Abstract:
The disclosed invention provides a modular biofluid sensing device configured to be worn on an individual&#39;s skin. The device includes at least one primary module, at least one sensing module, and at least one specialized module. The various subsystems, components, and materials making up a biofluid sensing device are arranged for modular distribution and assembly according to a number of different organizational criteria. These criteria include distributing components into modules based on the requirements of a biofluid sensing device application, manufacturing considerations, component cost, and component lifespan.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application relates to U.S. Provisional No. 62/364,939, filed Jul. 21, 2016, the disclosure of which is hereby incorporated by reference herein in its entirety. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    The present invention was made outside any support from the U.S. Government. 
     
    
     BACKGROUND OF THE INVENTION 
       [0003]    Despite the many ergonomic advantages of eccrine perspiration (sweat) compared to other possible biofluids (particularly in “wearable” devices), sweat remains an underrepresented source of biomarker analytes compared to blood, urine, and saliva. Upon closer comparison to other non-invasive biofluids, the advantages may even extend beyond ergonomics: sweat might provide superior analyte information. A number of challenges, however, have historically kept sweat from assuming a more prominent place among clinical sampling modalities. These challenges include very low sample volumes (nL to μL), unknown concentration due to evaporation, filtration and dilution of large analytes, mixing of old and new sweat, and the potential for contamination from the skin surface. More recently, rapid progress in wearable sweat sampling and sensing devices has resolved several of these historical challenges. However, this recent progress has also been limited to high concentration analytes (μM to mM) sampled at high sweat rates (&gt;1 nL/min/gland, e.g. athletic applications). Progress will become much more challenging as sweat biosensing moves towards use with sedentary users (low sweat rates or not sweating at all) and/or towards low concentration analytes (pM to nM). Furthermore, the solutions to resolving these problems will be highly multidisciplinary, and may require source components that will be very dissimilar in their manufacturing infrastructure or cost profile. As a result, monolithic integration of all materials and components in a sweat sensing device, in many circumstances may be impractical, or render certain applications prohibitively expensive. Furthermore, some materials and components may be needed for nearly all sweat sensing applications, whereas other materials and components would be needed only for niche applications. In such cases, modular techniques are required to allow efficient integration of broadly applicable materials, or components with niche application materials or components. Additionally, modular techniques may allow the distribution of expensive components among disposable and reusable modules, or can allow one-use or limited-use components to be efficiently combined with components capable of longer lifespan. 
         [0004]    Many of the drawbacks and limitations currently facing sweat sensing and other biofluid sensing modalities can be resolved by creating novel and advanced interplays of chemicals, materials, sensors, electronics, microfluidics, algorithms, computing, software, systems, and other features or designs, in a manner that affordably, effectively, conveniently, intelligently, or reliably brings biofluid to sensors and to biofluid preparing or concentrating subsystems. By doing do, sweat sensing could become a much more compelling paradigm as a biosensing platform, and other biofluid sensing modalities can be improved. 
       SUMMARY OF THE INVENTION 
       [0005]    The disclosed invention provides a wearable biofluid sensing device configured for the modular distribution and assembly of a variety of subsystems, components, and materials. These include the modular distribution of components based on biofluid sensing device application, manufacturing considerations, cost considerations, and component lifespan. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0006]    The objects and advantages of the present invention will be further appreciated in light of the following detailed descriptions and drawings in which: 
           [0007]      FIG. 1  is a cross-sectional view of a prior art device lacking modular component distribution and assembly. 
           [0008]      FIG. 2A-2C  are cross-sectional views of embodiments of the disclosed invention with multiple modular subsystems. 
           [0009]      FIG. 3A  is a cross-sectional view of an embodiment of the disclosed invention with greater detail shown for modules  210  and  220  of  FIGS. 2A-2C . 
           [0010]      FIG. 3B  is a cross-sectional view of an embodiment of the disclosed invention with greater detail shown for module  230  of  FIGS. 2A-2C . 
           [0011]      FIG. 3C  is a cross-sectional view of an embodiment of the disclosed invention with greater detail shown for module  230  of  FIGS. 2A-2C . 
           [0012]      FIG. 3D  is a cross-sectional view of an embodiment of the disclosed invention with greater detail shown for module  210  of  FIGS. 2A-2C . 
           [0013]      FIG. 4  is a cross-sectional view of an embodiment of the disclosed invention with a modular assembly of subsystems, components, and materials. 
       
    
    
     DEFINITIONS 
       [0014]    Before continuing with the background, a variety of definitions should be made, these definitions gaining further appreciation and scope in the detailed description and embodiments of the present disclosure. 
         [0015]    As used herein, “sweat” means a biofluid that is primarily sweat, such as eccrine or apocrine sweat, and may also include mixtures of biofluids such as sweat and blood, or sweat and interstitial fluid, so long as advective transport of the biofluid mixtures (e.g., flow) is primarily driven by sweat. 
         [0016]    As used herein, “biofluid” may mean any human biofluid, including, without limitation, sweat, interstitial fluid, blood, plasma, serum, tears, and saliva. 
         [0017]    “Biosensor” means any type of sensor that measures a state, presence, flow rate, solute concentration, solute presence, in absolute, relative, trending, or other ways in a biofluid. Biosensors can include, for example, potentiometric, amperometric, impedance, optical, mechanical, antibody, peptide, aptamer, or other means known by those skilled in the art of sensing or biosensing. 
         [0018]    “Analyte” means a substance, molecule, ion, or other material that is measured by a fluid sensing device. 
         [0019]    “Measured” can imply an exact or precise quantitative measurement and can include broader meanings such as, for example, measuring a relative amount of change of something. Measured can also imply a binary or qualitative measurement, such as ‘yes’ or ‘no’ type measurements. 
         [0020]    “Chronological assurance” means the sampling rate or sampling interval that assures measurement(s) of analytes in sample in terms of the rate at which measurements can be made of new fluid analytes as they enter the sample. Chronological assurance may also include a determination of the effect of sensor function, potential contamination with previously generated analytes, other fluids, or other measurement contamination sources for the measurement(s). Chronological assurance may have an offset for time delays in the body (e.g., a well-known 5- to 30-minute lag time between analytes in blood emerging in interstitial fluid), but the resulting sampling interval is independent of lag time, and furthermore, this lag time is inside the body, and therefore, for chronological assurance as defined above and interpreted herein, this lag time does not apply. 
         [0021]    As used herein, “continuous monitoring” means the capability of a device to provide at least one measurement of sweat determined by a continuous or multiple collection and sensing of that measurement or to provide a plurality of measurements of sweat over time. 
         [0022]    “Biofluid sensor data” means all the information collected by fluid sensing device sensor(s) and communicated to a user or a data aggregation location. 
         [0023]    “Correlated aggregated fluid sensor data” means fluid sensor data that has been collected in a data aggregation location and correlated with outside information such as time, temperature, weather, location, user profile, other biofluid sensor data, or any other relevant data. 
         [0024]    “Sweat generation rate” is the rate at which sweat is generated by the sweat glands themselves. Sweat generation rate is typically measured by the flow rate from each gland in nL/min/gland. In some cases, the measurement is then multiplied by the number of sweat glands from which the sweat is being sampled. 
         [0025]    “Sweat volume” is the fluidic volume in a space that can be defined multiple ways. Sweat volume may be the volume that exists between a sensor and the point of generation of sweat or a solute moving into or out of sweat from the body or from other sources. Sweat volume can include the volume that can be occupied by sweat between: the sampling site on the skin and a sensor on the skin where the sensor has no intervening layers, materials, or components between it and the skin; or the sampling site on the skin and a sensor on the skin where there are one or more layers, materials, or components between the sensor and the sampling site on the skin. 
         [0026]    “Microfluidic components” are channels in polymer, textiles, paper, or other components known in the art of microfluidics for guiding movement of a fluid or at least partial containment of a fluid. 
         [0027]    “Sweat sampling rate” is the effective rate at which new sweat or sweat solutes, originating from the sweat gland or from skin or tissue, reaches a sensor which measures a property of sweat or its solutes. Sweat sampling rate, in some cases, can be far more complex than just sweat generation rate. 
         [0028]    “Sweat stimulation” is the direct or indirect causing of sweat generation by any external stimulus, the external stimulus being applied for the purpose of stimulating sweat. One example of sweat stimulation is the administration of a sweat stimulant such as pilocarpine. Going for a jog, which stimulates sweat, is only sweat stimulation if the subject jogging is jogging for the purpose of stimulating sweat. 
         [0029]    As used herein, “microfluidic components” are channels in polymer, textiles, paper, or other components known in the art of microfluidics for guiding movement of a fluid or at least partial containment of a fluid. 
         [0030]    As used herein, “advective transport” is a transport mechanism of a substance or conserved property by a fluid due to the fluid&#39;s bulk motion. 
         [0031]    “Diffusion” means the net movement of a substance from a region of high concentration to a region of low concentration. This is also referred to as the movement of a substance down a concentration gradient. 
         [0032]    A “module” is a component or components which are fabricated individually and integrated with at least one other modeling during assembly of a sweat sensing device. 
         [0033]    “Volume reducing component” means any component which reduces the sweat volume as taught in PCT/US15/32893, which is hereby incorporated by reference herein in its entirety. 
         [0034]    “Volume reducing wicking component” means any component as taught in PCT/US16/43771, which is hereby incorporated by reference herein in its entirety. 
         [0035]    “Sweat stimulating component” means any component as taught in PCT/US14/61083, PCT/US16/17726, U.S. Ser. No. 15/186,925, and PCT/US16/50928, which are hereby incorporated by reference herein in their entirety. 
         [0036]    “Electroporation component” means any component as taught in PCT/US17/13453, which is hereby incorporated by reference herein in its entirety. 
         [0037]    “Sensor component” means any component or components which measure a solute in sweat, a property of sweat, or the presence of sweat. Sensors can be thermal, flow, impedance, potentiometric, ion-selective, amperometric, enzymatic, aptamer, antibody, fluorescent, colorimetric, surface-plasmon resonance, acoustic, resonant, MEMs, or any other sensor suitable for sensing sweat in at least one measurement. 
         [0038]    “Flow rate sensor” means any component or components which measure the flow rate of sweat or other biofluid in at least one portion of a biofluid sensing device. 
         [0039]    “Primary module” means any component or components that may contain “sensor components”, “stimulating components”, “volume reducing components”, and/or “volume reducing wicking components”. 
         [0040]    “Sensing module” means any component or components fabricated separately from the primary module and specialized module, that provides one or more generally applicable sensors, such as one or more ion-selective electrodes, a biofluid flow rate sensor, a pH sensor, a temperature sensor, a galvanic skin response sensor, or a skin impedance sensor. 
         [0041]    “Specialized module” means any component or components, fabricated separately from the primary module and sensing module, that provides a specialized and application-specific purpose in a biofluid sensing device, such as one or more electrochemical aptamer-based sensors, ion-selective electrode sensors; amperometric sensor, potentiometric sensor, enzymatic sensor, antibody sensor, optical sensor, surface-plasmon sensor, acoustic sensor, resonant sensor, micro-electro-mechanical MEMs sensor, biofluid sample concentration component, osmotic pump component, wicking component, or a sample collection and storage component, including those as taught in PCT/US16/58356, and PCT/US17/23399 which are hereby incorporated by reference herein in their entirety. 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0042]    With reference to  FIG. 1 , a prior art device on skin  12  contains a skin-adhesive polymer seal  172 , such as medical adhesive on PET film; at least one sensor  120 ,  122 ; at least one substrate  170 , such as a PET film; and at least one wicking material  180 , such as a hydrogel. The entire device is fabricated monolithically, by adding basic materials step-by-step. For instance, sensors  120 ,  122  could be ion-selective electrodes deposited by screen printing on PET, attached to substrate  170 , surrounded with hydrogel  180 , and then encapsulated by seal  172 . 
         [0043]    With reference to  FIG. 2A , a modular biofluid sensing device  200   a  contains a primary module  210  which comprises at least one of the following: a sweat stimulating component; a thermal flow measurement sensor; a volume reducing component; a wicking volume reducing component; and an electroporation component.  FIG. 2A  further contains at least one sensing module  220 , and at least one specialized module  230 . Each of the modules  210 ,  220 ,  230 , is functionally connected as needed and integrated with the others into a single device. Sweat or other biofluid is transported in a manner that is dominantly horizontal along skin  12 , from skin in the direction of the arrow  14  through the primary module  210 , through sensing module  220 , and to specialized module  230 . 
         [0044]    With reference to  FIG. 2B , a biofluid sensing device  200   b  with an alternate arrangement of the modules of  FIG. 2A  is shown, where sweat is transported in a manner that is dominantly away from skin  12 , in the direction of the arrow  14  through the primary module  210 , through sensing module  220 , and to specialized module  230 . 
         [0045]    With reference to  FIG. 2C , a device  200   c  with an alternate arrangement of the modules of  FIGS. 2A and 2B  are shown, including modular electronics  290 , which can be integrated using one or more techniques, including those taught in PCT/US15/32843. A primary module  210  carries sweat from skin  12  in the direction of the arrow  14  into contact with and over a sensing module  220  which contains sweat sensors, e.g., ion selective electrode sensors or a pH sensor, and to a specialized module  230 . A more detailed description of this example embodiment will be provided in  FIG. 3A . 
         [0046]    With reference to  FIG. 3A , a biofluid sensing device includes a wicking volume reducing component as a primary module  310  and at least one specialized module  330  (one is shown) that receives sweat from the primary module  310 . Specialized module  330  could be simply a wicking hydrogel, but could also include specialized sensors  328 , or be otherwise more sophisticated, as will be described for  FIG. 3B . The device includes a sensing module  320 , which is composed of at least one biofluid sensor  322 ,  324 ,  326 , and a substrate  350 . In an exemplary embodiment, the sensing module  320  includes at least one sensor for Na +  or Cl − , at least one sensor for K + , at least one pH sensor, and at least sweat rate sensor, e.g., a thermal flow rate sensor from Sensiron Corporation, a volumetric sweat rate sensor, or other suitable biofluid flow rate sensor. This suite of sensors chosen for the sensing module is intended to provide key information for at least one specialized sensor  328 , e.g., an electrochemical aptamer-based sensor for cortisol, located in the specialized module  330 . The interpretation of sweat measurements taken by the specialized sensor  328  could be affected by changes in sweat sample pH or salinity, and the sensor&#39;s chronological accuracy is dependent on sweat flow rate to the sensor. 
         [0047]    To illustrate the modular nature of component distribution and assembly, the primary module  310  is, e.g., a disposable microfluidic wicking component, that interfaces with the reusable sensing module  320  and its sensors  322 ,  324 ,  326 , by pressing the primary module against the sensing module, and securing the modules together by means of a simple mechanical interaction, such as an adhesive or click attachment means. Interfacing the primary module  310  with the sensing module  320  thus puts the wicking component in fluid communication with the sensors  322 ,  324 ,  326 . An optional hydrogel or other wicking material  329  can be placed between at least one of the sensors  322 ,  324 ,  326  and wick  310 , to improve the transfer of biofluid sample or biofluid analytes from the wick  310  to the sensors  322 ,  324 ,  326 . Additionally, a reusable specialized module  330  is connected to the primary module  310  by means similar to the connection of the primary module to the sensing module, e.g., by simple physical contact or a mechanical interaction, so that the wick is in fluid communication with the specialized module. In some embodiments, the device includes a vapor barrier layer (not shown) over primary module  310 , which prevents or reduces biofluid sample evaporation out of the device. In other embodiments, a vapor barrier layer (not shown) could be located above the substrate  350  and below the sensors  322 ,  324 ,  326  to prevent vapor from escaping once it has entered the device. Alternatively, the device may have both such vapor barrier layers, which may be separate component(s) or ray be manufactured/integrated with the substrate  350 , the primary module  310 , or another module as necessary. Alternatively, the sensing module  320  could have its own microfluidic component that is placed in fluidic communication with both the primary module and the specialized module (not shown). 
         [0048]    With reference to  FIG. 3B , which represents the portion of the device of  FIG. 3A  that appears to the right of the line  300 , an example specialized module  330   b  is illustrated in greater detail. A portion of the primary module  310 , e.g., a wicking or volume reducing component, and a substrate  350  are shown for reference. A wicking or microfluidic component  314  brings a sweat sample to at least one sensor  332 ,  334 ,  336 , and a sensor suite  338  which includes for, example, three sensors of the same sensor type, e.g., three EAB sensors for detecting sweat cortisol, or three amperometric sensors for lactate or glucose. The specialized module sensors  332 ,  334 ,  336  may also include a pH sensor, a salinity sensor, a sweat flow rate sensor, or a temperature sensor. These sensors would, for example, provide additional data relative to sweat sample pH or temperature near the sensor suite  338 , which may experience different conditions than near the skin  12 , or upstream within the device. The specialized module  330   b  also includes a wicking component  339 , e.g., a hydrogel, and a substrate  338 , upon which the sensors  332 ,  334 ,  336 ,  338  are fabricated and mounted. The wicking or microfluidic component  314  could be fabricated along with the substrate  338 , gel  339 , and the sensors  332 ,  334 ,  336 ,  338 , e.g., the specialized module components are fabricated together as one complete and reusable module and interfaced with a disposable primary module and a limited-reuse sensing module. 
         [0049]    With reference to  FIG. 3C , which represents the portion of the device of  FIG. 3A  that appears to the right of the line  300 , an alternate embodiment of a specialized module  330   c  includes a biofluid sample concentration component and at least one sensor  332 . A wicking material  339  is also provided, as is a wicking or microfluidic component  331 . The module  330   c  is fabricated upon a substrate  338 . The biofluid (in this case sweat) sample concentration component includes an osmotic pumping material  336 , which could be a large organic salt or sugar, or a strongly wicking material, such as a hydrogel. Sweat sample concentration also includes a selectively permeable membrane  337 , e.g., a forward osmosis membrane, that is in fluidic communication with the wicking component  331 . The sensor  332  could be a μM EAB sensor for cortisol. The concentration component achieves, for example, a 10× to 1000× concentration of cortisol relative to the original sweat cortisol concentration prior to the sweat sample entering the concentration component. 
         [0050]    With reference to  FIG. 3D , an embodiment of a primary module  310   d  depicted in additional detail. the primary module  310   d  includes a hydrophilic gold electroporation electrode  312  that is interfaced with a geometric channel  314 , constructed of, e.g., a polymer. The hydrophilic properties of the electrode  312  allow the geometries of the channel  314  both to wick sweat and to act as a wicking volume reducing component. The primary module also includes a sweat stimulation component  316  comprised of sweat stimulant gel  317  and iontophoresis electrode  319 . Sweat stimulation and collection, in this example, may be accomplished via sudo-motor axon reflex sweating. 
         [0051]    With reference to  FIG. 4 , a partial view of a fully detailed embodiment of the disclosed invention is provided. The modular device contains a primary module, a sensing module, and a specialized module, as well as the following: a filler material constructed of sponge or memory foam  402 ; an adhesive  403 , e.g., an acrylate or medical adhesive; a textile covering  404 ; and a substrate  450 . The primary module includes the following: a wicking volume reducing component  410 ; an iontophoresis electrode  419 ; a &lt;1 mm thick sweat stimulant gel comprising a carbachol sweat stimulant and agar  417 ; a first rigid molded polymer  412 ; a second rigid molded polymer  414  designed to interact with the first molded polymer  412 ; and an electroporation electrode  415 . The sensing module includes the following: at least one sensor, reference electrode or counter electrode  422 ,  424 ; a memory foam or other self-leveling material  427 ; a hydrogel spacer  429  for enhancing fluidic, adventive or diffusive contact between the substrate  450  and a rigid polymer or metal component  428 ; where the spacer  429  further provides a clamping pressure between the rigid component  428  and the substrate  450  such that the wicking volume reducing component  410  and the sensors  422 ,  424  are in fluidic communication at all times. The specialized module includes the following: a wicking or microfluidic component  431 ; at suite of three EAB sensors for vasopressin  432 , where the EAB sensors have a linear range of detection centered around 100 nM; an osmosis pumping material  436 ; a forward osmosis membrane  437  with a molecular weight cutoff of approximately 100 to 200 Da; a polymer seal  438 ; and a wicking pumping material  439 . 
         [0052]    With further reference to  FIG. 4 , the modular device operates as follows: the first rigid molded polymer  412  is mechanically actuated in the direction of the arrow  14  so that the first polymer  412  interacts with and lifts up the second molded polymer  414 , so that the iontophoresis electrode  419 , and sweat stimulant gel  417  are moved underneath the electroporation electrode  414  to provide iontophoretic sweat stimulation every 2 to 12 hours, or as needed. The first molded polymer  412  can then be retracted after stimulation (typically after several minutes or less). Some embodiments include an additional polymer film (not shown) that separates the sweat stimulant gel  417  from skin  12  when the first molded polymer  412  is in the retracted position to help preserve the gel and prevent potential skin irritation. Once sweat is stimulated, the electroporation electrode  414  introduces electrical current into the skin  12  at low voltage (&lt;5 V) and short (˜10 μs) pulses once every second or longer to increase the concentration of vasopressin that partitions into sweat from tissues surrounding the sweat gland. 
         [0053]    In some embodiments, the electroporation electrode  414  can also function as a skin impedance sensor, which can provide information useful for controlling the electroporation or sweat stimulation functions. The wicking volume reducing component  410  transports stimulated sweat from the skin surface and carries the sweat sample to the sensing module sensors  422 ,  424 , which would measure, e.g., Na + , K + , and pH. The sensing module may also include a sweat flow rate sensor. The wicking component  410  then transports the sweat sample to the specialized module sensors  432 , which are EAB sensors for vasopressin. The vasopressin will be concentrated as water and small sweat solutes are transported through the forward osmosis membrane  437 , into the osmosis material  436 , and out of the sweat sample. Because the sweat sample will gradually increase in vasopressin concentration as the sample moves toward the pump  439 , the sensors in the sensor suite  432  will see increasing amounts of vasopressin. By measuring vasopressin concentration with three sensors (each with ˜80× linear range), and with a measured sweat flow rate, the device determines the original sweat sample concentration of vasopressin. Finally, wicking pump  439 , which could have a total wicking capacity of 10&#39;s to 100&#39;s of μL, absorbs the sweat sample, and at least partially pulls sweat sample flow through the device. 
         [0054]    Embodiments of the present invention may be useful for a variety of sweat sensing applications. For example, low sweat rates enabled by embodiments of the present invention can also allow otherwise impractical sensing of some solutes. For example, a large sweat rate can cause sweat glands to generate significant quantities of lactate, making correlation between sweat lactate concentration and blood concentration impossible. Because embodiments of the disclosed invention are capable of detecting lactate at very low sweat generation rates, blood lactate that partitions into sweat can dominate over lactate generated by the sweat gland. Therefore, embodiments of the present invention enable improved sweat-based estimates of blood lactate. Embodiments of the present invention could also help in sensing of cytokines, which partition into sweat very slowly and require low sweat rates for accurate sweat concentrations that can be correlated with blood levels. Embodiments of the disclosed invention also improve other sensing applications by reducing the amount of stimulation needed for a given chronologically assured sampling interval by reducing the sweat volume needed by the sensors, which reduces needed sweat generation rate to refresh that sweat volume. Similarly, the present invention could also reduce the time for a new concentration of biomarkers to move from blood into sweat and onto the sensors, therefore providing sweat measurements that are closer to real time blood concentrations. 
         [0055]    This has been a description of the disclosed invention along with a preferred method of practicing the invention, however the invention itself should only be defined by the appended claims.