other features, aspects and advantages of the present disclosure will be better understood when the following detailed description is read with reference to the accompanying drawings, in which like characters refer to like parts throughout, and in which:

[0013] Figure 1 is a plan view of an exemplary wearable ISF sensing module.

[0014] Figure 2 yes Figure 1 An exploded perspective view of the wearable ISF sensing module shown in FIG.

[0015] Figure 3 yes Figure 1 Plan view of the top patch layer of the wearable ISF sensing module shown in .

[0016] Figure 4 yes Figure 1 Plan view of the bottom patch layer of the wearable ISF sensing module shown in .

[0017] Figure 5 yes Figure 1 A plan view of the electronics module component layers of the wearable ISF sensing module shown in FIG.

[0018] Figure 6 yes Figure 1 A plan view of the first adhesive layer of the wearable ISF sensing module shown in FIG.

[0019] Figure 7 yes Figure 1 A plan view of the second adhesive layer of the wearable ISF sensing module shown in FIG.

[0020] Figure 8 yes Figure 1 An exploded perspective view of the microneedles of the wearable ISF sensing module shown in FIG.

[0021] Fig. 9 yes Figure 8 Perspective view of the top patch layer of the microneedle module.

[0022] Fig.10 yes Figure 8 A plan view of the top patch layer of the microneedles shown in FIG.

[0023] Fig.11 yes Figure 8 A plan view of the bottom patch layer of the microneedle shown in FIG.

[0024] Fig.12 yes Figure 8 A plan view of the component layers of the microneedle electronics module shown in FIG.

[0025] Fig.13 is a block diagram of an exemplary electronic device architecture.

[0026] Fig.14 It is printed on Figure 5 Electrical diagram of multiple sensors on a substrate of an electronics module component layer shown in FIG.

[0027] Fig.15 yes Figure 1 FIG. 1 is a diagram of a wearable ISF sensing device positioned on a user's skin, wherein Figure 8 The microneedles shown in are inserted into the dermis of the user's skin.

[0028] Unless otherwise indicated, the drawings provided herein are intended to illustrate features of the embodiments of the present disclosure. These features are believed to be applicable to a variety of systems including one or more embodiments of the present disclosure. Therefore, the drawings are not meant to include all conventional features required for practicing the embodiments disclosed herein known to those of ordinary skill in the art. DETAILED DESCRIPTION

[0029] In the following specification and claims, reference will be made to several terms which shall be defined as having the following meanings.

[0030] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0031] As used herein throughout the specification and claims, approximating language may be applied to modify any quantitative representation that allows variation without causing a change in the basic function associated therewith. Thus, values ​​modified by one or more terms (such as "approximately," "substantially," and "about") are not limited to the exact values ​​specified. In at least some cases, approximate language may correspond to the precision of the instrument used to measure the value. Here and throughout the specification and claims, range limitations may be combined and / or interchanged, and such ranges may be identified and include all subranges contained therein unless otherwise indicated by context or language.

[0032] The system and method described herein provide a wearable interstitial fluid (ISF) sensing device. The device includes multiple layers laminated together to form a patch component and at least one microneedle extending from the patch component. These layers include a first patch layer, a first adhesive layer, an electronic device module component layer, a second adhesive layer, and a second patch layer. The first patch layer and the second patch layer structurally support the electronic device module component layer, and the first adhesive layer and the second adhesive layer laminate the first patch layer and the second patch layer to the electronic device module component layer. The lamination of each layer ensures that the microneedle remains intact when inserted into the user's skin. Therefore, the microneedle of the wearable ISF sensing device described herein is structurally stronger than the previous microneedle and remains intact when monitoring the biomarkers in the user's ISF.

[0033] The microneedle comprises a microneedle base, a body and a tip. The microneedle has a substantially flat or planar profile, and a slot is defined in the body of the microneedle. The slot has a first opening and a second opening on opposite sides of the microneedle. The electronic device module component layer comprises a sensor positioned above the second opening, so that the sensor and the slot define a channel for guiding ISF to the sensor. The microneedle and the sensor are inserted into the skin of the user so that the sensor is positioned in the dermis of the user's skin. ISF flows into the channel from adjacent tissues, and the sensor detects and measures biomarkers in the ISF. The user, observer, trainer, coach and / or medical professional can then monitor a medical condition or performance / readiness metric based on the data collected by the sensor.

[0034] Because the sensor is embedded in the dermis, the ISF flowing to the sensor is continuously balanced with the surrounding ISF without the need for a mechanical mechanism to replenish the ISF. In addition, embedding the sensor in the dermis enables the wearable ISF sensing device to detect biomarkers without extracting fluid from the user's body, thereby reducing the body fluid removal and processing work generated for the detection and measurement of biomarkers. In addition, the capillary pressure and compression force generated during insertion will cause the ISF to flow into the channel, so that no fluid dynamic device such as a vacuum pump or mechanical compression is required to replenish the ISF at the sensor. After insertion, passive diffusion from the ISF and the balance with the ISF inside the channel replenish the ISF at the sensor. Therefore, the wearable ISF sensing device is able to detect biomarkers while reducing body fluid removal and processing work, and reducing the equipment required to measure biomarkers within the ISF. In addition, directly measuring the ISF in the interstitial space reduces the lag time between changes in biomarker concentrations and readings.

[0035] Now refer to the attached drawings, Figure 1 is a plan view of an exemplary embodiment of a wearable ISF sensing module 100, and Figure 2 FIG. 1 is an exploded perspective view of the wearable ISF sensing module 100. Figure 1 and Figure 2As shown, the wearable ISF sensing module 100 is formed by a plurality of layers 102-110 laminated together to form a patch component 112 and a plurality of microneedles 114 integrally formed with the patch component 112 for inserting into the user's skin and sensing the user's ISF, as described in detail below. The patch component 112 supports the microneedles 114 during insertion into the user's skin and adheres the wearable ISF sensing module 100 to the user's skin, as described below. The microneedles 114 detect and measure at least one biomarker within the user's ISF, so that the wearable ISF sensing module 100 can monitor medical conditions and / or performance metrics based on data collected by the microneedles 114. In an exemplary embodiment, the wearable ISF sensing module 100 is disposable (i.e., the wearable ISF sensing module 100 is typically used once). In an alternative embodiment, at least a portion of the wearable ISF sensing module 100 can be reusable (i.e., the wearable ISF sensing module 100 can be used for multiple purposes).

[0036] The wearable ISF sensing module 100 includes a top patch layer or first patch layer 102, a first adhesive layer 104, an electronic device module component layer 106, a second adhesive layer 108, and a bottom patch layer or second patch layer 110 laminated together to form the wearable ISF sensing module 100. The adhesive layer 104 and the adhesive layer 108 attach the top patch layer 102, the electronic device module component layer 106, and the bottom patch layer 110. The top patch layer 102 and the bottom patch layer 110 structurally support the electronic device module component layer 106, and the electronic device module component layer 106 senses the user's ISF and reports the collected data to the user and / or a medical professional, as described herein. In addition, the size and shape of the microneedle 114 are designed to enable the user's ISF to flow to the electronic device module component layer 106 so that the electronic device module component layer 106 can detect the ISF.

[0037] like Figure 2As shown, the top patch layer 102, the first adhesive layer 104, the electronic device module component layer 106, the second adhesive layer 108 and the bottom patch layer 110 are arranged and laminated in a layered configuration. The bottom patch layer 110 is a base layer attached to the user's skin. The second adhesive layer 108 is applied on the top of the bottom patch layer 110, and the bottom patch layer 110 is adhered to the electronic device module component layer 106, so that the second adhesive layer 108 is positioned between the bottom patch layer 110 and the electronic device module component layer 106. The first adhesive layer 104 is applied on the top of the electronic device module component layer 106, and the electronic device module component layer 106 is adhered to the top patch layer 102, so that the first adhesive layer 104 is positioned between the top patch layer 102 and the electronic device module component layer 106. In an exemplary embodiment, the first adhesive layer 104 and the second adhesive layer 108 are curable adhesives positioned between the top patch layer 102, the electronic device module component layer 106, and the bottom patch layer 110, as described above. Specifically, in an exemplary embodiment, the first adhesive layer 104 and the second adhesive layer 108 are curable adhesive sheets positioned between the top patch layer 102, the electronic device module component layer 106, and the bottom patch layer 110, as described above. The lamination of the wearable ISF sensing module 100 is achieved by heating the first adhesive layer 104 and the second adhesive layer 108 until the first adhesive layer 104 and the second adhesive layer 108 are thermally cured, bonding the top patch layer 102, the electronic device module component layer 106, and the bottom patch layer 110.

[0038] In an alternative embodiment, the first adhesive layer 104 and the second adhesive layer 108 are pressure sensitive adhesives applied to the top patch layer 102 and the bottom patch layer 110. The lamination of the wearable ISF sensing module 100 is achieved by pressing the top patch layer 102 and the first adhesive layer 104 to the electronics module component layer 106 and pressing the bottom patch layer 110 and the second adhesive layer 108 to the electronics module component layer 106 so that the pressure sensitive adhesive bonds the top patch layer 102, the electronics module component layer 106, and the bottom patch layer 110 together.

[0039] In another alternative embodiment, the wearable ISF sensing module 100 does not include the first adhesive layer 104 and the second adhesive layer 108. Instead, the top patch layer 102, the electronic device module component layer 106, and the bottom patch layer 110 are mechanically laminated together. For example, the top patch layer 102, the electronic device module component layer 106, and the bottom patch layer 110 are mechanically laminated together in a manner similar to Figure 2 The layer configuration shown in FIG. 1 is arranged, and mechanical fasteners (not shown) couple the top patch layer 102 , the electronics module component layer 106 , and the bottom patch layer 110 together.

[0040] The patch components 112 of bottom patch layer 110 are attached to the skin of user using sticky surface 116 or foam. Alternatively, in some embodiments, patch components 112 can be integrated into clothes and use suction device or compression clothes to remain in place. The patch components 112 of bottom patch layer 110 can be attached to the parts of user's body, including but not limited to trunk, leg, back, neck, arm etc. For example, the patch components 112 of bottom patch layer 110 can be placed on the lower back (for example, above waistline, below rib cage and adjacent to spine on either side), on the upper back (for example, above or above the shoulder blade), on the chest (for example, below the pectoralis or centered above the sternum), on the calf (for example, above the gastrocnemius or on the side above the tibialis anterior), or on the thigh (for example, on the inner thigh).

[0041] In an exemplary embodiment, the patch components 112 of the top patch layer 102 and the bottom patch layer 110 are formed of a pliable material, such as, but not limited to, a pliable metal, a pliable plastic, and / or any other material that enables the wearable ISF sensing module 100 to operate as described herein. In some embodiments, the patch components 112 of the top patch layer 102 and the bottom patch layer 110 are formed by additively manufacturing, casting, and / or molding a pliable metal or plastic into the patch components 112 of the top patch layer 102 and the bottom patch layer 110. In other embodiments, the patch components 112 of the top patch layer 102 and the bottom patch layer 110 are formed by machining (e.g., laser cutting) a pliable metal or plastic into the patch components 112 of the top patch layer 102 and the bottom patch layer 110.

[0042] The wearable ISF sensing module 100 includes a plurality of wearable ISF sensing modules 118 that are separable from one another such that each wearable ISF sensing module 118 operates independently of the other wearable ISF sensing modules 118. In the illustrated embodiment, the wearable ISF sensing module 100 includes four wearable ISF sensing modules 118 that are separable from one another. In alternative embodiments, the wearable ISF sensing module 100 may include any number of wearable ISF sensing modules 118 that enables the wearable ISF sensing module 100 to operate as described herein. After the layers 102-110 have been laminated together to form the wearable ISF sensing module 118, the wearable ISF sensing modules 100 are separated from one another. In some embodiments, the wearable ISF sensing modules 118 are separated from one another before being shipped to a user. In an alternative embodiment, after the wearable ISF sensing module 100 is shipped to a user, the wearable ISF sensing modules 118 are separated from one another by the user and / or a medical professional. As Figures 1 to 3 and Figure 7As shown, the top patch layer 102 and the bottom patch layer 110 define a plurality of separation slots 120 between the wearable ISF sensing modules 118 and enable the wearable ISF sensing modules 118 to be separated from each other.

[0043] The patch component 112 of the top patch layer 102 includes a plurality of cutouts 122 to allow a user and / or medical professional to access the electronic device module component layer 106 positioned between the top patch layer 102 and the bottom patch layer 110. Specifically, as shown in FIG. Figures 1 to 3 As shown, the cutout 122 is formed so that portions of the electronics module component layer 106 are accessible to a user and / or a medical professional. The size and shape of the cutout 122 are designed to allow a user, a medical professional, a battery, and / or an electronic device to access the electronics module component layer 106. In an exemplary embodiment, the cutout 122 has an oval shape. However, the cutout 122 can have any shape that enables the wearable ISF sensing module 100 to operate as described herein.

[0044] In an exemplary embodiment, patch component 112 may have a patch component length 124 of about 25 millimeters (mm) and a patch component height 126 of about 13 mm, microneedles 114 may have a microneedle length 128 of about 800 micrometers (μm) and a microneedle width 130 of about 100 μm, and incision 122 may have an incision length 132 of about 7.5 mm and an incision width 134 of about 2.25 mm. Alternatively, patch component 112, microneedles 114, and / or incision 122 may have any dimensions that enable wearable ISF sensing module 100 to function as described herein. In addition, the top patch layer 102 and the bottom patch layer 110 each have a patch layer thickness 136 of approximately 75 μm, the electronic device module component layer 106 has an electronic device module component layer thickness 138 of approximately 25 μm, and the first adhesive layer 104 and the second adhesive layer 108 each have an adhesive layer thickness 140 of approximately 25 μm, so that the patch component 112 and the microneedle 114 have a thickness 142 of approximately 325 μm.

[0045] In an exemplary embodiment, the patch component 112 has a rectangular shape. In alternative embodiments, the patch component 112 may have any shape that enables the wearable ISF sensing module 100 to operate as described herein, including but not limited to oval, elongated, circular, and / or any other shape that enables the wearable ISF sensing module 100 to operate as described herein. In some cases, a user may want to hide that they have a particular medical condition, and may want to disguise the wearable ISF sensing module 100. Therefore, in some embodiments, the size and shape of the wearable ISF sensing module 100 and the patch component 112 may be similar to a common adhesive bandage, or mounted on an appropriately sized insertion device.

[0046] In the illustrated embodiment, the wearable ISF sensing modules 118 each include three microneedles 114 attached to the patch component 112. In alternative embodiments, the wearable ISF sensing modules 118 may include any number of microneedles 114 that enable the wearable ISF sensing module 100 to operate as described herein. Specifically, as described in detail below, at least one sensor 144 (i.e., electrode) is attached to each microneedle 114 to detect biomarkers within the ISF. Some medical conditions may require monitoring of multiple biomarkers in order to properly monitor and manage the medical condition. Therefore, each wearable ISF sensing module 118 may include any number of microneedles 114 and sensors 144 that enable the wearable ISF sensing module 100 to properly monitor the medical condition.

[0047] The microneedles 114 each include a microneedle base 146, a body 148, and a tip 150. The microneedle base 146 is attached to the patch component 112, the body 148 is attached to the microneedle base 146, and the tip 150 is attached to the body 148. The wearable ISF sensing module 100 is formed so that the microneedle base 146 extends from the patch component 112 and is substantially coplanar with the patch component 112. In addition, the body 148 extends from the microneedle base 146, and the tip 150 extends from the body 148, so that the microneedle base 146, the body 148, and the tip 150 are substantially coplanar with the patch component 112. The microneedles 114 can then be bent to an appropriate angle for insertion into the user's skin. In an exemplary embodiment, the microneedles 114 are bent during the manufacturing process before the wearable ISF sensing module 100 is sent to the user. In an alternative embodiment, when the microneedles 114 are delivered to the user, they are coplanar with the patch component 112, and the user and / or medical professional bends the microneedles 114 before inserting them into the user's skin. In another alternative embodiment, the microneedles 114 remain unbent and are supported by a microneedle insertion device (not shown) during insertion into the user's skin.

[0048] In an exemplary embodiment, each of the microneedles 114 includes a first surface 152, a second surface 154 opposite the first surface 152, a third surface 156, and a fourth surface 158 opposite the third surface 156. The first surface 152 and the second surface 154 each have a length equal to the microneedle length 128 and a width equal to the microneedle width 130. The third surface 156 and the fourth surface 158 each have a length equal to the microneedle length 128 and a width equal to the thickness 142. In an exemplary embodiment, the first surface 152, the second surface 154, the third surface 156, and the fourth surface 158 each have a flat or planar profile. Therefore, each of the microneedles 114 includes at least one surface having a flat or planar profile. In an exemplary embodiment, each of the microneedles 114 includes four surfaces having a flat or planar profile.

[0049] In an exemplary embodiment, the microneedle base 146 is formed of a flexible material to enable the microneedle base 146 to bend. In some embodiments, the patch component 112 and the microneedle 114 are formed of the same flexible material. In an alternative embodiment, the patch component 112 is formed of a first material, and the microneedle 114 is formed of a second material different from the first material. In yet another alternative embodiment, the patch component 112 and the microneedle 114 can be formed of multiple materials. For example, the patch component 112 can be formed of a first material, the microneedle base 146 can be formed of a second flexible material, the body 148 can be formed of a third material different from the first material and the second material, and the tip 150 can be formed of a fourth material different from the first material, the second material, and the third material.

[0050] In an exemplary embodiment, the first material, the second material, the third material and the fourth material are the same material. Specifically, in an exemplary embodiment, the first material, the second material, the third material and the fourth material can be stainless steel or a stainless steel alloy. In an alternative embodiment, the first material, the second material, the third material and the fourth material can be a polymer. In another alternative embodiment, each of the first material, the second material, the third material and the fourth material can be selected based on the function of the component they form. For example, the third material and the fourth material that form the body 148 and the tip 150, respectively, can be a material whose hardness (a measure of the resistance to local plastic deformation caused by mechanical indentation or wear) is greater than the hardness of the second material, because the body 148 and the tip 150 pierce the skin of the user. Since the microneedle base 146 is bent, the second material can be a material with greater flexibility than the first material, the third material and the fourth material.

[0051] In an exemplary embodiment, each top patch layer 102 of each microneedle 114 defines a slot 160 extending through the microneedle base 146 and the body 148. In the illustrated embodiment, the slot 160 does not extend into the tip 150. In an alternative embodiment, the slot 160 extends through only a portion of the body 148. In another alternative embodiment, the slot 160 extends through the microneedle base 146, the body 148, and the tip 150. However, the slot 160 may extend through any portion of each top patch layer 102 of each microneedle 114 that enables the wearable ISF sensing module 100 to operate as described herein. The slot 160 has a slot length 162 and a slot width 164. In an exemplary embodiment, the slot length 162 is substantially greater than the slot width 164, and the slot 160 forms a channel that guides the ISF to the sensor 144 to detect biomarkers, as described herein. Slot 160 extends through top patch layer 102 of microneedle 114, and thus slot 160 has a slot depth 166 approximately equal to patch layer thickness 136 of approximately 75 μm. In alternative embodiments, slot 160 can have any size and shape that enables wearable ISF sensing module 100 to operate as described herein.

[0052] Turning now to the electronics module component layer 106, the electronics module component layer 106 includes a substrate 168, at least one circuit 170, a sensor 144, and communication and energy management components. Fig.131 is a block diagram of an exemplary electronic device architecture of a communication and energy management component. The communication and energy management components described above may include an on-patch control module 172, an off-patch control module 174, and a cable (not shown) that couples the circuit 170, the sensor 144, and / or the on-patch control module 172 to the off-patch control module 174. The electronic device module component layer 106 may include any one of the on-patch control module 172, the off-patch control module 174, and the cable. The off-patch control module 174 may include a data storage device, a power management, and a communication component, as described herein. The on-patch control module 172 may also be referred to as an analog-digital signal module in this article. Performing analog-to-digital conversion near the sensor 144 minimizes noise and stray signals that may interfere with the signal generated by the sensor 144 and the piezoelectric voltage generated in the connecting cable. The distributed configuration of the electronic device module component layer 106 enables the area and weight of the portion of the electronic device module component layer 106 that is in direct contact with the skin (i.e., the on-patch control module 172) to be reduced. Specifically, the control module 172 on the patch can be relatively lightweight and have a thin form factor, thereby increasing user comfort and improving the robustness of attaching the patch component 112 to the user and the wearable ISF sensing module 100 itself. In addition, because the control module 172 on the patch is separated from the control module 174 outside the patch, the control module 174 outside the patch can be located away from the patch component 112. Alternatively, the control module 172 on the patch and the control module 174 outside the patch are incorporated in the same component and are not far away from each other. As another alternative, in some embodiments, the control module 172 on the patch and the control module 174 outside the patch are far away from each other, but are not coupled to the communication ground using a cable. On the contrary, in such embodiments, the control module 172 on the patch and the control module 174 outside the patch use any suitable wireless communication protocol to communicate with each other in a wireless communication manner.

[0053] The off-patch control module 174 can be located away from the on-patch control module 172 using a cable. For example, the off-patch control module 174 can be stored in a pocket of clothing (e.g., pants or a shirt), or can be attached to, for example, a belt or heart rate monitor band (e.g., using a clip or hook-and-loop fastener). In an embodiment where the off-patch control module 174 is incorporated into clothing (e.g., elastic and form-fitting clothing), the cable can be a flexible conductor that is sewn or otherwise incorporated into the clothing to allow the wearable ISF sensing module 100 to be attached to a specific location, while the off-patch control module 174 is located in an inconspicuous location (e.g., on the back of a collar or on a sleeve of a shirt, on the sternum, on the hem of pants, in a waistband, in a pocket, etc.) or distributed on other parts of the clothing.

[0054] When the wearable ISF sensing module 100 includes both the on-patch control module 172 and the off-patch control module 174, the cable connects the on-patch control module 172 and the off-patch control module 174. For example, the cable can be a headphone audio extension cable, etc. In an exemplary embodiment, the on-patch control module 172 includes an amplifier (e.g., for amplifying the signal from the sensor 144), a voltage reference circuit, and an analog-to-digital converter (ADC) / multiplexer (MUX) 176. In addition, the ADC / MUX 176 can activate the insertion mechanism 178 to insert the microneedle 114 into the user's skin. Therefore, in an exemplary embodiment, the on-patch control module 172 converts the measured values ​​from analog signals to digital signals and then transmits those signals to the off-patch control module 174. Alternatively, the on-patch control module 172 can include any circuit that enables the on-patch control module 172 to function as described herein. The on-patch control module 172 has a small footprint and is lightweight and low-profile, thereby improving device comfort and wearability, and improving the mechanical and electrical reliability of the device during natural body movements because internal mechanical stresses are significantly reduced.

[0055] In addition, in an exemplary embodiment, the off-patch control module 174 includes a memory device and a microcontroller (MCU) 180. The off-patch control module 174 may also include a wireless communication unit 182 (e.g., a Bluetooth unit), a sensor data interface unit 184, a battery unit 186, and a microneedle actuation unit 188. The battery unit 186 may be rechargeable, for example, using inductive charging. In some embodiments, the memory device 180 may be a microSD card or other data storage device that is removably inserted into or permanently installed in the off-patch control module 174.

[0056] The off-patch control module 174 may be capable of wirelessly communicating with a remote computing device (e.g., a mobile computing device) using Bluetooth communications or alternative methods such as direct Wi-Fi. In addition, the off-patch control module 174 may have two-way communication capabilities, allowing the off-patch control module 174 or the remote computing device to store and recall previous data in the event of a communication failure.

[0057] In some embodiments, the off-patch control module 174 communicates with an associated software application installed on a computing device. The software application may include multiple functions that help the user use the wearable ISF sensing module 100. The software application may upload all data to a cloud storage system, including algorithms for analyzing trends in the data, and enable the user to customize data analysis. The software application may also enable data (in its original form or subsequently analyzed) to be displayed on a computing device. For example, in some embodiments, a software application (or the off-patch control module 174 itself) may analyze biochemical data collected by the wearable ISF sensing module 100. In addition, when a biomarker deviates from an expected range, the software application may generate an alarm. In addition, the data may be stored on the off-patch control module 174 as a backup and downloaded to the computing device when communication is reestablished.

[0058] In an exemplary embodiment, the substrate 168 includes a patch of patch components 112 attached to the top patch layer 102 and the bottom patch layer 110. Specifically, in an exemplary embodiment, the substrate 168 is formed of polyethylene terephthalate (PET) and is attached to the patch components 112 of the top patch layer 102 and the bottom patch layer 110 as described above. The circuit 170, the sensor 144, and / or the on-patch control module 172 can be printed on the substrate 168, and the substrate 168 can be attached to the patch components 112 of the top patch layer 102 and the bottom patch layer 110. In addition, after the substrate 168 has been attached to the patch components 112 of the top patch layer 102 and the bottom patch layer 110, at least a portion of the substrate can be laminated to the patch components 112 of the top patch layer 102 and the bottom patch layer 110 to maintain the position of the circuit 170, sensor 144 and / or on-patch control module 172 on the substrate 168 and / or the patch components 112 of the top patch layer 102 and the bottom patch layer 110 during use. In an alternative embodiment, the wearable ISF sensing module 100 does not include the substrate 168. Instead, the circuit 170, sensor 144 and / or on-patch control module 172 can be printed directly on the patch components 112 of the top patch layer 102 and / or the bottom patch layer 110.

[0059] In another alternative embodiment, the circuit 170, sensor 144, and / or on-patch control module 172 are printed on both sides of the substrate 168, and the size and shape of the bottom patch layer 110 are similar to the top patch layer 102, so that the circuit 170, sensor 144, and / or on-patch control module 172 are accessible on both sides of the substrate 168. That is, the substrate 168 can have the circuit 170, sensor 144, and / or on-patch control module 172 on both sides of the substrate 168, so that the wearable ISF sensing module 100 is double-sided, thereby improving the monitoring capabilities of the wearable ISF sensing module 100. The sensors 144 positioned on opposite sides of the substrate 168 can be configured to monitor the same biomarker or different biomarkers.

[0060] The circuit 170 communicatively couples the sensor 144 to the on-chip control module 172 and / or the off-chip control module 174. Specifically, the circuit 170 may be any circuit that transmits data from the sensor 144 to the on-chip control module 172 and / or the off-chip control module 174.

[0061] In the illustrated embodiment, each wearable ISF sensing module 100 includes twelve microneedles 114, and each microneedle 114 includes at least one sensor 144 positioned at least partially on a body 148 and a tip 150. Each sensor 144 is positioned on the body 148 and / or the tip 150 so that when the microneedle 114 is inserted into the user's skin, the sensor 144 is embedded in the dermis of the user's skin. In an exemplary embodiment, each sensor 144 includes a biosensor for sensing biomarkers within the ISF. Specifically, the sensor 144 detects and measures metabolites, small molecules, proteins, ions, electrolytes, enzymes, hormones, one or more biochemical parameters, and / or any other biomarker that helps monitor and control medical conditions and / or the performance of athletes.

[0062] In the illustrated embodiment, each wearable ISF sensing module 118 includes three microneedles 114, and each microneedle 114 includes at least one sensor 144, so that the electronic device module component layer 106 of each wearable ISF sensing module 118 includes a first sensor 190, a second sensor 192, and a third sensor 194. In some embodiments, the first sensor 190, the second sensor 192, and the third sensor 194 are the same sensors for detecting and measuring the same biomarker. More specifically, the first sensor 190, the second sensor 192, and the third sensor 194 can be configured to measure the same biochemical substance and report the results (data from all three sensors 190, 192, and 194 or the average of all three sensors 190, 192, and 194) to the user and / or medical professional. In an alternative embodiment, the first sensor 190, the second sensor 192, and the third sensor 194 are different sensors for detecting and measuring different biomarkers.

[0063] Fig.14 is an electrical diagram of the sensor 144 printed on the substrate 168. Figure 7 In the illustrated embodiment, each sensor 144 comprises a 2-electrode and / or 3-electrode biosensor for detecting biomarkers within the ISF. More specifically, the electronics module component layer 106 may include a 2-electrode biosensor 196 and / or a 3-electrode biosensor 198. The 2-electrode biosensor 196 is a 2-electrode system including a working electrode 200 and a counter / reference electrode 202 for detecting a specific biomarker. The 3-electrode biosensor 198 is a 3-electrode system including a working electrode 204, a reference electrode 206, and a counter electrode 208 for detecting a specific biomarker. The 2-electrode biosensor 196 and / or the 3-electrode biosensor 198 may detect the ISF using a variety of electroanalytical detection methods including, but not limited to, chronoamperometry, cyclic voltammetry, square wave voltammetry, and / or any other electroanalytical detection method that enables the sensor 144 to operate as described herein. In addition, the biomarker to be detected at least partially determines the type of sensor 144 embedded in the microneedle 114. Additionally, sensor 144 may include other types and / or categories of biosensors. For example, sensor 144 may include a field effect transistor biosensor (not shown) and / or any other type of sensor that enables wearable ISF sensing module 100 to operate as described herein.

[0064] For each of the biosensors described herein, the working electrode 200 and the working electrode 204 include a biorecognition element (BRE) (not shown). For example, when the working electrode 200 and the working electrode 204 detect metabolites, the BRE includes a metabolite sensing enzyme immobilized on the surface (not shown) of the working electrode 200 and the working electrode 204. The selection of the BRE and its kinetics are key to achieving a sustained equilibrium with the biomarker within the ISF, where high binding affinity (necessary for sensing low concentrations) is typically associated with poor reversibility (multiple sensor uses). Antibodies, short peptides, aptamers, and non-natural peptide-based BREs can also be used to achieve a target on / off equilibrium rate compatible with the dynamics of fluctuations in the concentration of the target biomarker in vivo. Aptamers and short peptide BREs can replace more commonly used antibodies to selectively and specifically recognize protein and hormone biomarkers. The use of aptamers and peptides as recognition elements will reduce costs and improve the simplicity and effectiveness of biosensor manufacturing. In particular, peptide and aptamer BREs enable the binding of target analytes (compared to much larger antibodies) in close proximity to the sensor surface, providing an effective approach to overcome the challenges associated with sensing in conductive biological media such as ISF. In addition, aptamer and peptide BREs are much more stable than commonly used antibodies, providing distinct advantages for in vivo monitoring in biological fluids. Other examples of BREs include non-natural peptides that provide thermal and enzymatic stability.

[0065] like Figure 1 , Figure 2 and Figure 8 As shown in , substrate 168 is positioned on patch component 112 so that electrodes 200, 202, 204, 206, and / or 208 are positioned within slot 160, and substrate 168 and slot 160 define a channel 210 for directing ISF to electrodes 200, 202, 204, 206, and / or 208. Fig. 9 As shown, the slot 160 extends through the body 148 of the top patch layer 102 to form a first opening 212 and a second opening 214. Figure 8As shown, the substrate 168 is positioned on the patch component 112 so that the second opening 214 is covered by the substrate 168. The first opening 212 remains uncovered and allows ISF to flow into the channel 210. More specifically, the pressure of the ISF causes the ISF to flow into the channel 210 and flow to the electrodes 200, 202, 204, 206 and / or 208 to be detected and measured. Since the microneedle 114 penetrates the skin of the user, the cells near the microneedle 114 can be stimulated by the microneedle 114 and / or the sensor 144. The cells near the sensor 144 can react to the stimulation by producing different biomarkers that can change the ISF near the microneedle 114. Therefore, if the sensor 144 is in close proximity to the stimulated cells, the measurement results reported by the sensor 144 may have errors caused by the reaction of the stimulated cells.

[0066] The slotted design of the microneedle 114 reduces errors caused by stimulated cells. Specifically, the electrodes 200, 202, 204, 206 and / or 208 are positioned in the slots 160 and the channel 210, and are not adjacent to the stimulated cells. In addition, since the ISF flows into the channel 210, the ISF detected by the electrodes 200, 202, 204, 206 and / or 208 includes the ISF surrounding the cells adjacent to and away from the microneedle 114. Therefore, the electrodes 200, 202, 204, 206 and / or 208 detect the average biomarker concentration from the cells whose positions change relative to the microneedle 114. In addition, guiding the ISF into the channel 210 enables the electrodes 200, 202, 204, 206 and / or 208 to detect and measure the ISF around different types of cells in the dermis. Thus, the slotted design of the microneedle 114 reduces errors caused by stimulated cells by directing the ISF into the electrodes 200 , 202 , 204 , 206 , and / or 208 .

[0067] Fig.15is a diagram of a wearable ISF sensing module 100 positioned on a user's skin 216, with microneedles 114 inserted into the dermis 218 of the user's skin 216. During operation, the user attaches the wearable ISF sensing module 100 to their skin 216, so that the microneedles 114 pierce and penetrate the epidermis 220 and dermis 218 of the user's skin 216. Specifically, when the microneedles 114 are inserted into the user's skin 216, the sensor 144 is embedded in the dermis 218 of the user's skin 216. Once inserted into the dermis 218, ISF from the vicinity of the cells surrounding the microneedles 114 flows into the channel 210 and contacts the electrodes 200, 202, 204, 206, and / or 208. The electrodes 200, 202, 204, 206, and / or 208 detect and measure at least one specific biomarker within the ISF. The electrodes 200, 202, 204, 206, and / or 208 then send electrical signals to the on-patch control module 172 and / or the off-patch control module 174. The on-patch control module 172 and / or the off-patch control module 174 may analyze the data from the electrodes 200, 202, 204, 206, and / or 208 and / or may transmit the data from the electrodes 200, 202, 204, 206, and / or 208 to a computing device. The user and / or a medical professional may then analyze the data to determine if further medical care is needed.

[0068] Because the sensor 144 is embedded in the dermis 218, the ISF flowing to the sensor 144 is constantly replenished, and no mechanical mechanism for replenishing the ISF is required to enable the wearable ISF sensing module 100 to operate as described herein. In addition, embedding the sensor 144 in the dermis 218 enables the wearable ISF sensing module 100 to detect biomarkers without extracting fluid from the user's body, thereby reducing the body fluid removal and processing work generated by the detection and measurement of biomarkers, and reducing the equipment required to measure biomarkers in the ISF. In addition, because the pressure of the ISF causes the ISF to flow into the channel 210, a fluid dynamic device such as a vacuum pump is not required to continuously replenish the ISF flowing to the electrodes 200, 202, 204, 206 and / or 208.

[0069] Embodiments described herein include systems and methods for wearable ISF sensing devices. The device includes multiple layers laminated together to form a patch component and at least one microneedle extending from the patch component. These layers include a first patch layer, a first adhesive layer, an electronic device module component layer, a second adhesive layer, and a second patch layer. The first patch layer and the second patch layer structurally support the electronic device module component layer, and the first adhesive layer and the second adhesive layer laminate the first patch layer and the second patch layer to the electronic device module component layer. The lamination of each layer ensures that the microneedle remains intact when inserted into the user's skin. Therefore, the microneedle of the wearable ISF sensing device described herein is structurally stronger than previous microneedles and remains intact when monitoring biomarkers in the user's ISF.

[0070] The microneedle includes a microneedle base, a body and a tip. The microneedle has a substantially flat or planar profile, and the slot is defined in the body of the microneedle. The slot has a first opening and a second opening. The electronic device module component layer includes a sensor positioned above the second opening, so that the sensor and the slot define a channel that guides ISF to the sensor. The microneedle and the sensor are inserted into the user's skin so that the sensor is positioned in the dermis of the user's skin. ISF flows into the channel from adjacent tissues, and the sensor detects and measures biomarkers in the ISF. Users, observers, trainers, coaches and / or medical professionals can then monitor medical conditions or performance / readiness metrics based on the data collected by the sensor.

[0071] Because the sensor is embedded in the dermis, the ISF flowing to the sensor is continuously balanced with the surrounding ISF without the need for a mechanical mechanism to replenish the ISF. In addition, embedding the sensor in the dermis enables the wearable ISF sensing device to detect biomarkers without extracting fluid from the user's body, thereby reducing the body fluid removal and processing work generated for the detection and measurement of biomarkers. In addition, the capillary pressure and compression force generated during insertion will cause the ISF to flow into the channel, so that no fluid dynamic device such as a vacuum pump or mechanical compression is required to replenish the ISF at the sensor. After insertion, passive diffusion from the ISF and the balance with the ISF inside the channel replenish the ISF at the sensor. Therefore, the wearable ISF sensing device is able to detect biomarkers while reducing body fluid removal and processing work, and reducing the equipment required to measure biomarkers within the ISF. In addition, directly measuring the ISF in the interstitial space reduces the lag time between changes in biomarker concentrations and readings.

[0072] Exemplary technical effects of the methods, systems, and devices described herein include at least one of the following: (a) detecting biomarkers within ISF; (b) reducing bodily fluid clearance and handling associated with biomarker detection; (c) reducing equipment required to measure biomarkers within ISF; and (d) reducing errors associated with detection of biomarkers within ISF.

[0073] Exemplary embodiments of wearable ISF sensing devices are described herein. These systems and methods are not limited to the specific embodiments described herein, but rather, components of the systems and / or steps of the methods may be used independently and separately from other components and / or steps described herein. For example, these methods may also be used in combination with other systems and are not limited to practice with only the systems described herein. Rather, the exemplary embodiments may be implemented and utilized in conjunction with many other systems.

[0074] Although specific features of various embodiments of the present disclosure may be shown in some drawings and not in other drawings, this is for convenience only. According to the principles of the present disclosure, any feature of a drawing may be referenced and / or claimed in combination with any feature of any other drawing.

[0075] This written description uses examples to disclose embodiments, including the best mode, and also to enable those skilled in the art to practice the embodiments, including making and using any devices or systems and performing any included methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to fall within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with minor differences from the literal language of the claims.

Claims

1. A wearable interstitial fluid (ISF) sensing device (100), the wearable ISF sensing device comprising: A first patch layer (102); and An electronic device module component layer (106) laminated to the first patch layer (102) to form a patch component (112) and a plurality of microneedles (114) extending from the patch component (112), the electronic device module component layer (106) comprising a substrate (168) and at least one sensor (144) positioned on the substrate (168), each microneedle in the plurality of microneedles (114) comprising: a microneedle base (146) extending from the patch component (112); a body (148) extending from the microneedle base (146), the body (148) defining a slot (160) extending through the first patch layer (102) of the body (148), the slot (160) defining a first opening (212) and a second opening (214), the at least one sensor (144) being positioned above the second opening (214), wherein the first opening (212), the slot (160) and the at least one sensor (144) define a channel (210) exposed to an environment; and A tip (150) extends from the body (148), wherein the channel (210) is configured to direct ISF (210) to the at least one sensor (144).

2. The wearable ISF sensing device (100) according to claim 1, further comprising: A second patch layer (110) laminated to the first patch layer (102) and the electronic device module component layer (106), wherein the electronic device module component layer (106) is located between the first patch layer (102) and the second patch layer (110), and wherein the first patch layer (102) and the second patch layer (110) structurally support the electronic device module component layer (106).

3. The wearable ISF sensing device (100) according to claim 2, further comprising: A first adhesive layer (104) is positioned between the first die attach layer (102) and the electronic device module component layer (106), wherein the first adhesive layer (104) laminates the first die attach layer (102) to the electronic device module component layer (106).

4. The wearable ISF sensing device (100) according to claim 3, wherein the first adhesive layer (104) comprises a curable adhesive sheet.

5. The wearable ISF sensing device (100) according to claim 3, wherein the first adhesive layer (104) comprises a pressure sensitive adhesive.

6. The wearable ISF sensing device (100) according to claim 2, further comprising: A second adhesive layer (108) is positioned between the second die attach layer (110) and the electronic device module component layer (106), wherein the second adhesive layer (108) laminates the second die attach layer (110) to the electronic device module component layer (106).

7. The wearable ISF sensing device (100) according to claim 6, wherein the second adhesive layer (108) comprises a curable adhesive sheet.

8. The wearable ISF sensing device (100) of claim 6, wherein the second adhesive layer (108) comprises a pressure sensitive adhesive.

9. The wearable ISF sensing device (100) of claim 2, wherein the slot (160) comprises a first slot (160), wherein the body (148) defines a second slot (160) extending through the second patch layer (110) of the body (148), wherein the second slot (160) defines a third opening and a fourth opening, wherein the at least one sensor (144) comprises at least one first sensor (109), wherein the electronics module component layer (106) further comprises at least one second sensor (192) positioned on the substrate (168), wherein the at least one sensor (144) is positioned above the fourth opening, and wherein the third opening, the second slot (160), and the at least one second sensor (192) define a second channel (210) exposed to the environment.

10. The wearable ISF sensing device (100) of claim 1, wherein the microneedle base (146) comprises a flexible material.

11. The wearable ISF sensing device (100) of claim 1, wherein the electronics module component comprises an on-patch control module (172) configured to enable wireless communication with a mobile computing device.

12. The wearable ISF sensing device (100) of claim 1, wherein the electronics module component further comprises an on-patch control module (172) and an off-patch control module (174).

13. The wearable ISF sensing device (100) according to claim 12, further comprising: A cable communicatively couples the at least one sensor (144) and the on-patch control module (172) to the off-patch control module (174).

14. The wearable ISF sensing device (100) according to claim 12, wherein the on-patch control module includes an analog-to-digital conversion signal module component coupled to the base.

15. A method for detecting biomarkers in interstitial fluid (ISF) of a user, the method comprising: Adhering a wearable ISF sensing device (100) to the skin of the user, the wearable ISF sensing device (100) comprising at least one microneedle (114) and at least one sensor (144) positioned within the microneedle, the at least one microneedle (114) comprising a microneedle base (146), a body (148) extending from the microneedle base (146), and a tip (150) extending from the body (148), the body (148) defining a slot (160) extending through the body (148), the slot (160) defining a first opening (212) and a second opening (214), the at least one sensor (144) being positioned above the second opening (214), wherein the first opening (212), the slot (160), and the at least one sensor (144) define a channel (210); directing the ISF into the passage (210) leading to the at least one sensor (144); as well as At least one biomarker is detected using the at least one sensor (144).

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