WO2021252732A1 - Capteur d'hydratation pour la surveillance et le diagnostic de maladies de la peau dans un environnement quelconque et son application - Google Patents

Capteur d'hydratation pour la surveillance et le diagnostic de maladies de la peau dans un environnement quelconque et son application Download PDF

Info

Publication number
WO2021252732A1
WO2021252732A1 PCT/US2021/036765 US2021036765W WO2021252732A1 WO 2021252732 A1 WO2021252732 A1 WO 2021252732A1 US 2021036765 W US2021036765 W US 2021036765W WO 2021252732 A1 WO2021252732 A1 WO 2021252732A1
Authority
WO
WIPO (PCT)
Prior art keywords
skin
hydration sensor
hydration
thermal
sensor
Prior art date
Application number
PCT/US2021/036765
Other languages
English (en)
Inventor
John A. Rogers
Anthony R. BANKS
Kyeongha Kwon
Jan-kai CHANG
Original Assignee
Northwestern University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Northwestern University filed Critical Northwestern University
Priority to JP2022576512A priority Critical patent/JP2023530683A/ja
Priority to US18/009,384 priority patent/US20230255483A1/en
Priority to US18/031,389 priority patent/US20240023882A1/en
Publication of WO2021252732A1 publication Critical patent/WO2021252732A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4869—Determining body composition
    • A61B5/4875—Hydration status, fluid retention of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6879—Means for maintaining contact with the body
    • A61B5/688—Means for maintaining contact with the body using adhesives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00—Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/04—Constructional details of apparatus
    • A61B2560/0406—Constructional details of apparatus specially shaped apparatus housings
    • A61B2560/0412—Low-profile patch shaped housings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0271—Thermal or temperature sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0004—Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network characterised by the type of physiological signal transmitted
    • A61B5/0008—Temperature signals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0537—Measuring body composition by impedance, e.g. tissue hydration or fat content
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6814—Head
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6825—Hand
    • A61B5/6826—Finger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6828—Leg
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7225—Details of analog processing, e.g. isolation amplifier, gain or sensitivity adjustment, filtering, baseline or drift compensation

Definitions

  • the invention relates generally to biosensors, and more particularly, to wireless hydration sensors for rapid, multisensor measurements of hydration levels in healthy and/or diseased skin.
  • Skin the largest organ of the human body, is a complex, multilayered functional structure that supports an essential collection of protective, sensory, thermoregulatory, and immunological functions.
  • a core function of skin is to act as a protective interface to the surrounding environment.
  • Failure of the protective function can result in a range of deleterious health effects, as an impaired skin barrier can lead to infection, insensible water loss, tissue necrosis, and death.
  • Deficiencies in barrier function are also the underlying drivers of atopic dermatitis (AD), commonly known as eczema.
  • AD atopic dermatitis
  • AD is the most common inflammatory skin condition, affecting 20% of children and 3% of adults worldwide.
  • Dry skin, or xerosis cutis (XC) is another common skin condition associated with barrier impairment, affecting up to 85% of older adults.
  • Skin barrier dysfunction in neonates can also predict for the development of AD in subsequent years. These and other types of degradation can also increase the systemic absorption of exogenous chemicals and toxic metals, with serious health sequelae.
  • TEWL transepidermal water loss
  • Existing TEWL instruments and skin capacitance methods are available only as expensive devices whose accuracy can be influenced by small changes in ambient temperature, by subtle variations in angle and pressure at the skin interface, and by slight user-related differences in testing protocols. Such limitations confine these methods to use in highly controlled clinical and research studies.
  • TPS transient plane source
  • the invention relates to a hydration sensor comprising a sensing module operably disposed on a target area of interest of skin of a living subject for detecting data associated with thermal properties of the skin; and a wireless platform coupled with the sensing module for wireless data transmission between the sensing module and an external device.
  • the sensing module comprises a thermal actuator operably disposed on the target area of interest of the skin for heating the target area of interest thereof; and a sensing circuit for simultaneously detecting a transient temperature change (D7) thereof to determine thermal properties of the skin.
  • the thermal actuator and the sensing circuit are interconnected by serpentine traces to form a flexible structure that facilitates soft, intimate contact to the skin with robust mechanical and thermal coupling.
  • the thermal actuator comprises at least one resistor.
  • the thermal actuator comprises two or more of surface-mount thin film resistors, thick film resistors, through-hole resistors, and ultrathin-film metal resistors, coupled to each other in series.
  • the sensing circuit comprises one or more of negative temperature coefficient thermistors, positive temperature coefficient thermistors, resistance temperature detectors (RTD), and thermocouples.
  • the sensing circuit comprises a first pair of negative temperature coefficient thermistors (NTCs) arranged in a first Wheatstone bridge circuit.
  • NTCs negative temperature coefficient thermistors
  • the first pair of NTCs is disposed on a layer different from the thermal actuator, and the first pair of NTCs is directly on the top of the thermal actuator. In another embodiment, the first pair of NTCs is disposed on a layer same as the thermal actuator, and each first NTC has a first distance from the thermal actuator.
  • the sensing circuit further comprises a second pair of NTCs arranged in a second Wheatstone bridge circuit serving to compensate for changes in an ambient temperature.
  • the second pair of NTCs is disposed on the same layer as the first pair of NTCs, and each second NTC is spatially apart from the first pair of NTCs and has a second distance from the thermal actuator.
  • the first and second distances are determined by the design requirement of depth sensitivity into the skin, and ranges from 10s of pm to a few mm.
  • the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
  • the wireless platform comprises a Bluetooth low energy system on a chip (BLE SoC).
  • BLE SoC Bluetooth low energy system on a chip
  • the BLE SoC comprises a general-purpose input/output (GPIO) electrically coupled to the thermal actuator for providing a periodic current to activate the thermal actuator; a differential amplifier (AMP) electrically coupled to the sensing circuit for amplifying a difference of bridge voltages; an analog-to-digital converter (ADC) electrically coupled to the AMP to digitize output voltages of the AMP; and a BLE radio configured to wirelessly transmit output signals of the ADC to the external device for processing to determine the hydration status of the skin, and receive data from the external device to activate a GPIO pin to provide the periodic current to the thermal actuator.
  • GPIO general-purpose input/output
  • AMP differential amplifier
  • ADC analog-to-digital converter
  • BLE radio configured to wirelessly transmit output signals of the ADC to the external device for processing to determine the hydration status of the skin, and receive data from the external device to activate a GPIO pin to provide the periodic current to the thermal actuator.
  • a digital on/off switch controlled through a custom application on the external device is adapted to enable BLE-connection and activation of the GPIO pin to source the periodic current into the thermal actuator.
  • the BLE SoC further comprises a microcontroller (pC) configured to activate the GPIO pin to source the periodic current into the thermal actuator.
  • pC microcontroller
  • the hydration sensor further comprises a power module for providing power to the sensing circuit and the wireless platform.
  • the power module comprises a battery.
  • the battery is a rechargeable battery operably rechargeable with wireless recharging.
  • the power module further comprises a wireless charging module for wirelessly charging the rechargeable battery.
  • the power module further comprises a failure prevention element including a short-circuit protection component or a circuit to avoid battery malfunction.
  • the hydration sensor further comprises a flexible substrate in the form of a flexible printed circuit board (fPCB) with circuit traces that interconnect the thermal actuator on a skin side, the NTCs on an air side, and the BLE SoC.
  • fPCB flexible printed circuit board
  • the flexible substrate is formed of a flexible material comprising polyimide (PI) and/or polyethylene terephthalate (PET).
  • PI polyimide
  • PET polyethylene terephthalate
  • the flexible substrate is a flexible copper-clad polyimide (Cu/PECu) sheet.
  • the hydration sensor further comprises an encapsulating enclosure enclosing the thermal actuator, the wireless platform, the battery, and the fPCB.
  • the encapsulating enclosure comprises a top layer for thermal, chemical and mechanical isolation of the hydration sensor from the environment; and a bottom layer for providing a direct interface between the thermal actuator at the skin side of the fPCB and the skin.
  • the top layer is a shell-like top encapsulation layer including small air gaps for thermally, mechanically, and chemically insulating the critical sensing components.
  • the top layer is formed of a flexible material including silicone or silicone gel, low/high density polyethylene (LDPE/HDPE), polystyrene, Teflon ® , and various other flexible polymers.
  • LDPE/HDPE low/high density polyethylene
  • polystyrene polystyrene
  • Teflon ® Teflon ®
  • the bottom layer comprises a flexible adhesive for attaching the hydration sensor to the skin.
  • the bottom layer further comprises an ultrathin fabric of fiberglass/reinforcement material embedded in the flexible adhesive layer for enhancing the mechanical robustness of the hydration sensor.
  • the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
  • the flexible adhesive layer is formed of silicone or silicone gel, or double-sided skin-safe adhesives, with the ratio of silicone and silicone gel being adjusted to co optimize mechanical integrity and tackiness of the adhesive.
  • the external device is a smartphone, a tablet, a computer, or any electronic device with data reading/processing capability.
  • the thermal properties of the skin comprise thermal conductivity and thermal diffusivity of the skin that are related to water content of the skin, wherein the water content is a function of a skin depth.
  • the water content is determined from the measured temperature change AT vs. time t.
  • the water content and skin surface temperature are used to determine a normal state or a disease state of the skin.
  • the water content and skin surface temperature serve as quantitative metrics of an efficacy of a treatment of a skin disease, or other health and wellness products including skin moisturizers, lotions, and/or creams.
  • the hydration sensor is usable for monitoring the skin condition in a clinical setting and/or an at-home setting.
  • the hydration sensor is usable for delivering treatment, monitoring the effects, modulating the treatment protocol as necessary, and/or potentially predicting for flares based on quantitative, individualized measurements on specific lesion sites.
  • the hydration sensor is usable for monitoring water content of internal organs for various diseases where traditional monitoring techniques fail to offer continuous assessment of organ health.
  • the hydration sensor is usable for monitoring organs during organ transport for applications in organ transplant.
  • the hydration sensor is usable for applications to measure thermal conductivity, thermal diffusivity, heat capacity and other thermal properties of any material as a function of depth.
  • the hydration sensor is usable for applications to measure water content of any material surface as a function of depth, including hydrogels, plants (irrigation and agriculture applications), food preservation (dried food products, grains, fruits, meats), and/or concrete (industrial applications).
  • the hydration sensor is usable for monitoring composition of food/beverages, medicines/industrial chemicals.
  • the hydration sensor is re-usable and removal without irritation to the skin or damage to the hydration sensor.
  • the hydration sensor is compatible with alcohol-based cleaning wipes allowing for re-use across different users, without any damage to the hydration sensor or loss in efficacy of the hydration sensor adhesive.
  • the hydration sensor is sterilizable using alcohol, autoclave steam sterilization, and gas phase sterilization.
  • the invention in another aspect, relates to a method of fabricating a hydration sensor.
  • the method includes forming a flexible printed circuit board (fPCB) that interconnects electronics of the hydration sensor; and forming an encapsulating enclosure enclosing the sensing module, the wireless platform and the fPCB, wherein the encapsulating enclosure comprises a top layer and a bottom layer.
  • fPCB flexible printed circuit board
  • the fPCB is formed of a flexible material comprising polyimide (PI), polyethylene terephthalate (PET), or any one of them in combination with stiff PCB material including FR-4.
  • PI polyimide
  • PET polyethylene terephthalate
  • the bottom layer comprises a layered structure of a first flexible layer, a second flexible layer, and a fabric of fiberglass/a reinforcement material embedded between the first flexible layer and the second flexible layer.
  • each of the first flexible layer and the second flexible layer is formed of silicone or silicone gel, or double-sided skin-safe adhesives, with the ratio of the silicone and silicone gel being adjusted to co-optimize mechanical integrity and tackiness of the adhesive.
  • the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
  • the bottom layer adheres to the f-PCB through use of silicone bonding material, epoxy, glue, or commercial adhesive.
  • the top shell layer is formed of silicone or silicone gel, low/high density polyethylene (LDPE/HDPE), polystyrene, Teflon ® , and various other flexible polymers.
  • LDPE/HDPE low/high density polyethylene
  • polystyrene polystyrene
  • Teflon ® Teflon ®
  • the electronics comprises a sensing module for detecting data associated with thermal properties of the skin; and a wireless platform coupled with the sensing module for wireless data transmission between the sensing module and an external device.
  • the sensing module comprises a thermal actuator for heating a target area of interest of the skin; and a sensing circuit for simultaneously detecting a transient temperature change (D7) thereof to determine thermal properties of the skin.
  • the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
  • the wireless platform comprises a Bluetooth low energy system on a chip (BLE SoC).
  • BLE SoC Bluetooth low energy system on a chip
  • the invention relates to a method of monitoring and/or diagnosing a condition of a skin.
  • the method comprises attaching a hydration sensor onto a target area of interest on the skin, wherein the hydration sensor comprises a thermal actuator, a sensing circuit, and a wireless platform for two-way data communication with an external device; heating the target area of interest of the skin by the thermal actuator, simultaneously detecting data associated with thermal properties of the skin by the sensing circuit, and wirelessly transmitting the detected data, by the wireless platform, to the external device to determiner a transient temperature change (D7) thereof; obtaining water content of the target area of interest of the skin from the temperature change (D7); and determining a condition of the skin at the target area of interest based on the obtained water content.
  • D7 transient temperature change
  • the water content comprises water content F E of the epidermis and water content ⁇ 3 ⁇ 4 of the dermis.
  • the step of obtaining the water content comprises separately determination of FE and F ⁇ from the temperature change AT.
  • the wireless platform transmits data through a wireless communication protocol including Near Field Communication (NFC), Wi-fi/Internet, Bluetooth/Bluetooth low energy (BLE), or GSM/Cellular Communication.
  • NFC Near Field Communication
  • Wi-fi/Internet Wi-fi/Internet
  • BLE Bluetooth/Bluetooth low energy
  • GSM/Cellular Communication GSM/Cellular Communication
  • said heating the target area of interest of the skin is formed by providing a periodic current to the thermal actuator.
  • activation of the periodic current is controlled by a digital on/off switch through a custom application on the external device.
  • said determining the condition of the skin at the target area of interest comprises comparing the obtained water content to a standard water content at the target area of interest so as to determine a normal state or a disease state of the skin.
  • said determining the condition of the skin at the target area of interest comprises diagnosing a skin disease at the target area of interest based on wherein the obtained water content thereof.
  • said determining the condition of the skin at the target area of interest comprises evaluating an efficacy of a treatment of the skin disease.
  • said obtaining water content of the target area of interest of the skin, and said determining a condition of the skin are performed in the external device.
  • the method further comprises displaying the condition of the skin at the target area of interest in the external device.
  • the method further comprises forwarding the condition of the skin at the target area of interest to a professional and/or a service provider.
  • the method further comprises one or more steps of delivering treatment, monitoring the effects, modulating the treatment protocol as necessary, and/or potentially predicting for flares based on quantitative, individualized measurements on specific lesion sites.
  • the method is performed under one or more optimized measurement conditions of (1) the measurement being performed rapidly, to minimize effects of occlusion of natural processes of water vapor release from the skin due to the presence of the hydration sensor; (2) very light or zero applied pressure being used during the measurement, to minimize perturbations to the skin; (3) the adhesive being patterned such that it is present only across regions of the hydration sensor device adjacent to the sensor itself, to avoid exfoliation of the skin at the measurement site during peel back, for improved repeatability; (4) the temperature of the hydration sensor being comparable to that of the skin; and (5) skin itself being allowed to acclimate to the surrounding environment prior to the measurement.
  • FIGS. 1A-1F show soft, skin-interfaced platforms for automatic, wireless sensing of thermal transport properties of the skin, according to embodiments of the invention.
  • FIG. 1 A Picture of a thin, flexible thermal actuator/sensor (TAS) module integrated with electronics to provide Bluetooth Low Energy (BLE) communication capabilities, resting on the tip of an index finger. The Inset features an image of the device bent between the thumb and index finger.
  • FIG. IB Circuit and block diagrams of the design.
  • the TAS module includes a thermal actuator (Joule heater; R H X 2), and Wheatstone bridge circuits that include two thermistors (NTC + , NTC-) with a known resistor (R) on each bridge.
  • a digital on/off switch on the user interface activates a general-purpose input/output (GPIO) pin to source a predetermined periodic current (6.8 mA for 10 s, and 0 mA for 50 s in a l-min cycle) into the resistive heater.
  • GPIO general-purpose input/output
  • a differential amplifier (AMP) in a BLE system-on-a-chip (SoC) amplifies the difference of the bridge voltages (V + , V-).
  • the subsequent analog-to-digital converter (ADC) samples the AMP output voltages for transmission to a smartphone via BLE radio communication.
  • FIG. 1C Exploded-view illustration of the constituent layers and components: silicone encapsulation layers, battery, and a flexible copper-clad polyimide (Cu/PI/Cu) sheet with circuit traces that interconnect the thermal actuator (skin side), NTCs (air side), and the BLE SoC.
  • the Inset highlights an air pocket structure defined by the top silicone encapsulation layer as thermal insulation around the TAS module.
  • FIG. ID Picture of an encapsulated device adhered to the thenar eminence.
  • FIG. E Schematic layered view of the TAS module.
  • FIG. F Schematic top view of the TAS module.
  • FIGS. 2A-2I show finite-element analysis (FEA) of thermal transport throughout the system as the basis for device optimization and data analysis.
  • FIG. 2A Schematic illustration of the thermal actuator (R H X 2) with two pairs of thermistors: NTCi (NTCi + , NTCi-; resting on the top of the thermal actuator), and NTC2 (NTC2 + , NTC2-; resting at the same distance, d, from the actuator).
  • FIG. 2B Schematic illustration of the FEA model of dual-sided (Left) and single-sided (Right) sensor designs.
  • DT12 DTi - DT2.
  • FIG. 2G Comparison between FEA and experiment (SD ⁇ 3.5%) for PDMS structures described above.
  • FIGS. 3A-3H show experimental studies under various practical conditions.
  • FIG. 3 A Wireless measurements of Ti (blue) and T2 (red) in various ambient temperatures (T A ) in an oven and a refrigerator (red and blue background, respectively), and at room temperature (RT).
  • FIG. 3B Measurements of DTi (blue), DT2 (red), and DT12 (black) as a function of TA.
  • FIG. 3 A Wireless measurements of Ti (blue) and T2 (red) in various ambient temperatures (T A ) in an oven and a refrigerator (red and blue background, respectively), and at room temperature (RT).
  • FIG. 3B Measurements of DTi (blue), DT2 (red), and DT12 (black) as a function of TA.
  • FIG. 3 A Wireless measurements of Ti (blue) and T2 (red) in various ambient temperatures (T A ) in an oven and a refrigerator (red and blue background, respectively), and at room temperature (RT).
  • FIG. 3B Measurements of DTi
  • FIGS. 3C Wireless measurements of Ti (blue), T2 (red), and substrate temperature (7s; green dashed line) on/off the hot plate (heating/cooling, respectively) and with different levels of airflow, as a function of time.
  • the surface temperature of the top encapsulation corresponds to that directly above the heating/sensing elements of the device (T D ; purple) and the ambient temperature (T A ; black) was determined using a commercial thermometer.
  • FIGS. 3D-3E Measurements of DTi (blue), DT2 (red), and DT12 (black) as a function of TA (FIG. 3D) and as a function of time (FIG. 3E).
  • a pneumatic flow valve controls the flow of air over the device.
  • FIG. 3F-3G Wireless measurements of Ti (blue), T2 (red), and the difference (Ti - T2; black) as a function of time (FIG. 3F), and of DTi (blue), DT2 (red), and DT12 (black) as a function of time (FIG. 3G) underwater.
  • FIG. 3H Skin hydration levels (F) measured by three users at the same set of body locations using the BLE device ( ⁇ E>BLE) , and commercial devices for measuring tissue water content ( ⁇ E>CML,I) and skin surface hydration levels ( ⁇ 1>CML,2). Five different body locations: forehead (FIG. 3F), right arm (AR), left arm (AL), right leg (LR), and left leg (L l ).
  • FIGS. 4A-4F show experimental studies on the near surface layers of the skin, and on a sample of porcine skin with different, known levels of hydration.
  • FIG. 4A Optical image of a stripping disk (D-Squame; CuDerm) on the forearm, as a simple and painless means to uniformly remove a fixed area of SC from the skin.
  • FIG. 4B Measurements of ⁇ E>BLE (black) and ⁇ I>c ML,i (blue), and SC hydration levels ( ⁇ E>CML,3; red) measured using a commercial device (MoistureMeterSC; Delfin Technologies) as a function of the number of cycles of adhesive disk stripping.
  • FIG. 4A Optical image of a stripping disk (D-Squame; CuDerm) on the forearm, as a simple and painless means to uniformly remove a fixed area of SC from the skin.
  • FIG. 4B Measurements of ⁇ E>BLE (black) and
  • FIG. 4D Optical image of the device mounted on a sample of porcine skin, next to a commercial device (MoistureMeterSC; Delfin Technologies) for measuring SC hydration levels.
  • FIG. 4E Measured F for a sample of porcine skin with different, known levels of hydration controlled by placing the sample in a food dehydrator (33 °C).
  • FIGS. 5A-5E show on-body measurements of skin hydration levels.
  • FIGS. 5A-5C Pictures of devices mounted on the forehead (FIG. 5 A), forearm (FIG. 5B), and lower leg (FIG. 5C) of a healthy female volunteer.
  • FIG. 5D Wireless measurements of AT from NTCi and NTC2, and the differences (DTi, DT2, and DT12 , respectively) acquired from three female (subjects 1, 2, 9; age range: 25 to 27) and seven male (subjects 3 to 8, 10; age range: 17 to 37) healthy volunteers. Mounting positions on the body: forehead (F), right arm (AR), left arm (AL), right leg (LR), and left leg (LL).
  • FIG. 5A-5C Pictures of devices mounted on the forehead (FIG. 5 A), forearm (FIG. 5B), and lower leg (FIG. 5C) of a healthy female volunteer.
  • FIG. 5D Wireless measurements of AT from NTCi and NTC2, and the differences (DTi, DT
  • FIGS. 6A-6I show wireless measurements of skin hydration on human subjects with atopic dermatitis.
  • FIGS. 6A-6B Mounting positions on the back of the hand (atopic eczema) and the forearm (control) of a young adult patient with severe AD (subject 1; FIG.
  • FIGS. 6A-6D Wireless measurements of DT12 before and after (B&A) application of moisturizer from subjects 1 (FIG. 6C) and 2 (FIG. 6D).
  • FIGS. 6C-6D Wireless measurements of DT12 before and after (B&A) application of moisturizer from subjects 1 (FIG. 6C) and 2 (FIG. 6D).
  • FIGS. 6G-6H Pictures of the device mounted on the forehead (FIG. 6G) and leg (FIG. 6H; visibly dry skin) of a toddler.
  • FIG. 8 shows a picture of an encapsulated device next to a 12 mAh Li -polymer battery.
  • FIG. 9 shows wireless read-out of the temperature change measured from NTCi (DTi) and NTC2 (DT2) as a function of time for 10 s of heating every one min.
  • DT12 DTi - DT2.
  • FIGS. 10A-10B show schematic illustration of the FEA model of dual-sided (FIG. 10 A) and single-sided (FIG. 10B) sensor designs.
  • FIGS. 10C-10D show sensitivities of the temperature difference (DT12) between NTCi (DTi) and NTC2 (DT2) to skin hydration level of dual-sided (FIG. IOC) and single-sided (FIG. 10D) designs 10 s after the heater is activated.
  • DT12 temperature difference
  • DTi NTCi
  • DT2 NTC2
  • FIGS. 11 A-l IE show comparisons between FEA and measurement for a thick layer of SI 84 (FIG. 11 A) and S170 (FIG. 1 IB), and a thin layer of S184 (70 pm, FIG. 11C; 100 pm, FIG. 1 ID; 200 mih, FIG. 1 IE) on top of the SI 70.
  • FIGS. 13A-13B show computational predictions of DT12 with different sizes of actuators (width and length of RH) for 30 % (FIG. 13A) and 95 % (FIG. 13B) hydrated skin.
  • FIGS. 14A-14B show an effect of design parameters on the temperature change.
  • FIG. 14A A simplified, analytical model of a disk-shaped thermal actuator (radius, R) and NTCs.
  • FIG. 14B Analytical scaling law for DT12.
  • FIG. 15 shows ambient temperatures. Measurements of DTi (blue), DT2 (red), and DT12 (black) as a function of time (min). The values of DTi and DT2 fluctuate at the moment the device enters and exits the oven (yellow background).
  • FIG. 16A shows a picture of conventional devices based on skin capacitance measurements for monitoring tissue water content (MoistureMeterD; top), SC hydration levels (MoistureMeterSC; middle top), and skin surface hydration levels (Gpskin; middle bottom), and a BLE device (bottom).
  • FIG. 16B shows a picture of devices on the forearm, according to embodiments of the invention. The commercial devices require care by the user to hold the probe and apply a certain pressure against the skin for each measurement.
  • FIG. 17 shows mounting positions on the body: forehead (F), right arm (A R ), left arm (A l ), right leg (L R ), and left leg (L l ).
  • FIG. 18 shows SD for F tested by 3 users using BLE ( ® BLE > and commercial (F O E I and F OME 2 devices at five different body locations, forehead (F), right arm (A R ), left arm (A L ), right leg (L R ), and left leg (L L ), for subject 1 to 3.
  • BLE BLE > and commercial (F O E I and F OME 2 devices at five different body locations, forehead (F), right arm (A R ), left arm (A L ), right leg (L R ), and left leg (L L ), for subject 1 to 3.
  • FIG. 19 shows a positive correlation between ® BLE and F OME I (black), and between ® BLE and ® CML ,2 (red), and their linear fits (lines).
  • FIGS. 20A-20B show bland- Altman plots of ® BLE, c aii and ®CML,I (FIG. 20A), and ® BLE, c ai 2 and F OME 2 (FIG. 20B). Horizontal lines represent the mean (red), and mean ⁇ 1.96 SD (blue) values of F BLE, Cal - Fana where SD is the standard deviation.
  • the mean ⁇ SD values of the differences (®CML,I - ®BLE,caii, and FOME2 - ®BLt.cai2) are 0.00 ⁇ 0.02 and 0.00 ⁇ 0.04, respectively.
  • FIG. 21 shows pictures of an encapsulated device mounted on a pediatric hand.
  • FIG. 22 shows SD for DTi, DT2, and DT12 at five different body locations, forehead (F), right arm (A R ), left arm (A L ), right leg (L R ), and left leg (L L ), for subjects 1 to 10.
  • FIG. 24 shows a Bland-Altman plot (difference plot) of ⁇ l>BLE , caii and ⁇ 1>CML,I. Horizontal lines represent the mean (red; -0.00), and mean ⁇ 1.96 SD (blue; ⁇ 0.00 ⁇ L96 0.05) values of t&BLE.caii - cML . 1 where SD is the standard deviation.
  • FIG. 25 A shows pictures of the device on a subject’s leg before (left) and after (right) shaving the skin. Insets show the sensing point.
  • FIG. 25B shows wireless measurements of DTi (blue), DT2 (red), and DT12 (black) before and after shaving the sensing area.
  • FIG. 26A shows an optical image of the device mounted on the forehead of a healthy male subject.
  • FIG. 26B shows wireless measurements of ⁇ E>BLE before, during and after a workout.
  • Vertical bar denotes the error bar over 3-time measurements.
  • FIG. 27 shows an optical image of the device mounted on the atopic hand of a subject 1, next to a BLE-enabled smartphone.
  • 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.
  • 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.
  • “around”, “about”, “approximately” or “substantially” shall 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.
  • 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.
  • the term “and/or” includes any and all combinations of one or more of the associated listed items.
  • Interfacing refers to the positioning of the device with tissue such that the device may affect the tissue, and vice versa.
  • a thermal actuator of the device may result in a thermal load provided to the tissue in the form of a “thermal input”.
  • the thermal input is preferable a heating action, although the device is also compatible with a cooling action.
  • tissue parameters may be determined, such as tissue hydration, inflammation, blood flow, UV damage.
  • 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.
  • 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 mesh geometries.
  • any of the devices provided herein may be described in terms of elasticity or elastic.
  • “Elasticity” refers to a measure of a non-plastic deformation, such as a deformation that can undergo deformation and relaxation back to the original undeformed, state without substantial creep, including under repeated deformatory stresses and relaxation cycles. The creep may be defined as less than a 5%, less than 2%, or less than 1% permanent deformation or change in the original material property.
  • Stretchable refers to the ability of a material, structure, device or device component to be strained without undergoing fracture.
  • a stretchable material, structure, device or device component may undergo strain larger than 0.5% without fracturing, for some applications strain larger than 1% without fracturing and for yet other applications strain larger than 3% without fracturing.
  • many stretchable structures are also flexible.
  • Some stretchable structures e.g., device components
  • Stretchable structures include thin film structures comprising stretchable materials, such as elastomers; bent structures capable of elongation, compression and/or twisting motion; and structures having an island - bridge geometry.
  • Stretchable device components include structures having stretchable interconnects, such as stretchable electrical interconnects.
  • “Two-way communication” refers to the ability to wirelessly communicate with the device, such that power, commands or queries are sent to, and acted on, the device and the device itself can send information or diagnostics to an external controller that is wirelessly connected to the device.
  • an “external controller” refers to an off-board component that can control and received information from the device. Examples include hand-held devices, computers, smartphones, and the like.
  • the devices and methods provided herein are suited for long-term use in that the device may be “worn” over long periods of time and remain functional. Accordingly, “continuous” refers to the time period any of the devices provided herein are deployed on or in biological tissue and is ready for use. While the device is continuously deployed, the measurement may be described as intermittent or periodic, such as for a continuous measurement time on the order of minutes, such as greater than or equal to 1 minute, 5 minutes, 10 minutes or 20 minutes. The periodic measurement, however, can be repeated over the time period the device is worn, such as in the morning, during the day, and in the evening, including on the order of 12 hours or more, 1 day or more, or 7 days or more.
  • Thermal parameter” or “thermal transport property” may refer to a rate of change of a temperature-related tissue property, such as a heat-related tissue property, over time and/or distance (velocity).
  • the heat-related tissue property may be temperature, conductivity or humidity.
  • the heat-related tissue property may be used to determine a thermal transport property of the tissue, where the “thermal transport property” relates to heat flow or distribution at or near the tissue surface.
  • thermal transport properties include temperature distribution across a tissue surface, thermal conductivity, thermal diffusivity and heat capacity.
  • Thermal transport properties, as evaluated in the present methods and systems may be correlated with a physical or physiological property of the tissue.
  • a thermal transport property may correlate with a temperature of tissue.
  • a thermal transport property may correlate with a vasculature property, such as blood flow and/or direction.
  • Substrate refers to a portion of the device that provides mechanical support for a component(s) disposed on or within the substrate.
  • the substrate may have at least one skin- related function or purpose.
  • the substrate may have a mechanical functionality, for example, providing physical and mechanical properties for establishing conformal contact at the interface with a tissue, such as skin or a nail surface.
  • the substrate may have a thermal loading or mass small enough so as to avoid interference with measurement and/or characterization of a tissue parameter.
  • the substrate of any of the present devices and methods may be biocompatible and/or bioinert.
  • a substrate may facilitate mechanical, thermal, chemical and/or electrical matching to the underlying tissue, such as skin or nail of a subject such that the mechanical, thermal, chemical and/or electrical properties of the substrate and the tissue are within 20%, or 15%, or 10%, or 5% of one another.
  • Devices and methods described herein may incorporate mechanically functional substrates comprising soft materials, for example exhibiting flexibility and/or stretchability, such as polymeric and/or elastomeric materials.
  • a mechanically matched substrate may have a Young’s modulus less than or equal to 100 MPa, and optionally for some embodiments less than or equal to 10 MPa, and optionally for some embodiments, less than or equal to 1 MPa.
  • a mechanically matched substrate has a thickness less than or equal to 0.5 mm, and optionally for some embodiments, less than or equal to 1 cm, and optionally for some embodiments, less than or equal to 3 mm. In an embodiment, a mechanically matched substrate has a bending stiffness less than or equal to 1 nN m, optionally less than or equal to 0.5 nN m.
  • a mechanically matched substrate is characterized by one or more mechanical properties and/or physical properties that are within a specified factor of the same parameter for an epidermal layer of the skin or nail, such as a factor of 10 or a factor of 2.
  • a substrate may have a Young's Modulus or thickness that is within a factor of 20, or optionally for some applications within a factor of 10, or optionally for some applications within a factor of 2, of a tissue, such as an epidermal layer of the skin or of the nail surface, at the interface with a device of the present invention.
  • a mechanically matched substrate may have a mass or modulus that is equal to or lower than that of skin.
  • a substrate that is thermally matched to skin has a thermal mass small enough that deployment of the device does not result in a thermal load on the tissue, such as skin, or small enough so as not to impact measurement and/or characterization of a physiological parameter.
  • a substrate that is thermally matched to skin has a thermal mass low enough such that deployment on skin results in an increase in temperature of less than or equal to 2 degrees Celsius, and optionally for some applications less than or equal to 1 degree Celsius, and optionally for some applications less than or equal to 0.5 degree Celsius, and optionally for some applications less than or equal to 0.1 degree Celsius.
  • a substrate that is thermally matched to skin has a thermal mass low enough that is does not significantly disrupt water loss from the skin, such as avoiding a change in water loss by a factor of 1.2 or greater. Therefore, the device does not substantially induce sweating or significantly disrupt transdermal water loss from the skin, while maintaining an effectiveness of determining hydration sate of the skin.
  • the substrate may have a Young’s modulus less than or equal to 100 MPa, or less than or equal to 50 MPa, or less than or equal to 10 MPa, or less than or equal to 100 kPa, or less than or equal to 80 kPa, or less than or equal to 50 kPa.
  • the device may have a thickness less than or equal to 5 mm, or less than or equal to 2 mm, or less than or equal to 100 pm, or less than or equal to 50 pm, and a net bending stiffness less than or equal to 1 nN m, or less than or equal to 0.5 nN m, or less than or equal to 0.2 nN m.
  • the device may have a net bending stiffness selected from a range of 0.1 to 1 nN m, or 0.2 to 0.8 nN m, or 0.3 to 0.7 nN m, or 0.4 to 0.6 nN m.
  • epidermal tissue refers to the outermost layers of the skin or the epidermis.
  • the epidermis is stratified into the following non-limiting layers (beginning with the outermost layer): stratum comeum, stratum lucidum (on the palms and soles, i.e., the palmar regions), stratum granulosum, stratum spinosum, stratum germinativum (also called the statum basale).
  • epidermal tissue is human epidermal tissue.
  • Encapsulate refers to the orientation of one structure such that it is at least partially, and in some cases completely, surrounded by one or more other structures, such as a substrate, adhesive layer or encapsulating layer. “Partially encapsulated” refers to the orientation of one structure such that it is partially surrounded by one or more other structures, for example, wherein 30%, or optionally 50%, or optionally 90% of the external surface of the structure is surrounded by one or more structures. “Completely encapsulated” refers to the orientation of one structure such that it is completely surrounded by one or more other structures. The encapsulation may be described in functional terms, such as being a fluid or electrical barrier, particularly in those locations where a fluid or electrical field would lead to an adverse impact on the device.
  • Conformable refers to a device, material or substrate which has a bending stiffness that is sufficiently low to allow the device, material or substrate to adopt any desired contour profile, for example a contour profile allowing for conformal contact with a curvilinear surface, including a surface whose shape may change over time, such as with physical exertion or normal every day movement, such as skin.
  • Conformal contact refers to contact established between a device and a receiving surface.
  • conformal contact involves a macroscopic adaptation of one or more surfaces (e.g., contact surfaces) of a device to the overall shape of a surface.
  • conformal contact involves a microscopic adaptation of one or more surfaces (e.g., contact surfaces) of a device to a surface resulting in an intimate contact substantially free of voids.
  • conformal contact involves adaptation of a contact surface(s) of the device to a receiving surface(s) such that intimate contact is achieved, for example, wherein less than 20% of the surface area of a contact surface of the device does not physically contact the receiving surface, or optionally less than 10% of a contact surface of the device does not physically contact the receiving surface, or optionally less than 5% of a contact surface of the device does not physically contact the receiving surface.
  • Devices of certain aspects are capable of establishing conformal contact with internal and external tissue.
  • Devices of certain aspects are capable of establishing conformal contact with tissue surfaces characterized by a range of surface morphologies including planar, curved, contoured, macro-featured and micro-featured surfaces and any combination of these.
  • Devices of certain aspects are capable of establishing conformal contact with tissue surfaces corresponding to tissue undergoing movement, including an internal organ or skin.
  • Young’s modulus is a mechanical property of a material, device or layer which refers to the ratio of stress to strain for a given substance. Young’s modulus may be provided by the expression: _ (stress)
  • Young’ s modulus may also be expressed in terms of Lame constants via the equation: where l and m are Lame constants. High Young’s modulus (or “high modulus”) and low Young’s modulus (or “low modulus”) are relative descriptors of the magnitude of Young’s modulus in a given material, layer or device.
  • a high Young’s modulus is larger than a low Young’s modulus, preferably about 10 times larger for some applications, more preferably about 100 times larger for other applications, and even more preferably about 1000 times larger for yet other applications.
  • a low modulus layer has a Young’s modulus less than 100 MPa, optionally less than 10 MPa, and optionally a Young’s modulus selected from the range of 0.1 MPa to 50 MPa.
  • a high modulus layer has a Young’s modulus greater than 100 MPa, optionally greater than 10 GPa, and optionally a Young’s modulus selected from the range of 1 GPa to 100 GPa.
  • a device of the invention has one or more components having a low Young’s modulus.
  • a device of the invention has an overall low Young’s modulus.
  • Low modulus refers to materials having a Young’s modulus less than or equal to 10 MPa, less than or equal to 5 MPa or less than or equal to 1 MPa.
  • Use of the term “effective” with any physical parameter reflects an average or bulk parameter. This reflects, for example, that the devices are not formed of a single unitary material, but can have materials ranging from elastomers, adhesives, thin films, metals, semiconductors, integrated circuits and other materials that span orders of magnitudes.
  • An effective device modulus accordingly, can reflect physical properties of the entire device, with a special geometry and configuration of components to ensure the bulk behavior of the device is tailored to the application of interest.
  • the entire device can be configured to be highly flexible and stretchable, with certain portions that are by necessity less flexible and stretchable due to material requirements.
  • the entire device need not be so stretchable, but should still conform to the nail curvilinear surface contour.
  • Bending stiffness is 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.
  • tissue parameter refers to a property of a tissue including a physical property, physiological property, electronic property, optical property and/or chemical composition.
  • Tissue parameter may refer to a surface property, a sub-surface property or a property of a material derived from the tissue, such as a biological fluid.
  • Tissue parameter may refer to a parameter corresponding to an in vivo tissue such as temperature; hydration state; chemical composition of the tissue; chemical composition of a fluid from the tissue; pH of a fluid from the tissue; the presence of absence of a biomarker; intensity of electromagnetic radiation exposed to the tissue; wavelength of electromagnetic radiation exposed to the tissue; and amount of an environmental contaminant exposed to the tissue.
  • Devices of some embodiments are capable of generating a response that corresponds to one or more tissue parameters, such as for a low hydration state application of a hydrating material (e.g., a moisturizer), or for a UV damage state application of a UV block (e.g., sunscreen) or a warning to the individual wearing the device, such as a haptic feedback actuator that provides a vibratory signal, optical signal, or electrical signal, warning the user to take appropriate action.
  • a tissue parameter may provide useful information about the health of a tissue.
  • a tissue parameter that is a “sunburn parameter” may be used to assess effectiveness of a compound as a sunscreen, to warn a user, or to automatically apply a treatment, including application of a sunscreen.
  • the sunburn parameter may be an optical property, such as color, or may be a hydration property that, in turn, is related to thermal conductivity of the underlying tissue.
  • any of the devices and methods provided herein may be personalized to a user.
  • “personalized” refers to the device or method that is tailored to that of an individual user, recognizing there may be relatively significant person-to-person variability with respect to one or more baseline tissue parameters, and tissue behavior to a stimulus. For example, some people may have higher inherent thermal conductivity, or high resting hydration level.
  • the devices or methods may accurately determine the baseline tissue parameter, with monitoring and corresponding treatment tailored to that individual’s baseline tissue parameter.
  • Hapic feedback element refers to a device component that generates a physically- detectable stimulus by a user, such as be a haptic feedback element that is selected from the group consisting of a vibrator, an optical light source, or an electrode.
  • “Environmental parameter” refers to a property of an environment of a device, such as a device in conformal contact with a tissue.
  • Environment parameter may refer to a physical property, electronic property, optical property and/or chemical composition, such as an intensity of electromagnetic radiation exposed to the device; wavelengths of electromagnetic radiation exposed to the device; a chemical composition of an environmental component exposed to the device; chemical composition of an environmental component exposed to the device; amount of an environmental contaminant exposed to the device; and/or chemical composition of an environmental contaminant exposed to the device.
  • Devices of some embodiments are capable of generating a response that corresponds to one or more environmental parameters. For example, in low humidity conditions, application of a hydrating material; high UV conditions, application of a UV block material.
  • Power harvesting refers to a process by which energy is derived from an external source and, thereby, may avoid the need for relatively large, bulky and expensive primary or secondary battery systems.
  • the devices provided herein may be compatible with batteries and/or supercapaciters, depending on the application of interest.
  • relatively heavy or bulky systems may be incorporated into clothing, shoes, hats, gloves, scarves, face masks, and the like, in a manner that would be unobtrusive, or minimally noticeable, to a user.
  • this invention discloses a set of ideas and technologies that overcome these drawbacks to enable high-speed, robust, long-range automated measurements of thermal transport properties via a miniaturized, multisensor module controlled by a long-range ( ⁇ 10 m) Bluetooth Low Energy (BLE) system on a chip (SoC), with a graphical user interface to standard smartphones.
  • BLE Bluetooth Low Energy
  • SoC system on a chip
  • the hydration sensor comprises a sensing module, i.e., thermal actuators/sensors (TAS) module, operably disposed on a target area of interest of skin of a living subject for detecting data associated with thermal properties of the skin; and a wireless platform coupled with the sensing module for wireless data transmission between the sensing module and an external device.
  • a sensing module i.e., thermal actuators/sensors (TAS) module
  • TAS thermal actuators/sensors
  • the TAS module comprises a thermal actuator operably disposed on the target area of interest of the skin for heating the target area of interest thereof; and a sensing circuit for simultaneously detecting a transient temperature change (AT) thereof to determine thermal properties of the skin.
  • the thermal actuator and the sensing circuit are interconnected by serpentine traces (FIG. IE) to form a flexible structure (FIG. 1 A, Inset) that facilitates soft, intimate contact to the skin with robust mechanical and thermal coupling.
  • the thermal actuator comprises at least one resistor.
  • the thermal actuator comprises two or more of surface-mount thin film resistors, thick film resistors, through-hole resistors, and ultrathin-film metal resistors, coupled to each other in series. As shown in FIG. IB, the thermal actuator includes two resistors R H in series.
  • the sensing circuit comprises a temperature sensor including one or more of negative temperature coefficient thermistors, positive temperature coefficient thermistors, resistance temperature detectors (RTD), and thermocouples.
  • a temperature sensor including one or more of negative temperature coefficient thermistors, positive temperature coefficient thermistors, resistance temperature detectors (RTD), and thermocouples.
  • the sensing circuit comprises a first pair of negative temperature coefficient thermistors NCT1 (NTC + , NTC + ) arranged in a first Wheatstone bridge circuit, as shown in FIG. IB.
  • NCT1 negative temperature coefficient thermistors
  • the sensing circuit may also have a second pair of NTCs (NTC2, FIGS. IE and 2A) arranged in a second Wheatstone bridge circuit serving to compensate for changes in an ambient temperature.
  • the first pair of NTCs is disposed on a layer different from the thermal actuator (heater). In this case, the two NTC1 are directly on the top of the heater. In another embodiment shown in FIG, 2B (Right), the two NTC1 are disposed on a layer same as the heater. In the case, each NTC1 has a first distance from the heater. In some embodiments, the second pair of NTCs (NTC2) is disposed on the same layer as the first pair of NTCs, and each NTC2 is spatially apart from NTC1 (FIG. IE) and has a second distance from the heater (FIG. 2A, Inset). In some embodiments, the first and second distances are determined by the design requirement of depth sensitivity into the skin, and ranges from 10s of pm to a few mm.
  • FIG. 2B, Left approximately triples the sensitivity (FIGS. 10C-10D) to the hydration levels of the skin compared to a corresponding single-sided layout (FIG. 2B, Right).
  • the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
  • the wireless platform comprises a Bluetooth low energy system on a chip (BLE SoC).
  • the BLE SoC comprises a general- purpose input/output (GPIO) electrically coupled to the thermal actuator for providing a periodic current to activate the thermal actuator; a differential amplifier (AMP) electrically coupled to the sensing circuit for amplifying a difference of bridge voltages; an analog-to- digital converter (ADC) electrically coupled to the AMP to sample/digitize output voltages of the AMP; and a BLE radio configured to wirelessly transmit output signals of the ADC to the external device for processing to determine the hydration status of the skin, and receive data from the external device to activate a GPIO pin to provide the periodic current to the thermal actuator.
  • GPIO general- purpose input/output
  • AMP differential amplifier
  • ADC analog-to- digital converter
  • BLE radio configured to wirelessly transmit output signals of the ADC to the external device for processing to determine the hydration status of the skin, and receive data from the external device to activate a GPIO pin to
  • the BLE based device provides a number of benefits including, but are not limited to, small size, automatic/remote wireless update, no need to hold the external device (e.g., phone) over the sensor, and better capability across different external devices.
  • the external device e.g., phone
  • a digital on/off switch controlled through a custom software application including a user interface (UI) on the external device is adapted to enable BLE- connection and activation of the GPIO pin to source the periodic current into the thermal actuator.
  • UI user interface
  • the periodic current has 6.8 mA for 10 s, and 0 mA for 50 s in a 1-min cycle.
  • Transport of heat from the actuator to the NTCs depends upon the thermal properties of the skin, and thus serves as the basis for the measurement of skin hydration.
  • the custom software application in the external device transforms the voltages into corresponding temperature values based on a calibration factor.
  • Theoretical models then convert these data into thermal transport properties of the skin, which, in turn, can be used to determine health-related parameters such as the hydration state using appropriate models.
  • the BLE SoC may also comprise a microcontroller (pC) configured to activate the GPIO pin to source the periodic current into the thermal actuator.
  • pC microcontroller
  • the pC may also be configured to process the detected data on site, and then transmit the processed data to the external device.
  • the hydration sensor further comprises a flexible substrate in the form of a flexible printed circuit board (fPCB) with circuit traces that interconnect the thermal actuator on a skin side, the NTCs on an air side, and the BLE SoC.
  • the flexible substrate is formed of a flexible material comprising polyimide (PI) and/or polyethylene terephthalate (PET).
  • the flexible substrate is a flexible copper- clad polyimide (Cu/PI/Cu) sheet.
  • the hydration sensor further comprises a power module for providing power to the sensing circuit and the wireless platform.
  • the power module comprises a battery (FIG. 1C).
  • the battery is a rechargeable battery operably rechargeable with wireless recharging.
  • the power module further comprises a wireless charging module for wirelessly charging the rechargeable battery.
  • the power module further comprises a failure prevention element including a short-circuit protection component or a circuit to avoid battery malfunction.
  • a failure prevention element including a short-circuit protection component or a circuit to avoid battery malfunction.
  • the battery is enclosed in the encapsulation layer.
  • the hydration sensor further comprises an encapsulating enclosure enclosing the thermal actuator, the wireless platform, the battery, and the fPCB, as shown in FIGS. 1C and ID.
  • the encapsulating enclosure comprises a top layer for thermal, chemical and mechanical isolation of the hydration sensor from the environment; and a bottom layer for providing a direct interface between the thermal actuator at the skin side of the fPCB and the skin.
  • the top layer is a shell-like top encapsulation layer including small air gaps for thermally, mechanically, and chemically insulating the critical sensing components.
  • the top layer is formed of a flexible material including silicone or silicone gel, low/high density polyethylene (LDPE/HDPE), polystyrene, Teflon ® , and various other flexible polymers.
  • LDPE/HDPE low/high density polyethylene
  • polystyrene polystyrene
  • Teflon ® Teflon ®
  • the bottom layer comprises a flexible adhesive for attaching the hydration sensor to the skin.
  • the bottom layer further comprises an ultrathin fabric of fiberglass/reinforcement material embedded in the flexible adhesive layer for enhancing the mechanical robustness of the hydration sensor.
  • the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
  • the flexible adhesive layer is formed of silicone or silicone gel, or double-sided skin-safe adhesives, with the ratio of silicone and silicone gel being adjusted to co optimize mechanical integrity and tackiness of the adhesive.
  • the adhesive layer has a thickness of about 180 pm.
  • the mesh fiber/ silicone bottom layer encapsulation allowing for 25 micron to 700 micron ultra-thin bottom layer.
  • the external device is a smartphone, a tablet, a computer, or any electronic device with data reading/processing capability, e.g., with a central processing unit(CPU), or a microcontroller unit (MCU), or an external controller.
  • CPU central processing unit
  • MCU microcontroller unit
  • the thermal properties of the skin comprise thermal conductivity and thermal diffusivity of the skin that are related to water content of the skin, wherein the water content is a function of a skin depth.
  • the water content is determined from the measured temperature change AT vs. time t.
  • the water content and skin surface temperature are used to determine a normal state or a disease state of the skin.
  • the water content and skin surface temperature serve as quantitative metrics of an efficacy of a treatment of a skin disease, or other health and wellness products including skin moisturizers, lotions, and/or creams.
  • the hydration sensor is usable for monitoring the skin condition in a clinical setting and/or an at-home setting.
  • the hydration sensor is usable for delivering treatment, monitoring the effects, modulating the treatment protocol as necessary, and/or potentially predicting for flares based on quantitative, individualized measurements on specific lesion sites.
  • the hydration sensor is usable for monitoring water content of internal organs for various diseases where traditional monitoring techniques fail to offer continuous assessment of organ health.
  • the hydration sensor is usable for monitoring organs during organ transport for applications in organ transplant.
  • the hydration sensor is usable for applications to measure thermal conductivity, thermal diffusivity, heat capacity and other thermal properties of any material as a function of depth.
  • the hydration sensor is usable for applications to measure water content of any material surface as a function of depth, including hydrogels, plants (irrigation and agriculture applications), food preservation (dried food products, grains, fruits, meats), and/or concrete (industrial applications).
  • the hydration sensor is usable for monitoring composition of food/beverages, medicines/industrial chemicals.
  • the hydration sensor is re-usable and removal without irritation to the skin or damage to the hydration sensor.
  • the hydration sensor is compatible with alcohol-based cleaning wipes allowing for re-use across different users, without any damage to the hydration sensor or loss in efficacy of the hydration sensor adhesive.
  • the hydration sensor is sterilizable using alcohol, autoclave steam sterilization, and gas phase sterilization.
  • the invention in another aspect, relates to a method of fabricating a hydration sensor.
  • the method includes forming a flexible printed circuit board (fPCB) that interconnects electronics of the hydration sensor; and forming an encapsulating enclosure enclosing the sensing module, the wireless platform and the fPCB.
  • the encapsulating enclosure comprises a top layer and a bottom layer.
  • the fPCB is formed of a flexible material comprising polyimide (PI), polyethylene terephthalate (PET), or any one of them in combination with stiff PCB material including FR-4.
  • PI polyimide
  • PET polyethylene terephthalate
  • the bottom layer comprises a layered structure of a first flexible layer, a second flexible layer, and a fabric of fiberglass/a reinforcement material embedded between the first flexible layer and the second flexible layer.
  • each of the first flexible layer and the second flexible layer is formed of silicone or silicone gel, or double-sided skin-safe adhesives, with the ratio of the silicone and silicone gel being adjusted to co-optimize mechanical integrity and tackiness of the adhesive.
  • the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
  • the bottom layer adheres to the f-PCB through use of silicone bonding material, epoxy, glue, or commercial adhesive.
  • the top shell layer is formed of silicone or silicone gel, low/high density polyethylene (LDPE/HDPE), polystyrene, Teflon ® , and various other flexible polymers.
  • LDPE/HDPE low/high density polyethylene
  • polystyrene polystyrene
  • Teflon ® Teflon ®
  • the electronics comprises a sensing module for detecting data associated with thermal properties of the skin; and a wireless platform coupled with the sensing module for wireless data transmission between the sensing module and an external device.
  • the sensing module comprises a thermal actuator for heating a target area of interest of the skin; and a sensing circuit for simultaneously detecting a transient temperature change (D7) thereof to determine thermal properties of the skin.
  • the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
  • the wireless platform comprises a BLE SoC.
  • the invention relates to a method of monitoring and/or diagnosing a condition of a skin.
  • the method comprises attaching a hydration sensor onto a target area of interest on the skin, wherein the hydration sensor comprises a thermal actuator, a sensing circuit, and a wireless platform for two-way data communication with an external device; heating the target area of interest of the skin by the thermal actuator, simultaneously detecting data associated with thermal properties of the skin by the sensing circuit, and wirelessly transmitting the detected data, by the wireless platform, to the external device to determiner a transient temperature change (D7) thereof; obtaining water content of the target area of interest of the skin from the temperature change (D7); and determining a condition of the skin at the target area of interest based on the obtained water content.
  • D7 transient temperature change
  • the water content comprises water content F E of the epidermis and water content ⁇ 3 ⁇ 4 of the dermis.
  • the step of obtaining the water content comprises separately determination of FE and ⁇ E>D from the temperature change AT.
  • the wireless platform transmits data through a wireless communication protocol including Near Field Communication (NFC), Wi-fi/Internet, Bluetooth/Bluetooth low energy (BLE), or GSM/Cellular Communication.
  • NFC Near Field Communication
  • Wi-fi/Internet Wi-fi/Internet
  • BLE Bluetooth/Bluetooth low energy
  • GSM/Cellular Communication GSM/Cellular Communication
  • said heating the target area of interest of the skin is formed by providing a periodic current to the thermal actuator.
  • activation of the periodic current is controlled by a digital on/off switch through a custom application on the external device.
  • said determining the condition of the skin at the target area of interest comprises comparing the obtained water content to a standard water content at the target area of interest so as to determine a normal state or a disease state of the skin.
  • said determining the condition of the skin at the target area of interest comprises diagnosing a skin disease at the target area of interest based on wherein the obtained water content thereof.
  • said determining the condition of the skin at the target area of interest comprises evaluating an efficacy of a treatment of the skin disease.
  • said obtaining water content of the target area of interest of the skin, and said determining a condition of the skin are performed in the external device.
  • the method further comprises displaying the condition of the skin at the target area of interest in the external device.
  • the method further comprises forwarding the condition of the skin at the target area of interest, or sending an alert, to a professional, a caregiver and/or a service provider.
  • important biological tissue parameters may be obtained, even for a user outside of a controlled medical setting. Those parameters may be communicated at a distance for evaluation in real-time, or at a later time, such as by the user or a third party, such as a medical caregiver, friend or family member.
  • the devices and methods are also compatible with a more active intervention, ranging from a warning provided to the user to an automated response, such as application of a hydrating compound, sun block compound, or any other response depending on the application of interest.
  • the method further comprises one or more steps of delivering treatment, monitoring the effects, modulating the treatment protocol as necessary, and/or potentially predicting for flares based on quantitative, individualized measurements on specific lesion sites.
  • measurement conductions are optimized to obtain accurate and reproducible results. Accordingly, the method can be performed under one or more of the optimized measurement conditions: (1) the measurement is performed rapidly, to minimize effects of occlusion of natural processes of water vapor release from the skin due to the presence of the hydration sensor; (2) very light or zero applied pressure is used during the measurement, to minimize perturbations to the skin; (3) the adhesive is patterned such that it is present only across regions of the hydration sensor device adjacent to the sensor itself, to avoid exfoliation of the skin at the measurement site during peel back, for improved repeatability; (4) the temperature of the hydration sensor is comparable to that of the skin; and (5) skin itself is allowed to acclimate to the surrounding environment prior to the measurement.
  • Wireless electronics for monitoring of skin hydration in a quantitative fashion have broad relevance to the understanding of dermatological health and skin structure in both clinical and home settings.
  • the miniaturized, long-range automated system that adheres gently to the skin to yield quantitative recordings of skin water content for both epidermis and dermis supports capabilities in characterizing skin barrier, assessing severity of skin diseases, and evaluating cosmetic and medication efficacy, with high levels of repeatability and insensitivity to ambient.
  • Benchtop and pilot studies on patients with skin diseases highlight key features of these devices and their potential for broad utility in clinical research and in home settings to guide the management of disorders of the skin.
  • wireless systems for performing hydration level measurements routinely and reliably in healthy and diseased skin are disclosed.
  • Computational methods applied to the resulting data define the hydration levels using bilayer models for the skin, with clinical-grade levels of accuracy.
  • important advances of the wireless systems include, but are not limited to, 1) long-range wireless capabilities and high sampling rates with Bluetooth interfaces to the phone; 2) compact, dual-sided multi-sensor designs with enhanced sensitivity to the hydration levels of the skin; 3) multiple, redundant measurement modalities with minimized susceptibility to parasitic environmental, physiological, and user-related factors; and 4) full-waveform data analysis techniques with ability to determine hydration levels of both the epidermis and dermis, and with additional sensitivity to the SC.
  • This collective set of attributes forms the foundations for devices that allow rapid, accurate assessments of skin hydration and skin barrier function with almost zero user burden.
  • Simple interfaces that leverage smartphone technology suggest potential for frequent use in home settings, as preemptive management of skin disease prior to flares for conditions such as AD or XC.
  • Pilot scale clinical studies illustrate these and other capabilities in tracking improvements in skin hydration associated with application of topical moisturizers onto patients with a range of inflammatory skin conditions. Overall, this system has the potential to improve the quality of care for patients by providing objective and accurate measurements of skin barrier function.
  • Soldering wire MM01019; Multi core
  • soldering paste SMDLTLFP10T5; Chip Quik
  • a BLE mesh kit board (nRF52 DK; Nordic Semiconductor) facilitated development of software for the BLE SoCs.
  • a PC connected to the nRF52 DK with a USB cable for power enabled programming of the on-board BLE SoC.
  • a source-code editor (Visual Studio Code; Microsoft) supported authoring, modifying, compiling, deploying, and debugging software of BLE SoC.
  • a power profiler kit board (NRF6707; Nordic Semiconductor) interfaced with nRF52 DK provided real-time measurements of current consumption of the embedded applications.
  • Android s official inte grated development environment (IDE) (Android Studio; Google) provided tools to develop and build the custom Android application (user interface) on smartphones.
  • Elkem Silicones (80 pm/20 pm/80-pm thickness) served as the bottom encapsulation layer of the device.
  • the bottom adhesive silicone/ silicone gel layer provided a direct interface between the heater at the bottom side of the fPCB and the skin, as formed using a three-step process: 1) spin-coating the silicon e/silicone gel layer with 2,500 rpm for 30 s on a glass slide and curing on a hot plate at 85 C for 10 min, 2) gently placing a fiberglass fabric on top of the silicone/silicone gel layer, and 3) spin-coating the following silicone layer with 1,500 rpm for 30 s, placing the device on the uncured silicone layer with the heater side facing down, and curing on a hot plate at 85 C for 10 min to achieve adhesion between the fPCB and the silicone layer.
  • Adhesive Stripping Measurement Repeated application and removal adhesive disks (D- Squame; CuDerm; 14-mm diameter, ⁇ 100-pm thickness) several times on the same area of skin gradually removed the SC. Replacement of each disk occurred after five cycles. Measurements after 0, 10, 20, and 35 cycles involved two commercial devices (MoistureMeterSC and Moistur- eMeterD; Delfin Technologies) and the BLE device.
  • Porcine Skin Water-Loss Measurement DPBS solution (Gibco Dulbecco’s phosphate-buffered saline; 14190-136; Life Technologies) defrosted a piece of porcine skin ( ⁇ 25-mm thickness; 200 x 100 mm) at room temperature for 12 h.
  • a commercial dehydrator (Sedona Combo Rawfood Dehydrator SD-P9150; Tribest) controlled the hydration level of the porcine skin at 33 C for 10 min for each measurement.
  • Measured weights of the porcine skin determined with a balance (Ohaus Ax622 Adventurer Precision Balance; Ohaus) enabled a calculation of water loss.
  • the objective was to validate a BLE-based skin hydration monitor as a capable detector of differences in thermal conductivity between dry /hydrated skin and tissue affected and unaffected by skin diseases such as atopic dermatitis.
  • the sensor represents low to minimal risk to the patient, with no electrical component touching the skin. More than 10 healthy control adults/children and 3 patients with mild, moderate, or severe atopic dermatitis were engaged in a dermatology clinic and mea sured with the sensor by placing it on the skin at discrete locations of the body.
  • the baseline reference for determining TEWL of skin was also obtained using commercially available devices based on capacitance measurements of a dielectric medium in skin.
  • Body locations selected for studies included the forehead, left/ right forearm, and left/right lower leg.
  • Conventional devices with different probing depths provided baseline references for skin hydration in triplicate on each body location prior to the BLE measurements.
  • a 5-min, continuous measurement using the BLE device were then performed, without the need for a waiting period for the sensor to reach thermal equilibrium with the skin.
  • the subjects were allowed to move freely without any constraint on activities.
  • the tests were performed indoor under an air-conditioned environment.
  • the experimental protocol involves four steps: 1) perform three measurements on disease-affected and unaffected skin, 2) apply a moisturizer (Extremely Dry Skin Rescue Lotion; Vaseline) and wait for 15 min, 3) wipe away excess moisturizer from the surface of the skin, and 4) repeat three measurements at each location.
  • a moisturizer Extremely Dry Skin Rescue Lotion; Vaseline
  • the device (FIG. 1 A, shown here without the battery) is a small, wireless platform designed for noninvasive measurements of the temperature and the thermal transport properties of the skin.
  • the width, length, height, and weight of this example, excluding a battery, are 14.6 mm, 25.6 mm, 1.2 mm, and 193.0 mg, respectively.
  • the system includes a thermal actuator and multisensor (TAS) module interconnected by serpentine traces to form a flexible structure that facilitates soft, intimate contact to the skin with robust mechanical and thermal coupling ⁇ Inset).
  • TAS thermal actuator and multisensor
  • the TAS module presents circuit and block diagrams that highlight the Bluetooth Low Energy (BLE) system on a chip (SoC) for control and wireless data communication to a user interface (UI) (typically on a portable device such as a smartphone).
  • the TAS module includes a thermal actuator (Joule heating through 221 W x 2 resistors; R H X 2) and Wheatstone bridge circuits with a pair of negative temperature coefficient thermistors (NTC + , NTC-) and a known resistor (R) on each bridge for primary measurement purposes. Another pair of NTCs and bridge circuit serves to compensate for changes in the ambient temperature.
  • a digital on/off switch controlled through the UI enables BLE-connection and activation of a general-purpose input/output (GPIO) pin to source a periodic current (6.8 mA for 10 s, and 0 mA for 50 s in a 1-min cycle) into the thermal actuator.
  • V + voltages
  • a differential amplifier (AMP) in the BLE SoC further amplifies the voltage differences while eliminating common-mode noise to increase the signal-to-noise ratio (SNR).
  • SNR signal-to-noise ratio
  • the subsequent analog-to-digital converter (ADC) samples the voltage, for transmission to the UI via BLE radio communication protocols.
  • a software application transforms the voltages into corresponding temperature values based on a calibration factor.
  • Theoretical models then convert these data into thermal transport properties of the skin, which, in turn, can be used to determine health-related parameters such as the hydration state using appropriate models.
  • the exploded view schematic illustration in FIG. 1C highlights the constituent layers and components of the system: a shell structure formed in a biocompatible silicone material for packaging and thermal insulation; a Li-polymer battery (12 mAh); and a flexible copper-clad polyimide substrate (AP8535R; Pyr-alux) processed by laser ablation (Protolaser U4; LPKF) to define circuit traces that interconnect the thermal actuator (skin side), NTCs (air side), and the BLE SoC.
  • the shell ⁇ Inset creates an air pocket around the TAS module to optimize the flow of heat to the skin-facing side of the device and to thermally isolate this region from the ambient.
  • FIG. ID A picture of an encapsulated device adhered to the thenar eminence is in FIG. ID. Assuming that the system performs temperature measurements at a 200-Hz sampling rate, transmits an averaged value every 0.1 s (10 Hz) to the UI, and measures the hydration state over 1 min (actuator off for 50 s, on for 10 s) per day, a 12-mAh battery (FIG.
  • the system does not show capabilities in wireless recharging, such functionality can be easily included.
  • the system may include a rechargeable battery, which can be wirelessly recharged through a wireless battery charging module.
  • Standard modules for TPS measurements capture the time-dependent difference in temperature (DT) for cases when the thermal actuator is off and on (T 0ff and T on , respectively).
  • DT time-dependent difference in temperature
  • T 0ff and T on respectively.
  • TAS module in some embodiments, it includes two pairs of NTCs (NTCi and NTC2), as shown in FIG. 2 A.
  • NTC2 captures the temperature at a location distant from the thermal actuator, to eliminate the effects of uncontrolled temperature fluctuations, as demonstrated under various conditions in subsequent sections.
  • FIG. 2A An exploded-view illustration of the TAS module (FIG. 2A) highlights the constituent layers and components: adhesive (180 pm thickness), thermal actuator (two resistors in series; RH x 2), NTCi (NTC1 + and NTCi-), NTC2 (NTC2 + and NTC2-), and silicone encapsulation with air shell.
  • the Inset shows a top view of the assembled module. NTCi and NTC2 are directly above and 1.15 mm away from the center of the thermal actuator, respectively.
  • the widths (w) and lengths (1) of both RH and the NTCs are 0.3 and 0.6 mm, respectively.
  • the compact, dual-sided sensor design (FIG. 2B, Left) approximately triples the sensitivity (FIGS. 10A-10D) to the hydration levels of the skin compared to a corresponding single-sided layout (FIG. 2B, Right).
  • a microscale model of hydrated skin (as described in Micromechanics Model for the Thermal Properties of Hydrated Skin below) defines relationships between k and a, such that the thermal transport problem can be solved with only two parameters to be determined, i.e., the hydration levels FE and ⁇ 3 ⁇ 4 of the epidermis and dermis, respectively.
  • PDMS poly(dimethylsiloxane)
  • FIGS. 1 lA-1 IE highlight the FEA results and experimental data for samples described above. The FEA results agree well with the experimental values (Exp.) with SDs less than 3.5%, as shown in FIG.
  • the extracted values of Fo and FE are consistent with the expected water content at different skin depths. Similar considerations applied to further reduced time intervals allow for separate measurements of the SC and the epidermis.
  • the studies described in the following use, for simplicity, a single measurement at 10 s (i.e., DT12 at 10 s) with a single-layer skin model.
  • FEA Finite Element Analysis
  • a micromechanics model establishes a relationship between the thermal properties of hydrated skin and its hydration level 0 (volumetric water content).
  • the above micromechanics model applies to each layer, with the subscript ‘skin’ replaced by ⁇ ’ and ‘D’ for epidermis and dermis, respectively.
  • FIGS. 12A-12B A simplified model for the relationship between the NTCi-to-NTC2 spacing and their temperature difference is useful.
  • the value of DT12 increases as d and Q increase, and as F decreases.
  • the effect of actuator size (width and length of RH) on DT12 is in FIGS. 13A-13B. As shown in FIG.
  • a disk-shaped heater (radius R and heating power Q) and two infinitesimal sensors rest on a semi-infinite, homogenous substrate with the properties of skin (thermal conductivity k S kin and thermal diffusivity a S kin).
  • the heater and sensors have negligible thicknesses.
  • the temperature changes in NTCi and NTC2 are respectively, where Jo(x) and Ji(x) are Bessel functions of the first kind with zero- and first- orders, respectively, and erfc(x) is the complementary error function. Therefore, the temperature difference between the two sensors can be expressed in the following dimensionless form
  • the function f is plotted in FIG. 14B.
  • the measurement sensitivity increases with t a skin ⁇
  • FIG. 3 A shows wireless measurements of Ti (blue) and T2 (red) as a function of time, under conditions of varying ambient temperature, TA (black), measured using a commercial thermometer (GM 1361; BENETECH).
  • TA black
  • the value of TA increases from 23.3 to 36.6 °C for 15 min in an oven (red background), and then decreases from 36.6 to 8.0 °C for an additional 9 min in a room temperature ambient (RT; white background) and subsequently in a refrigerator (blue background).
  • Wireless measurements of DTi (black), DT2 (red), and DT12 (blue) as a function of TA are shown in FIG. 3B.
  • FIG. 3C shows wireless measurements of Ti (blue) and T2 (red) as a function of time on a sample with varying temperature Ts (green) across a physiologically relevant range (from 24.2 to 41.0 °C; FIG. 3D), and with airflow rates of 0 to - 13.6 m/s (FIG. 3E).
  • Ts (green dashed line) is the base temperature measured from NTCi while the thermal actuator is off for 50 s every l-min cycle. For measurements over a period of 90 min, Ts increases from 25.5 to 41.0 °C during the session labeled “heating” and decreases from 41.0 to 24.2 °C during the session labeled “cooling.”
  • the surface temperature of the shell structure above the actuator of the device (T D ; purple) changes accordingly (from 23.9 to 35.5 °C and then back to 21.8 °C), and TA (black) is constant as -22.2 ⁇ 0.3 °C. Varying the rate of airflow from the top (blue background) leads to abrupt changes in temperatures in the middle and toward the end of the heating and cooling process, respectively.
  • FIG. 3 F and G shows the results of Ti (blue), T2 (red), and the difference (Ti - T2; black), and DTi (black), DT2 (red), and DT12 (blue), respectively, for the case of immersing the device in cooled water (Ts from 33.1 to 27.3 °C).
  • the biocompatible silicone packaging provides robust protection against water penetration such that the SDs of DTi, DT2, and DT12 over measurement during a 30- min period are 0.07, 0.04, and 0.03 °C, respectively.
  • the hermetic sealing of the devices eliminates the effect of humidity of the surrounding environment on the circuit components.
  • Table 1 Signal-to-noise ratio (SNR) with different temperatures of the testing substrate (Ts) for natural air convection and for forced air flow at rates of 0-13.6 m/s from the top.
  • SNR Signal-to-noise ratio
  • the devices can laminate gently, without applied pressure, onto the skin for determining F via measurements of DT12 , as described previously.
  • the BLE interface supports wireless, long- range communication to smartphones, with user protocols that require almost no training or specialized skill (FIG. 3H).
  • Basic tests involve measurements of F at a given body location by three different users from three different healthy subjects using the device according to embodiments of the invention (®BLE) and commercial (CML) devices for measuring tissue water content (®CML,I; MoistureMeterD; Delfin Technologies) and skin surface hydration (F EME? ; Gpskin; gpower) via measurements of skin dielectric properties (FIGS. 16A-16B).
  • FIG. 3H shows the results for F at five different body locations (FIG. 17): forehead (F), right arm (AR), left arm (AL), right leg (LR), and left leg (LL).
  • F forehead
  • AR right arm
  • AL left arm
  • LR right leg
  • LL left leg
  • User variability associated with ®BLE, ®CML,I, and ®CML,2 at the same body location yields an average value of SDs of 0.00, 0.02, and 0.03, respectively.
  • the SDs of ®CML,I and ®CML,2 are the largest (0.04 and 0.09, respectively) on the forehead of subject 2 and 1, respectively, and that associated with ®BLE is constant (-0.00) across these five body locations, each with a different curvature and rigidity (FIG. 18).
  • the data show that ®BLE yields the most repeatable values of F.
  • the results show that ®BLE with calibration yields higher correlation with F OME I than with F I : ME 2 . likely due to the comparable sensing depths for ®BLE and ®CML,I.
  • FIG. 4B shows measurements of ⁇ E>BLE and ®CML,I (MoistureMeterD; Delfin Technologies) and SC hydration levels ( ⁇ 1>CML,3) determined using a commercial device (MoistureMeterSC; Delfin Technologies; measurement depth of 40 um) as a function of the number of cycles of applying and removing an adhesive disk (D- Squame; CuDerm; FIG. 4 A), as a simple and painless means to remove the SC.
  • ⁇ E>BLE increases in a systematic manner, as evidence of the sensitivity of the measurement to the SC.
  • FIG. 4E Studies of a sample of porcine skin (FIG. 4D) with different, known levels of hydration are in FIG. 4E.
  • FIGS. 5A-5C shows photographs of devices mounted on the forehead (FIG. 5A), forearm (FIG. 5B), and calf (FIG. 5C) of a human subject.
  • the Inset in FIG. 5A features a tilted side view.
  • Studies of hydration levels of the skin of 10 healthy volunteers involve evaluations at five different body locations (FIG. 17): forehead (F), right arm (A R ), left arm (A L ), right leg (L R ), and left leg (L L ).
  • FIG. 17 forehead
  • F right arm
  • a L left arm
  • L R right leg
  • L L left leg
  • 5D shows DTi, DT2, and DT12 over a 3-min measurement period from three female (subjects 1, 2, and 9; age range, 25 to 27) and seven male (subjects 3 to 8, 10; age range, 17 to 37) healthy volunteers (see Table 2)
  • the results show that the forehead has the highest hydration level (the lowest values of DTi, DT2, and DT12) across all subjects.
  • the values of SDs for DTi, DT2, and DT12 at each location for all subjects are less than -0.06, 0.08, and 0.01 °C, respectively (FIG. 22).
  • the data show that DT12 yields the most consistent values of F, consistent with findings described in the previous sections.
  • Table 2 Information of the 10 healthy normal subjects.
  • FIGS. 6A-6B show the mounting locations on the back of the hand (atopic eczema), and the forearm (control) of subject 1 (FIG. 6 A) and on the chest of subject 2 (inflamed, perilesional, and nonlesional skin from Left to Right; FIG. 6B).
  • the Insets in FIGS. 6A-6B feature pictures of the forearm of subject 1 after application of moisturizer, and the platform mounted on inflamed (Left) and perilesional (Right) skin on the chest of subject 2, respectively.
  • Table 3 Information of the patients who participated in the moisturizer study.
  • Table 4 F measurements of a young adult patient with severe AD (subject 1).
  • Table 5 F measurements of an elderly patient with inflammatory AD (subject 2).
  • the optical image in FIG. 27 shows the platform on the atopic eczema of subject 1, next to a smartphone to collect/ display/store the measurements.
  • Results for DT12 from subjects 1 and 2 are in FIGS. 6C-6D, respectively.
  • healthy skin control
  • lesional skin eczema in FIG.
  • FIG. 6C inflammation in FIG. 6D shows high values of DT12 and a decrease in DT12 before and 15 min after (B&A) applying moisturizer, respectively (see Methods for details).
  • FIGS. 6E-6F show the values of F from DT12 ( ⁇ 1>BLE; red) and from MoistureMeterD ( ⁇ 1>CML,I; sky blue) and Gpskin (®C ML, 2; light green), for subjects 1 and 2, respectively.
  • MoistureMeterD ⁇ 1>CML,I; sky blue
  • Gpskin ®C ML, 2; light green
  • atopic eczema and inflammation show low values of ⁇ 1>BLE (before) and an increase in ⁇ E>BLE after application of moisturizer.
  • ADCML,I 0.09.
  • the value of ®CML,I yields the largest SDs on lesions, lumpy and rigid area (0.03 on atopic eczema and inflamed skin, 0.01 on others), and an average value of SDs of 0.01, larger than that associated with ® BLE, c ai (0.00).
  • FIGS. 6G-6H show the optical images of the device mounted on the forehead (FIG. 6G) and the leg (visibly dry skin determined by a dermatologist; FIG. 6H) of a toddler (male; age, 2).
  • Measurements of ® BLE (blue), FO M E I (black), TEWL (red), and SC hydration (SCH; green) on the left leg (LL), right leg (RL), and forehead (FH) are in FIG. 61.
  • the values of TEWL and SCH measured using Gpskin device, and ® BLE are higher on the forehead where the hydration levels are expected to be higher than those on the leg.
  • Validation trials on three healthy adults focus on observing variations in b after the application of moisturizer ( ⁇ 4 h).
  • the experimental protocol involves five steps: 1) wash the forearm with soap; 2) perform measurements at three different locations (“control,” “short,” and “long”) on the forearm; 3) apply a moisturizer (Extremely Dry Skin Rescue Lotion; Vaseline) on short and long areas, and wait for 1 min on short and 15 min for long; 4) wipe away excess moisturizer from the surface of the skin; and 5) repeat measurements at each location.
  • FIGS. 7A-7I The changes in ® BLE and FO M E I normalized to each initial value at the control area are shown in FIGS. 7A-7I.
  • the results indicate a strong correlation between ⁇ E>BLE and ⁇ 1>CML,I.
  • the values of ⁇ 1>BLE at the short (FIG. 7B) and long (FIG. 7C) areas are 5% and 1% lower, respectively, at 0 min, and 20% and 23% higher immediately after the application of the moisturizer.
  • ⁇ E>BLE at the long area approaches to a value 20% higher than that at the control area.
  • the values of ⁇ 1>BLE at the short (FIG. 7E) and long (FIG. 7F) areas are 20% and 23% higher after application of the moisturizer, and approach values 10% and 1 1% higher after ⁇ 4 h.
  • the values of ⁇ E>BLE at the short (FIG. 7H) and long (FIG. 71) areas are 5% and 4% higher after application of the moisture, and approach values 0% and 1% higher after ⁇ 3 h.
  • the increase in ⁇ E>BLE after applying the moisturizer decreases with time.
  • Optimized Measurement Conditions The optimization of the measurement conditions is very important in obtaining accurate/precise, and reproducible results. For instance, the best results are obtained when (1) the measurement is performed rapidly, to minimize effects of occlusion of natural processes of water vapor release from the skin due to the presence of the device, (2) very light or zero applied pressure is used during the measurement, to minimize perturbations to the skin (3) the adhesive is patterned such that it is present only across regions of the device adjacent to the sensor itself, to avoid exfoliation of the skin at the measurement site during peel back, for improved repeatability, (4) the temperature of the device is comparable to that of the skin, (5) skin itself is allowed to acclimate to the surrounding environment prior to the measurement.
  • the soft, small, wireless platforms disclosed in the disclosure enable noninvasive, rapid monitoring of water content of healthy and diseased skin across a wide range of skin conditions, body locations, and subject backgrounds, with accuracy and precision superior to those of existing clinical or research-grade devices.
  • the combined use of an optimized, dual-sided TAS module with multiple, redundant measurement modalities supports repeatable, robust, user-independent measurements under various conditions relevant to practical use in both clinical and home settings.
  • a BLE SoC interface to the phone allows for rapid data acquisition, suitable for operation with minimal training or specialized skills.
  • Full-waveform fitting of the data captured using these systems to bilayer models of thermal transport yields hydration levels for both the epidermis and dermis.
  • results define the basis for versatile skin-interfaced devices that can support personalized and localized skin hydration strategies, with potential use as a diagnostic for skin disease states such as AD and XC, as a risk stratification tool for neonates at high risk for the development of AD, and as the basis for objective evaluation of the efficacy of topical medications and personal care product (e.g., topical moisturizers).
  • a diagnostic for skin disease states such as AD and XC
  • a risk stratification tool for neonates at high risk for the development of AD and as the basis for objective evaluation of the efficacy of topical medications and personal care product (e.g., topical moisturizers).
  • Additional potential applications include monitoring thermoregulation processes and managing heat-related disorders.

Abstract

L'invention concerne un capteur d'hydratation comprenant un module de détection disposé de manière fonctionnelle sur une zone cible d'intérêt de la peau d'un sujet vivant pour détecter des données associées à des propriétés thermiques de la peau ; et une plateforme sans fil couplée au module de détection pour une transmission de données sans fil entre le module de détection et un dispositif externe. Le module de détection comprend un actionneur thermique pour chauffer de manière fonctionnelle la zone cible d'intérêt de celui-ci ; et un circuit de détection pour détecter simultanément un changement de température transitoire de celui-ci afin de déterminer les propriétés thermiques de la peau.
PCT/US2021/036765 2018-03-30 2021-06-10 Capteur d'hydratation pour la surveillance et le diagnostic de maladies de la peau dans un environnement quelconque et son application WO2021252732A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2022576512A JP2023530683A (ja) 2020-06-10 2021-06-10 任意の環境下での皮膚病の監視および診断のための水分量センサーとその応用
US18/009,384 US20230255483A1 (en) 2018-03-30 2021-06-10 Hydration sensor for monitoring and diagnosis of skin diseases in any environment and application of same
US18/031,389 US20240023882A1 (en) 2018-03-30 2021-10-18 Hydration sensors for monitoring and diagnosis of skin diseases in any environment

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063037092P 2020-06-10 2020-06-10
US63/037,092 2020-06-10

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US18/031,389 Continuation-In-Part US20240023882A1 (en) 2018-03-30 2021-10-18 Hydration sensors for monitoring and diagnosis of skin diseases in any environment

Publications (1)

Publication Number Publication Date
WO2021252732A1 true WO2021252732A1 (fr) 2021-12-16

Family

ID=78845902

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/036765 WO2021252732A1 (fr) 2018-03-30 2021-06-10 Capteur d'hydratation pour la surveillance et le diagnostic de maladies de la peau dans un environnement quelconque et son application

Country Status (2)

Country Link
JP (1) JP2023530683A (fr)
WO (1) WO2021252732A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023130061A3 (fr) * 2021-12-30 2023-07-27 Rhaeos, Inc. Capteurs thermiques portés sur soi, systèmes et procédés associés

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130109998A1 (en) * 2010-05-28 2013-05-02 Shuntcheck, Inc. Real time csf flow measurement system & method
US20160120468A1 (en) * 2014-10-31 2016-05-05 Koninklijke Philips N.V. Non-invasive dehydration monitoring
US9612140B2 (en) * 2008-04-18 2017-04-04 Winmedical S.R.L. Support device for sensors and/or actuators that can be part of a wireless network of sensors/actuators
US20180014734A1 (en) * 2014-08-11 2018-01-18 The Board Of Trustees Of The University Of Illinois Epidermal Devices for Analysis of Temperature and Thermal Transport Characteristics
WO2019191693A1 (fr) * 2018-03-30 2019-10-03 Northwestern University Dispositifs électroniques épidermiques sans fil et non invasifs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9612140B2 (en) * 2008-04-18 2017-04-04 Winmedical S.R.L. Support device for sensors and/or actuators that can be part of a wireless network of sensors/actuators
US20130109998A1 (en) * 2010-05-28 2013-05-02 Shuntcheck, Inc. Real time csf flow measurement system & method
US20180014734A1 (en) * 2014-08-11 2018-01-18 The Board Of Trustees Of The University Of Illinois Epidermal Devices for Analysis of Temperature and Thermal Transport Characteristics
US20160120468A1 (en) * 2014-10-31 2016-05-05 Koninklijke Philips N.V. Non-invasive dehydration monitoring
WO2019191693A1 (fr) * 2018-03-30 2019-10-03 Northwestern University Dispositifs électroniques épidermiques sans fil et non invasifs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023130061A3 (fr) * 2021-12-30 2023-07-27 Rhaeos, Inc. Capteurs thermiques portés sur soi, systèmes et procédés associés

Also Published As

Publication number Publication date
JP2023530683A (ja) 2023-07-19

Similar Documents

Publication Publication Date Title
JP7258121B2 (ja) ワイヤレス皮膚センサ、ならびに方法および使用
Kwon et al. Wireless, soft electronics for rapid, multisensor measurements of hydration levels in healthy and diseased skin
Madhvapathy et al. Epidermal electronic systems for measuring the thermal properties of human skin at depths of up to several millimeters
Heikenfeld et al. Wearable sensors: modalities, challenges, and prospects
Ray et al. Soft, skin-interfaced wearable systems for sports science and analytics
Tamura et al. Current developments in wearable thermometers
Liu et al. A wearable conductivity sensor for wireless real-time sweat monitoring
Hattori et al. Multifunctional skin‐like electronics for quantitative, clinical monitoring of cutaneous wound healing
Webb et al. Ultrathin conformal devices for precise and continuous thermal characterization of human skin
EP3179902B1 (fr) Dispositif épidermique pour l'analyse de la température et de caractéristiques de transport thermique
Jin et al. Identifying human body states by using a flexible integrated sensor
Li et al. Telemedical wearable sensing platform for management of chronic venous disorder
Lee et al. All-day mobile healthcare monitoring system based on heterogeneous stretchable sensors for medical emergency
JPH08154903A (ja) 生体情報モニタリングシート
Crawford et al. Advanced approaches for quantitative characterization of thermal transport properties in soft materials using thin, conformable resistive sensors
US20170027513A1 (en) System and method for monitoring physiological parameters of a person
WO2021252732A1 (fr) Capteur d'hydratation pour la surveillance et le diagnostic de maladies de la peau dans un environnement quelconque et son application
Shin et al. Wireless, soft sensors of skin hydration with designs optimized for rapid, accurate diagnostics of dermatological health
Mahmud et al. Fiber Bragg Gratings based smart insole to measure plantar pressure and temperature
US20230255483A1 (en) Hydration sensor for monitoring and diagnosis of skin diseases in any environment and application of same
Chad Webb et al. Ultrathin, skin-like devices for precise, continuous thermal property mapping of human skin and soft tissues
Bodini et al. Low-power wireless system to monitor tongue strength against the palate
Tamura et al. Body temperature, heat flow, and evaporation
Islam Assistive sensing technology for the elderly health monitoring
US20230270372A1 (en) Systems and methods for wireless, real-time monitoring parameters of sweat and applications of same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21821140

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022576512

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21821140

Country of ref document: EP

Kind code of ref document: A1