Review

Hall of Fame Article www.advmattechnol.de

Wearable, Implantable, and Interventional Medical Devices

Based on Smart Electronic Skins
Lili Wang, Kai Jiang, and Guozhen Shen*

monitoring the health status in real-time

Recent advances in soft, flexible, and stretchable sensors have offered a good difficult. Therefore, the development of
opportunity to design various types of wearable flexible medical devices for personalized personal health diagnosis
achievement of continuous health monitoring, preventive medicine and robot and treatment systems will be key in the
field of medical care in the future.
feedback and control. The integration of biofunctionability with electronic
The rapid development of flexible and
skin is undoubtedly an attractive prospect in the sense that the successful stretchable electronic technology has ena-
medical device requires good biocompatibility, sensing capability, and high bled its application in the field of medical
degrees of mechanical flexibility. This work summarizes the last develop- diagnosis and treatment.[4–8] Such tech-
ments in electronic skin for next-generation medical devices that can simulta- nology can interface with human parts
neously detect a variety of physiological information of the human body. The (e.g., internal organs or skin surface) reli-
ably and without interference, and can be
key properties of e-skin that must be realized for their versatile use in medical
used to enhance health monitoring, diag-
applications are discussed in detail. Next, the paper outlines the overall appli- nosis and human-computer interfaces.[9–15]
cations of these sensors in wearable medicine, implantable medicine, and In fact, most commercial wearable devices
interventional medicine, and emphasizes how these devices monitor human appear in the form of preventive inter-
health status and may be expected to replace traditional clinical tools. Finally, vention. People urgently need wearable
devices for personalized molecular and
the challenges and future research opportunities in the field of wearable
physical detection to offer an in-depth
health monitoring are proposed. understanding of the individual physi-
ological state.[16] However, motion artifacts
and the mechanical mismatch between
1. Introduction traditional hard electronic materials and soft skin often lead
to serious errors in data acquisition.[17] For electrophysiological
The development of electronic technology, medical treatment signals especially, tissue contact of conformal devices can effec-
and the environment has greatly improved the quality of life tively reduce electronic skin mechanical sliding and the inter-
and life span of human beings worldwide, which has led to face impedance and minimize motion artifacts.[9,18,19] Therefore,
the aging of the global population.[1–3] While the most impor- the development of wearable and flexible electronic systems in
tant goal is to address the well-being of everyone, a concern in contact with skin and the integration of sensing capabilities are
health care is how to manage the human health states without of great significance for accurate dynamic health assessment.
increasing the burden or cost of doctors. A potential solution In the last few years, great progress has been made in elec-
to these concerns is the personal health monitoring system.[1] tronic skin (commonly known as e-skin) has made great progress
Unfortunately, the traditional health monitoring system is gen- due to its attractive features of high flexibility, low-cost, light
erally bulky and limited by the location of use, which makes weight, high transparency, and good ductility.[20–24] Innovations
in materials, manufacturing processes and mode of perception
play important roles in the development of the next generation of
Prof. L. L. Wang, Prof. G. Z. Shen
State Key Laboratory for Superlattices and Microstructures e-skins for chemical and physical monitoring in the future. Many
Institution of Semiconductors applications have been proposed that utilize the concept of e-skin,
Chinese Academy of Sciences such as healthcare, robotic and Internet of Things (IOT) applica-
Beijing 100083, China tions. Using ultrathin soft materials, soft bioelectronic devices
E-mail: [email protected]
can interact with human body parts such as internal organs and
Prof. K. Jiang
Faculty of Hepato-Pancreato-Biliary Surgery
skin reliably and without interference to detect human health
Chinese PLA General Hospital information with high precision and sensitivity.[9,25,26] In addition
Institute of Hepatobiliary Surgery of Chinese PLA & Key Laboratory of to its unique mechanical flexibility, e-skin uses biocompatible
Digital Hepetobiliary Surgery materials to obtain key physiological signal changes while elim-
Chinese PLA
inating the specificity of the device to reduce related complica-
Beijing 100853, China
tions and play a role in disease prevention.[27–30] To meet many
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/admt.202100107. challenges of the next class of electronics, macroscale and smart
e-skins need to be developed through the application of various
DOI: 10.1002/admt.202100107 materials, structures, manufacturing technologies and concepts.

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Figure 1.  Schematic of flexible electronics for medical application.

In this review, we highlight the latest progress in flex- electronics, soft robotics, and bionic electronics, especially in
ible medical applications, in which a variety of information, the field of health monitoring, which requires direct interaction
including that regarding internal organs and human skin, can with soft and curvilinear human bodies.[35–39] Stretchable sensors
be simultaneously detected (Figure  1). The detection mecha- can adapt to human mechanics and provide maximum compli-
nisms and device demonstrations are individually discussed, ance with organs and skin, resulting in enhanced comfort and
and the remaining key issues that must be solved for the ver- reduced restriction on the wearer’s daily activities.[40] In fact, if
satile use of e-skin in medical applications are analyzed. After medical devices are to be used in the human body for a long
reviewing the key factors in medical applications, we offer time, then they must meet specific requirements, such as safety,
recent works of e-skins with promising medical applications in nontoxicity, and biocompatibility.[41] If these requirements are not
respiration, cardiac therapy, health repair, and sweat diagnos- guaranteed or met, then users may experience some side effects,
tics. Finally, the challenges and future research directions of even death. Therefore, strict design and risk assessment must
wearable health monitoring are proposed. be carried out before the equipment is installed on the human
body. The additional characteristics of stretchable devices include
being light, viscous, mechanically flexible and hydrophobic to
2. Required Properties of E-Skin for Medical ensure that the devices are closely integrated with the human
body or organs (Figure  2).[9,42–46] The biocompatibility and fur-
Devices
ther bioabsorbability of the materials used allow these devices to
Medical devices refer to instruments, tools, machines, devices, in be used safely and for a long time while considering any harmful
vitro reagents, implants, or other similar/related items, including effects of them on the human body. This chapter introduces the
accessories recognized by or components in the official national required characteristics (such as mechanical flexibility, biodegra-
formulary, United States Pharmacopoeia (USP), or any sup- dability, biocompatibility, self-healing and adhesion) of stretch-
plement thereof.[31,32] These devices are intended to be used in able sensors in health monitoring applications.
the medical field to treat, alleviate or diagnose diseases, prevent
diseases of humans or other animals, and affect the structure
and function of humans or other animals.[33,34] However, these 2.1. Flexibility and Stretchability
devices do not realize any of the main intended purposes by
chemical action and metabolism in humans or other animals. Flexible and wearable sensors with high sensitivity can fit
E-skins have been rapidly developed in the fields of consumer human skin and monitor physiological or external signals of

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Figure 2.  Summarized important properties of e-skin in medical application. E-skin as medical device image: Reproduced with permission.[9]
Copyright 2019, John Wiley and Sons. Flexibility and stretchability image: Reproduced with permission.[42] Copyright 2017, Elsevier. Biodegradability
image: Reproduced with permission.[43] Copyright 2020, Exclusive Licensee Science and Technology Review Publishing House. Biocompatibility image:
Reproduced with permission.[44] Copyright 2018, Macmillan Publishers Limited. Self-healing image: Reproduced with permission.[45] Copyright 201,
Macmillan Publishers Limited. Adhesion image: Reproduced with permission.[46] Copyright 2016, American Chemical Society.

the human body or the surrounding environment, which has patterns to offer spatial control of the adhesion sites and elastic
aroused great interest.[47–50] However, the largest mismatch in deformation of the supporting substrate to induce control-
mechanical properties is generally found between the materials lable local displacement. Buckled GaAs ribbon structures with
(silicon, gold, etc.) used as the active functional layers in elec- thicknesses and widths of 120  nm and 100  µm were formed
tronic devices and biological tissues (skin, heart cartilage, brain, on flexible PDMS substrates, exhibiting high levels of stretch-
etc.).[51] Generally, the elastic modulus of some packaging and ability, compressibility and bendability (Figure  3a,b).[60] Recent
supporting materials (such as artificial and natural polymers, Si, work has also proposed a method to create large-area organic/
etc.) is closer to that of biological tissue.[51–55] Therefore, to suc- inorganic sensors on ultrathin flexible thin films (Figure 3c,d).[61]
cessfully manufacture flexible and stretchable medical devices, P3HT:PCBM (200  nm) and Ca/Ag (115)/PEDOT:PSS (150) are
they need to adapt to the bending caused by body movement, self-assembled on utlrathin flexible PET substrates (1.4  µm) to
as well as the deformation of skin showing complex terrain form ultrathin solar cells (less than 2 µm in thickness), showing
and reversible stretching up to 100%.[4,56] As a typical example, good mechanical flexibility and compressibility (Figure 3e).
depositing or embedding thin electrodes on a low modulus soft Encapsulation of the active layer on a flexible substrate
substrate can make electronic devices more prone to bending or is another strategy to achieve mechanical stability.[51,53] The
wrinkling. The most important thing is that these devices can using of materials with high fracture strength, such as gra-
maintain high deformation performance without any degrada- phene, carbon nanotubes (CNTs), or related materials, to pre-
tion of the conductivity or sensitivity, that is, when the max- pare flexible devices can enhance the mechanical robustness
imum strain is repeatedly applied, the devices can still maintain of electronic devices.[51] One work reported that a sub-300  nm
high sensitivity and ductility to achieve compliance and robust thick gold (Au) thin film was used as an electrode to design a
contact with the skin.[57,58] Therefore, any e-skin should not only wearable biosensor (Figure  3f).[62] The bending stiffness is a
be able to bend to adapt to the terrain of the skin, but also be quantitative index that used to determine the comfort of the
able to stretch to adapt to the tension of natural body movement. user experience. The calculated value of the bending stiffness
Currently, an effective method to solve or alleviate the mechan- is 0.33 pN m2, which is two orders of magnitude lower than
ical property mismatch between various materials is the reason- that of 3M sensor and equivalent to the top layer of human
able design and optimization of the device structure and active skin. Except for achieving high performance materials and
layer.[59] For example, Rogers et  al.[60] reported a strategy for reducing the thickness of these systems, the mechanical sta-
mechanically creating specific categories of 3D shapes in nano- bility of electronic devices can be further improved through
belts that are difficult to generate by other methods. This method structural design. Deterministic patterns including fractal and
includes combining surface chemistry using photolithography serpentine structures enable the device to be properly driven

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Figure 3.  Flexibility and stretchability of e-skin in medical application. PDMS substrates with GaAs ribbon structures under a) different prestrains and
b) different values of inactivated stripes. Reproduced with permission.[56] Copyright 2006, Nature Publishing Group. c) Structural illustration, d) flex-
ibility and e) stretchability of flexible organic solar cell (Scale bar: 2 mm). Reproduced with permission.[57] Copyright 2012, Macmillan Publishers Limited.
f) The structure of the thin film electrode laminated on human skin. g) Microscope images of the thin film electrode with the thickness of 300 nm (scale
bars: 400 µm). Reproduced with permission.[62] Copyright 2018, John Wiley and Sons. h) Multifunctional epidermal electronic systems (EES) attached
on the skin replica. Reproduced with permission.[63] Copyright 2013, John Wiley and Sons.

in the component interconnect and substrate interconnect treatment in an accurate, localized and direct manner.[65]
regions (Figure 3g).[62] The stretchable metal, which is based on However, the long-term presence of an implanted device can
a polymer substrate, then acts as a highly conductive electrode cause serious medical problems. The devices can, for example,
without causing significant changes in mechanical properties damage surrounding tissue and organs, leading to internal
during use on the skin. Yeo et al.[63] reported an ultrathin elec- hemorrhaging and secondary infection, or can continuously
tronic device with a thickness of 800  nm that is mainly com- affect metabolic activity.[66] Flexible and wearable sensors that
posed of a PI substrate, Si film, Pt lines and Au electrodes. The are biodegradable may have a significant influence in the bio-
device has a good geometric pattern, and the total thickness is medical field, especially in basic research, drug delivery and
less than 50 times the thickness of human skin (Figure  3h). therapeutics.[43] Biodegradable materials with slight conduc-
The combination of the snake like electrode and the ultrathin tivity can even record bioelectrical signals, which has been suc-
bandage (with a thickness of 200 nm) improves the bending and cessfully applied in tissue engineering. However, due to the
shape retention of the device when in contact with the surface risk of chronic inflammation caused by nondegradable stents,
of the human body/internal organs.[63] Specifically, the serpen- transience at the same time scale as healing or regeneration is
tine interconnection layer adopts a bending layout composed of crucial for such in vivo applications. In the longer term, these
several periodically distributed cells. The cells include two semi- devices could eliminate the need for a second surgery and pro-
circles connected by straight lines, which can be rotated in the vide a minimally invasive solution for implantable devices. For
plane or bent out of the plane to reduce the strain of serpen- practical biomedical applications, the materials required for
tine material under tensile strain. Simple serpentine was used devices and their degradation products must be biocompatible
as the first step. Multistep serpentine can be created by repro- or noncytotoxic, and be able to be disposed of by the human
ducing the geometric layout of the first order.[64] The fabrication body by bioabsorption, metabolization and phagocytosis. In
of flexible electrodes by geometric methods is now widely used this regard, Bao et  al.[67] demonstrated a stretchable and bio-
as the main strategy to improve the strain capacity of devices. degradable strain and pressure sensor that has low hyster-
esis, excellent cycling stability and well-controlled dissolution
and functional lifetime. The structure is made from different
2.2. Biodegradability biocompatible and biodegradable polymers (polylactic acid/
poly(octamethylene maleate (anhydride) citrate)/poly(glycerol
Implantable electronic devices are essential components of sebacate)) and magnesium electrodes (Figure  4a).[67] It has a
medical technologies that can provide sensing and therapeutic capacitive strain sensor in which two comb-shaped electrodes

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Figure 4.  Biodegradability of e-skin in medical application. a) Schematic diagram of the fully biodegradable strain and pressure sensor. b) In vivo study
and c) biodegradability of the biodegradable strain and pressure sensor. Reproduced with permission.[67] Copyright 2012, Macmillan Publishers Limited.
d) The acid-catalyzed hydrolysis mechanism of functional chitosan. e) Schematic diagram of structure of biodegradable humidity sensor. f) Optical
images of degradation of functional chitosan-based humidity sensor. Reproduced with permission.[43] Copyright 2020, Exclusive Licensee Science and
Technology Review Publishing House.

sandwiched by stretchable elastomers slide relative to each The monomers can be further decomposed via organisms in
other, leading to a measurable variation in capacitance, and the environment and immune systems of microorganisms.
it has a capacitive pressure sensor that incorporates a micro- This process can effectively reduce the need for invasive and
structured dielectric made from PGS in which changes in expensive retrieval procedures. Flexible respiration sensors
the distance between the top and bottom electrodes lead to a with functionalized chitosan have been fabricated using the
measurable variation in capacitance. Furthermore, to verify the biodegradable metal Mg/Fe as the electrode. This humidity
functionality and biocompatibility of the implanted sensors, sensor will not trigger any harm to biological environments or
Bao and colleagues carried out in vivo tests using a rat model the human body (Figure 4e,f).[43] The potential of bioresorbable
(Figure 4b).[67] Sensors implanted in the back of a rat operated electronic devices has already been utilized in a variety of appli-
for up to two weeks without a significant change in sensitivity. cations, including tracking the symptoms of diseases and post-
After three and a half weeks, the sensitivity exhibited nonlinear surgical diagnosis and treatment.
relaxation behavior under large strain and pressure conditions,
and the baseline of the sensors, which was generated by the
respiration of the rat, exhibited changes. This was presumably 2.3. Biocompatibility
due to the ongoing dissolution of the devices. Immunohisto-
chemistry results revealed that the associated materials of the Considering medical devices fully applied to the human body,
sensor did not lead to an inflammatory reaction compared to special emphasis should be placed on nonallergenic, non-
a silicon control sample at three and 8 weeks after implanta- toxic, and nonirritant features.[68,69] Beyond biodegradability,
tion, in contrast to an initial inflammatory reaction in the first the biocompatibility of flexible devices with the human body
week (Figure 4c). The device developed by Bao and colleagues is is very important to avoid causing an immune response. The
applicable in various medical situations that require temporary term “biocompatibility” represents the ability of a material to
mechanical monitoring. In addition, polysaccharides in nature respond appropriately to the host in a given situation.[70] Bio-
can also be used as building blocks for future biocompatible compatible materials are the first choice for flexible devices
electronic products.[43] Bioactive carbon-chitosan is a kind of with bio-multifunctional properties. Recently, Rogers and col-
biodegradable polysaccharide that is mainly composed of esters leagues[71] proposed a multifunctional brain sensor based on
and can be degraded into oligomers via acids (Figure  4d).[43] SiO2/Si/PLGA/nanoporous Si (Figure  5a,b). Interestingly, this

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Figure 5.  Biocompatibility of e-skin in medical application. a) Structural schematic diagram and b) application of a biodegradable pressure sensor.
c) Cytotoxicity test of the biodegradable pressure sensor. Reproduced with permission.[71] Copyright 2016, Macmillan Publishers Limited. d) Structural
schematic diagram of the silk/MXene-based flexible pressure sensor. e) Biocompatibility of the silk/MXene-based flexible pressure sensor. Reproduced
with permission.[76] Copyright 2020, Elsevier.

sensor is completely bioabsorbable after being used for med- biocompatibility, which reduces the risk of application in the
ical monitoring. The biocompatibility of sensors is crucial at all human body (Figure  5e).[76] Because the silk@MXene hybrid
stages of their life cycle.[72,73] By implanting the device onto the thin film has a 3D bionic hierarchical architecture and a low
cortical surface in the brain, the author observed the reaction elastic modulus (1.22  MPa), the flexible pressure sensor has
after 2, 4, and 8 weeks and did not find any obvious abnormal the characteristics of good stability (3500 cycles), subtle pres-
signal, indicating that the silicon-based flexible device had sure detection (9.8  Pa limit), high sensitivity (25.5 kPa−1), and
relatively good biocompatibility (Figure  5c).[71] Such conven- fast response/recovery time (40/35 ms). The reasonable design
tional semiconductors have biocompatibility and can be used of the silk@MXene biocomposite membrane provides a widely
for health monitoring and biomedical implants. More impor- applicable material for the development of high-performance
tantly, this kind of device can also be made with traditional and safe wearable medical sensors.[76] Other candidate mate-
microelectronics technology. Expect for the traditional semicon- rials, such as natural biomaterials (cellulose,[77] chitin[78] and
ductor materials, some composites such as biomaterials and silk[79]), are often used in medical devices due to their biore-
2D materials, have been evaluated by in vitro cytotoxicity tests, petitive sequence structure and biocompatibility.[80] Recently,
and been recently considered to be biocompatible and biode- bacterial cellulose (BC) has been demonstrated as conduc-
gradable.[74–76] Wang et  al.[76] reported a hierarchical cross-link tive and biocompatible fibers for flexible health monitoring
structure composite film composed of interpenetrating natural applications.[81]
silk fibroin (SF) and 2D MXene nanosheets, which shows reli-
able detection of subtle deformation (Figure 5d). The device can
be used for monitoring physiological characteristics, including 2.4. Self-Healing
finger motion, deglutition swallowing, and acoustic sound, for
pulse analysis, etc. In addition, the cytotoxicity test showed that To make a medical device that can be applied in the human
the silk@MXene-based flexible pressure sensor shows good body, the device must be stable not only during the implantation

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Figure 6.  Self-healing of e-skin in medical application. a) Schematic diagram of Self-healing working mechanism of an integrated e-skin system.
b) Health display of an integrated self-healable e-skin with LED system. Reproduced with permission.[44] Copyright 2018, Nature Publishing Group.

process but also during the entire time the object remains in a flexible substrate. Despite significant breakthroughs in the
the human body. The other challenge facing the development of development of self-healable materials, autonomous electrical
medical devices is stability and robustness. Due to fatigue, cor- and mechanical self-healing stretchable electrodes and their
rosion or damage during the working process, medical devices integration with multifunctional electronic systems still need
deteriorate with the passage of time, resulting in device failure. to be realized. Bao et  al. recently proposed a fully self-healing
Therefore, researchers hope to create self-healing flexible sensors electronic system composed of CNTs and PDMS–MPU0.4–
that can repair accidental internal or external damage, restore key IU0.6 that shows good self-healing, in which the conductivity is
functions and be applied to medical devices, similar to human restored after cutting and damage after 12 h (Figure 6a). Further
skin. Self-healable electronic components determine the appli- research on the self-healing chemistry of reconfigurable elec-
cation of flexible sensors in medicine.[82–86] They must exhibit trode components showed that an integrated self-healing e-skin
strong robustness and be able to resist accidental mechanical has high potential. This e-skin based on self-healing materials
damage caused by accidental cutting or scratching, and repeated consists of a light-emitting capacitor (LEC), a strain sensor, and
wear. In this regard, some self-healing materials have attracted an electrocardiogram sensor for electromyography (EMG), so
great interest because of their outstanding characteristics. They it can detect and record physiological signals in real time and
can even recover their original properties after damage and display feedback information by closed-loop communication
cutting, mainly in terms of the structure, physical properties, between the electronic device and user (Figure 6b). In addition,
chemical properties, and mechanical flexibility.[87,88] Regarding each part (including interconnects) is self-repairing and can be
mechanical stability, medical devices should also have the ability stretched to 100%.[44] For example, the stand-along LEC can heal
to withstand shocks and stresses because the human body may completely to restore its initial electrical and mechanical prop-
occasionally produce large and strong impulses during physical erties, even after undergoing complete cutting. After healing,
exercise and sudden movement.[31] At this time, when an implant the LEC continued to glow even at 100% strain.[44]
is used as an additional support for the body’s own joint repair
(such as in bone replacement), the medical device must be able
to withstand these forces. In addition, wearable medical sensors 2.5. Adhesion
are constantly affected by friction and severe stretching from
the human body, so wearable medical sensors must be able to Biomedical patches are commonly known as scaffolds, matrices
recover their mechanical properties and functions under normal or structures, which are important biomaterial-based medical
human activity for the required amount of time.[89] devices for clinical repair and treatment of organ and tissue
Previously, Dickey et al.[44] reported the merits of self-healing diseases.[90,91] In other words, during the process of tissue
materials by printing reconfigurable liquid-metal electrodes on regeneration, these biomedical patches provide support by

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Figure 7.  Adhesion of e-skin in medical application. a) Well-defined 3D printed architectures using graphene with high adhesion in biomedical applica-
tion. Reproduced with permission.[100] Copyright 2015, American Chemical Society. b) Octopus-inspired carbon-based conductive polymer composite
electronics. c) Carbon-based conductive polymer composite electronics with high adhesion. Reproduced with permission.[102] Copyright 2018, John
Wiley and Sons.

maintaining a space in specific bone tissues, while preventing printed on a carbon-based conductive polymer composite film
other unnecessary cells and tissues from invading the target (Figure  7b,c).[102] These bioinspired conductive suckers have
treatment area. In general, when a medical device contacts high adhesion, can adhere to skin replica (1.89 N cm2) and sil-
the human body, after a period of time, whether by design or icon (5.24 N cm2) surfaces under any conditions (such as dry
accidentally, it will inevitably disintegrate.[4] Although adhe- and wet states), and are easy to peel off without leaving any res-
sion to skin can produce highly accurate signals, the direct idue after use. By adjusting the proportion of the carbon fillers
disadvantage is that separating such devices from the skin is in a PDMS matrix (the best is 7 vol%), a penetration network
difficult.[4,92] In addition, medical adhesives, such as acrylic was successfully formed, and important biological signals, such
adhesives, are commonly used in tapes, dressings, electrocar- as wrist bending movement and ECG signals, can be detected
diography (ECG) electrodes and drug patches, and these adhe- even under water.[102] In addition, composite biomedical
sives may cause allergic contact dermatitis due to long-term patches based on graphene and CNTs show good healing prop-
application on skin.[93,94] Therefore, medical devices must have erties. However, from a clinical point of view, because synthetic
high adhesion. To meet practical applications, some natural materials have difficulty obtaining US Food and Drug Admin-
biopolymers and synthetic degradable polymers are consid- istration (FDA) approval, the commercialization of biomedical
ered good materials for the preparation and design of medical patches based on synthetic materials is still challenging, so
patches, such as polylactic co-glycolic acid (PLGA), chitosan, biological patches are still not used by most doctors in clinical
gelatin, collagen, polycaprolactone (PCL), and polylactic acid medicine.[31]
(PLA).[95] Degradable polymers with high adhesion are widely
used in the medical field because of their low price and good
mechanical properties.[96–99] However, the low mechanical prop- 3. E-Skins for Medical Applications
erties and surface hydrophobicity of natural biopolymers limit
their practical application. Therefore, a variety of new methods According to FDA regulations, medical devices are designed to
have been proposed to improve the biomedical patches made diagnose, prevent and treat diseases, rather than achieve their
of biodegradable polymers. For example, Han et al.[100] reported purpose through the body or chemical action in the body.[3]
that structural design increased the adhesion strength of a 3D Wearable sensor systems composed of flexible and stretch-
printed graphene (3DG) composite, which was synthesized able materials are likely to make better contact with human
by printing graphene-polylactide-co-glycolide-elastomer-based skin, while e-skin is very efficient in sensing signals and com-
liquid ink, resulting in good direct contact with the heart bining with the human body.[103–105] Due to the latest develop-
(Figure 7a).[100] In addition, many studies have focused on inter- ments in e-skin technologies, they can realize long-term and
facial adhesion.[101,63] continuous tracking of blood oxygen, blood flow, arterial pulse
Another example is a bioinspired flexible and stretch- pressure, heart rate, temperature and other important physio-
able sensor, which mainly consists of octopus-like patterns logical signals in daily activities, while the user is mechanically

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Figure 8.  Focused areas of flexible medical devices. Human body image: Reproduced with permission.[111] Copyright 2020, American Chemical Society.
Wearable Medical devices image: Reproduced with permission.[112] Copyright 2016, Nature Publishing Group. Implantable Medical Devices image:
Reproduced with permission.[113] Copyright 2016, Nature Publishing Group. Interventional medical devices image (Scale bars: 2 mm): Reproduced with
permission.[114] Copyright 2020, Springer Nature Limited.

comfortable.[106–108] In addition, glaucoma and diabetes diseases multiple sensing components[116] and individual devices such
can be diagnosed and treated by noninvasive e-skin technology as data loggers,[117] temperature sensors,[118] brain–computer
that provides real-time detection of indicators of percutaneous interfaces,[119,120] and hydration sensors.[121,122] Other formats
treatment, such as the intraocular pressure and blood glucose of e-skins can be achieved by thicker, and thus less stretch-
concentration. With the development of bioresorbable and bio- able, structures and the use of fixtures such as body straps and
compatible materials, flexible in vivo e-skin systems have been bandages to realize intimate skin contact. With assistance from
developed and demonstrated for electrocorticography (ECoG), silicone adhesive and stretchable fabric, rugged and breathable
electrospinography, electrophysiology (e.g., ECG), intracra- forms of stretchable electronics can be realized to achieve epi-
nial temperature/pressure monitoring, and clinical biomed- dermal or transcutaneous monitoring.[122,123] The main applica-
ical therapy, providing ideal quality and commercial clinical tions of e-skins include biomolecular analysis and biophysical
devices.[108–110] In this section, we will review various types of signal sensing. Recently, a variety of flexible temperature sen-
e-skins that exhibit the biological functions (mechanical prop- sors have been developed, which are mainly used to monitor
erties, biocompatibility, biodegradability, self-healing, and adhe- human body temperatures during treatment in the field of
sion) required to fabricate medical devices. For these sensors, medicine and health monitoring.[123] The real-time tempera-
we describe in detail their applications in the medical field ture tracking ability during treatment or surgery can improve
(such as wearable, Implantable, and Interventional medical the efficacy of clinicians and safety. For example, Ren et al.[124]
devices) (Figure 8).[111–114] applied organic field-effect transistors (OFETs) to detect the
temperature of the human body. By using pentacene/Ag NP
thermistors, this work achieved a high resolution (0.4 °C), a
3.1. Wearable Medical Devices wide detection range (20–100 °C), and a high temperature coef-
ficient resistance (TCR = 0.044). (Figure  9a,b). Compared with
Flexible and wearable sensors for health monitoring are pre- flexible thermistors, the temperature sensors based on OFETs
dominately realized by skin-mounted devices that are in direct have a good thermoelectric effect, which makes them show con-
contact with skin and measure diverse skin properties.[115] One siderable potential in health monitoring and other biomedical
innovative type of e-skin is based on soft and ultrathin materials and robotic applications. (Figure  9c).[124] In addition, visualiza-
whose mechanics are similar to the epidermis of the skin and tion of temperature changes offers a fast, simple, and intuitive
is thus termed e-skin. E-skin can be spontaneously attached to method to identify heat changes in the human body.[125] To visu-
skin, and conformably adapt to skin morphology. E-skin has alize temperature changes, colorimetry-based temperature sen-
been reported as constituting a conceptual system that contains sors are usually composed of thermochromic materials such as

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Figure 9.  E-skin as wearable medical devices. a,b) Optical image of flexible temperature sensor arrays (scale bar: 10 mm). c) Measured temperature
distribution of the forehead by flexible temperature sensor. Reproduced with permission.[124] Copyright 2016, John Wiley and Sons. d) Visual-aided
smart thermosensors on human body. e) The standard curve of the resistance changes versus the temperature of the paper-based Visual-aided smart
thermosensors. Reproduced with permission.[17] Copyright 2017, John Wiley and Sons. f) Optical image of fully printed SWNT TFTs on PET substrate
using the inverse gravure printer. g) Optical image of a fully printed 20 × 20 device array. h) Transfer characteristics of a TFT measured at VDS = −5
and −1 V. Reproduced with permission.[131] Copyright 2013, American Chemical Society.

inorganic compounds, leuco dyes, and thermochromatic liquid good on/off current ratio, and high flexibility (Figure  9f). The
crystals.[126–128] Zhang et  al.[17] reported a method for manu- surface chemistry of the substrates and the surface tension and
facturing a vision-assisted intelligent thermal sensor (VAT). viscosity of the inks are very important in this gravure printing
In this method, temperature-sensitive resin and liquid crystal process and need to be optimized to realize reproducible and
molecules are coated on the substrate, and polypyridine is poly­ uniform device performance.[131] Printing conductors based on
merized in a solvent-free manner to make a new sensor. This silver nanoparticle ink is often used to make electrodes. The
sensor mainly uses the color change to visually notify people role of the printed gate dielectric layer is more critical, which
of a temperature change, to remind them to avoid the safety directly affects the performance of the device. Figure  9g dis-
problems caused by high temperature and realize an alarm plays that the gravure TFT is integrated into a 20×20 pixel flex-
function. Due to its ultrahigh resolution (0.1 °C), high stability ible backplane, which can be used to drive e-skins and displays.
and excellent substrate adaptability, the sensor can be used as a The printed transistors on the active-matrix backplane show
clinical thermometer and can be worn on wrists, legs and other outstanding properties, such as a good field-effect mobility of
parts of the body (Figure 9d,e).[17] 9 cm2 V s–1, a large ON/OFF ratio (>104), and a small operating
Compared with modern integrated circuits, many of the voltage (<10 V) (Figure 9h).[131]
potential applications of e-skins require lower device perfor-
mance and speed. Instead, the main considerations are cost
and large-area manufacturability.[129] For example, e-skin can be 3.2. Implantable Medical Devices
ideally used as a disposable device in the biomedical field when
its cost is low enough. Alternatively, a recent work showed that In addition to the application of these wearable e-skins,
the widely adopted additive manufacturing strategy could also implantable subcutaneous e-skins are also of interest and have
be used for low-cost and large-scale fabrication of electronic received wide attention. Implantable medical electronics are
sensors and devices.[130] Javey et  al.[131] reported fully printed often used in clinical medicine to prevent, diagnose and treat
thin-film transistors (TFTs) based on semiconductor-enriched diseases.[132,133] For implantable neuromodulation devices, soft
single-walled CNTs (SWNTs), which exhibit a high mobility, a microelectronic devices with mechanical properties similar to

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Figure 10.  E-skin as Implantable Medical Devices. a) Lithographically patterned electrical hydrogel elastronics electrode array with PFPE-DMA encapsu-
lation attached on soft jelly (Scale bar: 2 mm). b) Illustration of hydrogel elastronics electrode for in vivo neural stimulation test. c) Confocal micrograph
of the MECH microelectrodes on a soft elastic substrate conformably wrapping around a sciatic nerve. Reproduced with permission.[137] Copyright 2018,
Nature Publishing Group. d) Optical image of a 2D fan-shaped cardiac mesh composed of Au-coated AgNWs in SBS elastomer. e) Optical image of the
cardiac mesh in implanted on a pig heart. f) Voltage map constructed from the intracardiac recording by the cardiac mesh. Reproduced with permis-
sion.[140] Copyright 2018, Nature Publishing Group.

those of biological systems are usually used to provide inti- sensors, the pressure and strain must be simultaneously
mate and stable electrical coupling with electrogenic neural measured with high sensing performance (such as high sen-
tissue for effective electrical stimulation.[134] In addition, recent sitivity and fast response time).[138] The strain level and strain
studies have shown that reducing the mechanical mismatch at rate are key factors that indicate the biomechanical properties
the electronic device-tissue interface can significantly reduce and healing stage of soft tissues. The sensor needs to meet the
the adverse immune reactions of chronic implantation.[135,136] high strain performance, that is, to measure the typical tendon
In fact, for neural prostheses and human-computer interfaces, strain (<10%) without hindering the natural movement of the
the design of soft and compliant electronic products has been tendon.[139] Recently, Kim et  al.[140] developed wearable bioelec-
actively sought. Most of the methods focus on the structural tronic devices using silver–gold nanocomposites to measure
design of flexible devices, such as macroporous mesh struc- electrophysiological signals and thermally/electrically stimu-
tures and ultrathin electronics, to reduce the bending stiffness late human skin. Ag/Au nanocomposite-based conductive
of stretchable sensors, achieved by strain engineering using nanocomposite electrode nets have been applied to pig hearts
rigid components. Recently, Bao et al.[137] reported implantable for in vivo measurements (Figure  10d).[140] The elastomer was
soft electronics based on an electrically conductive hydrogel configured as a 2D mesh in which 42 electrodes were inte-
(ECH) membrane with a low Young’ s modulus, which can grated. The mesh was designed to cover the entire ventricular
make contact with peripheral nerves for localized neuromodu- surface of the pig heart with high stretchability and high con-
lation. A thin film elastic electrode array was formed by com- ductivity (Figure 10e). The grid can be used to obtain an in vivo
bining a mesh as the electrode and PFPE-DMA as the top voltage map of the anterior and posterior parts of the heart
and bottom elastic packaging layers through micropatterning (Figure 10f).[140]
strategy (Figure  10a). Notably, the device does not produce With the rapid development of biomedicine and flexible elec-
cracks when it is stretched to 20%. Through rational design of tronics, the demand for and development of implantable med-
the electrodes, the device can provide up to a 10 mA cm–2 exci- ical electronics are increasing.[141] However, due to the power
tation current density for neural regulation at a low voltage of supply limitation, implantable electronic devices are hindered
50  mV.[137] For practical application, we directly contacted the in practical applications. Even if they are wirelessly powered by
exposed sciatic nerve of anesthetized mice with the mesh elec- an external radio-frequency source, a radio-frequency generator
trode to measure the responses of legs and toes after electrical has to be held nearby, which still limits mobility.[142] To address
stimulation in vivo. The mesh electrode was integrally wrapped the above limitations, researchers have invested great energy
around the sciatic nerve to achieve intimate contact and reduce and enthusiasm in studying the power supply. The solutions
the tissue-electrode impedance. For implantable rehabilitation usually focused on one of two aspects: increasing the power

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Figure 11.  Self-powered e-skin as implantable medical devices. a) Optical image of the triboelectric sensor attached on the heart site. b) R waves and
voltage curves under resting, active, and stressed states. Reproduced with permission.[46] Copyright 2016, American Chemical Society. c) Optical image
of the triboelectric generator implanted in porcine tissue. d) Voltage and current of the triboelectric generator implanted under 1.0 cm porin tissue.
Reproduced with permission.[147] Copyright 2019, Science.

capacity of implantable medical electronics or obtaining energy enzymatic biofuel cells and absorbable primary cells, which
from organisms or the surrounding environment.[143] can extract energy from the redox reaction of electrolytes and
Ideally, the implantable device can be self-powered by glucose in the gastrointestinal tract.[139,144] As early as 1963,
obtaining mechanical energy from the human body. Wang some people tried to implant implantable energy harvesters
et  al.[46] proposed a self-powered, flexible, one-stop implantable into living animals.[111] Parsonnet et  al.[145] demonstrated a
triboelectric active sensor (iTEAS), which can provide contin- piezoelectric sensor mounted on the dog aorta that can obtain
uous monitoring of a variety of physiological and pathological energy from aortic deformation and provide power for car-
signals (Figure 11b). This system can self-generate a short-circuit diac pacemakers. After more than half a century of develop-
current (ISC) of 4 A and an open-circuit voltage (VOC) of 10 V. ment, many achievements have been made in self-powered
They implanted the device without a battery into human-scale implantable medical electronics and implantable energy har-
animals, which could accurately monitor heart rate changes, vesters. From 2010 to 2014, device were developed to obtain
including ventricular premature beats, atrial fibrillation and energy from sources ranging from glucose in rats to respira-
other arrhythmias.[46] Two weeks after implantation, the biocom- tion.[111,146] Recently, Kim et  al.[147] demonstrated a kind of thin
patibility of the device in vivo was tested, which proved that it implantable vibration friction generator that can effectively
was suitable for practical use. As a multifunctional biomedical obtain mechanical energy. The device uses ultrasonic waves
monitor without an external power supply, this device has great to transfer mechanical energy through skin and liquid, that is,
development potential in the future health care industry. In addi- ultrasonic waves can cause polymer film displacement at the
tion, a new respiratory rate and phase monitoring method was micron level and generate electric energy through contact elec-
established by analyzing the changes of iTEAS output peak. With trification Lithium-ion batteries were charged in water at 166
the help of a single arterial pressure catheter, the blood pressure microcoulombs per second. The current and voltage generated
and blood flow velocity can be estimated independently.[142] by ultrasonic energy transfer under pig tissue were 156 mA and
Another way to solve the power limitation of implantable 2.4 V, respectively (Figure 11c,d).[147] These findings indicate that
medical electronics is to realize the transmission of light and capacitive friction power generation is a technology competitive
sound energy from the body to the device in a percutaneous with piezoelectricity, that can utilize ultrasonic waves in vivo to
way. Chemical types of implantable energy harvesters include provide power for medical implants.

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3.3. Interventional Medical Devices target locations for detecting and/or modulating the body’s
natural signals.[158] Recently, Rogers and his group reported on
Interventional minimally invasive surgery (IMIS) is an materials, device design and manufacturing methods that com-
advanced diagnostic and therapeutic technique involving inser- bine advanced electronic functions with catheters for minimally
tion of a tool via a small percutaneous incision for the treatment invasive forms of heart surgery (Figure  12d).[114] The integra-
of cardiovascular disease, cancer and other health states.[148,149] tion of this system with commercial and/or custom catheters
Compared with traditional surgery, it has a faster recovery time results in complex systems with multimodal sensing and actua-
and a lower risk. In general, in IMIS, two or three long and tion capabilities, high-density and conformality. In vitro experi-
hard tools are introduced into the inflatable abdomen via a ments, as well as computational studies and evaluations on
small incision (≈10–15  mm in diameter), and used to conduct human hearts and rabbits, have demonstrated that these sys-
surgical tasks with the help of a rigid laparoscope to obtain tems are superior to traditional heart devices in shape factor,
endoscopic vision.[150] For instance, a flexible endoscope with a function and programmability.[114] In addition, the multilayer
variety of microtools at the tip is introduced via the anus, vagina e-skin array on the endocardial balloon catheter can produce
or mouth and then perforates the inner wall of the organ.[151] conformal and good contact with the surface of the tissue, sup-
However, these systems usually lack tactile feedback and cannot port high-density spatiotemporal mapping of temperature, pres-
perceive and quantify the interaction between themselves and sure and electrophysiological parameters, and allow program-
soft organs. This deficiency can lead to organ damage due to mable electrical stimulation, radiofrequency ablation and irre-
unnecessary overexertion. In endoscopy and catheter-like sur- versible electroporation (Figure  12e).[114] Kim et  al.[159] reported
gery, flexible tools are needed that are less accurate but more a flexible pressure sensor, a contact sensor, and a temperature
suitable for navigation along tortuous paths and avoiding obsta- sensor based on the stretchable impedance on balloon catheters
cles to reach distal organs.[152] Therefore, using advanced e-skin to assess full contact with tissues (Figure  12f). The tempera-
sensors and actuators to detect the endoscope or catheter may ture sensor consisted of a Ti/Pt thin film with the thickness of
be a way to overcome these shortcomings. In the field of soft ≈5 nm/50 nm. Here, the Ti/Pt thin layer was deposited by elec-
electronics, emerging strategies that leverage the materials and tron beam evaporation and patterned by photolithography, and
manufacturing capabilities of the semiconductor industry are then, the complex micropattern of the sensor was produced by
likely to offer direct opportunities in this area. stripping. The Ti/Pt film was strategically attached on a flexible
Recently, many research groups have applied e-skin to flex- but nonstretchable polyimide island, which helped reduce the
ible endoscopic and catheter devices to solve the force and tem- effect of strain on temperature measurement during expansion
perature feedback problems in interventional medicine.[153–155] and outgassing.[159] The adhesion of Ti/Pt can be improved by
For example, to solve the problem that multichannel endoscope surface treatment of PI with UV/ozone or by depositing a thin
lacks the necessary spatial resolution, Kim et al.[156] proposed a layer of SiO2 (50 nm) on the surface of PI. These flexible devices
multifunctional interventional system based on endoscopy that are located near ablation electrodes decorating on the surface
combines a flexible sensing system with light-activated thera- of the balloon to offer accurate assessment of the tissue tem-
peutic nanoparticles in the highly localized space near a tumor perature during ablation (Figure  12g–i).[159] Calibration meas-
or benign growth. These advanced sensing systems together urements performed at very low (e.g., cryoablation) and elevated
realize the mapping based on photofluorescence, contact tem- (e.g., RF energy transfer) temperatures yielded a monotonic
perature monitoring, pH sensing, electrical impedance moni- relationship between the impedance and measurement temper-
toring, radiofrequency ablation and local light/chemotherapy, ature with a slope of 1:91 (Figure 12j). In the case of perfusion of
which are the basis of closed-loop solutions for colon cancer the radio frequency catheter and cryoballoon, the sensitivity is
treatment. In addition, effective treatment is helpful for pro- enough to offer accurate feedback on the thermal characteristics
viding good oncological and economic benefits for various gas- of the tissue-balloon interface.
trointestinal tumors or precancerous lesions. These systems
help enter the internal organs and provide much diagnostic
feedback in the process of treatment; thus, the application of 4. Challenges and Future Outlook
this technology in interventional medicine is emphasized. Liu
et  al.[157] proposed a flexible sensor with multi position micro- Developing high-performance flexible medical electronics for
sensors for temperature detection of the ablation area, which improved human–machine interfaces, diagnostics, and health
can be attached to the surface of a medical cryoballoon to offer monitoring has extensive practical significance. Various kinds
multiposition temperature information, as shown in Figure 12a. of technologies have been demonstrated to improve the con-
The sensor makes up for the deficiency of the existing cryoab- venience and personalization of patient medicine, such as
lation catheter, which only detects the internal temperature of wearable devices, implantable medical devices, and interven-
the cryoballoon during the operation (Figure 12b). The sensing tional medical devices. In the development of implantable and
curves of the sensor show that the device has a fast response wearable electronic technologies, flexible medical electronics
time (0.3 s), good linearity, and high repeatability in the tem- (such as self-powered physiological sensors, self-powered nerve
perature range of 295–200 K, (Figure  12c).[157] As a result, the stimulators, and symbiotic cardiac pacemakers) have been used
sensor can guarantee the reliability of temperature detection in clinical medicine to monitor human health. The extensive
and has broad application prospects in the field of cryotherapy. use of flexible medical electronics will have a profound impact
Catheter-based systems utilizing heterogeneous collections of on our daily life in the future, from wearable devices to health
e-skin sensors offer a platform to solve the issue of highly limited monitoring.

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Figure 12.  E-skin as interventional medical devices. a) Illustration and concept diagram of flexible temperature sensor in pulmonary vein isolation.
b) Optical images of flexible device around pulmonary vein ostium before and after cryoablation. c) Comparison of the temperature change plots
of flexible device and commercial temperature sensor during cryoablation. Reproduced with permission.[157] Copyright 2021, National Academy of
Sciences. d) Structural illustration of multimodal, multiplexed soft sensors for minimally invasive surgery (top: scale bars, 1 cm (main image); 2 mm
(inset); bottom: scale bar, 2 mm). e) Optical image of bipolar radiofrequency ablation attached on the epicardial surface of a rabbit heart. Reproduced
with permission.[114] Copyright 2020, Springer Nature Limited. f) Optical image of a sensor web without substrate attached on the surface of tissue and
optical image of a sensor with the silk substrate. g,h) Optical image of sensor webs on collapsible balloon catheters. i) X-ray images of balloon catheter
in a live porcine model with contact and noncontact conditions. j) Voltage of sensor webs in vivo. Reproduced with permission.[159] Copyright 2012,
National Academy of Sciences.

This paper reviews the progress in e-skin for medical appli- application, flexible medical electronics can be applied in
cations from the aspects of wearable electronics, biofunction- three ways: as wearable devices, implantable medical devices,
ality and performance, and medical applications. According to and interventional medical devices. Wearable electronics can
the different working features and requirements for medical continuously and long-term monitor and record physiological

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www.advancedsciencenews.com www.advmattechnol.de

information, such as blood oxygen, blood flow, arterial pulse Keywords

pressure, temperature and heart rate. Flexible implantable elec-
biofunctionability, e-skin, flexible electronics, health monitoring, medical
tronics can be used for recording of internal states in vivo (e.g.,
devices
intracranial temperature and pressure), electrophysiology (e.g.,
ECG, ECoG, and electrospinography), and clinical biomedical Received: January 28, 2021
therapy. Invasive e-skin can provide real-time detection of indi- Revised: February 19, 2021
cator levels (e.g., intraocular pressure and blood glucose con- Published online: May 2, 2021
centration) for transcutaneous therapeutic treatment. Finally,
the possible and key challenges and prospects of these flexible
medical devices have also been demonstrated.
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Lili Wang is a professor in the Institute of Semiconductors, Chinese Academy of Sciences, China.
She earned her B.S. degree (2010) in chemistry and Ph.D. degree in microelectronics and solid
state electronics from Jilin University in 2014. Her current research interests focus on the flexible
electronics based on biological materials, 2D materials, and semiconductor, including pressure
sensors, electronic-skin, biosensor, photodetectors, and flexible energy storage and conversion
devices.

Kai Jiang received his M.B./B.S. degree from Second Military Medical College, Shanghai, China,
in 1991, and M.D./Ph.D. degrees from Chinese PLA Postgraduate Medical College, Beijing, China,
in 1998. He further studied at the Queen Mary Hospital of University of Hong Kong in 2002, and
Universitat de Barcelona, Spain, in 2008. He has been with the Faculty of Hepoto-pancreato-biliary
Surgery, Chinese PLA General Hospital since 1991, where he is currently a professor of surgery.
His current research interests focus on surgical operation and applications of nanotechnology in
clinical medicine.

Guozhen Shen received his B.S. degree (1999) in chemistry from Anhui Normal University and
Ph. D degree (2003) in Chemistry from University of Science and technology of China. He joined
the Institute of Semiconductors, Chinese Academy of Sciences as a Professor in 2013. His current
research focused on flexible electronics and printable electronics, including transistors, photo­
detectors, sensors and flexible energy storage and conversion devices.

Adv. Mater. Technol. 2021, 6, 2100107 2100107  (18 of 18) © 2021 Wiley-VCH GmbH