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Lab-on-Skin: A Review of Flexible and Stretchable Electronics for Wearable Health Monitoring Yuhao Liu,*,† Matt Pharr,*,‡ and Giovanni Antonio Salvatore*,§
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Department of Materials Science and Engineering, Beckman Institute, and Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States ‡ Department of Mechanical Engineering, Texas A&M University, 3123 TAMU, College Station, Texas 77843, United States § Electronics Laboratory, ETZ H 90, Gloriastrasse 35, 8092 Zürich, Switzerland ABSTRACT: Skin is the largest organ of the human body, and it offers a diagnostic interface rich with vital biological signals from the inner organs, blood vessels, muscles, and dermis/epidermis. Soft, flexible, and stretchable electronic devices provide a novel platform to interface with soft tissues for robotic feedback and control, regenerative medicine, and continuous health monitoring. Here, we introduce the term “lab-on-skin” to describe a set of electronic devices that have physical properties, such as thickness, thermal mass, elastic modulus, and water-vapor permeability, which resemble those of the skin. These devices can conformally laminate on the epidermis to mitigate motion artifacts and mismatches in mechanical properties created by conventional, rigid electronics while simultaneously providing accurate, non-invasive, long-term, and continuous health monitoring. Recent progress in the design and fabrication of soft sensors with more advanced capabilities and enhanced reliability suggest an impending translation of these devices from the research lab to clinical environments. Regarding these advances, the first part of this manuscript reviews materials, design strategies, and powering systems used in soft electronics. Next, the paper provides an overview of applications of these devices in cardiology, dermatology, electrophysiology, and sweat diagnostics, with an emphasis on how these systems may replace conventional clinical tools. The review concludes with an outlook on current challenges and opportunities for future research directions in wearable health monitoring. KEYWORDS: lab-on-skin, wearable electronics, sensors, health monitoring, wireless technologies, diagnostics, flexible electronics, stretchable electronics, soft polymers, functional materials
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healthcare monitoring to clinical evaluation of disease states.12−14 Polymers represent the most promising platforms for wearable technologies due to their inherent low mechanical stiffness. Indeed, numerous soft, flexible, and stretchable electronic devices integrated with polymeric substrates have emerged as platforms capable of digitizing biological signals for healthcare monitoring.15 Advanced strategies in device design, materials selection, and fabrication of biointegrated electronics have provided routes toward establishing clinically relevant diagnostic and monitoring tools.16−21 Significant progress in the development of these devices has occurred in recent years by
ommercially established classes of wearable medical electronics exploit designs, structures, and materials that are fundamentally rigid and bulky.1−3 These existing systems provide robust and reliable functionalities for clinical applications,4 but their cumbersome wiring and poor integration with the skin preclude mobile, comfortable, and continuous longterm precision monitoring.5 Despite advances in the performance and miniaturization of integrated circuits, mechanical design in wearable technology remains conceptually old: brittle components, encapsulated in rigid packaging, leading to bulky devices that require straps and/or adhesive tapes for mounting on the skin.6−8 In particular, the mismatch in physical properties9,10 at the electronic−skin interface creates the most significant challenges in the development of next-generation, skin-integrated electronics,5,9,11 with applications from basic © 2017 American Chemical Society
Received: July 12, 2017 Accepted: September 13, 2017 Published: September 13, 2017 9614
DOI: 10.1021/acsnano.7b04898 ACS Nano 2017, 11, 9614−9635
Review
Cite This: ACS Nano 2017, 11, 9614-9635
Review
ACS Nano
Figure 1. Skin as a diagnostic platform. Diagnostic signals from muscles, blood vessels, free nerve endings, stratum corneum, wounds, and sweat glands.
A “LAB-ON-SKIN” Skin is the largest organ of the human body31 and an ideal surface for unobstructed access to vital biological signals from inner organs, blood vessels, muscles, and the dermis and epidermis. Indeed, skin can be regarded as a signal source: It can both generate and transmit biological signals that provide important health metrics of an individual. Figure 1 shows the primary biosignal sources in the skin anatomy and the typical physiological information available for sensing. In the muscle layer, major nerves such as the median nerve from the brachial plexus (central nervous system) innervate the muscle fibers to stimulate physical contraction32 and produce a summation of the action potential that can be recorded by electrodes placed near the targeted muscle group.32,33 Biopotential signals can also emanate from the cardiac systole-diastole cycle (electrocardiogram, ECG), brain activity (electroencephalogram, EEG), and eye movement (electrooculogram, EOG).1 In the hypodermis and dermis layers, major arteries provide cardiovascular information via the skin, such as body temperature, heart rate, blood pressure, oxygen level, and pulse wave velocity.32 In the epidermis, the stratum corneum consists of stacked layers of cells, including basal cells (live, reproducible) and corneocytes (dead cells), and serves as the water retention layer for hydration measurements.32,34 The epidermis is also an exhaust for sweat, which is a biomarker-rich analyte for pH, mineral ion, glucose,
constructing them from multilayer thin-film structures, assembled on ultrathin polymeric membranes. These structures are subsequently laminated conformally onto the surface of the skin by soft contact via van der Waals forces,5,10,21 resulting in mechanically invisible electronic interfaces with embedded sensors, power supplies, processing, memory, and communication components.22−28 We review the latest developments in a class of electronic devices, commonly referred to as “electronic skin,” “epidermal electronics,” or “electronic tattoos,” from the materials, devices, and medical applications perspectives. While such devices can also be used for prosthetics and rehabilitation,21 optogenetics,29 and human−machine interfaces (HMI),30 this review will focus on the properties of the materials that enable skin-mounted sensors for use as diagnostic tools in the medical field. After reviewing the latest developments in designs, materials, powering, and skin-integration strategies, we provide recent examples of devices for potential clinical applications in cardiology, dermatology, electrophysiology, and sweat diagnostics. The paper concludes with an overview of current challenges and possible future directions on wireless powering and communication, seamless skin integration, and application-specific design. 9615
DOI: 10.1021/acsnano.7b04898 ACS Nano 2017, 11, 9614−9635
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Figure 2. A lab-on-skin. Stretchable and flexible electronic devices as biosensors for measuring (clockwise from top right) skin modulus, electrocardiology, hydration, blood oxygen, wound-healing rate, sweat content, skin surface temperature, blood pressure, electromyography, and electroencephalography. (Reprinted with permission from (clockwise from top right) ref 16, Copyright 2013, Nature Materials; ref 41, Copyright 2014, Scientific Reports; ref 37, Copyright 2013, IEEE; ref 39, Copyright 2016, Science Advances; ref 40, Copyright 2015, Advanced Healthcare Materials; ref 42, Copyright 2016, Nature; ref 20, Copyright 2013, Nature Materials; ref 38, Copyright 2013, Nature Communications; ref 24, Copyright 2013, Advanced Materials; ref 19, Copyright 2015, PNAS.)
Table 1. Summary of Lab-on-Skin Devices Measurement
Method(s)
Signal
Location
Application
Refs
ECG
Electrical
Voltage
Chest, Autonomic Nervous System
EEG EMG
Electrical Electrical
Voltage Voltage
Forehead, Mastoid, Face Leg, Arm, Target muscle locations
Cardiovascular health, Fitness Cognition, Sleep, HMI Rehabilitation, Gait, HMI
EOG Pressure
Electrical Piezoelectric, Optical, Electrical Electrical, Thermal Electrical, Optical
Adjacent to eyes, Head Neck (carotid artery), Wrist (radial artery) Mastoid, Chest, Other Chest, Wrist
Sleep, Perception, HMI Hypertension, Blood pressure Overall health Overall health
5, 20, 28 44, 45, 49
Forearm, Leg, Face
Fitness, Overall health
18, 42, 46
Hydration Blood Oxygen Elastic Modulus
Electrochemical, Colorimetric Electrical Optical Piezoelectric
Voltage Voltage, Absorbance, Impedance Resistance, Radiation Resistance, Reflectance, Color Current, Voltage, Impedance, Color Impedance Absorbance Voltage
Forearm, Wrist, Face Wrist, Ear lobe, Forehead Anywhere on skin
20, 22, 26, 47 48 16
Wound Care Strain
Electrical Electrical
Resistance Resistance
Anywhere on skin Anywhere on skin
Skin health Cardiovascular health Clinical diagnostics of pathologies Wound healing monitoring Fluid/blood retention, Swelling
Temperature Thermal Transport Sweat
water, lactic acid, and urea concentrations.35 Additionally, in the presence of a wound, several physical and chemical metrics such as thermal conductivities, pH, and temperature can be measured on the stratum corneum near the wound site.36 Each of the
5, 26, 27, 41 5, 19, 26, 27 5, 21, 24, 26, 27, 30, 48 5, 26, 48 16, 25, 39, 43
40 5, 21, 47
aforementioned biosignals represents a unique opportunity to develop application-specific electronic sensing devices that utilize polymer-based skin-mounted substrates as supporting platforms. 9616
DOI: 10.1021/acsnano.7b04898 ACS Nano 2017, 11, 9614−9635
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Figure 3. Materials and techniques to achieve stretchable and flexible devices on skin. (a) Comparison of representative elastic moduli of various electronic, polymeric, and biological materials including human skin. (b) Single crystalline silicon nanomembranes with thicknesses of 200 nm bent to radii of approximately 100 μm (scale bar 100 μm). (c) Utraflexible electronics on a few micron thick substrate (scale bar 1 cm). (d) Stretchable system produced by patterning stiff islands of devices on soft substrates (scale bar 1 cm). (e) Island-bridge stretchable electronics with serpentine interconnects (scale bar 150 μm). (f) Cross-sectional schematic of representative layers in a core−shell package for strain isolation of electronic devices from skin. (g) Cross-sectional schematic of representative layers in a liquid-filled cavity package for strain-isolation of electronic devices from skin. (Reprinted with permission from ref 51, Copyright 2012, MRS Bulletin (rearranged); ref 53, Copyright 2006, Nature Nanotechnology; ref 54, Copyright 2013, Nature; ref 83, Copyright 2012, Nature Communications; ref 84, Copyright (2008), National Academy of Sciences, U.S.A.; ref 89, Copyright 2015, Advanced Functional Materials; ref 87, Copyright 2017, Small.)
Here, we introduce the concept of a “lab-on-skin” to describe a set of soft, flexible, and stretchable electronic devices, which conformally contact with the epidermis to deliver a range of functionalities, thereby resembling a clinical laboratory. The underlying concept is that these “lab-on-skin” devices can noninvasively measure most of the biometrics required for health monitoring and disease diagnosis. The robust and soft contact between the flexible/stretchable devices and the skin enables continuous, long-term, and accurate sensing, which is difficult to obtain with conventional wet electrodes due to their propensity for drying out. Figure 2 shows examples of soft electronic interfaces developed for both monitoring and diagnostic functions at various locations on the human body. Such devices provide tools to measure physiological status including temperature,20 hydration,37 blood pressure,38 blood oxygen level,39 skin mechanics,16 wound-healing,40 electrophysiology,19,24,41 and various biomarkers in sweat.42 Applications could span from dermatology, cardiology, neurology, and hematology to urgent care. For example, electrophysiological signals such as ECG provide detailed information on the activity in the ventricles and atria for cardiac disease;26 EEG shows electrical activity in the brain for studies of sleep apnea, epilepsy, and other neurological disorders;19 and EMG assesses nerve and muscle health.30 Multifunctional sensing designs further extend this idea of a “labon-skin.”21 A list of these “lab-on-skin” devices are summarized in Table 1 according to their signal type, measurement method, location, and applications.5,16,18−22,24−28,30,37,39−49
DESIGNS AND MATERIALS Mechanical Considerations. The terms “electronic tattoo,” “skin-like,” and “epidermal” refer to skin-mounted devices with physical properties (thicknesses, mechanical properties, thermal masses, etc.) that approximate those of the epidermis, thereby enabling compliant and robust contact with the skin. The epidermis can elastically deform up to 15% with an elastic modulus ranging from 10 kPa to a few hundred kPa.50 Thus, any epidermal electronic device must be capable of not only bending to conform to the topography of the skin but also stretching to accommodate strains during natural body motion. Figure 3 provides an overview of materials, ordered by their elastic modulus, and typical strategies used to realize highly flexible and stretchable devices on skin.51 As shown in Figure 3a, the largest mismatch in mechanical properties usually occurs between biological tissues (brain, skin, cartilage) and the materials used as the active functional layers in the electronic devices (silicon, gold, etc.). The supporting and encapsulating polymeric materials have elastic moduli much closer to those of the biological tissues. Structural optimization of the device layouts and development of assembly schemes for the active layers represent typical approaches to mitigate issues arising from this mismatch in mechanical properties among the various materials. The simplest approach to constructing highly flexible devices involves implementing thin layers. Indeed, Euler−Bernoulli beam theory predicts that the flexural rigidity, defined as the resistance of a material to bending, is proportional to the 9617
DOI: 10.1021/acsnano.7b04898 ACS Nano 2017, 11, 9614−9635
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ACS Nano thickness of the object to the third power.52 Fortunately, recent advances in thin-film processing and nanotechnology have enabled the construction and integration of ultrathin polymeric, metallic, and semiconducting materials to form active electronic devices (Figure 3). For example, single crystalline silicon nanomembranes (Si NMs), with thicknesses of 100−200 nm, can be transferred from silicon-on-insulator (SOI) wafers onto thin-polymer substrates. Such integration allows for bending to small radii of curvature without fracture, as a result of the decrease in bending stiffness by several orders of magnitude (once again by the cube of the thickness) (Figure 3b).53 Recent works have also reported methods to produce large area organic and/or inorganic devices, on ultrathin substrates, thus enabling bending radii as small as tens of microns, even when using materials with relatively large elastic moduli (Figure 3c).15,54,55 Encapsulating materials as to place the active layers on the zerostrain plane represents yet another technique for achieving mechanical stability.56 From a more materials-based approach, the use of materials with high fracture strengths, such as carbon nanotubes (CNTs),57 graphene,58,59 or related,60,61 constitutes an effective complementary strategy to further enhance the mechanical robustness of electronic devices. Likewise, a number of research groups have developed self-healing materials for flexible and stretchable electronics, details could be found in these topical reviews.62−66 Of particular note for epidermal systems, relevant studies have created self-healing conductors,67−72 electronic skins,62,73,74 microvascular networks,75 tough composites,76 coatings,77 and electrochemical devices.78 In addition to reducing the thickness and implementing highperformance materials in these systems, the mechanical stability of electronic devices can be further improved by structural design. In particular, integrating high-performance inorganic semiconductors and conductive metals with soft substrates has produced classes of electronic devices that can stretch, twist, and bend without permanent mechanical damage.15,38,79−82 The most prevalent strategy involves “island-bridge” layouts in which conductive traces (bridges) interconnect high-performance but rigid functional components (islands), as in Figure 3d,e.83,84 The conductive traces provide low effective stiffness, thus accommodating the stretching of the overall system while reducing strains in the functional components themselves. For long-term reliability, these interconnects must withstand repetitive strains due to natural motion of the body during daily use. As such, they must be designed to deform only elastically during use. By comparison, plastic deformation will lead to accumulated damage over time in the form of fatigue cracks, which increase the electrical resistivity and can eventually generate open circuits.82 Serpentine-shaped structures,17 consisting of periodic arcs and straight segments, have been widely adopted to connect rigid islands83 on top of soft elastomers (Figure 3d,e). Beyond the island-bridge layouts, additional strategies include transferring the devices to pretensioned elastomers85 and tiling techniques.86 Packaging. Packaging electronic devices in materials with low mechanical stiffness represents another strategy to mitigate mechanical issues in these systems. For comfortable, noninvasive operation of lab-on-skin devices, the overall package must place minimal constraints on the natural motion of the underlying skin.87−89 One such strategy utilizes a core/shell package in which a core with an ultralow elastic modulus (e.g., Silbione RT Gel 4717 A/B, E = 5 kPa) packaged in a silicone shell (e.g., Ecoflex, E = 60 kPa) separates the device from the skin, as shown in Figure 3f.89 These designs lead to peak values of shear
and normal stresses on the skin
