Bio‐Multifunctional Smart Wearable Sensors for Medical Devices

Advances in digital health care have driven innovations in high‐performance wearable and smart sensors. One requirement in this field is establishing healthy, secure, and reliable medical devices for precisely monitoring vital signs of the human body or the surrounding environment through flexible sensors with not only high‐sensing performance but also excellent biofunctionality. Smart wearable sensors with excellent biofunctionality furnish medical devices with various smart functions such as biocompatibility, biodegradability, and self‐healing, which have attracted widespread interest from device engineers and materials scientists. Herein, a comprehensive review of the latest progress concerning these smart wearable sensors is presented with a focus on bio‐multifunctional (biocompatible, biodegradable, and self‐healing) device designs. The medical applications of bio‐multifunctional smart wearable sensors are also briefly covered, and to conclude, a discussion of the challenges, opportunities, and future perspectives is provided.


Introduction
Over the past several decades, electronics have become central to many aspects of biomedicine. [1] The boosting desire for real-time fitness tracking, health monitoring, and disease forecasting has created a fast-growing market for flexible and wearable sensors. [2] Usually, wireless electronic devices are loosely coupled onto some parts of the human body, especially the wrist or chest, in the form of small or rigid blocks that can detect or record some important physiological indexes in real time without requiring the heavy-wired hardware present in clinical systems. This important and continuous human indicator information can alert users of abnormal health, allowing them to take preventive measures to protect their health and avoid serious medical conditions. [3] Continuous extension of smart wearable sensors in the scope and scale of their applications has driven the development of wearable devices to a new high. Five years from now, the worldwide revenue from wearable devices looks likely to reach $97.8 billion. [4] Although the continued need for smart wearable sensors in medical applications is growing, many sensors for practical applications have limited potential for qualitative improvements in biofunctionality.
The failure of flexible sensors without biofunctionality to provide a safe and reliable biological interface is a fundamental limitation in practical applications. For nonstandard health monitoring, these limitations may not affect the simple use of wearable devices to monitor daily pulse and heart rate changes. [5] For example, traditional wearable devices can provide acceptable performance in heart rate monitoring for entertainment applications. However, in real clinical applications or specific environments, even precise wearable devices cannot provide safe and reliable daily movement performance parameters, mainly due to the lack of specific biological functions in wearable devices. Thus, with constant innovations in device designs and manufacturing methods, the market demand for bio-multifunctional smart wearable sensors has increased. This increased market demand requires that sensors have the characteristics of biocompatibility, biodegradability, bioabsorbability, self-healing, and safe integrability with human and tissue surfaces. [6,7] The biofunctionality of these devices is significant in terms of both various practical applications and the accuracy/reliability of the resulting data. For example, from a medical perspective, the biocompatibility and biodegradability of devices significantly improve their intimacy and secure integration with the skin interface, whereas self-healing and water-proof wearable devices can reduce vulnerability and sensitivity to moisture, thereby enhancing the durability, reliability, and safety of devices. These biofunctions follow naturally from the flexible characteristics and requirements of wearable sensors for biophysical and biochemical measurements in medical applications, such as safety, robustness, and lack of irritation at interfaces. Combined with the recent development of personalized diagnosis and treatment technology, the improvement in postoperative tracking technology, and the objective of the early prevention of diseases, these kinds of bio-multifunctional smart wearable sensors are at a turning point in realizing widespread applications and have significant potential social benefits. [5] In this review, we highlight the latest advances and provide critical insights into bio-multifunctional smart wearable sensors for medical applications (Figure 1). First, the recent successful demonstrations of bio-multifunctional wearable sensors, including biocompatible, biodegradable, bioabsorbable, and self-healing wearable sensors, are briefly overviewed. The subsequent content highlights the most advanced medical applications of bio-multifunctional wearable sensors, classified into three main subfields: 1) biophysical monitoring (heart rate/pulse, human motion, and temperature); 2) biochemical tracking (biomolecule, blood glucose, and pH); and 3) real-time environmental information detection (gas molecules and humidity). Finally, this work concludes with an overview of key challenges and a summary of opportunities, ultimately determining that advances in smart wearable sensors are critical to their continuing progress.

Bio-Multifunctional Smart Wearable Sensors
The design concept of a multifunctional biosensor has many ideal characteristics, such as self-healing, biocompatibility and biodegradability, which will be highlighted in this section. To mimic biofunctions, the selection of nanomaterials with mechanical compatibility is an important factor for wearable sensors. The human body provides a variety of biological signals, including electrophysiological signals, physical signs, and habitual physical activity, which can indicate the existence of fatal diseases. Wearable health monitoring devices can detect these biological signals for the early diagnosis of diseases. [16,17] Proper materials can improve the performance and wear resistance of wearable equipment, thereby expanding its applications. In this section, we discuss current developments in the materials and techniques for obtaining biofunctional sensors with optimal properties.

Biocompatible Wearable Sensors
Because they are directly exposed to the human body, wearable medical devices are expected not to pose additional health risks and avoid restrictions on daily activities. [18][19][20] The biocompatibility of wearable sensors with the human body is essential to avoid, causing an immune response. [21] Therefore, biocompatible materials are the preferred materials for wearable smart sensors with bio-multifunctional properties. Recently, a silicon-based multifunctional brain sensor has been proposed by Rogers and coworkers. [22] The sensor for medical monitoring is completely bioabsorbable. The authors also confirmed that no glial cell response to the device was found 2, 4, and 8 weeks after implantation, indicating that the silicon circuit has acceptable biocompatibility. This traditional semiconductor is biocompatible and may be suitable for biomedical implants and health monitoring. More importantly, this sensor can also be manufactured using traditional microelectronics technology. In addition to traditional semiconductors, some conductive polymers have been assessed by in vitro cytotoxicity assessments. An implantable pressure-strain sensor made entirely of biocompatible conductive polymers was reported by Bao and coworkers (Figure 2a). [23] The sensor can test pressure and strain individually using two vertically isolated devices ( Figure 2a). The two devices can also recognize the pressure exerted by a salt (12 Pa) and a strain of 0.4% without interfering with each other. Because of this unique feature, the medical sensor proposed here can be used to evaluate real-time tissue healing, thereby realizing the personalization of rehabilitation programmers. The biocompatibility of this device was also investigated by the authors. In vivo studies have shown that the device has good functionality and biocompatibility in rat models, indicating the potential applicability of the device to real-time monitoring of tendon healing. Immunohistochemistry and Hematoxylin and eosin (H&E) staining showed that poly(octamethylene maleate anhydride citrate) (POMaC) had good biocompatibility 8 weeks after implantation. There was no significant difference between the POMaC and silica gel (control) samples ( Figure 2b).
The interaction between the human body and a single substance is difficult to predict due to biological reactions in the human body. The precise design of materials and rational in vivo testing are very critical to confirm whether a specific material is biocompatible in a particular application. [21] One plausible way to improve biocompatibility is to select natural biomaterials, such as sodium alginate, [24] silk, [25] chitin, [26] cellulose, [27] and wood [28,29] because of their excellent nontoxicity. In recent years, biomaterials serving as the active components and substrates of various biocompatible flexible sensors have been widely reported. [1] Chitosan is one of the most studied materials at present. [30,31] The tensile and conductive properties of chitosan are improved by various methods. For example, Wang and coworkers propose a simplified strategy for designing multifunctional biomaterials by integrating the fascinating structure of natural chitosan with the high conductivity of graphene. [32] Compared with other structural materials, biocomposites resulting from this material design method have advantages in high response, rapid response rate, and low detection limits (20 ppb), and the applicability of this approach to the design of chemical sensors for real-time diabetes monitoring has been further confirmed. With the effective adaptation of the core functions and physical and chemical properties of materials, a flexible, biocompatible, and high-performance sensor has been developed, thereby showing the prospects of wearable and implantable sensors. Some other biomaterials were also used Reproduced with permission. [8] Copyright 2010, Nature Publishing Group. "Compatible device." Reproduced with permission. [9] Copyright 2019, Nature Publishing Group. 2) Biodegradable flexible sensors: "Bioresorbale pressure sensor." Reproduced with permission. [10] Copyright 2019, Nature Publishing Group. "Biodegradable biosensor." Reproduced with permission. [11] Copyright 2018, Wiley-VCH. "Bioresorbale device." Reproduced with permission. [12] Copyright 2012, Science. 3) Self-healing flexible sensors: "Self-healing strain sensor." Reproduced with permission. [13] Copyright 2018, Wiley-VCH. "Self-healing electronic skin." Reproduced with permission. [14] Copyright 2018, Nature Publishing Group. "Self-healing pressure sensor." Reproduced with permission. [15] Copyright 2019, Nature Publishing Group.
for wearable medical devices. For example, Zhang and coworkers reported that carbonized silk fabrics (CSF) can be used to fabricate super-deformable and high-performance strain sensors with excellent pressure-sensing properties for monitoring various human body movements ( Figure 2c). [22] This kind of carbon material is derived from natural and renewable resources and has great production capacity and environmental friendliness.

Biodegradable Flexible Sensors
In recent years, biodegradable devices have shown great potential in enabling advanced health monitoring and reducing the amount of electronic waste. [33][34][35] The benefits of this no-trace behavior are decreases in the costs and health risks of wearable medical systems during medical treatment, especially in the context of temporary biomedical implants. For instance, Bao and coworkers designed and manufactured a high performance wearable pressure device based on biodegradable conductive polymers. [36] These sensors have good sensing performance and can be used as wearable medical devices for continuous cardiovascular monitoring, such as collecting blood pulse signals from human femoral, carotid, and radial arteries. More importantly, the authors claim that the fabrication of these sensors is the first step toward more complex biodegradable sensors that may be used in biomedical applications in humans to avoid further surgical interventions and reduce waste generation. Recently, their team also reported the design of a pressure sensor based on edge field capacitance and biodegradable technology, to measure arterial blood flow in both contact and noncontact modes, as shown in Figure 3a-c. [37] For real-time monitoring, a mature radio frequency coupling method is used to enable wireless operations. In addition, because the device is made entirely of biodegradable materials, it is reabsorbed in a few months, so there is no need to remove the device. The sensor can be used in a variety of applications including the heart, blood vessels, during transplantation and reconstruction, as well as in small and large vessels requiring vascular anastomosis. This technique is helpful for real-time monitoring of blood flow after reconstructive surgery.
Rogers's team has also pioneered in research about implantable silicon-based transient electronic devices that can be used in wearable medical systems (Figure 3d,e). [12] A silicon-based sensor using silk as a substrate is placed in an aqueous solution and rapid dissolution of the device can be observed within 10 min (Figure 3f). This implantable instantaneous device provides a system-level example of a programmable nanoantibiotic fungicide ( Figure 3a). Although these materials do not exist naturally, it is reported that each material is biocompatible. In addition to silk, other materials such as natural collagen, [38,39] gelatin, [40,41] shellac, [42] chitin [26,43] , protein, [44] and seminatural/semisynthetic materials [45] derived from natural materials can be used as biodegradable substrates. [46] Due to its lightweight property, seminatural property, inexpensive structure, environmental friendliness, and Figure 2. a) Illustration of the flexible medical sensor that can allow the rehabilitation protocol after a tendon repair to be personalized for each patient. b) Results of immunohistochemistry from 1 to 8 weeks. Scale bars: 100 μm. a-b) Reproduced with permission. [23] Copyright 2018, Nature Publishing Group. c) Illustration displaying the hierarchical structures and the fabrication of CSF strain sensors. c) Reproduced with permission. [22] Copyright 2016, Wiley-VCH.
www.advancedsciencenews.com www.advintellsyst.com flexibility, paper has become an attractive solution for the fabrication of flexible and wearable sensors. [47,48] A high-performance wearable electronic device based on cellulose nanofibers was demonstrated by Jung et al. [27] They successfully fabricated key electronic components on flexible cellulose nanofiber paper, whose properties are comparable with those of rigid cellulose paper, and they clearly demonstrated the fungal biodegradation of the cellulose nanofiber-based electronic components. As a result, the fabrication of biodegradable flexible electronic devices with environmental-friendly materials is feasible. In addition, Chen's group [49] used fine rice paper that consisted of tortuous bamboo-derived cellulose fibers with diameters of 5-40 μm to produce mesoporous membranes with thicknesses of approximately 110 μm. Compared with commercial polypropylene/polyethylene/polypropylene separator membranes, rice paper membranes exhibit low resistance at the same thickness due to less cost, good . a-c) Reproduced with permission. [37] Copyright 2019, Nature Publishing Group. d) Optical image and e) schematic diagram of a transient electronics with silk substrate. f ) Optical image of degradation process of the devices in deionized water. d-f ) Reproduced with permission. [12] Copyright 2012, Science.
www.advancedsciencenews.com www.advintellsyst.com flexibility, and a porous structure. As a result, rice paper membranes will offer attractive building blocks for applications in green electronics.

Self-Healing Flexible Sensors
At present, wearable medical devices are often limited by robustness because their components are easily scratched and damaged, which may damage their functions and reduce their sensing performance. These events may also severely limit their lifetime and affect their electronic properties. Ideal biomultifunctional wearable and intelligent sensors not only retain their electronic functions, but also repair themselves by maintaining their electrical and mechanical properties after mild micromechanical damage. [50] Wearable electronic skin devices need to self-repair automatically without external stimulation (e.g., heat) to restore the original mechanical and electrical connections. [13,[51][52][53] These properties can extend the life of the equipment and reduce maintenance costs. Some self-healing flexible sensors based on conductors and polymers have been investigated. Despite the rapid development of self-healing materials, only a few self-healing polymers have been used in the field of flexible electronics. Composite materials filled with healing agent-loaded capsules or conductive particles are commonly used to achieve self-healing ability. For example, Wang and coworkers make electronic devices via incorporating ionic liquids into selfhealing polymer channels. [54] Bandodkar et al. reported the introduction of a conductive ink, which contained 45% carbon and 5% capsules in an acrylic varnish binder, into a self-heating device. [55] For self-healing medical devices, Bao and coworkers reported an intrinsically self-healing conductive composite. [56] They presented a rubber-like bulk conductive composite based on inorganic micronickel (μNi) particles and organic supramolecular polymers, in which self-repair is driven via the recombination of hydrogen bonds between cut surfaces ( Figure 4a). In addition, when the material undergoes mechanical damage, 90% conductivity can be restored within 15 s, indicating that the material has inherent self-healing abilities ( Figure 4b).
The unique nanostructure of μNi particles contributes to the self-healing properties of the composites, and similar composites made of smooth μNi particles have low conductivity (10 to 6 s cm À1 ). Moreover, by keeping the volume loading of μNi particles below the osmotic threshold (15% volume loading), the composite exhibits good pressure-sensing performance. The bending and/or compressive stresses produced by tactile stimulation bring μNi particles closer to each other and produce an inductive response. In addition, the piezoresistive effect is restored by the bending force and tactile force exerted by reverse direction sensing. The good self-healing ability obtained by a simple contact fracture interface may prolong the service life of tactile sensors and expand the application range of the existing tactile-sensing systems ( Figure 4c). However, more work needs to be done to improve the stability and sensitivity of these materials. Dynamic polymer materials are another kind of self-healing materials based on reversible bonds and dynamic interactions. Recently, Tee and his team reported on a bio-inspired skin-like material that is transparent, conductive, and self-healing in dry and humid environments. [15] Amorphous polymers are combined with chemically compatible ions to form gelatinous, aqueous, stretchable, and self-healing electronic skin ( Figure 4d). As the emitter content increases from 10 to 30 wt%, the material exhibits a higher strain failure point, a lower Young's modulus, and a lower maximum tensile stress. As shown in Figure 4e, the material then heals under normal environmental conditions without adding foreign solvents or materials. After 24 h at room temperature, the material recovery rate is approximately 43.9%, and after 24 h of curing at 50 C, the material recovery rate is 99.1%. Interestingly, this material can heal even in various water environments, such as in deionized aqueous, seawater or extremely acidic and alkaline solutions. More importantly, the high optical transparency of these materials indicates that they can be used in autonomous underwater explorations and in emerging optoelectronic man-machine and communication interfaces (Figure 4f).

Promising Applications of Smart Wearable Sensors in Health Monitoring
Wearable sensors are very flexible. They can be placed not only at any position on or inside the human body, such as the human head, throat, chest, arm, wrist, finger, and organ, but also on any object, such as clothes, shoes, watches, glass, masks, and gloves. [57] In the last few years, flexible and wearable sensors have displayed great prospects in all fields due to their flexibility and versatility. In this section, we will focus on the applications of bio-multifunctional smart wearable sensors in biophysical monitoring, biochemical tracking, and real-time environmental information detection.

Biophysical Monitoring
The monitoring of biophysical signals has attracted widespread attention. [58,59] As an important branch of health monitoring, monitoring the heart rate/pulse, [60,61] human motion, [62,63] and temperature [64] is essential for health assessments. [65] Different types of physiological information can be quantified from body movements or body fluids. High-sensitivity wearable sensors have been used to continuously record pulse and heart rate to collect basic health information. [66,67] The following subsections will critically assess the main progress in measuring these signals, which are roughly divided into pulse and heart rate, exercise, and temperature regulation.

Heart Rate and Pulse Monitoring
In clinical practice, arterial pulse is an important index of arterial blood pressure, heart rate, and old or stiff blood vessels. [68] It also provides useful information on possible cardiovascular diseases, which are diagnosed by noninvasive medicine and are one of the most serious causes of death in humans. [69] Wearable pressure sensors, including radial artery pressure sensors for cardiovascular diagnosis, accurately monitor cardiovascular pulse pressure waveforms. [70] For instance, using carbon nanotube (CNT)polydimethylsiloxane (PDMS) composite materials, Lee and coworkers demonstrated a flexible, biocompatible electrode, which showed excellent long-term stability in wearable electrocardiogram (ECG) monitoring after being connected with traditional ECG equipment. [71] Cho and his team produced a bionic layered graphene/PDMS array for medical and health applications. [72] They demonstrated a highly sensitive piezoresistive pressure sensor, which responds linearly to applied pressure and uses a new layered structure capable of accurately monitoring wrist pulses. To date, various materials have been used to fabricate bendable/connectable devices for detecting wrist pulses, including metal-organic frameworks, polyvinylidene fluoride (PVDF) films, semiconducting polymers, CNT/PDMS composites, and ZnO-based flexible fibers.
To avoid the waste associated with wearable and point-of-care diagnostics, Bao and coworkers reported the application of a disposable and biodegradable pressure sensor patch in cardiovascular monitoring. [36] As shown in Figure 5a, they fixed the biodegradable pressure sensor on the human wrist above the radial artery, which is typical of an arterial sphygmomanometer. Real-time testing of several pulse cycles and an enlarged view of pulses with b) The resistance response of the self-healing composite during self-healing process within 15 s. The inset is microscope image of the self-healing composite under break state and healed state. c) Demonstration of the healing process for a conductive composite with an LED in series with a self-healing electrical conductor. a-c) Reproduced with permission. [56] Copyright 2012, Nature Publishing Group. d) Schematic illustration of principal component of the self-healing conductive polymer. e) Functionality of a gel-like, aquatic, stretchable, and self-healing electronic skin (GLASSES) dipped in water for 3 h. f ) Transmittance spectrum of 30 wt% 1-ethyl-3-methylimidazolium bis(trifuoromethylsulfonyl)imide (EMITFSI) film. d-f) Reproduced with permission. [15] Copyright 2019, Nature Publishing Group.
www.advancedsciencenews.com www.advintellsyst.com characteristic peaks, usually measured at the radial artery, were shown. Additionally, pulse wave velocity measurement using the same recording settings as those described earlier is successful. The pressure sensor is first connected above the adult carotid artery, and it recorded the arterial pulse wave, as displayed in Figure 5b. ECG was recorded as a time reference. Then the pressure sensor was attached to the femoral artery, and the pulse wave and ECG were recorded again. In addition, in vitro biodegradation tests were carried out to further study the adsorption characteristics of the equipment (Figure 5c,d). The results showed that the elastomer still had small hysteresis and viscoelastic behavior after 7 weeks of incubation in the phosphate-buffered saline (PBS) solution and that there was no obvious change. The authors envisage that their work will contribute to the biomedical application of completely biodegradable sensors in vivo.
Recently, human pulse and heart rate monitoring systems based on other biological functional materials (such as collagen and silk) have also been studied. [74,75] Bio-multifunctional flexible/wearable systems based on natural silk and electronic skin based on fish skin composed of collagen nanofibers are other significant developments in personalized medical monitoring systems. [73] Mandall and coworkers developed a wearable sensor for sustainable energy production based on fish skin (Figure 5e,f). [73] The sensor interacts with various parts of the human body and monitors physiological signals in real time, as illustrated in Figure 5g-i. Figure 5h displays that the wearable pressure sensor is connected to the upper radial artery of the human wrist because this artery is usually used for arterial sphygmomanometers and blood pressure meters. The characteristic pulse pressure shape (PPS) is formed by the superposition of the left ventricular systolic and lower limb reflex blood flow. The synchronous monitoring of wrist impulse pressure provides a new approach for wearable electronics with low power consumption. In addition, as shown in Figure 5i, the pressure sensor Optical image of flexible pressure sensors c) before in vitro degradation and d) after 7 weeks of incubation. a-d) Reproduced with permission. [37] Copyright 2015, Wiley-VCH. e) Schematic diagram of the preparation step for raw fish skin (FSK)-based device. f ) Optical image of the FSK-based device exhibiting the flexibility. g) Pressure response of the FSK-based device to natural butterfly with the weight of %58 mg. Current response of the FSK-based device to (h) radial artery and (i) carotid artery pulses. e-i) Reproduced with permission. [73] Copyright 2017, American Chemical Society.
www.advancedsciencenews.com www.advintellsyst.com also tests the real-time arterial pulse wave at the site where it is attached to the carotid artery of the neck. Because photoelectric devices can monitor human physiological characteristics in real time and provide corresponding clinical information, they are widely used in medical diagnosis and treatment. [76][77][78][79][80][81][82][83][84] Recently, many researchers have used photodetectors to achieve photoelectronic skin, showing super-flexible and integrated tricolor, high-efficiency polymer light-emitting diodes (PLEDs), and organic light detectors (OPDs), introducing a variety of electronic functions for the human skin surface. [76] Someya and coworkers recently reported on a new ultra-flexible reflective pulse sensor. The device combines red OPD with green light-emitting diode (LED) to detect oxygen concentration in blood on human fingers. In addition, sevensegment color and digital displays can display data directly on the human skin. For another report, LEDs and photovoltaics form flexible light sensors on thin films. The sensor can be closely attached to the human skin surface and has broad application prospects. [85,86]

Human Motion Monitoring
Tracking physical activity and habitual movements provide useful information to ensure good health and correct posture. Periodic analyses of body movements can detect abnormal gait patterns and sudden tremors in the hands, which are the precursors of fatal diseases such as Parkinson's disease, Alzheimer's disease, and diabetes, and contribute to the early diagnosis and treatment of such diseases [18] . The development of motion detection mechanical sensors also opens up potential applications in human-machine interfaces, rehabilitation, prosthesis, and sports training. In recent years, bio-multifunctional wearable sensors have been widely used for motion detection in our daily lives, including assisted living, rehabilitation, and monitoring. [87] Motion monitoring can be roughly divided into two categories: monitoring large-scale movements, such as finger, hand, and knee bending, and monitoring small-scale movements, such as subtle throat and chest movements during swallowing and breathing. [58,88,89] To date, efforts have been made to exploit multifunctional wearable sensors for tracking human motion through real-time continuous signals. [89] Recently, consumer devices such as Fitbit One and Fitbit Flex have been tested and checked to monitor patient steps, energy consumption, and activity levels. The results of reliability and validity tests show that wearable activity monitoring has broad prospects in many clinical environments, such as the postoperative recovery of heart disease patients, lung rehabilitation, activity counseling of diabetic patients, and assessment of patients undergoing chemotherapy. Wang et al. demonstrated the fabrication of a biocompatible flexible pressure sensor based on the incorporation of sunflower pollen microcapsules into bionic structures (Figure 6a,b). [46] This design represents a new biotechnology for the design of flexible motion sensors (Figure 6c). Complex deglutition behavior can be reliably and repeatedly identified through versatile biological wearable devices (when connected to a person's throat). During the swallowing process, the relative changes in the current are divided into two steps that correspond to the movement of the laryngeal muscles. Figure 6d,e shows the simultaneous detection of pressure and strain when the biocompatible, flexible pressure sensor is connected to a finger for continuous finger movement monitoring. According to the finger motion angles corresponding to motion I, motion II, and motion III, the relative current gradually increases. To demonstrate the characteristics important for electronic skin and wearable sensor applications, fast-tension release motion was detected and measured, displaying a fast response in four repetitive cycles. Looking ahead, this study opens up a new direction for incorporating stimuli-responsive microcapsules into the designs of wearable sensors and emphasizes the potential of using natural materials to enhance the function and performance of flexible sensors.
Similarly, Zhang and coworkers prepared smart multiwalled CNT/thermoplastic elastomer (MWCNT/TPE)-based flexible sensors with high tensile, bending, and torsional-sensing capabilities (Figure 6f). [21] As shown in Figure 6g, smart gloves can be easily obtained by applying multifunctional MWCNT/TPE films to monitor finger movements. Figure 6h shows real-time bending motion detection of an index finger of a person wearing smart gloves. With the slow and repeated bending and relaxation of the index finger, the normalized relative resistance increases and decreases gradually and periodically, achieving real-time detection of the movement of the index finger (the small difference between each cycle is caused by the small difference between each bending motion). In addition, there is no obvious change in the sensing performance of the MWCNT/TPE-based flexible sensor under intermittent droplets, because the droplets almost immediately roll down from the superhydrophobic surface, which indicates that the device can work in wet or rainy environments.

Temperature Monitoring
Body temperature provides insight into a person's physical state. [88] Although body temperature may vary slightly with environmental temperature or physical activity, irregular and abnormal changes in body temperature are indicators of some diseases that can be accompanied by acute fever and hypothermia. [91] Because heat transfer between the environment and biological organs may cause spatial and temporal changes, it is necessary to monitor body temperature in real time with high sensitivity and accuracy. [92,93] Moreover, changes in a human body's normal temperature are very small, and health-monitoring temperature sensors require not only high resolution, high precision, high sensitivity, and wide detection range, but also biocompatibility and mechanical flexibility. [94,95] At present, wearable temperature sensors also use a variety of nanomaterials, including conductive polymers, [96,97] graphene, [89,98] CNTs, [46,99] nickel, [100] silver, [101,102] and copper metal nanoparticles and nanowires [103] as thermal-sensing elements.
Recently, Rogers and coworkers suggested using a wearable temperature sensor to monitor blood perfusion and generate local heat in tissues for medical care and medical applications. [104] Salvatore et al. prepared highly deformable temperature sensors on Eco-Flex thin films using SiO 2 , Si 3 N 4, and Mg as biodegradable materials. [105] An ultra-thin temperature sensor can endure multiaxis deformation and maintain a dynamic www.advancedsciencenews.com www.advintellsyst.com response (10 ms), 41 mK resolution, high thermal sensitivity, and a stable sensing performance. For bio-multifunctional wearable temperature sensors, Zhang and coworkers reported a biocompatible flexible pressuretemperature sensors based on a sensing layer comprising silk nanofiber-derived carbon fiber films. [106] Figure 7a displays a schematic diagram of the preparation steps of the silk nanofiberderived carbon fiber flexible pressure-temperature sensor. The device can detect temperature changes by using the temperature dependence of the film resistance caused by thermal resistance effects (Figure 7b). The flexible pressure temperature sensor can detect not only sensations encountered by the human body in daily life, such as finger pressing and breathing frequency, but also the spatial distribution of external stimuli. This work shows great application potentials in human-machine interfaces and temperature detection. In addition, due to low cost and good biocompatibility of natural silk materials, flexible pressure and temperature sensors made of silk-driven carbon fibers possess  [46] Copyright 2017, Elsevier. f ) Optical image of flexibility and water repellency of as-prepared-coated cloth. g) Sensitivity of flexible sensors under dry and dropping water state. h) Dynamic response curve of device on the cloth for different human motion. f-h) Reproduced with permission. [90] Copyright 2017, Wiley-VCH.
www.advancedsciencenews.com www.advintellsyst.com obvious advantages and improvements over other temperature sensors. Wearable temperature sensors attached to the skin for medical care must be biocompatible and able to adapt to specific skin environments in terms of breathing and sweating.
Recently, Feng and coworkers reported a strategy of developing a biocompatible temperature sensor inspired by skin with a porous semipermeable membrane that has good permeability and is highly waterproof as the base (Figure 7c). [107] As shown in Figure 7d,e, the authors connect these temperature sensors to the armpit and forearm to test the temperature of the armpit and the body surface, respectively. Volunteers used the sensor for 24 h and took two showers. In vitro tests showed no signs of irritation. Moreover, falling water and blowing tests show that the device can cope with the tiny temperature changes triggered by the ambient environment, indicating that the device may be applied to the construction of an intelligent artificial skin system. Huang and coworkers also developed a biocompatible flexible temperature sensor using a 3D polylactic-co-glycolic acid and polylactide (PLA) composite as the dielectric and substrate layers. [108] These bio-multifunctional devices have comprehensive advantages such as biocompatibility, degradability, temperature sensitivity, transparency, and flexibility. They also have wide application prospects such as environmental protection, electronics, implantable medical devices, and artificial skin.

Biochemical Tracking
Wearable electrochemical sensors have been widely used in medical, fitness, safety, sports, and forensic monitoring fields. [109] Skin-mounted sensors can continuously monitor biochemical substances in body fluids (e.g., glucose/lactate, biomolecules, and pH) and alert users of fatigue, dehydration, and early disease symptoms. This application requires devices to maintain their biocompatibility, comfort, flexibility, and conformability when they are in contact with the human body. [109,110] In addition, wearable electrochemical sensors must also overcome the challenges associated with all analytical devices' reliability, accuracy, calibration, and lifetime. Combining the advantages of wearable and electrochemical technology opens the door for a large number of applications.

Blood Glucose Recording
According to World Health Organization statistics, 9% of adults worldwide currently suffer from diabetes. [2,111] Glucose monitoring is an important technique for assessing the health conditions of people with diabetes and must be performed frequently every day. Thus, glucose monitoring may require devices that are naturally conformable, biocompatible, flexible, stretchable, and nontoxic to adhere to the skin surface to minimize user awareness, while providing accurate data for the real-time detection of glucose oxidase (e.g., glucose values for a healthy person and a person with diabetes are 70-100 and 80-130 mg dL À1 , respectively). [4] In particular, biocompatible and biodegradable wearable glucose sensors have been widely used in human health monitoring and biomedical diagnostics because of their excellent biological functions. In addition, compared with traditional glucose sensors, bio-multifunctional wearable glucose sensors can improve the safety of devices and reduce electronic waste. www.advancedsciencenews.com www.advintellsyst.com For example, Pak and coworkers reported a glucose oxidase/ silk/graphene (GOx-silk/graphene) composite-based flexible field-effect transistor (FET) glucose sensor (Figure 8a). [112] This work mainly uses natural silk as a flexible, transparent substrate and enzyme immobilization matrix to detect glucose (Figure 8b). The flexible FET glucose sensor is mainly composed of a graphene/silk substrate, a silk/GOx sensitive layer, gold/titanium (Au/Ti) source/drain contacts at both ends, and a top-gate electrode (Figure 8c). The optical image in Figure 8d shows that the prepared GOx-silk/graphene FET glucose sensor is flexible and can be closely attached to the skin surface. Because GOx can react with glucose, the conductivity of the flexible FET glucose sensor channel increases with increasing glucose concentration. At the same time, the Dirac point of graphene has also been transferred, showing a p-doping effect (Figure 8e). The drain/source current of the flexible FET glucose sensor exhibited a high sensitivity of 2.5 μA mM À1 to 0.1À10 mM glucose at V ds ¼ 100 mV and V g ¼ 0 V (Figure 8f ). This work also implies that this biocompatible, flexible, and reliable silk-based FET glucose sensor has broad application prospects in implantable, portable, and wearable electronic devices in future.
It has been reported that glucose in sweat is also directly related to blood sugar metabolism. [114] Therefore, effective monitoring and collection of glucose in sweat or tears can also be used as an indicator for the diagnosis and treatment of diabetes. [115][116][117] Recently, Gao and coworkers developed a fully flexible biosensor array based on biocompatible chitosan/CNT-sensing materials capable of detecting glucose and lactate in sweat for multichannel in situ sweat analysis (Figure 8g). [113] In addition, these biocompatible flexible sensors can detect skin temperature and sodium and potassium ions. The biosensor uses mechanically flexible PET as the substrate, which can make the device conform well to the skin surface. Figure 8h shows a structural diagram of the multichannel sensor array for sweat detection. Glucose oxidase immobilization on chitosan-based sensitive membranes can cause current changes, thus realizing the detection of glucose. Figure 8i presents the dynamic sensing response curve of the biosensor to 0-200 μM glucose solutions, and the glucose sensitivity of this biosensor is 2.35 nA μM À1 (inset of Figure 8i). Because of the good biocompatibility and flexibility of chitosan devices, this wearable biosensor can be comfortably attached to all positions of the human body for a long time, such as the arms, wrists, and forehead. Figure 8j shows the wearable biosensor attached to the human wrist and forehead for real-time monitoring and analysis of human sweat during continuous exercise. Obviously, the concentration of glucose decreases gradually with continued perspiration during exercise, which may be due to the glucose dilution effect of glucose caused by the increase in sweat rate. The accuracy of the in situ wearable sensor is verified by comparing the sweat sample analysis data with the sweat sample analysis data collected by the body forehead sensor. (Figure 8k). Thus, the development of biomultifunctional smart wearable sensors is highly anticipated.

Biomolecule Recording
Biochemical sensors, unlike most flexible sensors intended to obtain vital signs, provide a more convenient platform for noninvasive personal health monitoring at the molecular level. [118] In recent years, many flexible biochemical sensors have been applied to real-time and in situ monitoring of human cancer molecules and protein markers. For instance, a biocompatible silk/graphene-based saliva sensor was reported by McAlpine and coworkers (Figure 9a). [119] The flexible saliva sensor not only recognizes Helicobacter pylori cells in human saliva but also exhibits a low limit of detection (LOD) of approximately 100 cells when this device is transferred to the surface of the tooth enamel (Figure 9b). Although the flexible saliva sensor exhibits high sensitivity to H. pylori cells, it is often affected by dietary habits, which limits its ability to accurately monitor health. Therefore, the design of a new flexible saliva sensor with high performance and resistance to environmental interference is very important.
In addition to the monitoring of protein molecules, the serum samples of patients contain abundant target molecules, so the detection of cancer biomolecules by flexible biochemical sensors provides an effective means of health and safety screening. Recently, Wang et al. demonstrated a biocompatible, flexible biosensor based on natural sunflower pollen surrounded by a graphene conducting layer (Figure 9c). [120] This biosensor not only provides a completely nontoxic and biocompatible sensing platform, but also permits intimate integration on the curvilinear surfaces of objects. Through the self-assembly of antibodies on the surface of biomaterials, we reported bio-selective detection of vital biomarker proteins for prostate cancer at ultra-low concentration levels in real time. Specific chemical treatment and antibody immobilization on rGO@SFP-based flexible biosensors facilitated pathogenic prostrate-specific antigen (PSA) cancer marker detection in real time with ultra-high sensitivity, a fast response time (4 s), LOD (1.7 fM), excellent reproducibility, and good bio-selectivity (Figure 9d). This combination of flexible biosensor features and nontoxic biomaterials holds considerable promise for creating an attractive class of biosensors with highly flexible contacts, good detection performance, and high biocompatibility that satisfy the requirements of diverse health care and point-of-care applications.
In addition to material biocompatibility, device design toward biodegradation is a challenging yet mandatory goal, particularly for implantable diagnostic applications. For flexible sensors used in clinical applications, their characteristics must be determined according to their biocompatibility, which should include biosafety (no cytotoxicity, mutagenesis, or carcinogenesis) and biofunctionality (biocompatibility, biodegradability, and self-healing). [122] Unfortunately, implanted biosensors often lose their function over time, mainly due to foreign body reactions caused by biofouling around biosensors. Thus, the development of biodegradable implantable biosensors to detect cancer molecules is necessary. Yadavalli and coworkers develop a biodegradable, flexible biosensor for the detection of vascular endothelial growth factors (VEGFs) (Figure 9e). [121] This flexible device was fabricated via a conducting ink with a photolithographic pattern consisting of a conductive polymer coupled with photoreactive silk sericin. This design enables the sensor to suitably match with human soft tissue to ensure the accuracy of data for the in situ detection of protein markers (Figure 9f,g). As a result, the device is highly sensitive to and selective for the target protein, even in human serum (Figure 9h). In addition, this flexible device exhibits biocompatibility and biodegradability, which can effectively reduce damage to human organs. This work demonstrates the clinical medicine www.advancedsciencenews.com www.advintellsyst.com Reproduced with permission. [113] Copyright 2016, Nature Publishing Group.
www.advancedsciencenews.com www.advintellsyst.com applications of biodegradation and biocompatible biosensors that are capable of monitoring cancer or target molecules in patient serum samples.

pH Recording
As another important property of bio-fluids, the solution pH value is also closely related to human health. Specifically, rapid, real-time, and accurate monitoring of the solution's pH value can effectively ensure early diagnosis of related diseases. [123] At present, the research emphasis regarding flexible pH sensors is on developing high-performance and sensitive sensing systems and effective sweat sampling methods. Various wearable pH sensors have been reported, such as flexible FETs or sensors. [124,125] A recent impressive biodegradable pH sensor was reported by Rogers and coworkers (Figure 10a-c). [126] By incorporating single-crystalline silicon nanomembranes into a biodegradable elastomer (poly(1,8-octanediol-co-citrate), POC), they obtained a biodegradable flexible pH sensor that exhibited high strain capacity (strain up to 30%) and high sensitivity (0.3 AE 0.02 and 0.1 AE 0.01 μS pH À1 for borondoped Si nanoribbons (NRs) and phosphorus, respectively) (Figure 10d,e). In addition, the pH sensor exhibited excellent biodegradation, and all components completely disappeared after several weeks (Figure 10f). In addition, the ability to simultaneously monitor physical and chemical characteristics is very important to obtain effective, high-value, and complementary reference data for the diagnosis and prediction of human health. For example, dehydration caused by exercise can be effectively predicted by monitoring the pH value concurrently in skin temperature and sweat. Some studies on detecting physical and chemical characteristics have been reported. For example, Takei and coworkers recently reported a new flexible pH chemical sensor, consisting mainly of temperature sensors and ion-sensitive field-effect transistors (ISFETs), that can detect pH and human body temperature in real time (Figure 11a-d). [127] The advantage of combining a temperature sensor with a flexible ISFET-based pH chemical sensor is that the resulting sensor is able to compensate for the temperature effect on the flexible ISFET-based pH chemical sensor www.advancedsciencenews.com www.advintellsyst.com ( Figure 11b). The ISFET is composed of a pH-sensing membrane, Al 2 O 3 , and InGaZnO ( Figure 11c). As a result, the newly designed flexible sensor can detect temperature and pH simultaneously. The sensor can also compensate for the potential displacement caused by temperature and pH, thus achieving accurate pH measurement in a wide temperature range. Figure 11e shows that the current (IDS) increases when the sensor temperature changes from 24.2 to 47.2 C, which may be because the InGaZnO transistors are more sensitive to temperature changes than to pH changes. By comparing the results of temperature compensation experiments, we can find that after the compensation test, the pH value (pH ¼ 7.2) of the solution remains stable as the temperature increases (from 29 to 44 C), whereas without the compensation test, the measured pH value of the same solution still decreases as the temperature increases (Figure 11f). Therefore, we can see that by compensating for a temperature of 43.4 C in ISFET-based sensors, the detection error of the pH value decreases from %7.64% to %0.97%. In addition, the device exhibits excellent mechanical flexibility (Figure 11g).

Real-Time Detection of Environmental Information
Wearable environmental sensors, which mainly monitor environmental parameters, such as various environmental gases, [128][129][130][131][132][133][134] breathing gases, [32,135,136] and humidity, [137][138][139] have received extensive attention. This information can not only protect people from adverse environments, enhancing awareness of the impact of the environment on health care, but also the interaction between people and the environment, improving humancomputer interactions. Although traditional sensors allow rapid www.advancedsciencenews.com www.advintellsyst.com field analysis, [140][141][142] in most cases, their structure, size, weight, and biofunctional factors hinder their direct integration with the human body and limit their application in certain fields. In this context, improving a biosensor's biofunctions and flexibility to improve its ability to adapt to the skin or human tissue can make real-time and accurate detection of environmental hazards possible. The following subsections mainly review the development of wearable environmental-sensing platforms designed for collecting signals from the environment.

Gas Detection
Flexible gas sensors have been widely used to detect ambient gases in our daily lives. [128,143,144] These devices are the basis of realizing unmanned control and automatic detection for advanced electronic technology. For example, a wire-based printable flexible gas sensor with a polycrystalline Zn 2 GeO 4 (pZGO) sensing layer can effectively detect 20 ppm of NH 3 gas molecules compared with single-crystalline Zn 2 GeO 4 (sZGO) (Figure 12a,b and Figure 12d). [128] In this regard, integrating grain boundaries into polycrystalline materials has been displayed to result in rich new mechanical properties, catalytic activities, and electronic structures for flexible sensors (Figure 12a,b). The adsorption of gas molecules at a grain boundary dramatically changes the resistivity of pZGO (Figure 12c). Moreover, after two cycles of mechanical bending (60 ), the pZGO-based flexible device still exhibits high sensitivity for 200 ppm ammonia molecules, a fast recovery time, and good mechanical properties (Figure 12e). In fact, most flexible gas sensors are used in special environments, such as settings where they are often moved, shocked, ISFET-based device with (blue) and without (red) temperature compensation. g) Optical image of flexible ISFET-based device attached on the curved tube. a-g) Reproduced with permission. [127] Copyright 2015, American Chemical Society.
www.advancedsciencenews.com www.advintellsyst.com or touched. As a result, they are very fragile, so accidental scratching and dropping can cause sensor failures. If biomultifunctional (biocompatible or self-repairing) sensors are used, we can effectively prolong the lifetime of such devices, especially in both their sensing performance and their functional aspects. Chen and coworkers reported the introduction of functional CNTs on a flexible and healable substrate to fabricate a novel transparent room-temperature gas sensor (Figure 12f,g). [145] The special feature of this device is that it has self-healing properties. If the device is cut off, the device can heal automatically after 30 min in the presence of water. This healing is mainly due to the high interdiffusion and fluidity of the polyelectrolyte multilayer (PEM) film. The transparent, healable, and flexible sensing device exhibited high selectivity for ammonia (NH 3 ) gas molecules over other gas molecules (water, ethanol, acetone, dichloromethane, and toluene) (Figure 12h). In addition, mechanical stability ( Figure 12i) and repeated healability (Figure 12j) of the flexible sensing device, which can detect down to 25 ppm ammonia gas molecules, were studied. Overall, the flexible device exhibits good mechanical stability and self-healing. In addition to the detection of environmental gases, monitoring gases in exhaled breath, specifically volatile organic compounds (VOCs), is of growing scientific and clinical interest. Wang et al. demonstrated a biocompatible flexible butterfly wing-based gas sensor that could record current changes in real time under bending and exposure due to their high sensing response to acetone gas in exhaled breath (Figure 13a,b). [32] (60 ). a-e) Reproduced with permission. [128] Copyright 2019, Wiley-VCH. f ) Schematic diagram of the fabrication processes of the CNT-based healable flexible gas sensor. g) Optical image of flexible gas sensor. h) Dynamic response of flexible gas sensor to 5-100 ppm NH 3 gas. i) Sensitivity of flexible gas sensor to 25 ppm NH 3 under different bending cycles (0-500 cycles). j) Sensitivity of flexible gas sensor to 25 ppm NH 3 after healing for different times. f-j) Reproduced with permission. [145] Copyright 2015, Wiley-VCH.
www.advancedsciencenews.com www.advintellsyst.com This sensor enables the detection of acetone gas in breath for the early diagnosis of diabetes. Sensing analysis shows a histogram response to exhaled breath exposure (Figure 13c). Butterfly wing/ graphene composite films exhibit the highest sensitivity for acetone gas molecules over water and other gas molecules. In addition, no significant decrease in the sensor sensitivity was observed when the device was suddenly bent (Figure 13d). As a result, the sensor demonstrates ultrahigh sensitivity and selectivity and features real-time monitoring capabilities, making it a highly desirable platform for portable and wearable sensor applications ( Figure 13e).

Humidity Detection
Humidity is one of the common contact parameters used to monitor tactile behavior in an artificial medical-sensing system. [146] Relative humidity (RH), the basic physical quantity of humidity, refers to the ratio of water vapor's partial pressure to saturated vapor pressure at a certain temperature and is used in daily life. Currently, the reports on humidity sensors are mainly focused on capacitive and resistive sensors. [147][148][149] For example, the existence of ionic conductivity and proton transfer on the surface functional groups of graphene oxide is affected by humidity, as the capacitance increases with increasing humidity. Borini and coworkers demonstrated a wearable breath humidity sensor with a thin graphene oxide-sensing film and measured the performance of the sensor using a controllable humidity generator (Figure 14a). [150] Significantly, sensors can distinguish different human behavior patterns (such as different whistles, breathing frequencies, and different languages) by responding to different humidities, which may be of great significance for identifying different users by breath monitoring (Figure 14b,c). In addition, Kulkarni and coworkers also used humidity as an index of expiration. Resistance changes of graphene oxide were measured, and respiratory activity was monitored in real time. [151] To achieve sustainable development, electronic biomaterials with good biological properties have attracted extensive attention from researchers. To date, a large number of bio-based humidity sensors have been reported. Rolandi and coworkers reported the first demonstration of a proton FET with protontransparent PdHx contacts (Figure 14d). [152] As shown in Figure 14e, when a bias voltage is introduced between contacts, the current increases with an increase in RH (and the hydration level of the polysaccharides).
In addition, the same trend is also observed in the hysteresis curve, which is mainly due to the increase in charge accumulation/ loss at the contact point. Zhang and coworkers reported a bright color humidity-sensitive submicron film prepared by using a natural silk fibroin solution. [153] The silk fibroin-based device shows a rapid response and obvious color change within 5 s due to the excellent hydrophilicity of silk fibroin. With a peak redshift of more than 130 nm, the film is better than many other multilayer or photonic crystal humidity sensors. A strategy of manufacturing humidity sensors by host-guest interactioncoupled polymer networks and conductive single-walled carbon nanotubes (SWCNTs) has also been demonstrated. [154] The polymer-based humidity sensor has high humidity sensitivity due to the large resistance variation of the polymer in a humid environment. Specifically, the resistance of the sample in dry air (10% RH) is %8.62 kW, which is two and six times higher than that in 30% RH and 60% RH, respectively. In addition, the www.advancedsciencenews.com www.advintellsyst.com obtained materials have the advantages of humidity sensitivity, volume conductivity, and rapid self-healing without external stimulation.

Challenges and Future Outlook
Considering that most laboratory-on-a-chip testing tools, healthcare monitoring devices, and wearable electronics can be expected to come into contact with the human skin, organ, and tissue interfaces, the biofunctionality of flexible sensors is very important for improving man-machine interactions and enhancing the safety, reliability, and stability of tests. In this review paper, we detailed and discussed smart wearable sensors, focusing on biofunctionality, such as biocompatibility, biodegradable, and self-healing. In particular, different wearable sensors for vital sign monitoring (biophysical, biochemical, and environmental signals) were discussed, whereas the advantages of bio-multifunctional sensors for use in wearable medical devices are presented. These applications are in fields where there is a demand for biocompatibility, safety, accuracy, mechanical flexibility, high sensitivity, reproducibility, and stability. As the range of functionalities of flexible and wearable sensors is continuously growing, the identification of novel wearable sensors that can fulfill the demands of medical applications is highly desired.
Although multifunctional wearable sensors have made tremendous progress, they still respond to multiple stimuli at the same time, which makes the device very sure of the intensity and type of each stimulus. Therefore, the study of wearable sensors with low cross sensitivity and high recognition is a direction of the future development of flexible electronics. Another challenge is fabricating smart multifunctional sensors by developing new material to provide a robust sensing platform, such as the development of wearable devices with biofunctionality to copy the characteristics of the human skin and make smart devices work in harsh environments. We hope that this work will convince readers that with the further development of smart  [150] Copyright 2013, American Chemical Society. d) Schematic of the biocompatible maleic-chitosan nanofiber-based FET humidity sensor and atomic force microscope (AFM) image of the biocompatible maleic-chitosan nanofiber. e) The biocompatible maleic-chitosan nanofiber-based FET humidity sensor under different humidities (50-75% RH). d-e) Reproduced with permission. [152] Copyright 2011, Nature Publishing Group.
www.advancedsciencenews.com www.advintellsyst.com wearable sensors coupled with bio-functionalities, the promise of bioelectronic devices and their applications in medical diagnosis and treatment is limitless.