Patent Application
20230255483
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.
The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art.
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. The three main layers of the skin, stratum corneum (SC), epidermis and dermis, serve as dynamic physical barriers to exogenous insults and active interfaces to maintain homeostasis. 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 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.
Quantitative evaluations of skin barrier function can provide essential information to guide clinical decision making. Current methods involve a determination of transepidermal water loss (TEWL) via a measurement of water vapor pressure at the skin surface, or an assessment of the high-frequency electrical properties of the skin itself as a surrogate marker of its water content. 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. As an alternative, recent research demonstrates that transient plane source (TPS) methods can be adapted for noninvasive measurements of thermal transport properties of the skin, where simple models quantitatively connect the thermal properties of the skin to its hydration level. Precise, quantitative measurements of the hydration status of skin can yield important insights into dermatological health and skin structure and function, with additional relevance to essential processes of thermoregulation and other features of basic physiology. Existing tools for determining skin water content exploit surrogate electrical assessments performed with bulky, rigid, and expensive instruments that are difficult to use in a repeatable manner.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.
In one aspect, 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.
In one embodiment, 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 (ΔT) thereof to determine thermal properties of the skin.
In one embodiment, 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.
In one embodiment, the thermal actuator comprises at least one resistor.
In one embodiment, 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.
In one embodiment, the sensing circuit comprises one or more of negative temperature coefficient thermistors, positive temperature coefficient thermistors, resistance temperature detectors (RTD), and thermocouples.
In one embodiment, the sensing circuit comprises a first pair of negative temperature coefficient thermistors (NTCs) arranged in a first Wheatstone bridge circuit.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, the first and second distances are determined by the design requirement of depth sensitivity into the skin, and ranges from 10s of μm to a few mm.
In one embodiment, the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
In one embodiment, the wireless platform comprises a Bluetooth low energy system on a chip (BLE SoC).
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, the BLE SoC further comprises a microcontroller (μC) configured to activate the GPIO pin to source the periodic current into the thermal actuator.
In one embodiment, the hydration sensor further comprises a power module for providing power to the sensing circuit and the wireless platform.
In one embodiment, the power module comprises a battery.
In one embodiment, the battery is a rechargeable battery operably rechargeable with wireless recharging.
In one embodiment, the power module further comprises a wireless charging module for wirelessly charging the rechargeable battery.
In one embodiment, the power module further comprises a failure prevention element including a short-circuit protection component or a circuit to avoid battery malfunction.
In one embodiment, 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.
In one embodiment, the flexible substrate is formed of a flexible material comprising polyimide (PI) and/or polyethylene terephthalate (PET).
In one embodiment, the flexible substrate is a flexible copper-clad polyimide (Cu/PI/Cu) sheet.
In one embodiment, the hydration sensor further comprises an encapsulating enclosure enclosing the thermal actuator, the wireless platform, the battery, and the fPCB.
In one embodiment, 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.
In one embodiment, the top layer is a shell-like top encapsulation layer including small air gaps for thermally, mechanically, and chemically insulating the critical sensing components.
In one embodiment, 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.
In one embodiment, the bottom layer comprises a flexible adhesive for attaching the hydration sensor to the skin.
In one embodiment, 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.
In one embodiment, the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
In one embodiment, 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.
In one embodiment, the external device is a smartphone, a tablet, a computer, or any electronic device with data reading/processing capability.
In one embodiment, 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.
In one embodiment, the water content is determined from the measured temperature change ΔT vs. time t.
In one embodiment, the water content and skin surface temperature are used to determine a normal state or a disease state of the skin.
In one embodiment, 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.
In one embodiment, the hydration sensor is usable for monitoring the skin condition in a clinical setting and/or an at-home setting.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, the hydration sensor is usable for monitoring organs during organ transport for applications in organ transplant.
In one embodiment, 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.
In one embodiment, 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).
In one embodiment, the hydration sensor is usable for monitoring composition of food/beverages, medicines/industrial chemicals.
In one embodiment, the hydration sensor is re-usable and removal without irritation to the skin or damage to the hydration sensor.
In one embodiment, 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.
In one embodiment, the hydration sensor is sterilizable using alcohol, autoclave steam sterilization, and gas phase sterilization.
In another aspect, the invention relates to a method of fabricating a hydration sensor. In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
In one embodiment, the bottom layer adheres to the f-PCB through use of silicone bonding material, epoxy, glue, or commercial adhesive.
In one embodiment, the top shell layer is formed of silicone or silicone gel, low/high density polyethylene (LDPE/HDPE), polystyrene, Teflon®, and various other flexible polymers.
In one embodiment, 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.
In one embodiment, 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 (ΔT) thereof to determine thermal properties of the skin.
In one embodiment, the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
In one embodiment, the wireless platform comprises a Bluetooth low energy system on a chip (BLE SoC).
In yet another aspect, the invention relates to a method of monitoring and/or diagnosing a condition of a skin. In one embodiment, 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 (ΔT) thereof; obtaining water content of the target area of interest of the skin from the temperature change (ΔT); and determining a condition of the skin at the target area of interest based on the obtained water content.
In one embodiment, the water content comprises water content ΦE of the epidermis and water content ΦD of the dermis.
In one embodiment, the step of obtaining the water content comprises separately determination of ΦE and ΦD from the temperature change ΔT.
In one embodiment, 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.
In one embodiment, said heating the target area of interest of the skin is formed by providing a periodic current to the thermal actuator.
In one embodiment, activation of the periodic current is controlled by a digital on/off switch through a custom application on the external device.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, said determining the condition of the skin at the target area of interest comprises evaluating an efficacy of a treatment of the skin disease.
In one embodiment, 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.
In one embodiment, the method further comprises displaying the condition of the skin at the target area of interest in the external device.
In one embodiment, the method further comprises forwarding the condition of the skin at the target area of interest to a professional and/or a service provider.
In one embodiment, 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.
In one embodiment, 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.
These and other aspects of the invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the invention.
The accompanying drawings illustrate one or more embodiments of the invention and together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.
The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.
One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.
It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.
It will be understood that when an element is referred to as being “on”, “attached” to, “connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.
It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.
Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element's relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.
It will be further understood that the terms “comprises” and/or “comprising”, or “includes” and/or “including”, or “has” and/or “having”, or “carry” and/or “carrying”, or “contain” and/or “containing”, or “involve” and/or “involving”, “characterized by”, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this disclosure, they specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the invention, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used in the disclosure, “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.
As used in the disclosure, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
“Interfacing” refers to the positioning of the device with tissue such that the device may affect the tissue, and vice versa. For example, 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. “Thermally interfacing”, therefore, refers to the ability of the device to affect a thermal challenge on underlying tissue, and to detect a response thereto, such as a change in temperature over time, including for a time period after the thermal input ends. In this manner, one or more tissue parameters may be determined, such as tissue hydration, inflammation, blood flow, UV damage.
The terms “flexible” and “bendable” are used synonymously in the present description and refer to the ability of a material, structure, device or device component to be deformed into a curved or bent shape without undergoing a transformation that introduces significant strain, such as strain characterizing the failure point of a material, structure, device or device component. In an exemplary embodiment, a flexible material, structure, device or device component may be deformed into a curved shape without introducing strain larger than or equal to 5%, for some applications larger than or equal to 1%, and for yet other applications larger than or equal to 0.5% in strain-sensitive regions. As used herein, some, but not necessarily all, flexible structures are also stretchable. A variety of properties provide flexible structures (e.g., device components) of the invention, including materials properties such as a low modulus, bending stiffness and flexural rigidity; physical dimensions such as small average thickness (e.g., less than 100 microns, optionally less than 10 microns and optionally less than 1 micron) and device geometries such as thin film and 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. In an exemplary embodiment, 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. As used herein, many stretchable structures are also flexible. Some stretchable structures (e.g., device components) are engineered to be able to undergo compression, elongation and/or twisting so as to be able to deform without fracturing. 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. Accordingly, 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). In some embodiments, 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. In some embodiments, 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. In some embodiments, a thermal transport property may correlate with a temperature of tissue. In some embodiments, 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. For example, 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.
A flexible substrate that is mechanically matched to a tissue, such as skin, provides a conformable interface, for example, useful for establishing conformal contact with the surface of the tissue. 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. In an embodiment, 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.
In some embodiments, 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. For example, 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.
In some embodiments, 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. In some embodiments, for example, 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. In some embodiments, for example, 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 state 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. Further, in some embodiments, 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 μm, or less than or equal to 50 μm, 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. For example, 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.
In an embodiment, “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 corneum, stratum lucidum (on the palms and soles, i.e., the palmar regions), stratum granulosum, stratum spinosum, stratum germinativum (also called the statum basale). In an embodiment, 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. In one aspect, 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. In another aspect, 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. In an embodiment, 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:
where E is Young's modulus, Lo is the equilibrium length, ΔL is the length change under the applied stress, F is the force applied, and A is the area over which the force is applied. Young's modulus may also be expressed in terms of Lame constants via the equation:
where λ and μ 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. In some embodiments, 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. In an embodiment, 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. In an embodiment, 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. In an embodiment, a device of the invention has one or more components having a low Young's modulus. In an embodiment, 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. For skin, 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. For a nail, 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. For example, 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. In this context, “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.
“Haptic 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. Of course, the devices provided herein may be compatible with batteries and/or supercapaciters, depending on the application of interest. For example, 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.
Embodiments of the invention are illustrated in detail hereinafter with reference to accompanying drawings. The description below is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar elements. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the invention.
Precise, quantitative measurements of the hydration status of skin can yield important insights into dermatological health and skin structure and function, with additional relevance to essential processes of thermoregulation and other features of basic physiology. Existing tools for determining skin water content exploit surrogate electrical assessments performed with bulky, rigid, and expensive instruments that are difficult to use in a repeatable manner. Recent alternatives exploit thermal measurements using soft wireless devices that adhere gently and noninvasively to the surface of the skin, but with limited operating range (˜1 cm) and high sensitivity to subtle environmental fluctuations.
Accordingly, this invention, among other things, 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. Soft contact to the surface of the skin, with almost zero user burden, yields recordings that can be quantitatively connected to hydration levels of both the epidermis and dermis, using computational modeling techniques, with high levels of repeatability and insensitivity to ambient fluctuations in temperature. Systematic studies of polymers in layered configurations similar to those of human skin, of porcine skin with known levels of hydration, and of human subjects with benchmarks against clinical devices validate the measurement approach and associated sensor hardware. The results support capabilities in characterizing skin barrier function, assessing severity of skin diseases, and evaluating cosmetic and medication efficacy, for use in the clinic or in the home.
The following exemplary embodiments further illustrate the invention but should not be construed as in any way limiting its scope.
As shown in
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 (ΔT) thereof to determine thermal properties of the skin. The thermal actuator and the sensing circuit are interconnected by serpentine traces (
In some embodiments, the thermal actuator comprises at least one resistor.
In some embodiments, 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
In some embodiments, 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.
In some embodiments, 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
In one embodiment shown in
The compact, dual-sided sensor design (
In some embodiments, the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
In one embodiment shown in
Among other things, the BLE based device according to the invention 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.
In some embodiments, 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.
In one exemplary embodiment, the periodic current has 6.8 mA for 10 s, and 0 mA for 50 s in a 1-min cycle. This current can generate thermal power Q=20.4 mW at the top surface of the 1 actuator and thereby delivers heat to the skin below via thermal diffusion. 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. Wheatstone-bridge circuits convert the resistances of the NTCs into corresponding voltages (V+, V−) that vary in response to changes in temperature, with an opposite polarity (ΔV+=−ΔV−).
In some embodiments, 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.
In some embodiments, the BLE SoC may also comprise a microcontroller (μC) configured to activate the GPIO pin to source the periodic current into the thermal actuator. The μC may also be configured to process the detected data on site, and then transmit the processed data to the external device.
In some embodiments, 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. In some embodiments, the flexible substrate is formed of a flexible material comprising polyimide (PI) and/or polyethylene terephthalate (PET). In one example, the flexible substrate is a flexible copper-clad polyimide (Cu/PI/Cu) sheet.
In some embodiments, the hydration sensor further comprises a power module for providing power to the sensing circuit and the wireless platform. In some embodiments, the power module comprises a battery (
In some embodiments, the power module further comprises a wireless charging module for wirelessly charging the rechargeable battery.
In some embodiments, the power module further comprises a failure prevention element including a short-circuit protection component or a circuit to avoid battery malfunction. For example, as shown in
In some embodiments, the hydration sensor further comprises an encapsulating enclosure enclosing the thermal actuator, the wireless platform, the battery, and the fPCB, as shown in
In some embodiments, 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.
In some embodiments, the top layer is a shell-like top encapsulation layer including small air gaps for thermally, mechanically, and chemically insulating the critical sensing components.
In some embodiments, 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.
In some embodiments, the bottom layer comprises a flexible adhesive for attaching the hydration sensor to the skin.
In some embodiments, 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. In some embodiments, the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
In some embodiments, 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. In one exemplary embodiment shown in
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the water content is determined from the measured temperature change ΔT vs. time t.
In some embodiments, the water content and skin surface temperature are used to determine a normal state or a disease state of the skin.
In some embodiments, 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.
In some embodiments, the hydration sensor is usable for monitoring the skin condition in a clinical setting and/or an at-home setting.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the hydration sensor is usable for monitoring organs during organ transport for applications in organ transplant.
In some embodiments, 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.
In some embodiments, 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).
In some embodiments, the hydration sensor is usable for monitoring composition of food/beverages, medicines/industrial chemicals.
In some embodiments, the hydration sensor is re-usable and removal without irritation to the skin or damage to the hydration sensor.
In some embodiments, 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.
In some embodiments, the hydration sensor is sterilizable using alcohol, autoclave steam sterilization, and gas phase sterilization.
In another aspect, the invention relates to a method of fabricating a hydration sensor. In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the reinforcement material is flexible and has varying mesh density and thickness to lend tear resistance to the bottom layer.
In some embodiments, the bottom layer adheres to the f-PCB through use of silicone bonding material, epoxy, glue, or commercial adhesive.
In some embodiments, the top shell layer is formed of silicone or silicone gel, low/high density polyethylene (LDPE/HDPE), polystyrene, Teflon®, and various other flexible polymers.
In some embodiments, 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.
In some embodiments, 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 (ΔT) thereof to determine thermal properties of the skin.
In some embodiments, the wireless platform comprises at least one of Wi-Fi, BLE, and NFC communication protocols.
In some embodiments, the wireless platform comprises a BLE SoC.
In yet another aspect, the invention relates to a method of monitoring and/or diagnosing a condition of a skin. In some embodiments, 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 (ΔT) thereof; obtaining water content of the target area of interest of the skin from the temperature change (ΔT); and determining a condition of the skin at the target area of interest based on the obtained water content.
In some embodiments, the water content comprises water content ΦE of the epidermis and water content ΦD of the dermis.
In some embodiments, the step of obtaining the water content comprises separately determination of ΦE and ΦD from the temperature change ΔT.
In some embodiments, 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.
In some embodiments, said heating the target area of interest of the skin is formed by providing a periodic current to the thermal actuator.
In some embodiments, activation of the periodic current is controlled by a digital on/off switch through a custom application on the external device.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, said determining the condition of the skin at the target area of interest comprises evaluating an efficacy of a treatment of the skin disease.
In some embodiments, 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.
In some embodiments, the method further comprises displaying the condition of the skin at the target area of interest in the external device.
In some embodiments, 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. For example, 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.
In some embodiments, 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.
In some embodiments, measurement conductions arc 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. According to the invention, 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. These and other aspects of the present invention are further described in the following section. Without intending to limit the scope of the invention, further exemplary implementations of the present invention according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for the convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way should they, whether they are right or wrong, limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.
In this exemplary example, 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. Relative to other technologies, 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. Numerical modeling results and benchtop characterization tests under various practical conditions define the key physical effects and guide the selection of optimized designs and modes of operation. Validation studies involve porcine skin with known levels of hydration and human subjects with benchmarks against clinical devices. Here and in other practical scenarios, the soft mechanical properties and compliant construction of the sensor enable intimate coupling to the skin without applied force and hold, to avoid angle or pressure-related sources of variability that degrade the accuracy and repeatability of conventional devices. These same features in form factor and performance allow for routine measurements at nearly any location on the body and on subjects of any age.
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.
Fabrication of the Electronics: Prototype devices, as shown in
Software Development Environment: 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 integrated development environment (IDE) (Android Studio; Google) provided tools to develop and build the custom Android application (user interface) on smartphones.
Design of the Encapsulating Enclosure: A triple-layered structure of silicone (Ecoflex 00-30; Smooth-On)/silicone gel (Ecoflex gel; Smooth-On), fiberglass fabric (optional, not shown explicitly in
Adhesive Stripping Measurement: Repeated application and removal adhesive disks (D-Squame; CuDerm; 14-mm diameter, ˜100-μm 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 MoistureMeterD; 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; 200×100 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.
Human Subject Evaluations: 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 measured 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. During the BLE measurements, the subjects were allowed to move freely without any constraint on activities. The tests were performed indoor under an air-conditioned environment.
Moisturizer studies on two patients with AD. 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.
Moisturizer studies on three healthy adults. A thin standardized layer (˜1 to 2 g/cm2) of a commercially available, fragrance-free moisturizer was applied to each location. Repeat measurements were performed at 1 min and 15 min after application of the moisturizer.
Patients (Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.) and healthy/normal subjects (Northwestern University, Evanston, Ill.) recruited were voluntary and provided full informed consent. This study was approved by the Northwestern University institutional review board (IRB) (IRB study STU00209010). Single-use alcohol wipes (Sterile Alcohol Prep Pads; Dynarex) provided sterilization of the BLE and commercial devices.
System Configurations: The device (
The exploded view schematic illustration in
In this exemplary embodiment, the system does not show capabilities in wireless recharging, such functionality can be easily included. For example, in certain embodiments, the system may include a rechargeable battery, which can be wirelessly recharged through a wireless battery charging module.
Thermal Transport Physics and Applications to Measurements of Skin Hydration: Standard modules for TPS measurements capture the time-dependent difference in temperature (ΔT) for cases when the thermal actuator is off and on (Toff and Ton, respectively). The simplest approach to analysis uses a value ΔT=Ton−Toff at a single time point, often in a quasi-steady-state regime where the rate of change of temperature with time is relatively small. This parameter then determines an effective thermal transport characteristic, using appropriate models and calibration procedures. Measurement and analysis of the full-time dependence, starting immediately after the actuator is turned on and continuing to the quasi-steady-state regime, can yield substantial information on thermal transport, as described subsequently. In all cases, changes in skin temperature or variable environmental conditions (air currents, ambient temperature fluctuations) that may occur between or during the measurements of Toff and Ton within a given measurement cycle can affect the value of ΔT, thereby degrading the accuracy and precision of the system. A key feature of the TAS module in some embodiments is that it includes two pairs of NTCs (NTC1 and NTC2), as shown in
An exploded-view illustration of the TAS module (
Test structures built with formulations of poly(dimethylsiloxane) (PDMS) that have thermal transport properties similar to those of dehydrated (S184) and hydrated (S170) skin illustrate the key effects.
Macroscale Modeling by Finite Element Analysis (FEA): At the macroscale, FEA establishes a relationship between ΔT12 and the thermal conductivity and thermal diffusivity of the epidermis and dermis (kE, αE, kD and αD) based on the transient heat transfer analysis using the software ABAQUS. A schematic illustration of the FEA model is given in
Micromechanics Model for the Thermal Properties of Hydrated Skin: A micromechanics model establishes a relationship between the thermal properties of hydrated skin and its hydration level 0 (volumetric water content). The hydrated skin is modeled as a composite of dry skin (thermal conductivity kdry=0.2 W·m−1·K−1, thermal diffusivity αdry=0.15 mm2·s−1) and water (kW=0.6 W·m−1·K−1, αW=0.14 mm2·s−1) which gives the thermal conductivity kskin and thermal diffusivity αskin of the hydrated skin as
respectively.
For the bi-layer model of the epidermis and dermis layers for the skin, the above micromechanics model applies to each layer, with the subscript ‘skin’ replaced by ‘E’ and ‘D’ for epidermis and dermis, respectively.
A Simplified Analytical Model: A simplified model for the relationship between the NTC1-to-NTC2 spacing and their temperature difference is useful. The data in
respectively, where J0(x) and J1(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
Experimental Studies: The use of ΔT12, as measured with the two pairs of NTCs (NTC1 and NTC2) described previously, minimizes sensitivity to changes in skin temperature or variations in environmental conditions (air currents, ambient temperature, etc.). Demonstrations of the effects involve measurements of samples of S184 in an oven or refrigerator, or on a hot plate as the basis for varying the ambient temperature (TA;
The devices can laminate gently, without applied pressure, onto the skin for determining Φ via measurements of ΔT12, as described previously. The BLE interface supports wireless, long-range communication to smartphones, with user protocols that require almost no training or specialized skill (
The measurement is sensitive to the presence and properties of the near surface layers of the skin, including the SC. As a demonstration,
Studies of a sample of porcine skin (
Human Subject Evaluations: These miniaturized, flexible platforms can be used on nearly any part of the human body, for adults and children (e.g., hand of a pediatric subject;
Additional experiments reveal the effect of hair-bearing skin on measurements of ΔT′, ΔT2, and ΔT12 (
Evaluation of the Hydration Status of Pathological and Healthy Skin: Water originates from deep epidermal layers and gradually diffuses upward to hydrate cells of the SC, eventually leaving the skin via evaporation at volumes that are comparable to those lost on a daily basis by urination. Impaired skin increases this TEWL due to loss of barrier function from desiccation, infection, and mechanical stress. The following studies examine changes in the hydration status of disease-affected and clinically unaffected skin. Validation trials involve two patients with AD (subject 1 and 2, Tables 3-5), a toddler with visibly dry skin (
The optical image in
Validation trials on three healthy adults (subject 1 with visible dry skin, and subjects 2 and 3 with not visible dry skin determined by a dermatologist) 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. The changes in ΦBLE and ΦCML,1 normalized to each initial value at the control area are shown in
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. Evaluations of skin phantoms and partially hydrated porcine skin validate these measurement and analysis approaches. Pilot scale clinical studies with healthy and diseased subjects (n=19) illustrate a range of capabilities with clinical relevance. The 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). Additional potential applications include monitoring thermoregulation processes and managing heat-related disorders.
The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the present invention pertains without departing from its spirit and scope. Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.
Some references, which may include patents, patent applications and various non-patent literature publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.
This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/037,092, filed Jun. 10, 2020, which is incorporated herein in its entirety by reference. This application is also a continuation-in-part application of U.S. patent application Ser. No. 17/043,161, filed Sep. 29, 2020, which is a national stage entry of PCT Patent Application No. PCT/US2019/025031, filed Mar. 29, 2019, which itself claims priority to and the benefit of U.S. Provisional Patent Application Nos. 62/650,826, filed Mar. 30, 2018, 62/791,390, filed Jan. 11, 2019, and 62/696,685, filed Jul. 11, 2018, which are incorporated herein in their entireties by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/036765 | 6/10/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63037092 | Jun 2020 | US | |
| 62650826 | Mar 2018 | US | |
| 62696685 | Jul 2018 | US | |
| 62791390 | Jan 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17043161 | Sep 2020 | US |
| Child | 18009384 | US |
