Method and apparatus for quantifying outward and inward dermal flux

Abstract

An apparatus for quantifying outward and / or inward dermal flux of a skin of a subject comprises one or more sensor systems, each sensor system comprising a chamber configured to be positioned immediately adjacent to a surface of the skin to define an enclosed microclimate therein and including a sensor member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin; and a valve coupled with the chamber and configured to modulate diffusive interactions with a surrounding environment, thereby modifying characteristics of the microclimate inside the chamber.

Description

[0001] Attorney Docket No.: 0116936.310WO2

[0002] METHOD AND APPARATUS FOR QUANTIFYING OUTWARD AND INWARD

[0003] DERMAL FLUX

[0004] CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0005] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 696,910, filed September 20, 2024, which is incorporated herein in its entirety by reference.

[0006] FIELD OF THE INVENTION

[0007] The invention relates generally to biosensors, and more particularly to methods and apparatuses for quantifying outward and inward dermal flux.

[0008] BACKGROUND OF THE INVENTION

[0009] The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions. Work of the presently named inventors, to the extent it is described in the background of the invention section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the invention.

[0010] The skin forms our primary interface with the surrounding environment. Passage of chemical species into and out of the surface of the skin can have profound effects on health status. These bilateral material fluxes include those associated not only with water, the most significant species due to its abundance in the body and the atmosphere, but also many types of volatile organic compounds (VOCs), carbon dioxide (CO2) and others. Bio-molecular mechanisms for cutaneous homeostasis encoded in the stratified structures of the epidermis ensure that these fluxes are balanced at certain levels. Imbalanced outward fluxes imply either degradation or anomalies in cutaneous homeostasis. Inward fluxes of exogenous substances provide a reliable metric of the health effects of such species in the atmosphere.

[0011] Unlike transdermal transport of liquids, such as sweat, existing wearable devices do not Attorney Docket No.: 0116936.310WO2 allow for continuous measurements of fluxes of gaseous species. Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.

[0012] SUMMARY OF THE INVENTION

[0013] In one aspect, the invention relates to an apparatus for quantifying outward and / or inward dermal flux of a skin of a subject, comprising one or more sensor systems. Each sensor system comprises a chamber configured to be positioned immediately adjacent to a surface of the skin to define an enclosed microclimate therein and including a sensor member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin; and a valve coupled with the chamber and configured to modulate diffusive interactions with a surrounding environment, thereby modifying characteristics of the microclimate inside the chamber.

[0014] In one embodiment, the chamber is configured to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

[0015] In one embodiment, the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified using the sensor member.

[0016] In one embodiment, when the chamber is an open state, a basal flux passes in or out through the opening, and wherein rapid (<10 ms) closing of the chamber yields dynamic changes in the concentrations of the targeted species in the microclimate, which are dictated by flux into or out of the skin.

[0017] In one embodiment, the sensor member comprises a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

[0018] In one embodiment, the targeted species comprise water vapor, volatile organic compounds (VOCs), and / or carbon dioxide (CO2).

[0019] In one embodiment, the plurality of off-skin sensors comprises a gas sensor for measuring the fluxes of the targeted species in the microclimate, and a temperature sensor for measuring the temperature in the microclimate.

[0020] In one embodiment, the sensor member further comprises one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity. Attorney Docket No.: 0116936.310WO2

[0021] In one embodiment, the one or more on-skin sensors comprise one or more temperature sensors, one or more impedance sensors, one more thermal conductivity sensors, one or more transient plane source (TPS) sensors, and / or one or more skin hydration sensors.

[0022] In one embodiment, the modulations associated with cycles of valve opening and closing render opposite variations in the microclimate, corresponding to the outflux and influx of these gaseous substances at the skin surface.

[0023] In one embodiment, the valve is configured to dynamically control access to the surrounding environment, thereby creating a transient response that is quantitatively related to inward and outward flux of the targeted species through analysis of the time dependent measurements by the sensor member.

[0024] In one embodiment, the valve is a programmable valve or switch that is configured to operably be in an open state or a close state.

[0025] In one embodiment, when the valve is in the open state, the chamber is in an open state in which the microclimate is in fluidic communications with the surrounding environment, and when the valve is in the close state, the chamber is in a close state in which the microclimate is not in fluidic communications with the surrounding environment.

[0026] In one embodiment, the valve comprises a magnetic bistable valve mechanism.

[0027] In one embodiment, the valve comprises a pair of magnet members, a plunger positioned between the pair of magnet members and in relation with the chamber, and an electromagnetic (EM) coil configured to actuate the plunger to switch the chamber between the open state and the close state across a bistable magnetic potential created by the pair of magnet members.

[0028] In one embodiment, the pair of magnet members is formed of a soft magnetic material; the plunger is formed of a hard magnetic material having permanent magnetism; and the EM coil includes a multilayer PCB (printed circuit board) coil.

[0029] In one embodiment, the plunger is in the form of a disc and is operably attracted or repelled by the EM coil situated on a top of the valve, and wherein the pair of magnet members is in the form of paramagnetic rings and operably holds the plunger in place when the plunger reaches both ends of the operating area.

[0030] In one embodiment, the opening and closing of the valve are determined by the position of the plunger inside the valve.

[0031] In one embodiment, to close the valve, thereby closing the chamber, a current is applied to the EM coil in the direction that pushes the plunger away, and wherein the current in the opposite direction is applied to attract the plunger back to open the chamber, thereby opening the Attorney Docket No.: 0116936.310WO2 chamber.

[0032] In one embodiment, each sensor system further comprises a control unit configured to perform operational control, data acquisition and two-way wireless communication with a user interface operating on an external device.

[0033] In one embodiment, the user interface is configured to support the operational control of the sensor member and the valve, and / or serve as an interface to display the measured data, and / or monitor conditions of the subject.

[0034] In one embodiment, the external device includes a mobile device, a smartphone, a tablet, a computer, a cloud server, and / or any electronic device with data reading / processing / displaying capability.

[0035] In one embodiment, the control unit comprises a microcontroller electrically coupled with the sensor member and the valve, and configured to receive operating parameters wirelessly specified through the user interface from the external device; actuate the valve to modify the characteristics of the microclimate based on the operating parameters; control the sensor member to measure the properties of the skin and the concentrations of the targeted species in the microclimate inside the chamber based on the operating parameters; and receive data measured from the sensor member and wirelessly transmit the received data to the external device for data processing therein.

[0036] In one embodiment, the valve is actuated through a series of voltage adjustments in response to instructions from the microcontroller.

[0037] In one embodiment, the microcontroller is integrated with a system-on-chip (SoC) and a built-in antenna.

[0038] In one embodiment, the control unit further comprises a power management circuit including a low-dropout (LDO) regulator electronically coupled with a power supply for providing power to the sensor system and a boost converter electronically coupled with the microcontroller and the LDO regulator for voltage boosting.

[0039] In one embodiment, the power supply comprises a rechargeable battery.

[0040] In one embodiment, the control unit further comprises an H-bridge circuit electronically coupled with the microcontroller, the boost converter, and the EM coil for actuating the EM coil to operate the plunger with a voltage with a specific polarity and within a defined duration under the control of the microcontroller.

[0041] In one embodiment, each sensor system further comprises a sensor-valve platform comprising first, second and third decks, which, in combination with the chamber, are located on Attorney Docket No.: 0116936.310WO2 the skin, inside the chamber, and on a top of the chamber, respectively, to accommodate the on- skin sensors, the off-skin sensors, and the EM coil for valve actuation.

[0042] In one embodiment, said one or more sensor systems are operably mounted onto one or more locations across the body for quantitative monitoring of the transdermal flux of multiple species simultaneously.

[0043] In one embodiment, said one or more sensor systems are time-synchronized to each other.

[0044] In one embodiment, the measured properties of the skin and the measured concentrations of the targeted species in the microclimate have distinct relevance to clinical care and / or exposure to hazardous vapors.

[0045] In one embodiment, the apparatus is usable for the clinical care related to assessments of skin barrier function, full body homeostasis, environmental safety, and / or wound healing.

[0046] In one embodiment, the apparatus is usable for monitoring healing processes associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone- associated disruption of the skin.

[0047] In one embodiment, the apparatus is usable for aiding in clinical decision making for care of conditions associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone-associated disruption of the skin.

[0048] In one embodiment, the apparatus is usable for early detection of the onset of organ dysfunction or cancer.

[0049] In one embodiment, the apparatus is usable for monitoring entry of hazardous chemicals from the environment into the body through the skin.

[0050] In another aspect, the invention relates to a method for quantifying outward and / or inward dermal flux of a skin of a subject, comprising defining an enclosed microclimate immediately adjacent to a surface of the skin, wherein the microclimate is in fluidic communication with the surface of the skin; modulating diffusive interactions of the microclimate with a surrounding environment, thereby modifying characteristics of the microclimate therein; measuring properties of the skin and concentrations of targeted species that emerge from or pass into the skin in the microclimate; and processing the measured properties of the skin and the measured concentrations of the targeted species to quantify the outward and / or inward dermal flux of the skin.

[0051] In one embodiment, the targeted species comprise water vapor, volatile organic compounds (VOCs), and / or carbon dioxide (CO2). Attorney Docket No.: 0116936.310WO2

[0052] In one embodiment, the properties of the skin comprise skin temperature, galvanic response, thermal conductivity, and / or skin hydration.

[0053] In one embodiment, the microclimate is defined by a chamber to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

[0054] In one embodiment, the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified.

[0055] In one embodiment, when the chamber is an open state, a basal flux passes in or out through the opening, and wherein rapid (<10 ms) closing of the chamber yields dynamic changes in the concentrations of the targeted species in the microclimate, which are dictated by flux into or out of the skin.

[0056] In one embodiment, said modulating the diffusive interactions of the microclimate is performed by actuating a valve coupled with the chamber to be operably in an open state or a close state.

[0057] In one embodiment, when the valve is in the open state, the chamber is in an open state in which the microclimate is in fluidic communications with the surrounding environment, and when the valve is in the close state, the chamber is in a close state in which the microclimate is not in fluidic communications with the surrounding environment.

[0058] In one embodiment, said measuring the properties of the skin and the concentrations of targeted species is performed by a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

[0059] In one embodiment, said measuring the properties of the skin and the concentrations of targeted species is further performed by one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

[0060] In one embodiment, said processing the measured properties of the skin and the measured concentrations of the targeted species is performed by an external device including a mobile device, a smartphone, a tablet, a computer, a cloud server, and / or any electronic device with data reading / processing / displaying capability.

[0061] In one embodiment, the measured properties of the skin and the measured concentrations of the targeted species in the microclimate have distinct relevance to clinical care and / or Attorney Docket No.: 0116936.310WO2 exposure to hazardous vapors.

[0062] In one embodiment, the method is usable for the clinical care related to assessments of skin barrier function, full body homeostasis, environmental safety, and / or wound healing.

[0063] In one embodiment, the method is usable for monitoring healing processes associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone- associated disruption of the skin.

[0064] In one embodiment, the method is usable for aiding in clinical decision making for care of conditions associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone-associated disruption of the skin.

[0065] In one embodiment, the method is usable for early detection of the onset of organ dysfunction or cancer.

[0066] In one embodiment, the method is usable for monitoring entry of hazardous chemicals from the environment into the body through the skin.

[0067] In a further aspect, the invention relates to a skin-interfaced apparatus comprising a chamber configured to define an enclosed microclimate adjacent to the skin; a valve that modulates diffusive interactions between the microclimate and the ambient; and a sensor member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin.

[0068] In one embodiment, the valve is configured to dynamically control access to the surrounding environment, thereby creating a transient response that is quantitatively related to inward and outward flux of the targeted species through analysis of the time dependent measurements by the sensor member.

[0069] In one embodiment, the valve is a programmable valve or switch that is configured to operably be in an open state or a close state.

[0070] In one embodiment, the valve is a magnetically actuated, bistable valve with sub- 10 ms actuation for generating transient concentration profiles directly linked to flux.

[0071] In one embodiment, the chamber is configured to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

[0072] In one embodiment, the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified using the sensor member.

[0073] In one embodiment, the sensor member comprises a plurality of off-skin sensors Attorney Docket No.: 0116936.310WO2 suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

[0074] In one embodiment, the plurality of off-skin sensors comprises a gas sensor for measuring the fluxes of the targeted species in the microclimate, and a temperature sensor for measuring the temperature in the microclimate.

[0075] In one embodiment, the sensor member further comprises one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

[0076] In one embodiment, the one or more on-skin sensors comprise one or more temperature sensors, one or more impedance sensors, one more thermal conductivity sensors, one or more transient plane source (TPS) sensors, and / or one or more skin hydration sensors.

[0077] These and other aspects of the invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.

[0078] BRIEF DESCRIPTION OF THE DRAWINGS

[0079] The accompanying drawings illustrate one or more embodiments of the invention and together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.

[0080] FIG. 1 shows schematically a skin-interfaced system for epidermal flux monitoring according to embodiments of the invention. Panel a, Illustration of various epidermal fluxes, including water vapor, carbon dioxide (CO2), and volatile organic compounds (VOC). Panel b, Images of epidermal flux sensor (EFS) systems mounted on the skin with major units highlighted: the sensor-valve unit and circuit-battery assembly. Scale bar, 1 cm. Panel c, Cross- sectional (left) and bottom-view (right) illustrations of the sensor-valve unit, featuring the major components: a skin-interfaced chamber with gas and temperature sensors, an electromagnetic valve, and skin-interfaced sensors for temperature, electrical impedance, and thermal conductivity. Panel d, Magnetic bistable valve mechanism for power-efficient actuation. Panel e, Time series data from gas sensors as the valve opens and closes through multiple cycles, showing effects from outflux (upper, biogenic water vapor) and influx (lower, atmospheric ethanol vapor) cases. Panel f, A single measurement signal. The initial slope of the signal reflects Attorney Docket No.: 0116936.310WO2 the flux density, f, just before the valve closes to isolate the chamber. The k is the correction coefficient that accounts for the spatiotemporal nonuniformity of concentrations in the microclimate of the isolated chamber.

[0081] FIG. 2 shows schematically monitoring of skin barrier properties and fluid loss through measurements of water flux according to embodiments of the invention. Panel a, Epidermal water flux (fw) and its contributions from transepidermal water loss (TEWL; fTEWL) and evaporation of sweat (fse). Panel b, Resistance model of the epidermal water transport. The effective diffusive resistances, RTEWL and / ?se, forming Rsas a parallel connection. The Raand Rdware constants. Panel c, Computational analysis results that indicate that Rdwis invariant to Rsand skin temperature Ts. Panel d, An exponential decrease in the skin impedance (rs) follows from different levels of perspiration. Skin barrier assessment is most valid at the ‘Absent’ regime. Panel e, The Rsrecovery after partial removal of the stratum corneum (SC), (n = 5) Panel f, Comparisons to measurements with conventional clinical apparatus indicate linear correlations (r = 0.98). Location, 3 cm below the antecubital fossa. Clinical conditions in red. (n = 14) Panels g-j, Monitoring of fluid balance through measurements of water flux. Panel g, Time series data for detemining fwat six representative skin regions. The periodic positive variations allow for flux measurements. Panel h, Agreement between the estimated epidermal water loss Esum) and body mass loss (BML). The data in blue follows from the recordings in Panel h. Panel i, Collective data from five measurements of three subjects, (r = 0.99) Panel j, A reduced set of skin regions (anterior thigh and posterior lower leg) yields a similar correlation level, (r = 0.99).

[0082] FIG. 3 shows schematically epidermal flux of VOCs, CO2, and exogenous agents according to embodiments of the invention. Panel a, Illustration of modes of VOC and CO2 fluxes at the skin, associated with epidermal hygiene status and environmental safety. Panel b, Example of outward (upper) and inward (lower) epidermal VOC fluxes. Panels c-d, Epidermal flux for hygiene assessment. Panel c, Changes of epidermal VOC flux density by skin hygienic status. Panel d, Time series data associated with outward flux of CO2, corresponding to higher and lower diffusive resistances. Panels e-i, Epidermal flux and environmental skin assaults. Panel e, Illustration of the concept of transepidermal chemical diffusive resistance. Panel f, Changes in the ethanol vapor concentration in the chamber microclimate for cases with (grey) and without (green) an aluminum foil barrier. Panel g, Comparison of water (RSw) and ethanol (RsEt0H) diffusive resistances with three skin conditions: with and without aluminum barrier and Attorney Docket No.: 0116936.310WO2 with compromised SC. Panels h-i, Epidermal outward flux of VOCs in response to radiative assaults. Panel h, VOC flux following UV irradiation of porcine skin (ex vivo). Panel i, Increase in the flux density with increasing irradiation dosage.

[0083] FIG. 4 shows schematically monitoring of outward VOC and water flux for applications in wound healing according to embodiments of the invention. Panel a, Compromised skin barriers at wounds result in elevated epidermal flux, both outward and inward. Panel b, Transitions of water vapor (left) and VOC (right) flux values throughout the wound healing process of a normal mouse model. Panel c, Normalized recovery parameters (WC for wound closure and BR for barrier restoration) and VOC flux changes for normal (upper, n = 7) and type- 2 diabetic (lower, n = 12) mice. The time axis is shared. The vertical dashed lines mark the healing completion. Panel d, Visual transition of the wound sites of the two groups. Panel e, Comparison of normal and diabetic wound healing pathways by water vapor flux (fw) analysis. Panel f, Immunofluorescence analysis of delayed keratinocyte terminal differentiation of diabetic group. Left: Stained dissection images of the wound tissues. (Green: CK14, Red: Filaggrin) Right: Post-closure Filaggrin activity increase. The dashed line is the native level. Scale bar, 50 pm. Panel g, Early increases in the VOC flux (fvoc) indicate the normal and anomalous inflammatory phases of the normal and diabetic mice groups. The dashed line is the native level. Panel h, Wound infection monitoring capability. Onset and exponential increase of VOC emission from E. coli-loaded ex-vivo porcine wound models captured by EFS.

[0084] FIG. 5 shows schematically the architecture, integration scheme, and illustration of the electronics and electromagnetic mechanical structures of the EFS according to embodiments of the invention. Panel a, Image of the circuit with highlighted major components. Scale bar, 1 cm. Panel b, Integration of the sensor platform into the chamber. Panel c, Magnified image of the control circuit unit with main functional subunits - ISP (Antenna integrated MCU), Battery Charger, LDO, Boost Converter, and H-bridge. Scale bar, 3 mm. Panel d, Schematic diagram of the circuit architecture. The MCU unit orchestrates the coil actuation system, gas sensor-valve system, and skin-contacting sensors. The data collected and processed at the MCU passes via the Bluetooth low energy (BLE) protocols through an antenna that integrates with the MCU in a single ISP package. Commands pass from a user interface on a smartphone to the device using the same BLE process.

[0085] FIG. 6 shows schematically microclimate control using electromagnetic valve according to embodiments of the invention. Panel a, Cross-sectional schematic illustration of an EFS in the open state. PM ring corresponds to the paramagnetic ring. Panel b, Schematic illustration of the Attorney Docket No.: 0116936.310WO2 signal flow during valve actuation and the resulting measurement method. Panel c, Schematic showing the movement of the plunger and the resulting change in ccvalue.

[0086] FIG. 7 shows schematically the diffusive mass transport model of the EFS according to embodiments of the invention. Panel a, Concentration distribution of gaseous substances in open (left) and closed (right, at 30 s after the isolation) states of the EFS, generated by the diffusive mass transfer model. The boundary conditions (BC-1, 2, and 3) are highlighted. Panel b, Time series change of the spatial flux density inside the chamber after the valve is closed. The timevarying nonuniformity lasts for the first few seconds of the chamber isolation. Unlike in a, the color gamut denotes the flux density. Panel c, Time dependent changes in f , dcc / dt, and corresponding k values after the chamber is closed. The value of k converges to a level <ZcJt=0), of which the value depends on the diffusivity of the substance in air. Results correspond to the case when D = 5 mm2 / s. The initial dynamic changes are highlighted in red. Panel d, Plot showing that the value of fcjt=ois invariant to the temperature and diffusive resistance of the skin (f?s). Results when D = 5 mm2 / s. Panel e, Plot showing that the variation in the value of kjt=owith diffusivity in air. Different values apply to the compensation for each gaseous substance.

[0087] FIG. 8 shows Panel a, Graphical definition of sensor latency, T. Panel b, Application of the T definition to continuous actual change and the resulting derivation of the governing differential equation.

[0088] FIG. 9 shows an analogous resistance model. Panel a, Schematic representation of process for evaluating (Rs, f) from EFS data. Panel b, Fraction of Rdto Rdland Rd2. Panel c, Rdland Rd2, invariant to Rs. Data when D = 5 mm2 / s. Panel d, Derivation of Ac by introducing Rd2. Panel e, Results of Rsmeasurements on a PDMS membrane (86 i m thick) artificial skin model. Data in the left and right graphs are identical. Panel f, Values of Rswith various PDMS membrane thicknesses. Resulting DPDMSW= 7.3 x 10-3mm2 / s.

[0089] FIG. 10 shows a system for measuring the impedance of the skin and the near-surface regions of the skin. Panel a, Skin impedance measurement unit at the bottom of the EFS. Panel b, Changes in the impedance measurement values (rs) and the chamber absolute humidity (cCw) induced by various levels of perspiration. Panel c, Illustration of a possible scenarios for reduction in rs.

[0090] FIG. 11 shows measurements of water flux during sleep, after disruption of the stratum comeum and after application of an occlusive cream. Panel a, Continuous, overnight epidermal water flux measurement using the EFS. The value of the chamber absolute humidity (ccupper) Attorney Docket No.: 0116936.310WO2 and the processed flux density (fw) and skin diffusive resistance (RSw) are inthe below. Panel b, Left, Changes in cCwfollowing tape stripping and subsequent application and washing out of occlusive cream. Right, the processed data of RSw, highlighting the effects of the SC and occlusive cream in transepidermal water transport. Panel c, Left, Restoration of skin barrier function from abrasions of the skin. Barrier recovery (BR) is defined in EXAMPLE 1. Right, The digital images of abrasions by elapsed days. Dashed circles for measurement locations. Scale bar, 1 cm.

[0091] FIG. 12 shows basic measurements for selecting representative measurement skin locations for epidermal water loss. Panel a, Baseline measurement locations based on the Lund and Browder chart and digital images of the actual measurement. Panel b, Diffusive resistance (RSw) measurements by skin region (left) and their descending sorting data (right). Panel c, Values of r, the ratio of regional skin area to BSA, by skin region. Weighted permeability data sorted in descending order (Panel d), and cumulative ratio of estimated water loss by regions (Panel e).

[0092] FIG. 13 shows experimental data of fluid balance monitoring by the EFS. Data collected over 3 h from six skin locations of subject- 1 (Panel a, 181 cm, 88 kg, M), subject-2 (Panel b and Panel c, 168 cm, 66 kg, M), and subject-3 (Panel d, 157 cm, 51 kg, F).

[0093] FIG. 14 shows Panel a, Exploded schematic illustration of the sample enclosure for ex- vivo skin experiments. Panel b, Sample and sensor integration sequence. Panel c, Cross-sectional illustration near the skin sample.

[0094] FIG. 15 shows Panel a, Enclosure with a porcine skin sample loaded. Panels b-c, IR images of the field-of-view marked with the dashed rectangle in a, before (Panel b) and after (Panel c) a UV irradiation for 10 min.

[0095] FIG. 16 shows the association between delayed wound healing and compromised barrier restoration. Panel a, H&E staining images of samples from normal and diabetic mice served as comparisons between native skin and after wound closure. Following complete wound closure, all groups exhibited full epidermal growth. Scale bar, 100 pm. Panel b, Epidermis-highlighted images for unwounded, D+30, D+37, and D+44 post-closure of diabetic mice. After full wound closure, all groups showed intact stratified epithelial structures, including the stratum corneum (above the yellow dotted line). Scale bar, 25 pm. Panel c, Immuno-fluorescence staining of CK14 and Filaggrin Panel d, Keratin 14 shows native levels of signal immediately after wound closure. Filaggrin, which is synthesized in the stratum granulosum and represents terminal Attorney Docket No.: 0116936.310WO2 differentiation of keratinocytes, slowly increases over the course of about two weeks after wound closure. The tables display p-values from t-tests for each of proteins. Scale bar, 50 pm.

[0096] FIG. 17 shows changes in appearance of ex vivo wound samples, comparing the control (Panel a) with E. coli loaded samples (Panel b), both before and after a 20-h incubation period. The liquids on the surface of the as-prepared samples are pure broth and E. coli-loaded broth, respectively.

[0097] FIG. 18 shows cartoon depictions of promising applications of the EFS. Panel a, Various EFS coupling strategies. Panel b, Concept of a sensor-integrated smart dressing. Panels c-d, Opportunities in medicine. Homeostasis monitoring of patients for (Panel c), normal (Panel d) and chronic (Panel e) wound management and tracking. Panel f, Multifaceted skin barrier function monitoring opportunities for vulnerable populations. Panel g, Disease control opportunity via comprehensive assessment of hygiene status of individuals.

[0098] DETAILED DESCRIPTION OF THE INVENTION

[0099] The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.

[0100] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no Attorney Docket No.: 0116936.310WO2 way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0101] One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0102] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.

[0103] It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0104] It will be understood that when an element is referred to as being “on”, “attached” to, “connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed Attorney Docket No.: 0116936.310WO2

[0105] “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0106] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.

[0107] Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element’s relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.

[0108] It will be further understood that the terms “comprises” and / or “comprising”, or “includes” and / or “including”, or “has” and / or “having”, or “carry” and / or “carrying”, or “contain” and / or “containing”, or “involve” and / or “involving”, “characterized by”, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this disclosure, they specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0109] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the invention, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0110] As used in the disclosure, “around”, “about”, “approximately” or “substantially” shall Attorney Docket No.: 0116936.310WO2 generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated.

[0111] As used in the disclosure, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0112] The term “flexibility” or “bendability”, as used in the disclosure, refers to the ability of a material, structure, device or device component to be deformed into a curved or bent shape without undergoing a transformation that introduces significant strain, such as strain characterizing the failure point of a material, structure, device or device component. In an exemplary embodiment, a flexible material, structure, device or device component may be deformed into a curved shape without introducing strain larger than or equal to 5%, for some applications larger than or equal to 1%, and for yet other applications larger than or equal to 0.5% in strain-sensitive regions. A used herein, some, but not necessarily all, flexible structures are also stretchable. A variety of properties provide flexible structures (e.g., device components) of the invention, including materials properties such as a low modulus, bending stiffness and flexural rigidity; physical dimensions such as small average thickness (e.g., less than 100 microns, optionally less than 10 microns and optionally less than 1 micron) and device geometries such as thin film and open or mesh geometries.

[0113] The term “bending stiffness” refers to a mechanical property of a material, device or layer describing the resistance of the material, device or layer to an applied bending moment. Generally, bending stiffness is defined as the product of the modulus and area moment of inertia of the material, device or layer. A material having an inhomogeneous bending stiffness may optionally be described in terms of a “bulk” or “average” bending stiffness for the entire layer of material.

[0114] Embodiments of the invention are illustrated in detail hereinafter with reference to accompanying drawings. The description below is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar Attorney Docket No.: 0116936.310WO2 elements. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the invention.

[0115] All existing wearable technologies rely on physical coupling to the body to establish optical, fluidic, thermal, and / or mechanical, measurement interfaces.

[0116] This invention in certain aspects introduces a fundamentally new approach to wearable biosensing by integrating programmable microclimate modulation, hybrid multi-modal sensing, and wireless control into a non-contact, skin-mounted system, which provides a class of wearable device platform that relies instead on physical decoupling to define an enclosed chamber immediately adjacent to the surface of the skin. Streams of vaporized molecular substances that pass out of or into the skin alter the properties of the microclimate defined within this chamber in ways that can be precisely quantified using an integrated collection of wireless sensors. A programmable, bistable valve dynamically controls access to the surrounding ambient, thereby creating a transient response that can be quantitatively related to the inward and outward flux of targeted species through analysis of the time dependent readings from the sensors. The systems disclosed in the disclosure offer unique capabilities in measuring the flux of water vapor, volatile organic compounds (VOCs), and carbon dioxide from various locations on the body, each with distinct relevance to clinical care and / or exposure to hazardous vapors. Studies of healing processes associated with dermal wounds in normal and diabetic small animal models and of responses in infected wounds of large animal models reveal characteristic variations in flux that provide important insights, as use cases where the non-contact operation of the devices avoids potential damage to fragile tissues.

[0117] Among other things, the invention provides the novel features including, but are not limited to:

[0118] Quantification of both outward and inward dermal flux'. Existing wearable devices are limited to outward liquid transport (e.g., sweat). The claimed system / apparatus uniquely enables continuous, bilateral measurement of gaseous species, including water vapor, volatile organic compounds (VOCs), and carbon dioxide (CO2), emerging from and entering into the skin.

[0119] Microclimate confinement via Nilsson ’s zone'. The invention introduces a skin-interfaced chamber that defines a controlled microclimate immediately above the skin, capturing the boundary layer of stationary air (Nilsson’s zone) for precise flux quantification, which has not been taught in the art.

[0120] Programmable bistable electromagnetic valve. The system employs a novel magnetic bistable valve, comprising a plunger, electromagnetic coil, and paramagnetic rings, to achieve Attorney Docket No.: 0116936.310WO2 ultra-fast (<10 ms) open / close actuation with minimal power consumption. This design allows modulation of diffusive interactions with the environment to induce measurable transient responses directly correlated with dermal flux.

[0121] Hybrid sensor integration'. The system combines off-skin suspended gas and temperature sensors with on-skin impedance, hydration, and thermal conductivity sensors. This hybrid arrangement provides complementary data on both environmental fluxes and intrinsic skin properties, a feature absent from conventional devices.

[0122] Non-contact sensing paradigm : Unlike existing wearables that require fluidic or mechanical coupling to the skin, the claimed system operates through non-contact vapor flux monitoring, thereby reducing tissue disturbance and enabling application on fragile surfaces such as wounds.

[0123] Wireless, multi-site deployment. The integration of a system-on-chip microcontroller, Bluetooth Low Energy communication, and rechargeable battery allows multiple synchronized units to be distributed across the body, enabling real-time whole-body flux monitoring.

[0124] Dynamic microclimate modulation'. The concept of deliberately creating transient microclimate changes through rapid valve actuation and extracting physiological flux information from resulting temporal concentration profiles is not obvious from known continuous sensing techniques.

[0125] Correction modeling for flu density'. The development of computational models and compensation schemes that account for spatiotemporal non-uniformity and occlusive effects of sensors represents a significant technical contribution, enabling accurate determination of natural dermal flux from transient signals.

[0126] Cross-parameter integration. The combination of bilateral gaseous flux measurements with simultaneous skin impedance, hydration, and thermal metrics provides a multidimensional physiological profile. This integrated approach yields insights into barrier function, metabolic state, and environmental exposure, which are not derivable from single-sensor systems.

[0127] Miniaturized, programmable architecture'. The integration of a bistable valve, hybrid sensing suite, and wireless control circuitry into a compact, skin-mounted platform represents a non-obvious engineering achievement over traditional benchtop or invasive systems.

[0128] Application-driven innovation'. The invention enables new use cases — such as non- invasive wound infection monitoring via VOC flux, diabetic wound healing assessment, detection of environmental toxin ingress, and systemic disease monitoring — none of which are achievable with conventional wearable sensors. Attorney Docket No.: 0116936.310WO2

[0129] These features provide significant clinical, technical, and societal advances including, but are not limited to:

[0130] Technical Advantages'. It is a first wearable platform enabling continuous bilateral dermal flux monitoring of gases. Magnetic bistable valve provides rapid actuation with ultra-low power consumption. Synchronized multi-sensor arrays across the body permit whole-body assessment of insensible water loss and metabolic status. Compensation algorithms ensure translation of transient microclimate data into accurate physiological flux metrics.

[0131] Clinical and Practical Advantages'. Non-invasive wound monitoring, including early infection detection and barrier restoration assessment without disturbing fragile tissues. Quantitative wound healing trajectories distinguishing normal from impaired (e.g., diabetic) healing processes. Environmental exposure monitoring for hazardous vapors, ozone, and radiative insults. Skin barrier function evaluation for dermatological diseases, burns, and radiation injuries. Early systemic disease detection, including potential biomarkers for organ dysfunction and cancer.

[0132] Broader Impact. Establishes new physiological biomarkers related to hydration, metabolism, and environmental safety. Enables population-scale hygiene and disease control monitoring through scalable, wireless deployment. Provides a transformative platform for clinical decision support, home-based care, and occupational safety monitoring.

[0133] Without intent to limit the scope of the invention, examples according to the embodiments of the invention are given below.

[0134] In some embodiments, the apparatus for quantifying outward and / or inward dermal flux of a skin of a subject comprises one or more sensor systems. Each sensor system comprises a chamber configured to be positioned immediately adjacent to a surface of the skin to define an enclosed microclimate therein and including a sensor member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin; and a valve coupled with the chamber and configured to modulate diffusive interactions with a surrounding environment, thereby modifying characteristics of the microclimate inside the chamber.

[0135] In some embodiments, the chamber is configured to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

[0136] In some embodiments, the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate Attorney Docket No.: 0116936.310WO2 in ways that are precisely quantified using the sensor member.

[0137] In some embodiments, when the chamber is an open state, a basal flux passes in or out through the opening, and wherein rapid (<10 ms) closing of the chamber yields dynamic changes in the concentrations of the targeted species in the microclimate, which are dictated by flux into or out of the skin.

[0138] In some embodiments, the sensor member comprises a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

[0139] In some embodiments, the targeted species comprise water vapor, volatile organic compounds (VOCs), and / or carbon dioxide (CO2).

[0140] In some embodiments, the plurality of off-skin sensors comprises a gas sensor for measuring the fluxes of the targeted species in the microclimate, and a temperature sensor for measuring the temperature in the microclimate.

[0141] In some embodiments, the sensor member further comprises one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

[0142] In some embodiments, the one or more on-skin sensors comprise one or more temperature sensors, one or more impedance sensors, one more thermal conductivity sensors, one or more transient plane source (TPS) sensors, and / or one or more skin hydration sensors.

[0143] In some embodiments, the modulations associated with cycles of valve opening and closing render opposite variations in the microclimate, corresponding to the outflux and influx of these gaseous substances at the skin surface.

[0144] In some embodiments, the valve is configured to dynamically control access to the surrounding environment, thereby creating a transient response that is quantitatively related to inward and outward flux of the targeted species through analysis of the time dependent measurements by the sensor member.

[0145] In some embodiments, the valve is a programmable valve or switch that is configured to operably be in an open state or a close state.

[0146] In some embodiments, when the valve is in the open state, the chamber is in an open state in which the microclimate is in fluidic communications with the surrounding environment, and when the valve is in the close state, the chamber is in a close state in which the microclimate is not in fluidic communications with the surrounding environment.

[0147] In some embodiments, the valve comprises a magnetic bistable valve mechanism. Attorney Docket No.: 0116936.310WO2

[0148] In some embodiments, the valve comprises a pair of magnet members, a plunger positioned between the pair of magnet members and in relation with the chamber, and an electromagnetic (EM) coil configured to actuate the plunger to switch the chamber between the open state and the close state across a bistable magnetic potential created by the pair of magnet members.

[0149] In some embodiments, the pair of magnet members is formed of a soft magnetic material; the plunger is formed of a hard magnetic material having permanent magnetism; and the EM coil includes a multilayer PCB (printed circuit board) coil.

[0150] In some embodiments, the plunger is in the form of a disc and is operably attracted or repelled by the EM coil situated on a top of the valve, and wherein the pair of magnet members is in the form of paramagnetic rings and operably holds the plunger in place when the plunger reaches both ends of the operating area.

[0151] In some embodiments, the opening and closing of the valve are determined by the position of the plunger inside the valve.

[0152] In some embodiments, to close the valve, thereby closing the chamber, a current is applied to the EM coil in the direction that pushes the plunger away, and wherein the current in the opposite direction is applied to attract the plunger back to open the chamber, thereby opening the chamber.

[0153] In some embodiments, each sensor system further comprises a control unit configured to perform operational control, data acquisition and two-way wireless communication with a user interface operating on an external device.

[0154] In some embodiments, the user interface is configured to support the operational control of the sensor member and the valve, and / or serve as an interface to display the measured data, and / or monitor conditions of the subject.

[0155] In some embodiments, the external device includes a mobile device, a smartphone, a tablet, a computer, a cloud server, and / or any electronic device with data reading / processing / displaying capability.

[0156] In some embodiments, the control unit comprises a microcontroller electrically coupled with the sensor member and the valve, and configured to receive operating parameters wirelessly specified through the user interface from the external device; actuate the valve to modify the characteristics of the microclimate based on the operating parameters; control the sensor member to measure the properties of the skin and the concentrations of the targeted species in the microclimate inside the chamber based on the operating parameters; and receive data measured Attorney Docket No.: 0116936.310WO2 from the sensor member and wirelessly transmit the received data to the external device for data processing therein.

[0157] In some embodiments, the valve is actuated through a series of voltage adjustments in response to instructions from the microcontroller.

[0158] In some embodiments, the microcontroller is integrated with a system-on-chip (SoC) and a built-in antenna.

[0159] In some embodiments, the control unit further comprises a power management circuit including a low-dropout (LDO) regulator electronically coupled with a power supply for providing power to the sensor system and a boost converter electronically coupled with the microcontroller and the LDO regulator for voltage boosting.

[0160] In some embodiments, the power supply comprises a rechargeable battery.

[0161] In some embodiments, the control unit further comprises an H-b ridge circuit electronically coupled with the microcontroller, the boost converter, and the EM coil for actuating the EM coil to operate the plunger with a voltage with a specific polarity and within a defined duration under the control of the microcontroller.

[0162] In some embodiments, each sensor system further comprises a sensor-valve platform comprising first, second and third decks, which, in combination with the chamber, are located on the skin, inside the chamber, and on a top of the chamber, respectively, to accommodate the on- skin sensors, the off-skin sensors, and the EM coil for valve actuation.

[0163] In some embodiments, said one or more sensor systems are operably mounted onto one or more locations across the body for quantitative monitoring of the transdermal flux of multiple species simultaneously.

[0164] In some embodiments, said one or more sensor systems are time-synchronized to each other.

[0165] In some embodiments, the measured properties of the skin and the measured concentrations of the targeted species in the microclimate have distinct relevance to clinical care and / or exposure to hazardous vapors.

[0166] In some embodiments, the apparatus is usable for the clinical care related to assessments of skin barrier function, full body homeostasis, environmental safety, and / or wound healing.

[0167] In some embodiments, the apparatus is usable for monitoring healing processes associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone-associated disruption of the skin.

[0168] In some embodiments, the apparatus is usable for aiding in clinical decision making for Attorney Docket No.: 0116936.310WO2 care of conditions associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone-associated disruption of the skin.

[0169] In some embodiments, the apparatus is usable for early detection of the onset of organ dysfunction or cancer.

[0170] In some embodiments, the apparatus is usable for monitoring entry of hazardous chemicals from the environment into the body through the skin.

[0171] In another aspect, the invention relates to a method for quantifying outward and / or inward dermal flux of a skin of a subject, comprising defining an enclosed microclimate immediately adjacent to a surface of the skin, wherein the microclimate is in fluidic communication with the surface of the skin; modulating diffusive interactions of the microclimate with a surrounding environment, thereby modifying characteristics of the microclimate therein; measuring properties of the skin and concentrations of targeted species that emerge from or pass into the skin in the microclimate; and processing the measured properties of the skin and the measured concentrations of the targeted species to quantify the outward and / or inward dermal flux of the skin.

[0172] In some embodiments, the targeted species comprise water vapor, volatile organic compounds (VOCs), and / or carbon dioxide (CO2).

[0173] In some embodiments, the properties of the skin comprise skin temperature, galvanic response, thermal conductivity, and / or skin hydration.

[0174] In some embodiments, the microclimate is defined by a chamber to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

[0175] In some embodiments, the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified.

[0176] In some embodiments, when the chamber is an open state, a basal flux passes in or out through the opening, and wherein rapid (<10 ms) closing of the chamber yields dynamic changes in the concentrations of the targeted species in the microclimate, which are dictated by flux into or out of the skin.

[0177] In some embodiments, said modulating the diffusive interactions of the microclimate is performed by actuating a valve coupled with the chamber to be operably in an open state or a close state.

[0178] In some embodiments, when the valve is in the open state, the chamber is in an open state Attorney Docket No.: 0116936.310WO2 in which the microclimate is in fluidic communications with the surrounding environment, and when the valve is in the close state, the chamber is in a close state in which the microclimate is not in fluidic communications with the surrounding environment.

[0179] In some embodiments, said measuring the properties of the skin and the concentrations of targeted species is performed by a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

[0180] In some embodiments, said measuring the properties of the skin and the concentrations of targeted species is further performed by one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

[0181] In some embodiments, said processing the measured properties of the skin and the measured concentrations of the targeted species is performed by an external device including a mobile device, a smartphone, a tablet, a computer, a cloud server, and / or any electronic device with data reading / processing / displaying capability.

[0182] In some embodiments, the measured properties of the skin and the measured concentrations of the targeted species in the microclimate have distinct relevance to clinical care and / or exposure to hazardous vapors.

[0183] In some embodiments, the method is usable for the clinical care related to assessments of skin barrier function, full body homeostasis, environmental safety, and / or wound healing.

[0184] In some embodiments, the method is usable for monitoring healing processes associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone- associated disruption of the skin.

[0185] In some embodiments, the method is usable for aiding in clinical decision making for care of conditions associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone-associated disruption of the skin.

[0186] In some embodiments, the method is usable for early detection of the onset of organ dysfunction or cancer.

[0187] In some embodiments, the method is usable for monitoring entry of hazardous chemicals from the environment into the body through the skin.

[0188] In a further aspect, the invention relates to a skin-interfaced apparatus comprising a chamber configured to define an enclosed microclimate adjacent to the skin; a valve that modulates diffusive interactions between the microclimate and the ambient; and a sensor Attorney Docket No.: 0116936.310WO2 member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin.

[0189] In one embodiment, the valve is configured to dynamically control access to the surrounding environment, thereby creating a transient response that is quantitatively related to inward and outward flux of the targeted species through analysis of the time dependent measurements by the sensor member.

[0190] In some embodiments, the valve is a programmable valve or switch that is configured to operably be in an open state or a close state.

[0191] In some embodiments, the valve is a magnetically actuated, bistable valve with sub-10 ms actuation for generating transient concentration profiles directly linked to flux.

[0192] In some embodiments, the chamber is configured to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

[0193] In some embodiments, the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified using the sensor member.

[0194] In some embodiments, the sensor member comprises a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

[0195] In some embodiments, the plurality of off-skin sensors comprises a gas sensor for measuring the fluxes of the targeted species in the microclimate, and a temperature sensor for measuring the temperature in the microclimate.

[0196] In some embodiments, the sensor member further comprises one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

[0197] In some embodiments, the one or more on-skin sensors comprise one or more temperature sensors, one or more impedance sensors, one more thermal conductivity sensors, one or more transient plane source (TPS) sensors, and / or one or more skin hydration sensors.

[0198] Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the Attorney Docket No.: 0116936.310WO2 scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.

[0199] EXAMPLE 1:

[0200] AN APPROACH FOR CONTINUOUS MONITORING OF MOLECULAR FLUX INTO AND OUT OF THE SKIN

[0201] The skin forms our primary interface with the surrounding environment. Passage of chemical species into and out of the surface of the skin can have profound effects on health status. These bilateral material fluxes include those associated not only with water, the most significant species due to its abundance in the body and the atmosphere, but also many types of volatile organic compounds (VOCs), carbon dioxide (CO2) and others. Bio-molecular mechanisms for cutaneous homeostasis encoded in the stratified structures of the epidermis ensure that these fluxes are balanced at certain levels. Imbalanced outward fluxes imply either degradation or anomalies in cutaneous homeostasis. Inward fluxes of exogenous substances provide a reliable metric of the health effects of such species in the atmosphere. Unlike transdermal transport of liquids, such as sweat, existing wearable devices do not allow for continuous measurements of fluxes of gaseous species.

[0202] In this example, we disclose a compact, wireless platform / apparatus that can be mounted at one or more locations across the body for quantitative monitoring of the transdermal flux of multiple species simultaneously. The capabilities derive from the creation and time-dependent modulation of an enclosed microclimate immediately adjacent to the skin. The non-contact, proximity principle of operation of this system is qualitatively different from that of traditional wearable devices that rely on direct physical coupling to the body. The unique insights from this technology can aid in clinical decision making for care of conditions ranging from dermatological diseases to dermal wounds. Additional applications are in monitoring entry of hazardous chemicals from the environment into the body through the skin. The following describes these and other applications, after a presentation of the fundamental engineering and physics aspects that allow for quantitative extraction of intrinsic parameters from the measured data.

[0203] Design and operating principles

[0204] The epidermal flux sensor (EFS) device / system presented here focuses on, but is not limited to, water vapor, volatile organic compounds (VOCs) and CO2, as illustrated in Panel a of Attorney Docket No.: 0116936.310WO2

[0205] FIG. 1. These species are important because they relate directly to a range of needs in patient care related to assessments of skin barrier function, full body homeostasis, environmental safety, and wound healing. The device takes the form of a compact module that can couple onto the surface of the skin at a range of body locations (Panel b of FIG. 1). The functional elements exist in three main subsystems: (1) a chamber that includes a collection of sensors to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin, (2) a programmable valve to modulate diffusive interactions with the surrounding environment, thereby influencing the characteristics of the microclimate inside the chamber and (3) an electronic circuit and rechargeable battery to perform operational control, data acquisition and two-way wireless communication with a user interface (smartphone). The chamber forces confinement or allows escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin. Sensors suspended within the chamber capture dynamic information on temperature and concentrations of gaseous species within the microclimate (cc) before and after activating the valve. Additional sensors at the base of the chamber contact the skin to measure its temperature, galvanic response and thermal conductivity, to provide additional contextual information. Panel c of FIG. 1 illustrates the overall structure of the device, and details associated with the first subsystem (e.g., the chamber) and the second subsystem (e.g., the programmable valve). EXAMPLE 4 describes the third subsystem (e.g., electronic circuit and rechargeable battery).

[0206] As illustrated in Panel d of FIG. 1, a thin electromagnetic coil in the valve actuates a disk of a hard magnetic material to switch the chamber between open and closed states across a bistable magnetic potential created by soft magnets. When open, a basal flux passes in or out through the opening. Rapid (<10 ms) closing of the valve yields dynamic changes in the concentration of species in the microclimate, dictated by flux into or out of the skin. Panel e of FIG. 1 displays the time dependence of the ccvalues of water vapor due to transepi dermal water loss (TEWL) and of ethanol vapor due to inward diffusion of ethanol present in the ambient. Modulations associated with cycles of valve opening and closing render opposite variations in cc, corresponding to the outflux and influx of these gaseous substances at the skin surface. The initial change of cc(dcc / dt\t=Q) immediately after activating the valve reflects the unperturbed, natural flux density, / As shown in Panel f of FIG. 1, a precise calculation of / requires compensation for spatiotemporal nonuniformities in concentrations within the microclimate and for the occlusive effect of the sensors themselves.

[0207] The compensation scheme and other aspects of quantitative analyses relies on results Attorney Docket No.: 0116936.310WO2 from a computational model developed for this purpose. The lower frame of Panel f of FIG. 1 displays simulations of flux density profiles within the microclimate during the first few seconds after closure of the valve. The findings establish an empirical relationship that is valid across practical ranges relevant to the application presented here, as written <» where f is the flux density through the open chamber immediately before the valve actuation, k is the correction coefficient and Land S are the chamber volume, and the skin area under the chamber, respectively. For example, the value of k for water vapor is 0.92, determined by simulation. EXAMPLE 5 provides details. Methods for compensation the occlusive effects of the sensors appear in the following section.

[0208] Epidermal flux of water

[0209] Epidermal flux of water vapor represents a crucial aspect of thermoregulatory behavior and overall homeostasis. The flux (fw) of water vapor includes contributions from TEWL (frEwi , the direct diffusion of water across the epidermis and through the stratum corneum (SC), and the evaporation of sensible and insensible sweat (fse) released from eccrine and / or apocrine glands. (Panel a of FIG. 2) Regardless of the source, fwis proportional to the difference in water concentration across the epidermis and a reference point within Nilsson’s zone, where diffusion dominates over convection. For ease of analysis, this reference point can be set to a location of the valve opening, 6 mm above the skin surface, which lies within the typical Nilsson's zone (6 ~ 12 mm from the skin surface). Under the quasi-steady state, Fick’s first law applies to fw. where R is the effective diffusive resistance, including contributions from the epidermis (RSw) and from the air above the skin to the reference level (Raw),' is the difference between the water vapor concentrations at the dermis (cs) and the reference level (ca). The value of cSwis equivalent to the saturated value at the skin temperature (Ts). Panel b of FIG. 2 depicts an equivalent resistance circuit model for epidermal flux, where RSwand Raappear as resistors in series. The contributions of TEWL (RTEWL) and sweat evaporation (Rse) form RSwas a parallel connection.

[0210] The right half of Panel b of FIG. 2 depicts an EFS system on the skin, in the open state, Attorney Docket No.: 0116936.310WO2 where the path of the flux differs from that of the bare skin. The geometries of the chamber and valve define the diffusive resistance of this new path through the system leading to the following expression valid for the skin coupled with an EFS. (Equation 3) where fwis the f for water vapor. Water vapor diffusion through 6 mm distance of air with a diffusivity (Dw= 24 mm2 / s)21yields Raw= 250 s / m. Rigorous simulation based on the computational model indicates that Rdwfor the device reported here is approximately 6 ks / m and invariant across the practical ranges of the epidermal and atmospheric conditions. (Panel c of FIG. 2) The value of Rdis higher than Radue to the occlusive effects by the sensors themselves, yielding values of fwlower than values of fw.

[0211] The compensation of the occlusive effect involves the sequential application of Equations 3 and 2, as supported by the computational model. The model estimates cawfrom fwand cCw. This value defines Ac, along with the cSw, the value derived from measurements of the skin temperature. Substitutions of these values, Ac and fw, along with Rdinto Equation 3 gives RsThe subsequent substitution of this value into Equation 2, along with Ac and Rafinally yields fw, the natural flux density. EXAMPLE 6 presents additional computational results and measurements from benchtop studies.

[0212] Since fwis proportional to Ac, which varies according to atmospheric conditions, Rsbetter represents the intrinsic skin properties than fw. When evaporation of sweat is negligible (Rse=°°), Rswmeasures the skin barrier properties (RTEWL), largely determined by the health status of the SC. Measurements of the electrical impedance of the skin (rs) provide information on the onset and magnitude of perspiration, and thus the contribution of this mechanism to RsData in FIG. 2d show that rsdetermined using a sensor that couples to the skin enclosed by the chamber, defines three stages of perspiration: absent, insensible, and sensible sweating. Collectively, these measurements allow reliable operation in different ambient conditions and use scenarios over multiple days, in hospital or home settings, as illustrated in Panels e-f of FIG. 2. EXAMPLE 7 further outlines the impedance measurement.

[0213] As a simple example, Panel e of FIG. 2 shows the recovery of RSwfollowing the partial removal of the SC from five healthy adults. The native level of Rsfrom the forearm decreases from 25 ks / m to about 7 ks / m on average after 30 cycles of tape stripping to remove the SC. The subsequent recovery in Rsexhibits a characteristic time (15.2 days) that is similar for all Attorney Docket No.: 0116936.310WO2 subjects, consistent with the timescale for the SC turnover (14 days). The value of fwalso correlates well (r = 0.98) with measurements performed using clinical standard instruments for normal and impaired skin conditions, including psoriasis, atopic dermatitis (AD), ichthyosis, and xerosis (XC). (Panel f of FIG. 2) EXAMPLE 8 summarizes some additional capabilities.

[0214] This type of flux assessment also has relevance in monitoring fluid homeostasis. In healthy normal adults, insensible water loss accounts for -15% of the total water loss associated with respiration, perspiration, urination, and defecation, with increasing contributions for vulnerable groups, reaching levels as high as 50% in the most severe cases of neonates. Continuous measurements of epidermal water flux are thus of fundamental importance in active management of proper fluid balance. Panels g-j of FIG. 2 summarize the unique capabilities of the EFS system in this context. Simultaneous recordings with devices at six regions of the body capture fwof a subject every 3 min (At) for 3 h. For reference, separate measurements quantify body mass loss (BML) every 15 min. In the absence of water intake and excretion, BML is equal to the insensible water loss. The accumulation of measurement results ( / y ) weighted by the regional skin area (Ay) yields the estimated epidermal water loss (Ey) as a function of time. (Equation 4) The superscript and subscript here denote the measurement order and skin region, respectively.

[0215] Panel g of FIG. 2 displays the absolute humidity values (cc) within the microclimate of the chamber, vertically shifted for ease of visualization. The periodic flux measurements associated with closing and opening of the valve yield features similar to those in the upper frame of Panel e of FIG. 2; other transients follow from motion artefacts caused by measurements of BML. Elevations in the baseline, one of which is indicated by a dashed rectangle, arise due to brief periods of perspiration following emotive stimuli. The most pronounced such elevations occur at the forehead, consistent with the highest sweat rate in the region.

[0216] Panel h of FIG. 2 overlays the summation of Ey over all measured regions (Esum) and the BML from experiments featured in Panel g of FIG. 2 (blue). The inflection that occurs at short times follows from accelerated loss of water due to sweating. The data in red in Panel h of FIG. 2 correspond to similar experiments but with reduced levels of sweating. Additional measurements from three subjects present remarkable levels of agreement between Esumand BML (r = 0.99). (Panel i of FIG. 2) This finding suggests a proportionality between epidermal and respiratory Attorney Docket No.: 0116936.310WO2 water fluxes, consistent with previous studies. Further analysis shows that a reduced set of measurement locations (anterior thigh and calf) yield similar results (r = 0.99) (Panel j of FIG. 2), thus demonstrating a simple means to accurately define whole-body insensible water loss. EXAMPLE 9 provides additional information on these and other examples of fluid homeostasis monitoring.

[0217] Epidermal flux of VOCs, CO2, and exogenous agents

[0218] Carbon dioxide (CO2) and various volatile organic compounds (VOCs) contribute additional sources of flux from the skin, as a consequence of cutaneous respiration and metabolic processes of skin microbiome. Likewise, exogenous VOCs can flow into the skin from the environment. Measurements of both inward and outward flux yield unique, complementary insights. As examples, Panel a of FIG. 3 illustrates modalities relevant to epidermal hygiene and environmental safety, enabled by this bilateral flux measurement capability. (Panel b of FIG. 3).

[0219] Inadequate skin hygiene, as well as skin disorders that disrupt the epidermal barrier, can lead to unregulated proliferation of microorganisms in the genera Corynebacterium, Staphylococcus, and Propionibacterium. The result increases the outward flux of VOCs (fVOc), including volatile fatty acids and thioalcohols from the bacterial degradation of biogenic precursors. Illustrative measurements of these processes involve daily evaluations of fvocnear the axilla of four adult subjects, over the course of four days without washing. Mild exercise to induce sensible sweating precedes the fourth measurement by several hours. The subjects then resume hygienic activities before the last measurement on the fifth day. The results show that sweat production leads to a five-fold average increase in fvocfor the male subjects and a meaningful but less significant increase (57%) for the female subjects, consistent with previous reports. (Panel c of FIG. 3) The presence of the hypomorphic allele of the ABCC11 gene in these particular subjects may explain the insignificant changes in the first four days.

[0220] In another context, the flux of VOCs, as well as the release of CO2, serve as attractants for insects that practice hematophagy. An integrated sensor for CO2 allows precise and simultaneous measurements of transcutaneous flux of this species (ftco?)-.asshown in Panel d of FIG. 3. Combined analysis of these channels can aid in a comprehensive assessment of hygienic status. Characterizing epidermal CO2 emission has additional many other uses in clinical medicine, including for noninvasive estimation of arterial CO2 and determination of metabolic and / or respiratory acidosis, currently performed in an episodic fashion using hospital systems that require trained personnel and specialized facilities. Attorney Docket No.: 0116936.310WO2

[0221] Measurements of inward flux serve complementary purposes. Specifically, entry of exogenous atmospheric volatile substances into the body through the skin (xi) can represent health hazards The x and i in the subscript denote substance and inward flux, respectively. Panel e of FIG. 3 illustrates the concept of transepidermal chemical diffusive resistance, RSx, a measure of skin barrier function against the penetration of atmospheric chemical species, such as concentrated solvent vapors that are present in some industrial settings. This value can differ from Rsas a metric to determine the effect of specific chemical substances of interest on the skin and the underlying tissues. The compensation scheme described previously applies to yield fc, RsRdx, fx, Ac, and subsequently Rsand fxt as in the case of water vapor, with a minor modification for material diffusivity and the inverted concentration gradient. For example, ethanol diffusivity in air (DEt0H= 16 mm2 / s) yields a k value of 0.81. For xenobiotic solvents, c. can be assumed to be zero. The details of this scheme are described in EXAMPLE 6.

[0222] A demonstration experiment involves measurements of inward flux of concentrated (~ 200 ppm; below the recommended exposure limit, 1000 ppm) ethanol vapor on the volar forearm, of interest because of its potential to enhance the penetration of other compounds. The experiments compare the behavior of bare skin, skin after tape-stripping of the SC and after applying an aluminum foil patch as an additional barrier. The data in Panel f of FIG. 3 shows that the additional barrier impedes inward flux of ethanol into the skin, as evident from decreases inccEtoH °f bare skin when the chamber is closed and inflow from the atmosphere is not possible. The graphs are vertically shifted for ease of visualization. Panel g of FIG. 3 presents results for all three conditions. Unlike R<. , which shows a constant value over consecutive measurements, RSEt0Hincreases and converges to certain levels over approximately 20 min of exposure. The RSEtoHvaluesinPanel g of FIG. 3 correspond to these saturation values. For bare skin, the saturation EtOH is about one-third of Rs<-w ,’ consistent with literature reports of skin permeabilities that are higher for ethanol than water. Measurements with the SC partially removed exhibit an increase in RSEt0H, perhaps counterintuitively. The reason may be that the ethanol dissolves into, rather than permeates through, the SC, as a lipid-rich membrane in which the ethanol is soluble. This same effect could also exprlain the observed saturation of R ^^EcttnOHu.

[0223] Radiative forms of energy represent a different kind of environmental hazard to the skin, also quantifiable through measurements of flux. Experiments to demonstrate an accelerated assault of this type use porcine skin models exposed to a high dose (above the exposure limit, 10 mJ / cm2) of ultraviolet light (UV; peak A = 253 nm). Panel h of FIG. 3 displays the cCyocthat Attorney Docket No.: 0116936.310WO2 results. Each cycle of irradiation induces immediate rises in the baseline cCvocand fvoc-, which gradually decrease over time. The first, thus the highest value of fvocafter each irradiation increases with UV dosage and converges to a constant level. These behaviors are consistent with flux from a transient source with a limiting factor. (Panel i of FIG. 3) Experimental evidence suggests that the effects of UV-induced heating and ozone are negligible. The UV photons can, however, break proteomic bonds, and thus cause photolysis of keratin, abundantly present in comeocytes, which includes sulfur-containing cysteine. Such reactions, known to lead to intercellular fracture of corneocytes, can generate thiols, as detectable VOCs. These data thus capture signs of cellular, molecular-level skin damage, at levels that are not detectable by visual inspection. EXAMPLE 10 covers the details.

[0224] Comprehensive wound monitoring

[0225] As with UV-induced damage to the skin, wounds create sources of outward flux, although in this case by altered skin barrier function and pathogenic processes. These fluxes can yield important insights into the wound status. (Panel a of FIG. 4) Experiments to explore this possibility examine wound healing processes with normal and type-2 diabetic (db / db) murine models over the course of reepithelialization. Panel b of FIG. 4 exhibits the time evolution of chamber concentrations of water and VOCs from an excisional dermal wound on the back of a normal mouse. While fwgradually decreases to a baseline level characterized by healthy skin, fvoc temporarily increases during the early stages of recovery before a gradual return to baseline. These two flux values thus convey correlated, yet independent, information.

[0226] Panel c of FIG. 4 summarizes healing processes of these two groups quantified through fvocand barrier restoration (BR) and wound closure (WC), the latter two normalized parameters (p) derived from Equation 5: where p is Rvfor BR and wound area for WC. The subscripts n and 0 denote the bare, native healthy skin and pristine wound bed, respectively. The full evolution of WC occurs within 13 days and 27 days on average for the normal and db / db groups, respectively, consistent with previous reports. Panel d of FIG. 4 displays images of representative wounds at various times.

[0227] Panel e of FIG. 4 summarizes qualitative differences in the two wound healing pathways captured by fw. By this metric, skin barrier function with normal mice tracks the wound closure process. By contrast, the db / db group fails to recover the barrier function by the point of wound Attorney Docket No.: 0116936.310WO2 closure (twcwith post-closure barrier restoration over the next 3 weeks. The results in Panel f of FIG. 4 suggest a linkage of this post-closure barrier restoration to impaired keratinocyte differentiation associated with hyperglycemic conditions. Filaggrin (FLG) is a hallmark of the matured stratum granulosum (SG), where the tight junctions form the secondary skin barrier mechanism. Animals in the db / db group after tvc(D+30) lack FLG activity, while the H&E staining results support formation of the SG. These results j ointly suggest the presence of immature SG, with an inability to restore normal skin barrier function. The right frame of Panel f of FIG. 4 shows that the FLG activity approaches the native level along the post-closure barrier restoration period, in line with the results based on fw. These findings demonstrate how measurements of flux can highlight these and other physiological anomalies in a non-contact manner, without disruption to the wound bed or interference with the healing process. EXAMPLE 11 presents some additional analysis.

[0228] Inflammation, an essential stage in healing, can lead to the production of various molecular markers, some of which contribute to VOC flux. The transient increase in this parameter early in the healing process for normal mice aligns with the expected timing of the inflammatory response. By contrast, measurements indicate anomalous behavior of the increase in VOC flux observed in the db / db group, consistent with a dysregulated inflammatory response. (Panel g of FIG. 4) Bacterial growth and biofilm formation at infected wounds can also contribute to the release of VOCs, as demonstrated in ex -vivo studies of porcine wounds. These studies involve loading a suspension of E. coli (105CFU) onto the wound bed to create an infected wound model. The initial fvocdecreases over time as the suspension dries on the wound bed. After the incubation phase, measurements of fvocshow an onset and subsequent significant increase in VOC generation until the end of the experiment. (Panel h of FIG. 4) The exponential increase in fvocaligns with an expected exponential growth in bacterial population. These results indicate that VOC flux can serve as a metric to monitor infections in wound beds. EXAMPLE 12 covers the details.

[0229] Outlook

[0230] The technology introduced here has broad implications in clinical care, of particular value for vulnerable populations such as infants, patients, and seniors with immature, damaged, or diminished skin barriers. These and other patients could also benefit from data to guide triage, treatment, and monitoring of chemical or radiative burns or ozone-associated disruption of the skin. Measurements of VOC and CO2 fluxes have further potential benefits across the general Attorney Docket No.: 0116936.310WO2 population, as related to disease control and exposure to hazardous agents in the environment. Future possibilities include the development of gas sensors with high chemical selectivity for early detection of the onset of organ dysfunction or cancer (EXAMPLE 13).

[0231] EXAMPLE 2:

[0232] DEVICE FABRICATION

[0233] Soft magnet: Magnetite nanoparticles (50-100 nm, Merck, USA) mixed and dispersed thoroughly in a prepolymer to PDMS (Sylgard 184, Dow, USA, 10:1 mixing ratio) at 20 wt. % served as the base material for the soft magnet component of the programmable, bistable valve assembly. Degassing the mixture, spin-coating it on a petri dish for 30 s at 400 rpm and then thermally curing at 50 °C for 12 h completed the process. A laser cutting process defined the required annulus shapes (ID: 8.4 mm, OD: 14.2 mm) for integration into the valve.

[0234] Circuit: A flexible printed circuit board (fPCB) with planar electromagnetic coil formed the platform for mounting a Li-polymer battery (20 mAh) and various commercial electronic components, including sensors for water vapor (BME280, Bosch, Germany) VOCs (BME580, Bosch, Germany) and CO (STC31-R3, Sensirion, Swiss). EXAMPLE 4 presents details on the circuit architecture.

[0235] Device assembly: A 3D printing process (Form3+, Formlabs, USA) defined the frame of the system to house the circuit-battery assembly and the soft magnet structures and magnetic plunger. A mechanical locking mechanism joined the top and bottom frames to complete the enclosure.

[0236] EXAMPLE 3:

[0237] DATA ACQUISITION

[0238] Bench-top tests: Uncured PDMS resin bonded PDMS membranes with various thicknesses to the lids of a small container with a circular opening at the center. Liquid water or gaseous substances filled the container for different experimental settings. Measurements quantified the temperature at the center of the PDMS membrane and transmembrane permeation in the form of gaseous fluxes. Measurement of influx used a device interfaced to the side of the membrane facing the interior of the container.

[0239] Human tests: All subject participation was fully voluntary with informed consent obtained before the experiments. Research protocols were approved by the Institutional Review Board at Northwetern University (STU00220121). Before mounting the device, each subject Attorney Docket No.: 0116936.310WO2 remained quiet in a resting state for 15 min in an ambient laboratory atmosphere. Data acquisition began 15 min after mounting, again with the subject in a resting state.

[0240] Animal tests: The Institutional Animal Care and Use Committee (IACUC) at Northwestern University approved the in vivo animal studies under protocol IS00018748.

[0241] Rodent wound healing model'. Diabetic (db / db) mice (BKS.Cg-m + / + Leprdb, #000642; homozygous for Leprdb) and healthy mice (C57 / BL6J) were obtained from Jackson Laboratory, USA. The wound creation process began with shaving the fur from the dorsal side of each mouse, followed by excising the dermis using a 6 mm-diameter punch biopsy (Acuderm™, USA). Subsequently, 6-0 nylon (Ethicon, USA) sutured a sterilized annulus acrylate splint (ID 10 mm, OD 12 mm) around the wound to prevent skin contraction. Laser-cut annulus occlusive dressings (TegaDerm™, 3 M, USA) protected the splint and the outer skin. Daily measurements of fluxes served as the basis for monitoring the wound healing process until complete postclosure barrier restoration. Three blinded observers utilized ImageJ to estimate the percentage of wound closure.

[0242] Tissue processing and immunofluorescence staining: For tissue processing and histology, animals were euthanized either 44, 37, 30, 15, 8 or 4 days after wound creation. A 10 mm biopsy punch (Acuderm, USA) excised the regenerated wound tissue. The following process fixed the tissue with 4% paraformaldehyde and embedded in paraffin. The embedded tissues were sectioned and stained for keratin- 14 (Abeam, USA), filaggrin (Santa Cruz Biotechnology, USA) activities, and H&E. Secondary antibodies conjugated to Alexa Fluor 488 or Alexa Fluor 555 (Invitrogen, USA) were used. Control samples included those stained with the secondary antibody without primary antibody incubation. ImageJ was used to quantify the fluorescence intensity.

[0243] EXAMPLE 4:

[0244] CIRCUIT OF THE EES SYSTEM

[0245] Circuit configuration: The circuit includes a control unit, a battery terminal, and a sensor platform. (Panel a of FIG. 5) The control unit is configured to perform (1) two-way wireless communication with external terminals via Bluetooth® low energy (BLE), (2) measurement implementation through valve control, and (3) control of each sensor. The data collected from the sensors is interpreted and processed by the external terminal and the external server connected to it. The sensor platform is divided into three compartments, each of which, in combination with the EFS chamber, are located on the skin (1stdeck), inside the chamber (2nd Attorney Docket No.: 0116936.310WO2 deck), and on top of the chamber (3rddeck), respectively, to accommodate on-skin sensors (skin temperature, skin electrical impedance, and transient plane source (TPS) sensor units), gas and temperature sensors, and electromagnetic coil for valve actuation. (Panel b of FIG. 5) The electromagnetic coil includes a 6-layer PCB coil (PCBWay) with a total thickness 0.6 mm. Each layer is comprised of an Archimedean coil with 23 turns pitched at 350 pm. Gas measurements, including humidity, temperature, barometric pressure, VOC concentration, and CO2 concentration, are performed with the BME280 (Bosch), BME680 (Bosch) and STC31-R3 (Sensirion).

[0246] Control unit: The driving electronics for the EFS are mounted and soldered to a flexible printed circuit board (fPCB; PCBWay) of the control unit. The operation of the board is controlled with a Bluetooth 5.0 controller (ISP 1807, Insight SIP) integrated with the nRF52840 System-on-Chip (Nordic Semiconductor) and a built-in antenna. The device is powered by a rechargeable, 130-mAh lithium-polymer battery (PGEB571224). The power management includes a 5.1 V DC-DC boost converter (TPS61235, Texas Instruments) for driving the transducers and a low-dropout regulator (ISL9016, Renesas) for logic-level power. An H-bridge (DRV8837, Texas Instruments) is used to drive the shutter with the 5.1 V power supply. The logic inputs for the H-bridge are delivered from GPIO outputs of the controller. All the components and features appear in Panel c of FIG. 5. These integrated circuits communicate with the controller through a serial two-wire interface (TWI) line.

[0247] Operation scheme: The voltage supplied from the Li-polymer battery is stabilized by the low dropout (LDO) to provide reliable power (3.3 V) to all parts of the circuit. The MCU drives the valve actuation system and flux capture system based on the operating parameters wirelessly specified by the user from the smartphone to perform the actual measurement. In this process, raw data acquired from the gas sensors and on-skin sensors (skin temperature sensor, skin electrical impedance sensor, and transient plane source (TPS) sensor) is transmitted to the smartphone via BLE. The valve actuation system actuates the valve through a series of voltage adjustments in response to instructions from the MCU. The 3.3 V voltage supplied through the LDO is boosted to a level sufficient to actuate the EM coil (-5.0 V) by the boost converter under the control of the MCU. This voltage is supplied to the EM coil with a specific polarity and within a defined duration by the H-bridge, which is also dictated by the MCU, to operate the magnetic plunger. The information and current flow in this process is shown by the arrows in Panel d of FIG. 5. Attorney Docket No.: 0116936.310WO2

[0248] EXAMPLE 5:

[0249] MECHANICAL AND COMPUTATIONAL BASIS OF THE EFS MEASUREMENT

[0250] Valve actuation for flux measurements: Panel a of FIG. 6 shows a cross-sectional schematic illustration of the EFS, showing the chamber in contact with the skin and the valve structure placed on top of it. The opening and closing of the valve are determined by the position of the ferromagnetic plunger inside the valve. This ferromagnetic plunger is in the form of a disc, which is attracted or repelled by a disc-shaped EM coil situated on top of the valve structure. Two paramagnetic (soft magnet) rings, shown in blue, hold the plunger in place when it reaches both ends of the operating area. As a result, the plunger remains in place even when the EM coil is deactivated. To close the chamber, a current is applied to the EM coil in the direction that pushes the plunger away. A current in the opposite direction is applied to attract the plunger back to open the chamber. All these processes are regulated by the MCU through the H-bridge. At the same time, the gas sensor inside the chamber continuously collects gas concentration data (cc). (Panel b of FIG. 6) Panel c of FIG. 6 shows two serial opposing current signals for closing and opening the valve, and the resulting change in the ccvalue measured by the gas sensor. Since the MCU defines when the valve opens and closes, it is also possible to define the exact time of opening and closing (t = 0). This time stamp is used for data analysis. As described in EXAMPLE 1 and subsequently in the following, the initial rate of change of this data provides information about the flux density across the chamber. The valve operates even after a current application of about 10 ms, allowing long measurements with high power efficiency.

[0251] Mode of mass transport inside the microclimate: The dominating mode of mass transport inside the microclimate of the EFS system is examined based on the calculation of the Rayleigh number, Ra, which is calculated by formula below (Equation 6). where g is gravitational acceleration; is thermal expansion coefficient of air; v is the kinematic viscosity of air; a is the thermal diffusivity of air; Zsand 7aare the representative temperature values of the skin (Ts= 30 °C) and ambient air (Ts= 23 °C), respectively; L is the characteristic dimension of the chamber, for which the geometry of device in this current study gives 1 ~ 10 mm. The physical properties of ambient air yields [i = 0.0034 / X, v = 14.3 / m2 / s, and v = 18.46 mm2 / s1. Substitution of these values into Equation 6 yields values of Rafor the EFS that lie between 0.880 ~ 880, below the critical value of- 11001, indicating that the diffusion is the dominating mode of mass transport inside the chamber. Attorney Docket No.: 0116936.310WO2

[0252] Diffusion simulations: The commercial software ABAQUS is used to simulate gaseous diffusion through the microclimate of the EFS system for both open and closed states. Development of the simulation model begins with building axisymmetric models for gaseous domain for the interior of the chamber and a layer of skin (15 - 300 jim in thickness) coupled together. Four-node and three-node linear elements form the mesh. The convergence of the mesh is guaranteed for all cases of the simulation. The entire mass diffusion simulation involves two sub-steps for open and closed states of the chamber. For the open state, the steady-state mass diffusion method yields the nodal concentration profile across the gaseous domain and the skin layer based on two boundary conditions: constant concentrations along the skin surface (BC-1, cs= const.) and the boundary of the vents of the system (BC-2, ca= const.). The output of this simulation is applied to the next step for transient mass transport as the initial condition. Based on the previous discussion, convection is negligible. As a result, the simulation assumes that the convective effect of valve actuation can also be neglected. The same geometries and physical parameters as in the first step are used in this step. For boundary conditions, the additional default zero-flux boundary condition (BC-3) applies to the position of the bottom surface of the magnetic plunger when in the closed state. A diffusivity value of 4.3 x 10-3mm2 / s from empirical data applies to the skin, and various diffusivity values ranging from 5 mm2 / s to 25 mm2 / s are used to cover variety of gaseous substances.

[0253] Simulation-based compensation scheme: The chamber isolation by the valve actuation leads to dynamic changes in the concentration profile in the chamber. Since this change yields nonuniformity across the microclimate, the single-point sampling with the sensor located at the center of the chamber does not represent the epidermal flux. The compensation of this distortion involves the use of the computational model described in the previous section. Mass conservation inside the closed chamber yields the following equation (Equation 7) where c is the concentration of gaseous substance of interest in the microclimate; S is the area of the skin under the chamber; f is the average flux density across the skin surface with positive sign for flux toward the chamber, f is a function of time here. The integration is over the domain. An assumption in the compensation scheme is that the first term of Equation 7 is proportional to the rate of change of the value that the sensor is measuring (cc), as written in Equation 8: Attorney Docket No.: 0116936.310WO2 where k is the correction function, a function of time here. We assume that ccis the concentration value at the sensor location in the simulation. Rearranging Equation 8 yields the following expression (Equation 9).

[0254] Panel c of FIG. 7 displays the values of cl c f, and corresponding k, as functions of time.

[0255] Approaching to t = 0, the moment immediately after the valve closes, the value of k converges to a certain level (kt=0in Equation 10), which is invariant with temperature, skin diffusivity ( / ?s), (Panel d of FIG. 7) and concentration values for BC-1, 2, but depends on the diffusivity of the substance in air. (Panel e of FIG. 7) < 10)

[0256] In Equation 10, |t=0is the flux density value at the open state; kjt=ois the correction coefficient appears as k in EXAMPLE 1.

[0257] Sensor latency consideration: The data are interpreted with the assumption that the response of the sensor itself has negligible latency relative to actual changes. In this analysis, we examine the validity of this assumption. Let y be the actual value measured with a sensor that has a latency T. y is the sensor’s output, which differs from y by the latency. The general definition of sensor latency yields the following Equation 11. where t is time; Panel a of FIG. 8 explains the other variables. The following Equation 12 is a theoretical linkage between y and y. Panel b of FIG. 8 explains the derivation of Equation 12 from Equation 11. ty + y = y (12)

[0258] For a case of diffusive ingress into a closed area, we assume that y follows an exponential form shown in Equation 13. where T* is a characteristic time of the ground truth change of y. Equation 14 is the solution of Equation 13.

[0259] The second term in the RHS of Equation 14 indicates the error by sensor latency. For r* » r, the error diminishes and y asymptotes to y. For typical EFS measurements of water flux, Attorney Docket No.: 0116936.310WO2 characteristic time of the chamber humidity saturation is several minutes (T^, Panel f of FIG. 1), while the latency value for the humidity sensor (BME280, Bosch), presented by the manufacturer is 1 s. (T63O / O= 1 s). For the VOC sensor (BME680, Bosch), T63O / O< 1 S. The characteristic saturation time (Tvoc) isevenlonger than that of water vapor. (Panel b of FIG. 3) Therefore, errors in both water vapor and VOC measurements associated with sensor latencies are negligible.

[0260] EXAMPLE 6:

[0261] RESISTANCE MODEL OF EPIDERMAL FLUX

[0262] This example presents the details of the analogous resistance model based on diffusive mass transport through the EFS system. This section also reviews the process for deriving measurement results based on this model and for evaluating the validity of the model and resulting values. Panel a of FIG. 9 schematically illustrates the process for deriving diffusive resistance (Rs) starting from data from the gas sensor (cc) and skin temperature sensor (Ts). At each step, the derivation of the next step variable relies on a first-order equation of the form V = IR. In addition, the constants required at a step and their validity are provided and supported by the computational mass transport model, as discussed in detail in EXAMPLE 5. Deriving csfrom Tsis only valid for water vapor; for other exogenous substances, cscan be approximated as zero, without compromising the rigor of the model. For transcutaneous CO2 analysis, the same architecture can be achieved by approximating cato zero instead of cs. For the sake of simplicity, the present discussion is based on water vapor. The details of Panel a of FIG. 9 are discussed in EXAMPLE 1.

[0263] The part of the process that is not discussed in detail in EXAMPLE 1 is the derivation of Ac, the difference between csand ca. To illustrate this part, in Panel d of FIG. 9, we divide the original Rdinto two segments, Rdland Rd2, based on the sensor position, such that Rdl+ Rd2= Rd. Panel c of FIG. 9 shows the values of Rdland Rd2obtained by the computational mass transport model. Like the Rdvalue, these two resistance components are invariant to the other parameters of the model, Rsand Ts, across ranges relevant to the contemplated uses of the technology. These components only vary with the diffusivity of the gaseous material in air. The results in FIG. 9c are for d = 5 mm2 / s. Panel d of FIG. 9 schematically illustrates the process of deriving the value of ca. and subsequently Ac, using Rd2and the parameters previously obtained. All calculation steps can be incorporated directly into the firmware and software of the system.

[0264] Panels e-f of FIG. 9 present empirical results that support this model. As skin itself has Attorney Docket No.: 0116936.310WO2 long- and short-term intrinsic fluctuation mechanisms, an artificial skin model based on a polydimethylsiloxane (PDMS) membrane was used in controlled experiments. The EFS was mounted on PDMS membranes of different thicknesses and continuous measurements of at least three to six hours in length were repeated over several days and weeks in different atmospheres. The graphs in Panel e of FIG. 9 show the results obtained on a PDMS membrane with a thickness of 86 [im. The two graphs display the same data sorted by different criteria: the x-axis of the left graph is the cavalue at the time of measurement and the x-axis of the right graph is the membrane temperature (as a substitute for skin temperature) at the time of measurement. In addition, the blue color shows the diffusive resistance value (Rs) and the red color shows the flux density value ( / ) for the same measurement data. As shown in both graphs, the Rsvalue derived based on the resistance model remains constant regardless of the variables that characterize the ambient atmosphere or the membrane (skin). On the other hand, the flux density, , changes with the external environment. The left graph shows an overall increase in f as the atmosphere becomes drier, consistent with our expectations and thus supporting the validity of the model. The same form of experiment was performed for PDMS membranes of different thicknesses. The results are shown in Panel f of FIG. 9. The water diffusivity of PDMS can be derived from the diffusive resistivity data for different PDMS thicknesses. The derived value (DPDMSw= 7.3 x 10’3mm2 / s) agrees with the reported ranges of the value (DPDMSW~ 10’3mm2 / s')6. Differences in the values reported in the literature result from differences in the details of preparation and experimental conditions.

[0265] EXAMPLE 7:

[0266] SKIN IMPEDANCE MEASUREMENT

[0267] Panel a of FIG. 10 shows the bottom part of the EFS where it meets the skin. A pair of 2.5 mm thick annular electrodes are symmetrically placed around the perimeter of the chamber. These electrodes are 18 um thick copper electrodes with a thin film of gold deposited on a PI substrate. One of these electrodes is connected to the ground of the circuit and the other to an analogue input pin of the microcontroller (ISP 1807), collectively forming a voltage divider to which a constant voltage (3.3 V) is applied by a GPIO of the microcontroller. The center distance of these two electrodes is 16 mm, which is the same as the inner diameter of the chamber. The electrodes are designed to protrude approximately 200 micrometers beyond the bottom surface of the EFS to form a stable contact surface with the skin when the EFS is worn. Attorney Docket No.: 0116936.310WO2

[0268] Panel b of FIG. 10 shows an example of an electrical impedance (rsin ohm) measurement using this skin-interfaced voltage divider. In this example, the subject performed a moderate-intensity exercise for approximately 30 min while wearing the EFS on the volar forearm. Approximately 5 min after the start of the exercise, the subject reported the onset of a perspiration sensation, with an immediate impedance decrease measured simultaneously. A continuous decrease in impedance followed for the next 10 min, but no visible beads of sweat were observed on the skin. From 15 min into the exercise, the subject reported an enhanced sensation of perspiration with the emergence of visible sweat beads on the skin. Dripping of sweat from the skin began at about 30 min after the start of the exercise. The subject then started to rest in the resting position. The impedance exponentially decreased over the course of the entire exercise. The stage of dripping sweat corresponded to a decrease of approximately 500 times compared to the initial state. This decrease was followed by a gradual rise over the course of approximately 30 min after the end of the exercise.

[0269] Panel b of FIG. 10 displays the change in cCwvalues over the course of these measurements. Qualitatively, the data show trends that are the inverse of those for impedance. A key difference, however, is that impedance is on a logarithmic scale. In other words, the impedance shows a much greater magnitude of change than cCw. This result can be important in the development of a general sweat rate measurement system, more sensitive than measurements of humidity. This impedance sensing modality for perspiration can provide insights into the influence of this process on fwand the other fluxes.

[0270] Panel c of FIG. 10 illustrates a possible explanation for the exponential decrease in rs. The conducting path between the two electrodes at either end includes the contact resistance between the electrodes and the skin (rcontact) and the resistance component of the conduction path through the skin (rskin). In the first phase of perspiration, no visible liquid appears on the skin surface. Based on the subject’s reported sensations, however, it can be assumed that a low level of perspiration has begun but is unable to evaporate at the interface between the electrodes and the skin. The result is likely an occlusive sweat film that will induce an immediate reduction of rcontact. In the next phase of perspiration, the visible condensed liquid on the skin may form a separate conducting path, while reinforcing the previously formed occlusive sweat film. As perspiration continues, this conductive path may change from a percolative path to a thin film path progressively, leading to a continuous decrease in rs. The growth of the percolative conducting path generally shows an exponential characteristic. Attorney Docket No.: 0116936.310WO2

[0271] EXAMPLE 8:

[0272] EPIDERMAL WATER FLUX SENSING CAPABILITIES

[0273] Continuous monitoring of sleep epidermal water flux: FIG. I la shows the results of periodic measurements of epidermal water flux (fw) during sleep using EFS. This finding demonstrates the superiority of the EFS system, not only in terms of continuous measurement, but also in terms of continuous data collection in a comfortable manner that does not interfere with natural activities. The subject wore the EFS using a fabric strap on the volar forearm and slept for approximately 7 h without any physical restrictions. During this time, the device continuously collected data (cc) and transmitted it to the server via a nearby smartphone. In the top graph of Panel a of FIG. 11, three anomalies (shaded areas) are observed: the blue shaded area is caused by the wearer tossing and turning, and the other two red areas are presumed to be caused by the EFS moving closer to the nasal cavity as the subject's posture changes. (Periodic noise at around 0.25 Hz is observed throughout the open chamber periods in the red areas, likely due to respiration.) The inset of the graph shows a magnified view of the individual peaks.

[0274] The lower frame of the figure displays the flux density ( f) and diffusive resistance (Rs). The flux density is shown to undergo frequent changes in response to the above- mentioned fluctuations. The atmospheric conditions around the measurement site have a direct influence on fw. In contrast, diffusive resistance gives a very uniform measurement over the entire period, which is consistent with the analysis in EXAMPLE 6. The decreases in resistance values in the red bands may be due to the skin itself becoming moister due to exhaled air.

[0275] Impacts of SC removal and occlusive cream: In Panel b of FIG. 11, the EFS was used to quantitatively observe changes in the skin barrier caused by artificial treatments. A human subject wore an EFS on the volar forearm and followed a standard tape stripping protocol described in the IRB documentation for this study, with a total of 30 sessions of 10 sessions each. Four epidermal water flux (diffusive resistance) measurements were performed during each phase of tape stripping. Afterward, an appropriate amount of occlusive cream (Vaseline) was applied to the same area and the measurements were repeated. Finally, the occlusive cream was wiped off with a tissue and four measurements were taken.

[0276] The left frame of Panel b of FIG. 11 shows the change in cCwvalues following this series of artificial treatments. The data show not only a change in the magnitude of the peak corresponding to each measurement, but also changes in the base level. The right frame of Panel b of FIG. 11 shows the corresponding variation of RSw. These data suggest that each tape Attorney Docket No.: 0116936.310WO2 stripping cycle causes a uniform decrease in skin barrier function, and that this decrease can be temporarily compensated for by an application of occlusive cream.

[0277] Restoration of skin barrier function from human abrasions: In Panel b of FIG. 11 , the abrasion repair process in human skin can be monitored through epidermal water flux. Two healthy volunteers with daily abrasions participated in this study. Over a follow-up period of approximately two and a half weeks, the two volunteers showed different but similar recovery of skin barrier function, both reaching normal levels (levels of same site on opposite arm) on day 18 post-abrasion. These changes align well with visible changes in the abrasions (right frame). Prior to all measurements, the EFS was sterilized using an ethanol swab, and volunteers were asked to relax with the EFS on for 15 min before starting the measurements. These results, in addition to the animal wound healing models shown in FIG. 4 in EXAMPLE 1, support the feasibility of using the EFS for wound management in human patients.

[0278] EXAMPLE 9:

[0279] FLUID BALANCE MONITORING CAPABILITY

[0280] Selection of representative skin regions: The total epidermal water loss, Esum, can be estimated by Equation 15 below. where index j is for skin regions; £), fwAj, and Rsare epidermal water loss, water flux density, surface area, and water diffusive resistance of the skin region of index j; Ac is the water concentration difference between the skin level (cSw) and atmospheric level (caw). In this simplified estimation, we assume that Ac is constant across the skin regions for ease of analysis. In the calculation of Esumin Panels g-j of FIG. 2, however, realistic Ac values are applied based on the values of skin temperature and atmospheric condition at each measurement location. Here, the factor in the last summation of Equation 15 is called the weighted permeability.

[0281] For compartmentalization of the whole skin, this analysis uses the results of the Lund and Browder chart, which was designed for burn research. The first step it to measure the diffusive resistance using EFS in the major skin regions delineated along the chart. (Panel a of FIG. 12) Next, repeat the same measurement twice to derive the average value of RSwj- (Panel b of FIG. 12 left) These results, sorted in ascending order, are shown in the right frame of Panel b of FIG. 12. The volar hand (palm), where the sweat glands are most densely distributed, shows the lowest values, while the anterior lower leg shows the highest values. There is intersubject Attorney Docket No.: 0116936.310WO2 variation in these distributions of L .

[0282] The numerator of the weighted permeability, Aj, can be expressed as follows (Equation 16). where BSA is body surface area, which can be derived from empirical functions based on height (H) and body mass (M); r is the ratio of Aj to BSA. The subject of the data shown here is a 39 years-old male with body mass and height of 88 kg and 181 cm, which gives BSA value of 2.04 m2on average across different empirical functions of the references. The Lund and Browder chart provides with values of 7). Combination of these information with the data of RSw(Panel b of FIG. 12) yields the values of the weighted permeability, displayed in Panel d of FIG. 12 with descending order. Large values correspond to large levels of water loss in that area of the skin. Skin areas with high Rssuch as the back and post lower leg, also show high £)• values due to the large skin area. Panel e of FIG. 12 shows the cumulative amount from the top of this weighted permeability. The results show that the water loss through the top seven skin regions is approximately two-thirds (66.31%) of the total. These seven skin regions are volar hand, posterior thigh, volar foot, back, forehead, posterior lower leg, and anterior thigh. Of these, the top six were selected as representative skin regions, excluding the volar foot, which restricted movement during measurements.

[0283] Measurement protocol: Six EFSs are coupled via fabric straps to six pre-selected representative skin regions, followed by 15 min of acclimatization, during which the subjects rest in a sitting position with minimal body movement. The subjects wear short trousers and a short- sleeved T-shirt that exposes the measurement locations. The EFSs on the back are placed inside the T-shirt. After the acclimatization phase, the subjects use a smartphone with firmware to activate the EFSs. During the 3 h measurement, the subjects minimize unnecessary movements and walk to and back from the digital scale every 15 min to measure body mass. FIG. 13 displays data other than the data in Panel g of FIG. 2.

[0284] EXAMPLE 10:

[0285] UV IRRADIATION MODEL

[0286] Experimental setup: The 30 x 30 mm porcine skin samples were acquired posteuthanasia from the animal test facility at Northwestern University, Feinberg School of Medicine. The samples were then disinfected with ethanol (only the surface), flash-frozen, and transported to the lab for the experiments. The samples were stored at -80 °C and thawed in a Attorney Docket No.: 0116936.310WO2 sterilized refrigerator before immediate use. Visual inspection screened samples to be discarded after defrosting. The samples for this experiment were prepared for hair removal using an epilator. Selected samples were inserted into a specially designed, sterilized with 70% ethanol, instrumental enclosure, which comprises a petri dish, wicked gauze, pedestal, clamp, and lid. (Panel a of FIG. 14) The samples rested on an elevated pedestal, which was placed in a petri dish with wet gauze on the bottom to prevent the sample from drying over the course of experiment. A clamp was then fitted onto the pedestal to hold down the sample during measurement. A lid was placed at the top, directly contacting the clamp to guide chemicals and vapors towards the opening in the lid, where the sensor was placed (Panel b of FIG. 14). The clamp defined a closed space above the skin sample, and the analysis of data from the enclosure accounts for this space. (Panel c of FIG. 14) The liquid water did not physically contact the skin sample in the instrument. Pedestal, clamp, and lid were fabricated by a 3D printing process.

[0287] UV irradiation and VOC measurement: An ozone-free UV lamp with peak wavelength of X = 253 nm was used, but also with some emission below 240 nm. Bulbs with collective power of 25 W were guided with an aluminum reflector and positioned at 3 cm from the porcine skin sample surface. The irradiation calibrated dosage was 160 mJ / cm2, above the recommended safety limit corresponding to this wavelength. A series of UV irradiations was carried out continuously with each cycle of exposure varied in lengths for 30 s, 1 min, 2 min, 5 min, 10 min. Each cycle was separated by 1 h intervals in between to allow the increased levels of cCvocand fvocto decay. The interval of measurements and the length of each measurement were 30 min and 3 min, respectively. IR images taken from the porcine skin sample immediately before and after UV irradiation confirmed that photothermal effects are negligible. Panel a of FIG. 15 is a digital image of the experimental setting, with a porcine skin sample loaded in the enclosure. The dashed rectangle is the field of view for Panels b-c of FIG. 15. The temperature changed from 22.05 °C before irradiation for 10 min (Panel b of FIG. 15) to 26.25 °C after the irradiation (Panel c of FIG. 15), due to heat generated by the lamp. The temperature of the enclosure increased, but only to a maximum of 36 °C, which does not cause degradation of the plastic. All experiments were conducted in a normal fume hood environment in separate compartments.

[0288] EXAMPLE 11:

[0289] THE DELAYED WOUND HEALING OF DIABETIC MURINE MODEL

[0290] Full wound closure occurs after 13 days in normal mice and after 27 days in diabetic mice. While the restoration of the skin barrier in normal mice aligns with wound closure, the Attorney Docket No.: 0116936.310WO2 diabetic group fails to regain skin barrier function by the time of wound closure, with postclosure barrier restoration extending over the next 2-3 weeks, as depicted in Panel c of FIG. 4. Furthermore, H&E staining indicates that complete epidermal restoration can be observed by the time of wound closure in both normal and diabetic mice (Panel a of FIG. 16). No discernible difference was observed for epithelial structures of unwounded, D+30, D+37, and D+44 postclosure images of diabetic mice as they all exhibited intact stratified epithelial structures, including the stratum corneum (Panel b of FIG. 16).

[0291] Given the significance of complete keratinocyte differentiation in restoring and preserving barrier function, both early and late differentiation markers were investigated. Basal keratinocyte formation, facilitated by the activation of keratin 14, is crucial for re- epithelialization, as the stratified epithelium undergoes continuous self-renewal from basal to superficial layer. The formation of basal keratinocytes is important for re-epithelialization as stratified epithelium that undergoes continuous self-renewal in a basal to superficial direction. One of the late markers, filaggrin, binds and condenses the keratin cytoskeleton, thereby contributing to cell tight junction. Deficiency in filaggrin results in the formation of a poorly developed stratum corneum. Panel f of FIG. 4 and Panel c of FIG. 16 depict strong signals of keratin 14 in both normal and diabetic mice. Filaggrin presence was high in normal mice immediately after wound closure but absent in diabetic mice at D+30. However, filaggrin activity began to increase during the post-closure barrier restoration period and reached native tissue levels after D+44 (Panel d of FIG. 16). Unlike the normal healing process, these results indicate that tight junctions and stratum corneum development were achieved after wound closure for delayed wound healing. The detected flux not only monitors the wound closure but also provides insights into the quality of barrier function in the restored tissue.

[0292] EXAMPLE 12:

[0293] BACTERIAL GROWTH ON EX- VIVO SKIN WOUNDS

[0294] Experimental setup: The experiment shares the same instrumental enclosure and samples with the UV irradiation experimental setup that appears in EXAMPLE 10. Porcine skin samples were prepared by cutting them into 30 x 30 mm pieces. A precise artificial wound, measuring 5 x 5 mm and 1 mm in depth was formed at the center by mechanical abrasion of the surface. These samples were then placed in the instrumental enclosure described in EXAMPLE 10 (FIG. 14). All experiments were conducted in a sterilized fume hood environment in separate compartments. Attorney Docket No.: 0116936.310WO2

[0295] Bacterial growth: E. coli was cultured in a Luria-Bertani (LB) broth at 200 rpm and 37 °C overnight. To meet the threshold of greater than I O' CFU of bacteria per gram of tissue for inducing wound infection, an initial bacterial solution was prepared with a concentration of 105CFU using the DEN-1 Densitometer (Andwin Scientific, Schaumburg, IL). For both control samples and those loaded with bacteria, 100 pl of broth and 100 pl of 103CFU E. coli in broth were respectively drop-cast onto wound areas of the samples.

[0296] Samples were continuously monitored for over 20 h, maintaining them incubated at a constant temperature of 37 °C within in a biosafety cabinet. Images captured from both control and bacteria-loaded samples, before and after the 20-h incubation period, reveal no discernible signs of significant tissue decay or decomposition. This observation suggests that variation in VOC can primarily be attributed to bacterial activity. (FIG. 17).

[0297] EXAMPLE 13:

[0298] PROMISES OF THE EFS

[0299] The EFS introduced in this study can be attached to the skin in a variety of ways. The method can be optimized to suit the context and purpose. In addition to the conventional adhesive method, various schemes ranging from fabric straps, pneumatic adhesion mechanism, and flexible casts have been developed in this study (Panel a of FIG. 18). Normal operation in all cases has been confirmed. In particular, these results may lead to the development of sensor- integrated smart dressings that can be indirectly coupled with wounds of arbitrary shapes in the future. (Panel b of FIG. 18) This system is expected to enable comprehensive and proactive wound management by extracting important physiological information from the surface of the wound and its contents without physically touching the surface of the wound, as illustrated in EXAMPLE 1.

[0300] Due to this flexible form factor, EFS is expected to create a number of possibilities in healthcare, including 1) Homeostasis management in patients with reduced overall physical function - in addition to fluid balance, thermal flux monitoring technology based on the same operating principle could enable real-time management of a patient's thermal homeostasis. (Panel c of FIG. 18) 2) Management of the healing process of open wounds, (Panel d of FIG. 18) and 3) Management of chronic wounds, such as diabetic foot ulcers, and follow-up of wound recurrence. (Panel e of FIG. 18) This technology could be of great value also in everyday life. In particular, it could be applied to the seniors and infants or newborns with diminished or immature skin barrier function to quantify their compromised skin barrier function and Attorney Docket No.: 0116936.310WO2 subsequent risk. The results could play an important role in determining when and how to provide appropriate medical intervention. Furthermore, the technology may be useful in checking the overall hygiene status of individuals. The relevance extends to their vulnerability to infectious diseases through blood-sucking insect vectors. This approach may provide aid methodologies in epidemic prevention and disease control.

[0301] The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.

[0302] The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the invention pertains without departing from its spirit and scope. Accordingly, the scope of the invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.

[0303] Some references, which may include patents, patent applications and various publications, are cited and discussed in the description of this invention. The citation and / or discussion of such references is provided merely to clarify the description of the invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.

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Claims

1. Attorney Docket No.: 0116936.310WO2CLAIMSWhat is claimed is:

1. An apparatus for quantifying outward and / or inward dermal flux of a skin of a subject, comprising: one or more sensor systems, each sensor system comprising: a chamber configured to be positioned immediately adjacent to a surface of the skin to define an enclosed microclimate therein and including a sensor member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin; and a valve coupled with the chamber and configured to modulate diffusive interactions with a surrounding environment, thereby modifying characteristics of the microclimate inside the chamber.

2. The apparatus of claim 1, wherein the chamber is configured to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

3. The apparatus of claim 2, wherein the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified using the sensor member.

4. The apparatus of claim 3, wherein when the chamber is an open state, a basal flux passes in or out through the opening, and wherein rapid (<10 ms) closing of the chamber yields dynamic changes in the concentrations of the targeted species in the microclimate, which are dictated by flux into or out of the skin.

5. The apparatus of claim 1, wherein the sensor member comprises a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

6. The apparatus of claim 5, wherein the targeted species comprise water vapor, volatileAttorney Docket No.: 0116936.310WO2 organic compounds (VOCs), and / or carbon dioxide (CO2).

7. The apparatus of claim 5, wherein the plurality of off-skin sensors comprises a gas sensor for measuring the fluxes of the targeted species in the microclimate, and a temperature sensor for measuring the temperature in the microclimate.

8. The apparatus of claim 5, wherein the sensor member further comprises one or more on- skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

9. The apparatus of claim 8, wherein the one or more on-skin sensors comprise one or more temperature sensors, one or more impedance sensors, one more thermal conductivity sensors, one or more transient plane source (TPS) sensors, and / or one or more skin hydration sensors.

10. The apparatus of claim 1, wherein the modulations associated with cycles of valve opening and closing render opposite variations in the microclimate, corresponding to the outflux and influx of these gaseous substances at the skin surface.

11. The apparatus of claim 10, wherein the valve is configured to dynamically control access to the surrounding environment, thereby creating a transient response that is quantitatively related to inward and outward flux of the targeted species through analysis of the time dependent measurements by the sensor member.

12. The apparatus of claim 11, wherein the valve is a programmable valve or switch that is configured to operably be in an open state or a close state.

13. The apparatus of claim 12, wherein when the valve is in the open state, the chamber is in an open state in which the microclimate is in fluidic communications with the surrounding environment, and when the valve is in the close state, the chamber is in a close state in which the microclimate is not in fluidic communications with the surrounding environment.Attorney Docket No.: 0116936.310WO214. The apparatus of claim 12, wherein the valve comprises a magnetic bistable valve mechanism.

15. The apparatus of claim 14, wherein the valve comprises a pair of magnet members, a plunger positioned between the pair of magnet members and in relation with the chamber, and an electromagnetic (EM) coil configured to actuate the plunger to switch the chamber between the open state and the close state across a bistable magnetic potential created by the pair of magnet members.

16. The apparatus of claim 15, wherein the pair of magnet members is formed of a soft magnetic material; the plunger is formed of a hard magnetic material having permanent magnetism; and the EM coil includes a multilayer PCB (printed circuit board) coil.

17. The apparatus of claim 15, wherein the plunger is in the form of a disc and is operably attracted or repelled by the EM coil situated on a top of the valve, and wherein the pair of magnet members is in the form of paramagnetic rings and operably holds the plunger in place when the plunger reaches both ends of the operating area.

18. The apparatus of claim 17, wherein the opening and closing of the valve are determined by the position of the plunger inside the valve.

19. The apparatus of claim 18, wherein to close the valve, thereby closing the chamber, a current is applied to the EM coil in the direction that pushes the plunger away, and wherein the current in the opposite direction is applied to attract the plunger back to open the chamber, thereby opening the chamber.

20. The apparatus of claim 1, wherein each sensor system further comprises a control unit configured to perform operational control, data acquisition and two-way wireless communication with a user interface operating on an external device.

21. The apparatus of claim 20, wherein the user interface is configured to support theAttorney Docket No.: 0116936.310WO2 operational control of the sensor member and the valve, and / or serve as an interface to display the measured data, and / or monitor conditions of the subject.

22. The apparatus of claim 21, wherein the external device includes a mobile device, a smartphone, a tablet, a computer, a cloud server, and / or any electronic device with data reading / processing / displaying capability.

23. The apparatus of claim 22, wherein the control unit comprises a microcontroller electrically coupled with the sensor member and the valve, and configured to: receive operating parameters wirelessly specified through the user interface from the external device; actuate the valve to modify the characteristics of the microclimate based on the operating parameters; control the sensor member to measure the properties of the skin and the concentrations of the targeted species in the microclimate inside the chamber based on the operating parameters; and receive data measured from the sensor member and wirelessly transmit the received data to the external device for data processing therein.

24. The apparatus of claim 23, wherein the valve is actuated through a series of voltage adjustments in response to instructions from the microcontroller.

25. The apparatus of claim 23, wherein the microcontroller is integrated with a system-on- chip (SoC) and a built-in antenna.

26. The apparatus of claim 23, wherein the control unit further comprises a power management circuit including a low-dropout (LDO) regulator electronically coupled with a power supply for providing power to the sensor system and a boost converter electronically coupled with the microcontroller and the LDO regulator for voltage boosting.

27. The apparatus of claim 26, wherein the power supply comprises a rechargeable battery.Attorney Docket No.: 0116936.310WO228. The apparatus of claim 26, wherein the control unit further comprises an H-bridge circuit electronically coupled with the microcontroller, the boost converter, and the EM coil for actuating the EM coil to operate the plunger with a voltage with a specific polarity and within a defined duration under the control of the microcontroller.

29. The apparatus of claim 1, wherein each sensor system further comprises a sensor-valve platform comprising first, second and third decks, which, in combination with the chamber, are located on the skin, inside the chamber, and on a top of the chamber, respectively, to accommodate the on-skin sensors, the off-skin sensors, and the EM coil for valve actuation.

30. The apparatus of claim 1, wherein said one or more sensor systems are operably mounted onto one or more locations across the body for quantitative monitoring of the transdermal flux of multiple species simultaneously.

31. The apparatus of claim 30, wherein said one or more sensor systems are time- synchronized to each other.

32. The apparatus of any one of claims 1-31, wherein the measured properties of the skin and the measured concentrations of the targeted species in the microclimate have distinct relevance to clinical care and / or exposure to hazardous vapors.

33. The apparatus of claim 32, being usable for the clinical care related to assessments of skin barrier function, full body homeostasis, environmental safety, and / or wound healing.

34. The apparatus of claim 32, being usable for monitoring healing processes associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone- associated disruption of the skin.

35. The apparatus of claim 34, being usable for aiding in clinical decision making for care of conditions associated with dermatological diseases, dermal wounds, chemical or radiativeAttorney Docket No.: 0116936.310WO2 burns, and / or ozone-associated disruption of the skin.

36. The apparatus of claim 32, being usable for early detection of the onset of organ dysfunction or cancer.

37. The apparatus of claim 32, being usable for monitoring entry of hazardous chemicals from the environment into the body through the skin.

38. A method for quantifying outward and / or inward dermal flux of a skin of a subject, comprising: defining an enclosed microclimate immediately adjacent to a surface of the skin, wherein the microclimate is in fluidic communication with the surface of the skin; modulating diffusive interactions of the microclimate with a surrounding environment, thereby modifying characteristics of the microclimate therein; measuring properties of the skin and concentrations of targeted species that emerge from or pass into the skin in the microclimate; and processing the measured properties of the skin and the measured concentrations of the targeted species to quantify the outward and / or inward dermal flux of the skin.

39. The method of claim 38, wherein the targeted species comprise water vapor, volatile organic compounds (VOCs), and / or carbon dioxide (CO2).

40. The method of claim 38, wherein the properties of the skin comprise skin temperature, galvanic response, thermal conductivity, and / or skin hydration.

41. The method of claim 38, wherein the microclimate is defined by a chamber to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

42. The method of claim 39, wherein the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics ofAttorney Docket No.: 0116936.310WO2 the microclimate in ways that are precisely quantified.

43. The method of claim 39, wherein when the chamber is an open state, a basal flux passes in or out through the opening, and wherein rapid (<10 ms) closing of the chamber yields dynamic changes in the concentrations of the targeted species in the microclimate, which are dictated by flux into or out of the skin.

44. The method of claim 43, wherein said modulating the diffusive interactions of the microclimate is performed by actuating a valve coupled with the chamber to be operably in an open state or a close state.

45. The method of claim 44, wherein when the valve is in the open state, the chamber is in an open state in which the microclimate is in fluidic communications with the surrounding environment, and when the valve is in the close state, the chamber is in a close state in which the microclimate is not in fluidic communications with the surrounding environment.

46. The method of claim 44, wherein said measuring the properties of the skin and the concentrations of targeted species is performed by a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

47. The method of claim 46, wherein said measuring the properties of the skin and the concentrations of targeted species is further performed by one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

48. The method of claim 38, wherein said processing the measured properties of the skin and the measured concentrations of the targeted species is performed by an external device including a mobile device, a smartphone, a tablet, a computer, a cloud server, and / or any electronic device with data reading / processing / di splaying capability.Attorney Docket No.: 0116936.310WO249. The method of any one of claims 38-48, wherein the measured properties of the skin and the measured concentrations of the targeted species in the microclimate have distinct relevance to clinical care and / or exposure to hazardous vapors.

50. The method of claim 49, being usable for the clinical care related to assessments of skin barrier function, full body homeostasis, environmental safety, and / or wound healing.

51. The method of claim 49, being usable for monitoring healing processes associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone- associated disruption of the skin.

52. The method of claim 49, being usable for aiding in clinical decision making for care of conditions associated with dermatological diseases, dermal wounds, chemical or radiative burns, and / or ozone-associated disruption of the skin.

53. The method of claim 49, being usable for early detection of the onset of organ dysfunction or cancer.

54. The method of claim 49, being usable for monitoring entry of hazardous chemicals from the environment into the body through the skin.

55. A skin-interfaced apparatus, comprising: a chamber configured to define an enclosed microclimate adjacent to a skin of a subject; a valve configured to modulate diffusive interactions between the microclimate and the ambient; and a sensor member configured to measure properties of the skin and concentrations of targeted species that emerge from or pass into the skin.

56. The skin-interfaced apparatus of claim 55, wherein the valve is configured to dynamically control access to the surrounding environment, thereby creating a transient response that is quantitatively related to inward and outward flux of the targeted speciesAttorney Docket No.: 0116936.310WO2 through analysis of the time dependent measurements by the sensor member.

57. The skin-interfaced apparatus of claim 56, wherein the valve is a programmable valve or switch that is configured to operably be in an open state or a close state.

58. The skin-interfaced apparatus of claim 56, wherein the valve is a magnetically actuated, bistable valve with sub- 10 ms actuation for generating transient concentration profiles directly linked to flux.

59. The skin-interfaced apparatus of claim 55, wherein the chamber is configured to force confinement and / or allow escape / ingress of flux associated with a boundary layer of stationary air, called Nilsson’s zone, that exists within a few millimeters of the surface of the skin.

60. The skin-interfaced apparatus of claim 59, wherein the chamber is configured such that streams of vaporized molecular substances that pass out of or into the skin alter the characteristics of the microclimate in ways that are precisely quantified using the sensor member.

61. The skin-interfaced apparatus of claim 55, wherein the sensor member comprises a plurality of off-skin sensors suspended inside the chamber to detect dynamic information on temperature and fluxes of the targeted species in the microclimate before and after activating the valve.

62. The skin-interfaced apparatus of claim 61, wherein the plurality of off-skin sensors comprises a gas sensor for measuring the fluxes of the targeted species in the microclimate, and a temperature sensor for measuring the temperature in the microclimate.

63. The skin-interfaced apparatus of claim 61, wherein the sensor member further comprises one or more on-skin sensors positioned at a bottom of the chamber in contact with the skin to measure skin temperature, galvanic response, and / or thermal conductivity.

64. The skin-interfaced apparatus of claim 63, wherein the one or more on-skin sensorsAttorney Docket No.: 0116936.310WO2 comprise one or more temperature sensors, one or more impedance sensors, one more thermal conductivity sensors, one or more transient plane source (TPS) sensors, and / or one or more skin hydration sensors.

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