Patent Publication Number: US-2020275864-A1

Title: Sweat biosensing companion devices and subsystems

Description:
BACKGROUND 
     Non-invasive biosensing technologies have enormous potential for applications ranging from athletics, to neonatology, to pharmacological monitoring, to personal digital health, to name a few applications. The sweat ducts can provide a route of access to many of the same biomarkers, chemicals, or solutes that are carried in blood and can provide significant information enabling one to diagnose ailments, monitor health status, detect toxins, and monitor performance and other physiological attributes prior to other physical signs or symptoms. Sweat has many of the same analytes and analyte concentrations found in blood and interstitial fluid. Interstitial fluid has even more analytes at high concentrations than sweat does, especially for larger sized and more hydrophilic analytes such as proteins. 
     One challenge with sensing interstitial fluid is the lag time of sensor readings. Because the dermis itself does not require support of a very high amount of metabolic activity, its turnover rate for interstitial fluid is very slow (e.g., 10-30 minutes). Many sensors, be they needles, microneedles, implanted sensors in the dermis, or other biofluid compartments in the body, will therefore have sensor responses that lag behind blood concentration. For example, glucose sensors based on implanted needles can have a lag time of 10-20 minutes, and microneedle sensors that rely on diffusion of glucose to the sensor can be even slower and on the order of 20-30 minutes. Furthermore, continuous sensing could be challenging for implanted devices. For example, such devices would need to sample and sense in discrete samplings (e.g., non-continuous). 
     Eccrine sweat glands are also bathed in interstitial fluid, and many of the analytes found in sweat are transported into sweat by pathways such as paracellular pathways through the lining of the sweat gland. Analyte concentrations in sweat glands, however, can in some cases have much less lag time behind the changes of analyte concentrations in blood, as fast as 1-3 minutes depending on analyte and sweat generation rate. 
     SUMMARY 
     Many of the drawbacks and limitations stated above 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 sensing technology into intimate proximity with biofluid and analytes as they emerge from the blood compartment and into biofluid compartments such as interstitial fluid. 
     Advanced microfluidics and sensor integration strategies can allow sweat transport to sensors in just several minutes. Therefore, sweat biosensing as a companion device or subsystem for devices for sensing analytes in non-sweat biofluids could provide a potential method to correct for or mitigate the disadvantages of the lag time experienced for sensing analytes directly in non-sweat biofluids like interstitial fluid. Therefore, a sweat sensing device, which can sense sweat continuously, could be an advantageous companion device by providing continuous data. One might ask why not simply use sweat by itself for sensing the analyte, and why bother with needle, implanted, or other techniques necessary for detecting analytes in non-sweat biofluids? Detecting analytes in sweat alone may not always be superior to detecting analytes in non-sweat biofluids. For example, glucose and proteins in sweat are dilute compared to their concentrations in interstitial fluid. Furthermore, measuring biomarker panels in a temporal fashion can be limited if only a biofluid such as interstitial fluid is used, or if only sweat is utilized. Simultaneous measurements of analytes in one or more non-sweat biofluids alone or in combination with analytes in sweat may be advantageous. 
     Embodiments of the disclosed invention provide biofluid sensing devices capable of providing superior biosensing by coupling higher precision or accuracy concentration sensing of analytes in a non-sweat biofluid such as interstitial fluid with more rapid trending and continuous data provided by sensing of analytes in sweat. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The objects and advantages of the disclosed invention will be further appreciated in light of the following detailed descriptions and drawings in which: 
         FIG. 1  is a cross-sectional view of a portion of a wearable device for biosensing based on subsystems for measurement of analytes in interstitial fluid and for analytes in sweat. 
         FIG. 2  is a cross-sectional view of a portion of multiple coordinated wearable or implanted devices for biosensing based on measurement of analytes in interstitial fluid and of analytes in sweat. 
     
    
    
     DEFINITIONS 
     As used herein, “non-sweat biofluid” or “biofluid that is not sweat” means a fluid source of analytes that is not sweat. For example, a non-sweat biofluid could be a solution that bathes and surrounds tissue cells such as interstitial fluid. Embodiments of the disclosed invention may focus on interstitial fluid found in the skin and, particularly, interstitial fluid found in the dermis. However, interstitial fluid in other body compartments may also apply. Sensors could also be implanted in large arteries, the bladder, or other biofluid cavities, such that the term non-sweat biofluid may also apply to biofluids such as blood, urine, saliva, or other suitable biofluids for analyte sensing that are not sweat. 
     As used herein, “sweat” is a fluid source of analytes that is sweat from eccrine or apocrine glands. Sweat from eccrine glands may be easier to sense as apocrine glands are harder to access in their locations on the body, less controlled in sweat generation rate, and contain confounding challenges such as high bacterial counts, which can skew analyte readings. 
     As used herein, “continuous monitoring” means the capability of a device to provide at least one measurement of a biofluid, such as interstitial fluid, determined by a continuous or multiple collection and sensing of that measurement or to provide a plurality of measurements of that biofluid over time. 
     As used herein, “chronological assurance” is an assurance of the sampling rate for measurement(s) of a biofluid, such as sweat or a non-sweat biofluid like interstitial fluid, or solutes therein in terms of the rate at which measurements can be made of new biofluid or its new solutes as originating from the body. Chronological assurance may also include a determination of the effect of sensor function, potential contamination with previously generated biofluids, previously generated solutes, other fluid, or other measurement contamination sources for the measurement(s). 
     As used herein, “sampling rate” is the effective rate at which new biofluid or new solute concentrations reach a sensor that measures a property of the biofluid such as sweat or a non-sweat biofluid or the solutes therein. Sampling rate therefore could be the rate at which new biofluid is refreshed at the one or more sensors and therefore old fluid is removed as new fluid arrives. The inverse of sampling rate (1/s) could also be interpreted as a “sampling interval”. Sampling rates or intervals are not necessarily regular, discrete, periodic, discontinuous, or subject to other limitations. 
     As used herein, “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 measurement, such as ‘yes’ or ‘no’ type measurements. 
     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. 
     As used herein, “diffusion” is 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. 
     As used herein, “convection” is the concerted, collective movement of groups or aggregates of molecules within fluids and rheids, either through advection or through diffusion or a combination of both. 
     DETAILED DESCRIPTION 
     Embodiments of the disclosed invention apply at least to any type of sensor device that measures biofluid or analyte in a biofluid such as sweat, a non-sweat biofluid, or a combination of both sweat and a non-sweat biofluid. Further, embodiments of the disclosed invention apply to sensing devices, which can take on forms including adhesive patches, bands, straps, implants, transdermal patches, portions of clothing, wearables, or any suitable mechanism that reliably brings sensing technology into intimate proximity with a non-sweat biofluid, sweat, or both a non-sweat biofluid and sweat. 
     Certain illustrated embodiments of the disclosed invention show sensors as simple individual elements. It is understood that many sensors require two or more electrodes, reference electrodes, or additional supporting technology or features which are not captured in the description herein. In embodiments, sensors are preferably electrical in nature, but may also include optical, chemical, mechanical, or other known biosensing mechanisms. Sensors can be in duplicate, triplicate, or more, to provide improved data and readings. Sensors may be referred to by what the sensor is sensing, for example: a sweat sensor; an impedance sensor; a sample volume sensor; a sample generation rate sensor; and a solute generation rate sensor. Certain embodiments of the disclosed invention show sub-components of what would be sensing devices with more sub-components needed for use of the device in various applications, which are obvious (such as a battery, antenna, adhesive), and for purposes of brevity and focus on inventive aspects, such components are not explicitly shown in the diagrams or described in the embodiments of the disclosed invention. 
     Embodiments of the disclosed invention provide biofluid sensing systems capable of providing superior biosensing by coupling higher precision or accuracy concentration sensing of analytes in a first biofluid with more rapid trending and continuous data provided by sensing analytes in a second biofluid. In an exemplary embodiment the first biofluid may be a non-sweat biofluid and the second biofluid may be sweat. 
     With reference to  FIG. 1 , in an embodiment of the disclosed invention, a biofluid sensing system comprises a single device  100  that includes two subsystems  102 ,  104  for sensing analytes in different types of biofluids such as a sweat or a non-sweat biofluid or both. The device  100  is placed on or near skin  12 , which includes the epidermis  12   a  and dermis  12   b . The dermis  12   b  contains interstitial fluid. The device  100  may utilize any suitable substrate or material to hold it together, for example, such as a plastic nylon casing  110 . The device  100  contains sensors  120 ,  122 ,  124 ,  126 , each of which could be any sensor capable of measuring a property of a biofluid or an analyte in a biofluid. For example, each of the sensors  120 ,  122 ,  124 ,  126  may be an ion-selective senor, an amperometric (enzymatic) sensor, an electrochemical aptamer sensor, a fluorometric sensor, an antibody-based sensor, or may involve other suitable sensing modalities. As shown, each subsystem has a group of sensors, and each sensor in the group may be configured to sense the same or different analytes in a single type of biofluid. In the illustrated embodiment, sensors  120 ,  122  are grouped together and sensors  124 ,  126  are grouped together. It should be recognized that the number of sensors in each group of sensors may vary. 
     Each of the sensors  120 ,  122 ,  124 ,  126  may be for sensing the same or different analytes in one or more than one type of biofluid. In the illustrated embodiment, sensors  120 ,  122  are for sensing analytes in a non-sweat biofluid such as interstitial fluid, and sensors  124 ,  126  are for sensing analytes in sweat. In that regard, the device  100  includes first subsystem  102  for sensing analytes in interstitial fluid that comprises a microneedle array  180  that provides a pathway  190  for diffusion of analytes between the dermis  12   b  and the sensors  120 ,  122 . If the pathway  190  is initially dry, biofluid may also enter into the pathway  190  through the microneedle array  180  such that the analyte diffuses through the biofluid inside pathway  190  to the sensor. In another embodiment, pathway  190  may be preloaded with a fluid that allows analytes in the biofluid to diffuse from the microneedle array  180  through the fluid in pathway  190  to the sensors  120 ,  122 . The microneedle array  180  can comprise any suitable material used for fabrication of microneedle arrays, such as glass, silicon, skin-compatible metals, polymers, etc. The device  100  also includes a subsystem  104  for sensing analytes in sweat comprising a wicking component or microfluidic channel  130  to transport sweat generated on the skin  12  to the sensors  124 ,  126 . Suitable materials for the wicking component or microfluidic channel  130  include paper, rayon, and a polymer microchannel. The subsystem  104  for sensing sweat further includes a reservoir  132  for storage of old/waste sweat, which could be for example a hydrogel. Further included in the subsystem  104  for sensing sweat is a sweat stimulating component comprising a membrane  170 , a sweat stimulation gel or solution  140 , and an iontophoresis electrode  150  to drive sweat stimulants from the stimulation gel or solution  140  into the skin  12 . The stimulation gel  140  may be, for example, agar containing sweat stimulants such as pilocarpine or carbachol. Suitable materials for the membrane  170  include a forward osmosis membrane or a dialysis membrane. The membrane  170  serves to decrease fluid and or solution contamination and mixing between the stimulation gel or solution  140 , the skin  12 , and the microfluidic component  130 . 
     Still referring to  FIG. 1 , the device  100  may be applied to the skin  12 . The microneedle array  180  pierces the skin  12  to provide the pathway  190  for diffusion of analytes in a non-sweat biofluid between the dermis  12   b  and the sensors  120 ,  122 . The sensors  120 ,  122  sense the same or different analytes that diffuse through the microneedle array  180  into the pathway  190 . Additionally, the sweat sensing subsystem  104  may stimulate sweat thereunder by iontophoretically driving the sweat stimulant from the stimulation gel or solution  140  through the membrane  170  and microfluidic channel  130  into the skin  12  using the iontophoresis electrode  150 . As sweat emerges from the skin  12 , the microfluidic channel  130  transports sweat across the sensors  124 ,  126  and into the reservoir  132 . Where the subsystems are configured to sense analytes in at least two different biofluids, an effect of lag time on the measurements of an analyte in one biofluid may be determined at least in part by the measurements of an analyte in a different biofluid. For example, sensors  120  and  122  and sensors  124  and  126  could communicate with an electronic microcontroller that could be part of the device  100 . The microcontroller could communicate with a wireless communication component, such as Bluetooth, and then to a smartphone with software that could analyze the data and lag times. Applications of the device  100  are provided in the Examples below. 
     With reference to  FIG. 2 , in an embodiment of the disclosed invention, a biofluid sensing system  200  is comprised of a plurality of separate subsystems or devices  200   a ,  200   b ,  200   c . The subsystem  200   a  is a transdermal sensor that includes a sensor  220  at the end of a needle or wire  282  that extends into the skin  12 . The needle or wire  282  electrically connects the sensor  220  to the subsystem  200   a , which may also include electronics and a housing, such as a plastic housing. The needle or wire  282  may be, for example, like that used for continuous wearable glucose monitors. 
     The subsystem  200   b  is an implantable sensor system that can be electronic or optical. In the illustrated embodiment, the subsystem  200   b  is electronic and comprises, for example, a sensing and transmission component  222 , which includes a microcircuit and sensor and communication antenna, embedded in a biocompatible casing  272 . The biocompatible casing  272  may be made of, for example, a hydrogel, block co-polymer, or other suitable material that is porous to the analyte of interest. In an embodiment, an optical subsystem  200   b  could be, for example, a fluorometric or colorimetric sensor that is optically interrogated through the epidermis  12   a.    
     The subsystem  200   c  is for sensing sweat and comprises a sweat sensor  224  in a casing  210 . In various embodiments, sweat may be stimulated before the subsystem  200   c  is applied to skin or naturally induced sweat may be utilized. Alternately, sweat stimulation could be integrated into  200   c  using suitable approaches such as the approach show for the device  100 . 
     While the embodiment illustrated in  FIG. 2  includes three types of sensor subsystems  200   a ,  200   b ,  200   c , embodiments of the invention may include two of the three types of illustrated sensor subsystems. For example, an embodiment of the invention may include subsystem  200   a  and subsystem  200   b  or subsystem  200   c  and another embodiment may include subsystem  200   b  and subsystem  200   c . It is further contemplated that one or more of the subsystems  200   a ,  200   b ,  200   c  may be included in duplicate or triplicate or more. 
     In order to facilitate a more complete understanding of the embodiments of the invention, the following non-limiting examples of the device  100  are provided below. 
     Example 1 
     The physiological lag between glucose levels in the blood and in interstitial fluid can be problematic in continuous glucose monitoring if the lag isn&#39;t considered when calibrating the monitors. Patients with diabetes who want to use continuous glucose monitors need to be instructed to calibrate the devices when their glucose levels are in a steady state rather than during a period of changing glucose levels. Finger-stick monitors and the electrochemical sensors in continuous glucose monitors (CGMs) work on the same principle, based on glucose oxidase breaking down glucose and generating electrons, which are measured by the monitor&#39;s sensors. Finger-stick monitors measure serum glucose, and continuous monitors measure glucose in the interstitial fluid. When glucose levels are changing—such as rising glucose levels seen particularly after meals—there can be as much as a 30-minute delay before a changed glucose level in blood is reflected in interstitial fluid. If patients calibrate the continuous glucose monitoring devices when their glucose is changing (i.e., not in steady state), their sensor could be calibrated inaccurately and not give them reliable readings. 
     With reference to  FIG. 1 , the sensor  120  senses glucose in interstitial fluid whereas sensor  124  senses glucose in sweat. In an embodiment, both sensors  120 ,  124  include glucose oxidase enzymatic electrodes. Additionally, or alternatively, one or both of the sensors  120 ,  124  may be an electrochemical aptamer-based sensor for glucose. Additionally, or alternatively, one or both of the sensors  122 ,  126  may sense pH to account for the effects of pH on operation of the sensors  120 ,  124 , respectively. The sensor  124  can alert the user that glucose levels are changing rapidly and warn of possible inaccurate calibration or even feed into an algorithm that provides a potential accuracy level for the calibration in numeric form, or such as ‘good—fair—poor’ indications. The sensor  124  could also be used to detect the rate of change in glucose during calibration, and then couple that information with the calibration data to correct for potential error in calibration. For example, if the sensor  124  measures glucose rising at 10% every 5 minutes, and the lag time for the sensor  120  is 15 minutes, then the device  100  calibration value used based on the sensor  120  can be increased by approximately 30% due to the information provided by the sensor  124 . Devices and subsystems in  FIG. 2  could provide similar advantages. In this example, two or more of the sensors sense the same 1 st  analyte, such as glucose, with one sensor sensing the 1 st  analyte in a biofluid that is not sweat and the other sensor sensing the 1 st  analyte in sweat. 
     Example 2 
     With reference to  FIG. 2 , in an embodiment, the sensors  220 ,  222 ,  224  may each sense a different analyte. For example, the sensor  220  could be for sensing an inflammatory marker, such as cytokine, that changes slowly in the body and slowly in interstitial fluid, the sensor  222  could be a fluorometric sensor for glucose in interstitial fluid, and the sensor  224  could be a sweat sensor for cortisol. The sensor  220  could measure the longer-term effects of stressors on the body (e.g., inflammation), whereas the sensor  224  could measure the short term effects of stress on the body. For example, if a patient had a panic attack, cortisol levels could rise rapidly, and the rate of rise of cortisol as sensed by the sensor  224  could provide an indication of the severity of the panic attack. The prolonged effect of the panic attack could also be measured by sensor  220  by measuring at least one cytokine level. The glucose sensor  222  could measure the effect of diet and health on the causality of the panic attack(s). Thus, in an embodiment, two or more of the sensors are for sensing a 1 st  analyte and 2 nd  analyte that are different, one sensor sensing the 1 st  analyte in a biofluid that is not sweat and the other sensor sensing the 2 nd  analyte in sweat. 
     Example 3 
     With reference to  FIG. 1 , the sensor  120  senses vasopressin, and the sensor  124  senses Na+, which is an indicator of sweat generation rate. The sensor  124  could therefore provide a leading warning of possible dehydration before dehydration occurs as recorded by sensor  220 , which measures changes in levels of vasopressin. 
     Example 4 
     With reference to  FIG. 1 , the sensors  120 ,  124  senses glucose, the sensor  122  senses insulin, and the sensor  126  senses adrenaline or cortisol, which are released when the body senses low glucose. This combined system could measure not only glucose like that of Example 1, but also circulating concentrations of delivered insulin, and the body&#39;s rapid response to the effects of low or high glucose, for a complete monitoring system that helps a patient or user avoid hypoglycemic shock. 
     While specific embodiments have been described in detail to illustrate the disclosed invention, the description is not intended to restrict or in any way limit the scope of the appended claims to such detail. The various features discussed herein may be used alone or in any combination. Additional advantages and modifications will readily appear to those skilled in the art. The invention in its broader aspects is therefore not limited to the specific details, representative apparatus and methods and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the scope of the general inventive concept.