Epidermal Bioelectronics for Management of Chronic Diseases: Materials, Devices and Systems

Chronic diseases are currently posing a major challenge not only to our life expectancy and healthspan but also to the healthcare system, as patients will need continual monitoring, treatment, and care to mitigate some of the severe health complications that may arise. Merely frequent visits to medical facilities and clinics may not be sufficient. Home‐based point‐of‐care diagnosis and monitoring may be needed for the prevention and/or management of long‐term complications. Recent advances in materials, fabrication methods, and bioelectronics have led to some epidermal systems that can measure critical physiological parameters and provide long‐term monitoring of several chronic diseases. In this review, it is systematically outlined the progress of epidermal bioelectronics aimed at managing common chronic diseases, such as cardiovascular diseases, diabetes, and chronic wounds. Flexible and stretchable materials with related engineering approaches that render wearability are also discussed. Finally, a list of current challenges, future perspectives as well as potential research directions with the aim towards better translation in bringing these wearable technologies from the laboratory to the clinic and market are presented.


Introduction
Chronic diseases, also known as noncommunicable diseases, are complex multifactorial diseases that are prone to impair human health for a long duration. Common chronic diseases include cardiovascular diseases, diabetes with correlated chronic wounds, and other diseases such as skin diseases and joint dysfunctions. The causes of chronic diseases can be attributed to genetic defects, [1] environmental conditions, [2] behavioral factors, [3] or their combinations. While people of all ages, ethnicities, and geopolitical regions can be affected by chronic diseases, the elderly are especially vulnerable. Improper management or treatment of chronic diseases can lead to severe complications and even death. [4] In fact, according to data from World Health Organization, [5] chronic diseases contribute to 41 million deaths worldwide annually, which is equal to about 71% of all death. The treatments and medications provided by clinics and hospitals usually aim at eliminating acute symptoms and preventing aggravation of the conditions. However, due to the recurring nature and the severity of chronic diseases, infrequent visits to clinics and hospitals are not sufficient to spot underlying symptoms and early onset of chronic diseases. As such, home-based smart monitoring systems can play a critical role in disease management, which not only can offer prolonged tracking of the key physiological parameters in real-time, but also allow clinicians to provide remote and long-distance healthcare to patients without having them to frequently visit medical facilities.
At present, commercial systems for home-based chronic disease monitoring still have their limitations. For example, chronic diseases usually require monitoring more than one parameter but most commercial devices only have one function. For example, patients with diabetic foot ulcers are required to monitor both blood glucose level and wound conditions, while cardiovascular patients need to frequently check their blood pressures and electrocardiography (ECG). However, current commercial glucometers and blood pressure meters are mostly designed for selfmonitoring and recording of a single physiological parameter at discrete time points. This lack of integration forces patients to spend effort on operating several different devices. On the other hand, most of the currently available monitoring systems are rigid, bulky, and stationary, making them unlikely to offer ondemand continuous measurements. Thus, patients using these Figure 1. Introduction to the materials, sensors, and integrated systems for the monitoring and management of chronic diseases. From top to bottom and right: "Physical sensors." Reproduced with permission. [9] Copyright 2018, Wiley-VCH. "Biochemical sensors." Reproduced with permission. [10] Copyright 2020, Wiley-VCH. "Liquid material." Reproduced with permission. [11] Copyright 2018, Wiley-VCH. "Composite materials." Reproduced with permission. [12] Copyright 2016, Royal Society of Chemistry. "Conductive polymer material." Reproduced under the terms of CC-BY-NC License. [13] Copyright 2017, The Authors. "Metal trace." Reproduced with permission. [14] Copyright 2004, Wiley-VCH. "Cardiovascular disease monitoring." Reproduced under the terms of CC-BY License. [15] Copyright 2019 Wiley-VCH. "Diabetes monitoring." Reproduced with permission. [16] Copyright 2016, Springer Nature. "Chronic wound management." Reproduced under the terms of CC-BY License. [17] Copyright 2021, The Authors, published by American Association of the Advancement of Science. "Skin disease detection." Reproduced under the terms of CC-BY-NC License. [18] Copyright 2020, The authors, published by American Association of the Advancement of Science. devices need to perform multiple measurements per day at some critical time points (for example, for diabetics, blood glucose levels should be tested after meals and blood pressure should be monitored after high-intensity activities [6] ), which is tedious and inconvenient. To address these issues, breakthroughs in epidermal bioelectronics have been reported in recent years for imperceptible, skin-adaptive, multifunctional, long-term, and intelligent chronic disease monitoring. Some of these breakthroughs include advances in materials, [7] fabrication methods [8] as well as innovations in artificial intelligence (AI), signal communication, and powering techniques.
In this review, we summarize and discuss recent progress made on epidermal bioelectronic systems for chronic disease management, including the monitoring of cardiovascular diseases, diabetes, chronic wounds, and other chronic diseases. Materials that provide wearability to the systems are introduced in the first section with an emphasis on stretchability. Devices and their working principles are then discussed in the context of specific chronic diseases. For example, the ECG, oximeter, pulse sensors, and blood pressure sensors that help monitor the progress of cardiovascular diseases will be discussed first. Following that, non-invasive and minimally invasive continuous glucose monitoring platforms that utilize various biofluids are reviewed with a focus on the lifetime of the device and level of integration.
Subsequently, sensors and systems that facilitate chronic wound management are revisited. Next, some novel platforms that target other chronic diseases are exemplified to demonstrate possibilities for detecting unconventional biomarkers. We will also discuss the challenges and promising future directions faced by epidermal bioelectronics, highlighting the gaps between the research side to the real-world scenario (Figure 1).

Materials for Stretchable Conductors, Flexible Sensors, and Flexible Electronics
Unlike solid silicon-based traditional electronics, flexible epidermal electronics require special considerations for their design. For example, all the physiological and biochemical signals acquired on the skin surface demand a seamless interface with the skin to obtain better readouts. [19] Movement of the human body naturally induces strains and deformation on the devices, making them easily detached from the body. To address this challenge, soft, flexible, and/or stretchable substrates and conductors are required to form a fully flexible [20] or strain-resistant system [21] that can conformably be attached to the skin. This section illustrates the key properties (including mechanical/electrical properties and biocompatibilities) of these materials that are used in epidermal bioelectronic monitoring systems.

Flexible/Stretchable Substrate
In epidermal bioelectronics, the substrate is one of the most critical building blocks that sustain the whole device and pave the foundation for their flexibility. The materials for epidermal bioelectronics are mostly flexible or even stretchable. Upon materials selection, elasticity (Young's modulus), processibility, and biocompatibility should all be taken into account when designing systems. These will determine not only conformability but also wearability and comfortability. Several widely used polymer substrates (Table 1) are discussed below to exemplify the properties required for well-defined epidermal bioelectronics. Polyethylene terephthalate (PET) and polyimide (PI) are two polymers mainly used as substrates for flexible electronics. [16,22] Although they have Young's modulus at the GPa level (5GPa for PET [23] and 3.2GPa for PI [24] ), they are flexible at thicknesses of hundreds of micrometers. However, the elongation at break for both materials is low, resulting in poor stretchability. It should also be noted that the melting point of PI is hundreds of degrees higher than the melting temperature of soldering paste, which provides the possibility to hybridize traditional electronic components with flexible substrates to realize complicated functions. [25] The cytotoxicity experiments both in vitro [26] and in vivo [27] also show excellent biocompatibility for these two materials making them suitable for direct attachment to the skin. Another widely used flexible material is PDMS and other silicon rubbers (Ecoflex, Dragon skin), which are a class of polysiloxane elastomers. High elongation at break (≈40%) provides the substrate ability to sustain local deformation and is therefore suitable for applications that involve large strain scenarios such as joint movements. The FDA-approved material has been widely used for substrate and encapsulation for epidermal [28] and implantable bioelectronics [29] arising from its biocompatibility. [30] Other thermoplastic rubber-like elastomers have also been used for epidermal electronics. These include thermoplastic polyurethane (TPU) and styrene-butylene-styrene (SBS) copolymers. Due to the variety of the monomers and the possibility to introduce crosslinking between polymer chains, TPU can have many distinct properties. For example, its Young's modulus can vary from 0.55 to 5.5 GPa [31] and the elongation at break can even reach about 550%. [32] Multiple epidermal bioelectronics platforms [33] and even strain/pressure sensors [34] are fabricated by taking advantage of their extreme stretchability. The usage of transparent medical dressing (3M Tegaderm) and implantable devices [35] suggests the material is biocompatible and has no cytotoxicity. SBS and its hydrogenated form, styrene-ethylenebutylene-styrene (SEBS), belong to another class of thermoplastic elastomers, which have excellent mechanical properties, including high stretchability and very high elongation at yield. [36] Be-cause of their thermoplastic properties, such materials can also be fabricated as a gas-permeable substrate [37] via electrospinning to improve wearability.

Flexible/Stretchable Conductors
The flexible conductor is another important building material for bioelectronics, as it can act as electrodes and electrical connections. Extra design considerations on the conductors should be taken into account to confer flexibility to the electrical circuitry. Strategies for constructing flexible and even stretchable conductors have been widely examined and several categories of engineering methods and new functional materials have been developed.

Solid Metals
Solid metal trace, owing to its excellent electrical conductivity, is the top choice of conductors for any integrated circuits. To render commonly used metal traces (Au, Cu) flexible, structural designs involving serpentines [41] and 3D buckling [42] are utilized. By distributing the strain to the out-of-plane serpentine (Figure 2A) or pre-stretched 3D structures ( Figure 2B), such traces can reach around 30% of stretchability. [41a] Another method is to engineer the substrate itself. By pre-stretching, [43] thermal expansion, [44] or creating interlocking microstructure [45] of the elastomer substrate, the crack propagation of the bulk metal materials under critical strains can be reduced, therefore demonstrating stretchability of up to 100%. [46] Because such engineering methods are compatible with the existing circuit fabrication techniques, various epidermal bioelectronics have been developed, including bioelectric sensors (ECG, [47] EMG, [48] EEG [49] ), biochemical sensors, [50] and stimulators. [51] However, as traditional metal materials are not intrinsically stretchable, a sudden large strain may introduce irreversible deformation of the conductor. Thus, intrinsically stretchable material with a feasible fabrication method is desired.

Micro/Nanocomposites
To overcome the drawbacks of the pure metal trace, some composites consisting of conductive materials (carbon particles, [52] carbon nanotube, [53] graphene, [54] silver nanowires, [55] silver flakes [56] ) and elastic polymer binders are proposed. The particle/sheet/wire forms of the conducting materials generate numerous conducting pathways that can facilitate the movement of charge carriers during stretching while the polymer [42a] Copyright 2017, Springer Nature. C) Ag micro-flake and nanoparticle compositing with fluorine rubber to enable stretchability. Reproduced with permission. [58] Copyright 2017, Springer Nature. D) PEDOT:PSS-based stretchable conductors. Reproduced under the terms of the CC-BY-NC license. [13] Copyright 2017, The Authors. E) Implantable PEDOT:PSS-based electrodes for neural transmitter analysis. The scale bar denotes to 1mm. Reproduced with permission. [71a] Copyright 2022, Springer Nature. F) EGaIn coated SBS fabrics conductor. Reproduced with permission. [37] Copyright 2021, Springer Nature. filler provides elasticity. Silver-based composites are the popular choice when building low-resistance and stretchable connections between electronics. Among them, the strategy using silver nanoparticles/micro-flakes ( Figure 2C) is the most promising one. By blending with either TPU, [33a,57] fluorine elastomers [58] or SBS, [59] the composite can reach an initial conductivity of 40 000 S cm −1 [60] and stretchability of ≈215%. [50] Carbon-based materials are often used as the replacement for metal owing to their low cost, ease of processing, and some special properties (e.g. possibility for chemical modification [61] ). However, the conductivity of the carbon-based composites is usually lower than 100 S cm −1 , [62] thus making them undesired for large area connections between electronics. Several resistive [62b,63] and capacitive strain sensors [64] and electrodes [20a,c] for bioelectric sensing [65] have been developed using such materials. Additionally, compositebased materials are compatible with other fabrication methods of electronics, such as screen printing, inkjet printing, [66] and 3D direct ink writing (3D-DIW). [57]

Conductive Polymers
Another category of stretchable conductors is the intrinsically conductive polymers, such as polyaniline (PANI) and poly(3,4ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS). Such polymers contain conjugated pi bonds and doping sites in their polymer backbones that facilitate the movement of both ions and electrons. Because of the stretchability and conductivity of the polymer chain itself, the variation of charge carriers, and the exceptional biocompatibility, conductive polymers are potential candidates for skin ( Figure 2D) and implantable interfaces ( Figure 2E). Among them, PEDOT:PSS is one of the www.advancedsciencenews.com www.advsensorres.com most promising materials for stretchable conductors as it has very high conductivity when in its pristine state. [67] Though the original stretchability is poor, which is around 5%, after adding plasticizer (nonionic surfactant, [68] ionic salts, [68b] and hydroxyl group-containing organic solvent [69] ) or blending with other stretchable polymers, [70] the elasticity of the material can be dramatically improved while still maintaining conductivity. Several epidermal sensors and soft electrodes have been developed to record physiological signals. [71]

Liquid Metal
Recently, liquid metal, a new category of stretchable conductor, has gained increasing attention. Owing to its liquid form at room temperature, such material has almost infinite stretchability and metal-like conductivity (over 10 4 S cm −1 ). Eutectic gallian/indium alloy (EGaIn) is one of the widely studied liquid metals for biomedical applications due to its good biocompatibility. However, such material is not ready for fabrication of devices because the liquid phase material is hard to be laminated on a soft substrate and easily leaks from its original site, thus causing short-circuit. One solution is to confine EGaIn in pre-defined channels, such as laser-engraved hydrogel microfluidics [20b,72] and PDMS microtubes. [28b] Another approach is to compose the liquid metal with elastomer fibers, such as polyurethane [73] and SBS. [37] The stretchability of EGaIn-based materials can reach as high as 1000% with negligible resistance loss ( Figure 2F). Also, similar to other composite materials, soft electrodes, strain, and pressure sensors [74] are also proposed.

Wearable Systems for Cardiovascular Disease Monitoring
Cardiovascular diseases are one of the leading causes of death globally. It covers vascular and cardiac disorders such as hypertension, hypotension, atrial fibrillation, myocardial infarction, venous thromboembolism, decompensated heart failure (HF), and stroke. [75] The diversity in clinical presentations, intermittence of traditional ambulatory rigid monitors, difficulty in fully interpreting the medical or clinical meanings of the recorded data, and difficulty in predicting cardiovascular adverse events have posed great challenges for cardiovascular disease management. To tackle these issues, several innovative wearable epidermal bioelectric, mechanical, and optoelectric sensors such as ECG sensors, [76] pulse oximetric sensors, [77] seismocardiography (SCG) sensors, [78] pulse sensors, [79] and blood pressure monitors [15,79a] have been reported. Advanced AI techniques [79b,80] are also incorporated with these sensors to precisely predict and even distinguish a specific cardiovascular event.

ECG Monitoring
ECG is one of the most important and widely used bioelectric techniques for cardiovascular diagnosis. However, at present, it is usually intermittently recorded by a portable or bulky cardiogram monitor or continuously recorded by a stationary Holter monitor with uncomfortable leads. To tackle this problem and realize continuous and imperceptible monitoring, a group of wearable epidermal ECG sensors is proposed based on hydrogel electrodes with low ionic impedance, [81] self-adhering, [76a] and compliant artifact-free [76] electrodes. For example, Zhao et al. reported an ultra-thin (≈100 nm) conformable dry artifact-free epidermal electrode based on PEDOT:PSS and graphene with synergistically enhanced conductivity ( Figure 3A [75a,76c] ). Zhang et al. reported a self-adhesive [75b,76a] WPU/D-sorbitol composite electrode with quite low skin-contact impedance for ECG sensing, which can work under various conditions such as on wet skin and stretched or deformed skin during body movement. [74] Though these prototype ultrathin electrodes were successfully demonstrated for artifact-free ECG recording with skin conformability, the wearable devices that can be directly used by the patients for continuous long-term monitoring are still difficult to realize as an ultrathin conformable flexible printed circuit board (FPCB) to match these sensors is still missing.

Blood Oxygen Saturation Monitoring
Optoelectronic pulse sensors are more robust, and durable as compared to ECG sensors in terms of exempting frequent replacement of electrodes and using long-lasting optoelectrical elements. They can not only be used for monitoring pulse waveform and heart rate (HR), but can also be used for blood oxygen saturation (SO 2 ) measurement. The working principle is mainly based on light-emitting diodes (LEDs) and photodiodes (PDs) pairs using photoplethysmography. Conventional pulse oximeters use inorganic LEDs and PDs, which require high power consumption (≈mW) and are mostly rigid. Organic optoelectronics can help achieve miniaturized, flexible, and ultralow-power pulse oximeters. [77b,f,82] A representative example is a flexible reflective organic pulse oximeter using a green organic LED, a red organic LED, and two organic PDs, consuming the power of only microwatts ( Figure 3B). [77a] Though these sensors hold many merits such as enhanced wearability and low power consumption, an intrinsic drawback is the interference of daylight.

Pulse and Seismocardiography (SCG) Monitoring
As an alternative, mechanical pressure, strain, and ultrasonic sensors can also be used for pulse monitoring. Compared with piezoresistive, and capacitive sensors, piezoelectric and triboelectric sensors are self-powered, have low power consumption, and thus can be considered very competitive. A number of piezoelectric, triboelectric pressure, strain, and ultrasonic sensors were reported for pulse sensing or SCG monitoring, as shown in Figure 3C using PVDF piezoelectric sensors and in Figure 3D using self-powered electret sensors. [15,79] Though SCG signals and pulse signals have some similarities, they are usually recorded at different locations and have different medical implications. [78,83] As both pulse and SCG-related mechanical signals are weak and easily interfered by the breath signals or movement, much of the signal recording or processing techniques are needed to retrieve relevant information, including using two sensors for artifact cancellation and removal ( Figure 3D) or signal filtration.  [77a] Copyright 2018, The Authors, published by American Association of the Advancement of Science. C) PVDF-based dual SCG sensor for motion artifact cancellation and D) a combination of SCG and ECG sensors for blood pressure monitoring. Reproduced under the terms of CC-BY License. [15] Copyright 2019, Wiley-VCH. E) Two nanogenerator-based SCG sensors for blood pressure monitoring and deep data processing for heart and artery condition prediction. Reproduced with permission. [79a] Copyright 2020, Elsevier. F) A wireless cardiovascular monitoring system capable of monitoring heartbeat, blood oxygen level, and blood pressure information. Reproduced with permission. [85] Copyright 2020, Springer Nature.

Blood Pressure (BP) Monitoring
BP as an important cardiovascular parameter can be measured by machine learning, pulse transient time (PTT), or pulse arrival time (PAT) method based on wearable ECG, SCG, or pulse sensors. [84] Figure 3D shows an SCG sensor and ECG sensor while Figure 3E demonstrates two self-powered pulse sensors for continuous BP monitoring, respectively. In addition to BP, more important cardiovascular information such as the vascular and heart state can also be obtained from these signals based on algorithms or AI ( Figure 3E). [79a,80]

Highly Integrated Systematic Cardiovascular Monitoring
Though significant advances in epidermal sensors have been made for cardiovascular monitoring, systematic devices with hardware, software, and user interfaces that can be directly used www.advancedsciencenews.com www.advsensorres.com by customers to visually access cardiovascular information are still challenging, due to the bottleneck of wearable flexible miniaturized power supply, communication, and signal possessing modules. A successful example to tackle this issue is a wireless skin-interfaced physiological monitoring system for neonatal and pediatric intensive care ( Figure 3F), where ECG, HR, SO 2 , and BP can be monitored simultaneously with a small epidermal path with sensors, chips, and wireless communication modules. [85]

Diabetes Management Systems
Diabetes mellitus, one of the most common chronic metabolic diseases, has affected more than 422 million people worldwide and has become the top 10 causes of death in 2019. The disease is characterized by abnormally high blood glucose levels.
If not controlled by either hypoglycemic agents (Metformin, alpha-glucosidase inhibitors) or routinely subcutaneous injection of insulins, the complications with the signal of the hyperglycemia can lead to severe organ damage including neuropathy, nephropathy, retinopathy, and cardiovascular diseases. [4b,86] Hence, controlling the blood glucose level at a normal physiological level is recommended by most physicians to deter the adverse scenario caused by hyperglycemia. In this case, continuous monitoring of glucose levels has become one of the most desirable methods to manage conditions of diabetes as it can precisely record the peaks and valleys of the glucose level and can promptly inform patients and clinicians to intervene if needed. Recently, several fully integrated and wearable platforms that involve continuous glucose sensing and even on-demand drugdelivery systems were reported. Epidermal bioelectronics commonly analyzes epidermal-accessible biofluids including sweat, tears, saliva, and interstitial fluids (ISF). Examples with emphasis on the continuous glucose level monitoring on those fluids and integration levels will be introduced in this section.

Sweat-Based Integrated Systems
Sweat, the most easily accessible form of epidermal biofluids, is utilized by many researchers as an analyte for non-invasive glucose determination. [87] Lee et al. [88] recently developed a flexible electrochemical patch that is based on CVD graphene and microneedle drug-delivery technologies ( Figure 4A). Multiple sensors, including a sweat glucose sensor, pH sensor, temperature sensor, humidity sensor, and tremor sensor, are integrated into the patch to achieve calibrated glucose sensing and detection of hyperglycemia and hypoglycemia (through tremor). Specifically, the glucose sensor can precisely determine the sweat glucose concentration (≈0.1 mM) for over 10 times of repetitive use. At the same time, a temperature-controlled drug delivery system, which consists of phase-changing materials (tridecanoic acid) encapsulated microneedles, is also included to release blood glucose-reducing drugs when hyperglycemia is detected by the sensor module. Gao et al., [16] Nyein et al., [89] and Lee et al. [90] also proposed multifunctional platforms that can detect similar parameters. Besides patch-like electrochemical systems, Bandodkor et al. [91] developed a sticker-like system that can determine glucose and lactate levels in a self-powered way together with colorimetric pH and chloride ion concentrations sensors ( Figure 4B). Biofuel cells that were powered through a tetrathiafulvalene (TTF) mediated enzymatic reaction were used to determine glucose and lactate concentration. The stability test shows that the sensor is able to maintain a consistent response in a 3000-s measurement with three rounds of glucose concentration fluctuation. An integration of near-field communication (NFC) chip also enables wireless retrieval of concentration information. Though the determination of the glucose level is non-invasive for sweat, several drawbacks make such biofluids less desirable for diabetes management. The correlation between glucose concentration in sweat and that of blood is still controversial. [87a,92] Besides, sweat-based platforms require users to excrete a certain amount of the sweat as an analyte and thus cannot easily perform on-demand monitoring of glucose level.

Interstitial Fluid (ISF) based Integrated Systems
Aiming at extracting more accurate and clinically significant glucose levels, ISF, as a replacement for whole blood, is considered by many researchers. ISF is the fluid that exists between cells and has a composition similar to the blood in capillaries. [93] Several technologies have been developed to access ISF underneath the skin, including reverse iontophoresis (RI) and microneedles. The previous one involves applying a small amount (less than 0.5 mA) of DC current on the skin to induce osmosis of ISFs to the skin. A commercial product (Glucowatch) was launched but eventually failed as RI has drawbacks of long activation time and potential skin irritation. Targeting to solve the long activation time issue, Pu et al. [66] recently proposed an inkjet-printing RI patch that has thermal activation and sodium ion (Na + ) calibration units ( Figure 4C). Through the active control of skin surface temperature, the efficiency of the RI is increased by about 100%. By combining the graphene/platinum nanoparticles as the sensing layer and the differential calibration of Na+ ions, the accuracy of the glucose measurement is excellent (100% predicted values located on zones A & B for Clarkes error grid). Other efforts include improving the conformability of the devices on the skin to reduce the amount of ISF needed for analysis. Chen et al. [22b] and Kim et al. [20a] proposed some tattoo-liked integrated devices, whose ultrathin form facilitates ISF to penetrate sensing layers and achieve simultaneous measurements without a fluid stimulation period.
Another method to analyze ISF is using microneedles. Needles that are less than 1mm can effectively penetrate the stratum corneum and epidermis to reach the ISF-abundant dermis region. Compared to RI, such a method can perform real-time and in vitro analysis of ISF but not cause significant irritation to the skin. Several microneedle-based glucose sensors [94] were developed but currently, few of them achieve high integration levels that can be applied to diabetes management. Aiming at improving the wearability and integration level, Tehrani et al. [95] recently come up with a wireless microneedle platform that is able to detect glucose, lactate, and alcohol concentrations simultaneously without any noticeable crosstalk ( Figure 4D). Specifically, the glucose sensors can continuously detect concentrations in simulated ISF for more than 12 h. The clinical trial that involves five human subjects showed that the sensor system can obtain Figure 4. A) Flexible, multiplexed, and sweat-based patch with microneedle-based insulin delivery systems for diabetes management. Reproduced with permission. [88] Copyright 2016, Springer Nature. B) Self-powered sticker like glucose/lactate sensor with colorimetric chloride and pH sensor. Reproduced under the terms of CC-BY-NC License. [91] Copyright 2019, The Authors, published by American Association of the Advancement of Science. C) Reverse Iontophoresis epidermal system that has thermal activation and sodium ion calibration units. Reproduced under the terms of CC-BY-NC License. [66] Copyright 2021, The Authors, published by American Association of the Advancement of Science. D) Fully integrated microneedle-based functional glucose/lactate/alcohol sensor. Reproduced with permission. [95] Copyright 2022, Springer Nature. E) Closed-loop microneedle glucose sensor and insulin delivery system. Reproduced under the terms of CC-BY License. [96] Copyright 2021, Wiley-VCH. F) Smart contact lens with electrochemical glucose sensor and on-demand antiangiogenic drugs delivery system. Reproduced with permission. [97d] Copyright 2020, The Authors, published by American Association of the Advancement of Science. consistent glucose level readouts of the finger-pricking method. Instead of integrating multiple sensors into one device, Li et al. [96] alternatively choose the integration of RI, microneedle, and drug-delivery system to achieve automatic control of glucose levels ( Figure 4E). Through a porous microneedle patch as physical penetration and RI as ISF inducing method, the fluids can be efficiently extracted from the dermis to the skin surface for further accurate electrochemical measurements of glucose level. In vivo experiments on the rabbits suggested that the iontophoresis-induced insulin delivery can achieve a similar effect as the subcutaneous injections. Though microneedle-based platforms have been validated to continuously monitor glucose levels, systematic evaluations on their reliability to withdraw clinically significant glucose information need to be conducted in future studies. Moreover, the currently reported microneedle platforms are still based on rigid and solid materials.

Integrating System using Other Biofluids
Tear and saliva are another two epidermal biofluids that have been investigated for potential analytes for glucose. However, it is not easy to access those two biofluids as they only exist at special positions: the surface of the eyeballs and the oral cavity. Special sensors are required to collect these fluids. For tears, the contact lens is the most used form of device as it can seamlessly contact the eyeballs and collect tears for measurements. Multiple smart contact lenses [50,97] are developed to wirelessly detect glucose concentrations in tears. Enzyme-modified field effect transistor (FET) [97a,c] or an electrochemical cell with a chip [97d] was used to wirelessly retrieve signals. Among them, Keum et al. [97d] moved one step further that integrated a drug reservoir into the smart contact lens to make it to be a closed-loop diagnosis-therapy system ( Figure 4F). An electrochemical glucose sensor that can sustain storage for more than 2 months was integrated with a voltage-triggered on-demand drug delivery system. Microcontroller and an ASIC chip were included to facilitate data collection and RF communication. Through the data collected on other terminals, clinicians can initiate the release of antiangiogenic drugs to treat diabetic retinopathy. As for saliva, owing to the complications of the oral environment and the harsher biocompatibility requirement, devices that use saliva as analytes were not many, only Arakawa et al. [98] developed a smart mouthguard that has been placed inside the mouth.

Chronic Wound Management Systems
Chronic wounds refer to wounds that fail to go through an orderly and timely reparative process to produce anatomic and functional integrity of the injured site, which are generally associated with an underlying clinical condition, such as diabetes mellitus, vascular diseases, and pressure ulceration. [99] Over 6 million patients in the US suffer from chronic wounds with an annual healthcare bill of over 25 billion dollars. [100] As a result of the diversity of patients, their wound etiologies, and their comorbidities, an increasing consensus is established that treatments need to be tailored for a subset or even individual patients. [101] However, such personalized therapies will require improved diagnostic and prognostic tools that can identify delayed or non-healing and provide dynamic wound information, such as microbial composition, gene signatures as well as protein and lipid composition for each patient. Recent advances in epidermal bioelectronics open up avenues for unobtrusive wound management systems that can be conformably deployed over wound sites to collect physiological/pathological signals and deliver health interventions. [102] In comparison with conventional methods that require laborintensive and time-consuming analysis in the lab, epidermal bioelectronic systems can provide real-time wound monitoring and prompt treatment via caregivers and patients themselves, significantly enabling remote long-term wound care and patient adherence. There is a range of epidermal physical sensors for wound monitoring, such as temperature, [103] pressure, [28b,104] moisture, [105] and electrical impedance. [106] In this section, we will focus on the recent progress of epidermal biochemical sensors and integrated systems for wound management.

Sensors for pH, Oxygen, and Uric Acid
Healthy, intact skin has a slightly acidic pH ranging from 4.0 to 6.0, while increased pH values (e.g., from 7.15 to 8.93) are fre-quently reported in chronic non-healing wounds, which is associated with bacterial colonization, protease activity as well as cell migration. [107] Hence, pH sensors have been intensively explored to track wound healing conditions. [108] Among all sensing modalities, the reversible protonation/deprotonation of pHsensitive polymers, such as polyaniline and polypyrrole, is mostly used due to its facile preparation and appealing sensitivity (> −50.0 mV pH −1 ). [108c] The flexible polymer sensing structures facilitated seamless integration into bandages or dressings, allowing in-situ wound monitoring (Figure 5A). [108f] With such a pH-sensitive polymer, a battery-free wireless readout can be realized with the aid of NFC or radio-frequency identification (RFID) technique, which could substantially extend the lifetime of pH sensors. [108g] In addition to pH-sensitive polymers, pHsensitive poly(vinyl alcohol)-poly(acrylic acid) hydrogel is also demonstrated for passive wireless pH monitoring. The hydrogel swelling induced by acidic solution results in the displacement of inductive transducing structures, giving a sensitivity of > −100 kHz pH −1 . [108a] In addition to pH, wound oxygenation is another critical factor for wound healing. Moderate hypoxia level could trigger vascular regeneration and re-epithelization, [109] while sustained severe hypoxia will hinder proliferation. [110] Therefore, precise control of wound oxygenation is of great value for wound management. Figure 5B demonstrates a system for simultaneous oxygen sensing and controlled delivery. [111] This sensor leverages the oxygenresponsive fluorescence of (Ru(dpp) 3 Cl 2 )-based ink, which shows a 2 μs decrease in fluorescence lifetime with an increased oxygen concentration from 5 to 25 mg L −1 . Importantly, this system was tested in mice models, which is valuable for epidermal bioelectronic studies considering the huge difference between in vivo environment and benchtop. Separately, uric acid sensors were developed to detect wound severity or bacterial infection. With a non-enzymatic sensing strategy, a device based on carbon fiber mesh is able to cover the physiologically relevant range (0-500 μM). [112] Another enzymatic electrochemical sensor utilized uricase to oxidize uric acid into allantoin and showcased a sensitivity of −2.4 nA μM −1 , which can be further integrated into a wound bandage and wirelessly transmit the signal to a nearby smartphone. [113]

Sensors for Biomarkers
Currently, quantitative analysis of wound biomarkers still relies heavily on immunoassay in laboratories, which often delays diagnosis and provides limited information on the dynamic wound healing process. Recently, Gao et al. developed a flexible multiplexed sensing platform for point-of-care wound monitoring ( Figure 5C). [114] Such platform is equipped with temperature and pH sensors as well as graphene-gold electrodes functionalized by 5 distinct aptamers, targeting inflammatory mediators (tumor necrosis factor-, TNF-; interleukin-6, IL-6; and interleukin-8, IL-8), healing status biomarker (transforming growth factor-1, TGF-1), and pathogenic bacteria. After exposure to wound exudate from patients with venous ulcers, this platform can provide dynamic information on these biomarkers over weeks. Moreover, this platform has been tested on mice models, showing good biocompatibility and in situ multi-biomarker Copyright 2018, Elsevier. B) Photo of a wound dressing for simultaneous oxygen sensing and generation. Reproduced under the terms of the CC-BY license. [111] Copyright 2020, Springer Nature. C) Photo of a flexible aptamer-based multiplexed immunosensor. Reproduced under the terms of the CC-BY license. [114] Copyright 2021, The Authors. D) Schematic of battery-free wound infection sensor based on bioresponsive DNA hydrogel. Reproduced under the terms of the CC-BY-NC license. [116] Copyright 2021, The Authors. E) Schematic of a smart electronic dressing that utilizes UV-triggerable drug release based on pH signal. Reproduced under the terms of the CC-BY license. [117] Copyright 2020, Wiley-VCH. F) Schematic and photo (inset) of a closed-loop smart bandage that relies on pH and temperature sensing and executes antibiotic treatment by heating. Reproduced with permission. [118] Copyright 2018, Wiley-VCH. G) Schematic of a wireless closed-loop platform powered by a smartphone for temperature, pH, and uric acid sensing as well as controlled drug delivery. Reproduced with permission. [119] Copyright 2021, Wiley-VCH. www.advancedsciencenews.com www.advsensorres.com profiling of wound exudate over the duration relevant to wound healing.
The presence of pathogenic bacteria and their virulent factors are key factors that hinder normal wound healing. Although biosensors capable of detecting pathogenic bacteria have been developed based on either optical or electrochemical modalities, [115] integration of such sensors into an epidermal platform is limited because of the complexity of the required readout system. Figure 5D presents an infection sensor based on DNA hydrogel (DNAgel) that can generate a radiofrequency response detectable by a wireless NFC module. [116] The DNA gel was formed by chemically crosslinked DNA strands. After contact with deoxyribonuclease (DNase) secreted by pathogenic bacteria, the DNAgel can be degraded through an enzymatic reaction. The infection monitoring was demonstrated in a Staphylococcus aureus-colonized mice model, producing a 0.4 V signal after exposure to 10 5 and 10 6 colony-forming units (CFU) for 24 h.

Integrated System for Wound Therapy
In parallel to epidermal sensing systems, epidermal therapeutic systems are also of great interest to accelerate wound healing or treat abnormal wound conditions at the early stages. The emerging therapeutic systems have been summarized in a recent review.
[102c] Among them, closed-loop systems may serve as a revolutionary toolbox for timely digitalized wound management. Figure 5E shows an electronic wound dressing combining a temperature sensor and UV-cleavable drug-loaded hydrogel. [117] This platform can identify the hyperthermia caused by infection and trigger the release of antibiotics with the instruction of a nearby smartphone. Likewise, a smart bandage was designed to sense pH and temperature and release the drug upon controlled heating ( Figure 5F). [118] Most recently, Xu et al. developed a platform that is capable of sensing temperature, pH, and uric acid and electrically delivering broad-spectrum antibiotics ( Figure 5G). [119] Such a platform can be powered by a smartphone through NFC technology, which avoids bulky batteries and may favor long-term operation on wound sites.

Skin Diseases and Other Chronic Disease Management Systems
Being the largest organ in the human body, our skin has to face threats from more than 3000 possible skin disorders, such as inflammation, erythema, edema, atopic dermatitis, and even skin cancer. [120] Although clinical tools and procedures used for diagnoses such as biopsies, dermoscopy, magnetic resonance imaging (MRI), and craniometry are widely used, most of them are expensive, often not widely accessible, and typically uncomfortable for sensitive regions of the skin. Considering all the circumstances of recent clinical measurements and difficulties of a long time tracking for these unspecific symptoms of skin, the emergence of versatile epidermal bioelectronics [121] paves a new way to satisfy the most clinical requirements as efficient and intuitive instruments to manage chronic skin diseases regardless of the environment and location limitation.

Skin Inflammation Monitoring
Inflammation, as the most common skin symptom, can be caused by a wide range of skin diseases such as atopic dermatitis (AD), psoriasis, urticaria, xerosis cutis, and rosacea. [122] Although thermal sensing has been regarded as a facile and noninvasive approach to monitoring skin health, [123] this method is limited due to poor accuracy, complicated fabrication, need for battery, lack of clinical validation, etc. Here, by taking advantage of the transient plane source (TPS) technique to monitor the varying thermal properties (conductivity k and diffusivity) of the skin, Rogers et al. reported a soft, thin, wireless, and battery-free skin hydration sensor (SHS), which can be used to accurately assess water content of skin regardless of body location or environment ( Figure 6A). Further clinical tests validated the capability of SHS to quantitatively characterize the inflammation skin location. Besides the approaches that measure physical parameters, several molecular-level pieces of evidence [124] have been investigated to track the onset and severity of the inflammatory disease. For instance, cell-free DNA (cfDNA) has been found to link with the presence and propagation of psoriasis. Hence, tracking the level of these biomarkers can help to diagnose and formulate therapy plans. Recently, Fang et al. demonstrated a wearable CRISPRbased platform with graphene decorated microneedle structure for long-term monitoring of universal cfDNA ( Figure 6B). [125] Thanks to the synergetic effect of CRISPR-Cas9 and graphenedecorated microneedle bio-interfaces, it could extract reverse iontophoresis for the real-time assessment of versatile nucleic acids.

Skin Itch Monitoring
Compared with changes in thermal properties, the itch is a more obvious clinical symptom of skin disease-related morbidity across a wide range of medical conditions. [126] For now, measuring behaviors associated with scratching is regarded as a method to quantify the severity and frequency of itch. [127] However, recent assessment techniques are either labor-intensive and impractical in clinical practice or lack reliable accuracy. To address these substantial unmet needs, Xu et al. exploited a soft, flexible, and wireless acoustic-mechanical sensor which could be conformally attached to the skin for collecting both motions-induced low-frequency signals and high-frequency signals from skinconducted subtle vibrations during scratching ( Figure 6C). [128] Furthermore, by taking advantage of a machine learning-based algorithm, the detected signal could be characterized for uniquely scratching activities, which facilitates quantifying itch severity and assessing treatment outcomes.

Skin Biomechanics Monitoring
Morbidity of the skin could change the mechanical properties of its soft tissues. Hence, by characterizing biophysical variation, such as the changes in skin elasticity and surface hydration, the  Reproduced under the terms of CC-BY license. [18] Copyright 2020, AAAS. B) CRISPR-activated graphene biointerfaces featuring microneedle structures for monitoring universal cell-free DNA. Reproduced under the terms of CC-BY license. [125] Copyright 2022, Springer Nature. C) The clinical validation study of ADAM sensor for predominantly pediatric AD patients. Reproduced under the terms of CC-BY-NC license. [128] Copyright 2021, The Authors, published by American Association of the Advancement of Science. D) Schematic illustration of a miniaturized electromechanical device. Reproduced with permission. [130] Copyright 2021, Springer Nature. E) Overall structure and working mechanism of piezoelectric sensors for detection of neck/shoulder movement and position. Reproduced under the terms of CC-BY-NC license. [132] Copyright 2021, The Authors, published by American Association of the Advancement of Science. F) Exploded illustration of the dosimeter monitor platform and its circuit diagram of the system. Reproduced with permission. [134] Copyright 2018, AAAS. G) Laser-engraved graphene-based uric acid sensor with multimodal functions. Reproduced with permission. [142] Copyright 2020, Springer Nature. H) Wearable nutrients and metabolites sensors with a layer-by-layer illustration of functionality. Reproduced with permission. [146] Copyright 2022, Springer Nature. I) Schematic illustration of smartwatch-like acetaminophen sensor. Reproduced under the terms of CC-BY license. [149] Copyright 2020, National Academy of Science. severity of many skin diseases could be more precisely monitored and objectively evaluated. [129] Following this idea, Rogers et al. presented a miniaturized electromagnetic platform that integrated a vibratory actuator and a soft strain-sensing sheet (Figure 6D). This enabled attachment to the epidermal tissue for the precise and dynamic assessment of the variation of Young's modulus of skin tissues associated with deterioration of dermatological conditions. [130]

Joint Chronic Disease Monitoring
Besides, an increasing number of people also suffer from joint chronic diseases such as rheumatism, tendonitis, and arthritis, especially for the elderly and athlete populations. [131] Among them, work-related upper extremity musculoskeletal disorders, such as neck pains and shoulder stiffness, make up the largest number of clinical cases and account for nearly 70 million physician visits in USA. Proper monitoring and management of the sedentary posture can prevent further deterioration of the condition. Aiming at building a flexible and comfortable joint motion and posture sensor, Yang et al. [132] demonstrated a kirigami-based piezoelectric sensor that is highly anisotropic and can detect motion modes, bending radium, and bending direction of the neck and shoulder ( Figure 6E). By incorporating a kirigami lead zirconate titanate (PZT) network into PDMS, the as-fabricated sensor can sustain 100% strain change and produce voltage signals based on the bending angles. Successful detection of the motion mode was also demonstrated by experiments conducted on the human body.

Cancer Management
With advances in therapy, cancer is fast becoming another category of chronic diseases. Though the management of cancer and its related complications require hospitalized therapy and monitoring, monitoring of exposure to carcinogenic factors and early detection of cancer biomarkers are also helpful for the prevention and early intervention of cancers. For instance, skin cancers mainly result from exposure to UV radiation. [133] Although there are already many mature technologies that can accurately measure the intensity of UV exposure, long-term monitoring, stable accuracy, and broad adaptability are still some of the critical unmet needs. To solve all these issues, Rogers et al. presented a millimeter-scale, wireless, and battery-free UVA, UVB, visible, and IR radiation monitoring platform, which could not only detect a wide range of the electromagnetic spectrum but also utilize a visual indicator to reveal the digital readings of the measured intensity and temperature from skin or environment ( Figure 6F). [134] Other strategies, such as colorimetric chemistry-based sticker-like UVA/UVB dosimeters [135] and CNTbased wristband-like resistive type UV light sensors [136] were also incorporated to quantify daily UV exposure. Moreover, circulating biomarkers, such as interleukins, [137] cytokines, [138] and volatile organic compounds (VOCs), [139] are measured to screen cancers at an early stage and serve as prognostic parameters to determine the therapy effectiveness. Epidermal sensors can provide on-demand and laboratory-free determination of those molecules. For instance, a flexible graphene/Nafion-based field effect transistor (FET) [140] was introduced to detect the IFN-, which is a cytokine that can serve as a prognostic biomarker for breast cancer and non-small cell lung cancer (NSCLC), on sweat with nM resolution. Another example is a wearable patch based on dopamine-reduced graphene that change its resistance when encountering different VOCs. [141] Through the usage of the multilayer design and the deep neural network to discern the signals, the patch can determine the minor difference between cancerous tissue and normal tissue. Though several devices have been developed to address the detection of biomarkers, systematic integration of such sensors with other components such as wireless communication or therapeutic units is still limited. Further implementation and development are required to achieve point-ofcare cancer management.

Gout Management
Gout is a common chronic inflammatory disease that affects joints and can cause severe pain. This disease is mainly caused by hyperuricemia which resulted in the accumulation of crystallized uric acid salt (monosodium urate) in the joints. Owing to its repetitive nature and sustained pain that significantly reduces a patient's quality of life, gout management, especially the control of uric acid and its precursor intake, is recommended by most clinicians. To evaluate the progression of the disease and the prognostic effect of management, uric acid concentration in serum needs to be determined frequently. Here, several epidermal electronics platforms that can detect uric acid concentration in biofluids have been developed to perform continuous evaluation of uric acid concentration and as a replacement for blood tests. Among them, Yang et al. [142] recently used a laser-engraved graphene-based platform ( Figure 6G) to achieve multimodal monitoring of metabolic biomarkers (including uric acid) in sweat and other vital signs (such as temperature and respiration rate). The graphene-based sensor can detect as low as 0.74 μM uric acid in artificial sweat and can be massively produced. On-patient clinical studies also revealed that the sensors can detect concentration differences between healthy and hyperuricemia subjects and correlate well with serum concentration trends. Other integrating platforms including a smart mouth guard [143] and a glove based [144] system were also reported to detect uric acid in saliva and fingertip sweats. Though uric acid concentration in those biofluids has been claimed to have a good correlation with the serum concentration, clinical validations with a large number of subjects have not been conducted to systematically evaluate the accuracy to reflect uric acid level.

Nutrition and Therapeutic Drug Monitoring
To date, most epidermal electronics are targeting either disease monitoring through biomarkers and vital signs evaluation or disease management. However, daily nutrition concentration is also critical in personalized health management and POC of chronic diseases. The tracking of the nutrition amount helps in evaluating potential metabolism diseases and providing comprehensive health profiles. Some of the wearable patches [145] have been proposed to evaluate the nutrient concentrations in sweat using vitamin C as an example. To move one step further by integrating multiple sensors and specific designs on sweat inducing/collection, Wang et al. [146] designed a wearable patch based on laser engraved graphene ( Figure 6H) and molecularly imprinted polymers, that can achieve measurement of multiple amino acids and elevated branched-chain amino acids. Such platforms could precisely detect μM-level targets in sweat and the results aligned with the gas chromatography-mass spectrometry results. In vivo clinical studies also revealed that the sensor systems could provide a metabolic fingerprint for obese and diabetes patients with a correlation similar to that of blood serum. So far, because nutrient molecules are mostly electrochemical inert and scarce in epidermally accessible biofluids, some novel sensing mechanisms such as aptamer or antibody-based www.advancedsciencenews.com www.advsensorres.com sensors need to be developed with an emphasis on accuracy and long-term stability.
Therapeutic drug monitoring is another aspect of disease management as it enables clinicians to customize therapeutic plans given that pharmacokinetics is different from person to person. Similar to nutrient monitoring, therapeutic drug monitoring suffers from being electrochemically inert and having a low concentration in biofluids. Only a few of the electrochemical active drugs such as caffeine, [147] levodopa, [148] and acetaminophen, [149] were monitored using epidermal electronics-based platforms. Among them, Lin et al. [149] integrated multiple units, including a microfluidics sweat collector, a wireless communication module, and a user-end screen, with highly sensitive acetaminophen sensors ( Figure 6I). Their system successfully tracked the pharmacokinetics in sweat and saliva with validation using a lab-based assay. To further extend the range of the monitoring to those unconventional drug molecules, the same author further designed a microneedle-based sensor [150] that uses an aptamer binding mechanism to sense antibiotics (vancomycin and tobramycin). The sensor also provided readouts comparable to the reference blood drug concentration in in vivo experiments and more than 12 h of operational stability.

Commercialization of Epidermal Bioelectronics Platforms for Chronic Diseases
Epidermal bioelectronics platforms developed in the laboratories should aim toward commercialization for eventual biomedical applications. In fact, the market of wearable devices has grown dramatically in the last decade and multiple products have both been approved by FDA as well as gained significant market share in consumable medical devices. To date, the commercialized products of epidermal bioelectronics for chronic diseases are mainly in two fields -cardiovascular diseases (involving blood pressure, ECG, and PPG monitoring) and diabetes management (involving blood glucose concentration monitoring).

Cardiovascular Disease Management
Currently, many smartwatches have integrated ECG and PPG units into their designs. Such products include the Apple Watch, Samsung Galaxy Watch, Mi Band, Huawei Watch, and Amazfit Bip. By placing multiple electrodes and LED/photodiode pairs on the back of the watch, an ECG diagram, PPG monitoring, and blood oxygen level can be extracted continuously. The accuracy of the measurements is comparable to traditional monitoring devices. Specifically, with the help of AI and machine learning (ML) algorithms, the irregularity of the ECG can be detected automatically to warn the user about potential atrial fibrillation. Moreover, owing to the global pandemic of COVID-19 which may induce severe respiration issues, the blood oxygen level measurement function helps COVID-19 patients to check the severity of their disease so that they can react promptly. Other forms of devices with those mentioned functions are also introduced by different companies, including iRhythm (patch) and toSense (necklace). So far, most of the wearable ECG devices only have one lead monitoring capability except for AliveCor KardiaMobile, which consists of six ECG leads (I, II, III, aVL, aVR, and aVF) and can detect most of the common arrhythmias. Besides ECG measurements, wearable BP monitoring is also very attractive to those patients with hypertension. Though the desktop BP meter has already been commercialized into a low-cost and easy-to-use home-based medical device, it still requires users to perform the measurement manually. Some of the above-mentioned smartwatches can estimate BP based on the user's PPG signals and can predict hypertension events. However, such indirect measurement is less accurate given that the PPG signal is easily affected by motion artifacts and the device's configuration. Recently, Omron launched its first FDA-cleared and clinical-grade smartwatch for BP monitoring. Integration with an inflatable wristband and miniaturized air pump, the device (HeartGuide) can perform traditional oscillometric measurements of blood pressure. A similar function was also developed by Huawei on their newest health watch, Huawei Watch D.

Diabetes Management
For diabetes management, most clinicians will recommend patients to measure their glucose levels up to four times a day to monitor their glucose level change in response to meals or medications (such as injectable insulin). The portable strip-based glucometer has been commercialized for more than 40 years and is still the first choice of most diabetes patients owing to its cheap and accurate measurements. However, the painful finger pricking is still dissatisfactory to most users. Aiming at solving this pain point, medical device companies such as Medtronic, Dexcom, and Abbott, developed continuous glucose monitoring devices, which can be used for up to 14 days once mounted on the skin. Among them, Abbott Freestyle Libre has the best long-term performance owing to their iconic osmium complex [151] technologies which dramatically improve the electron transferring efficiency between the glucose oxidase and electrode. Medtronic Guardian and Dexcom G7 also offer similar performances using the first-generation glucose sensor that is based on platinum electrodes but can only be functional for 7 days. Glucose concentration data collected by those sensors in a certain time interval (5 min for Freestyle Libre) will be transmitted to smartphones to generate a trendline. Besides the electrochemical measurement that is dependent on enzymatic reactions, METAmaterials is currently developing a spectroscopy-based non-invasive glucometer, which obtains glucose information by simply gripping the device. Despite the realization of finger pricking-free monitoring, the cost of such a device is still high and may deter some users.

Challenges and Future Work
To conclude, epidermal sensors are of great importance to chronic disease management. The miniaturization, flexibility, wearability, reliability, and system integration can all contribute to a user-friendly and smart chronic disease monitoring platform. At present, epidermal sensors developed for smart chronic disease management include wireless glucose sensors for diabetes management, [152] AI-based pressure sensors for hypertension management, [79b] and infection detection sensors for chronic wound management. [17] However, as chronic diseases are usually long-lasting with many complications and mainly Adv. Sensor Res. 2023, 2, 2200068 www.advancedsciencenews.com www.advsensorres.com occurred in the elderly, there are still many issues that must be addressed (Figure 7).

Long-Term, Durable, Stable Monitoring Issues
The durability and long-term reliable performance are big issues for many bioelectronics aiming toward long-lasting chronic disease monitoring. The functions of some aptamers, enzymes, and mediators of the sensing components may be affected when subject to long exposure to light, high temperature, bending, or stretching. The circuit or electrode may also suffer from a reduction in conductivity during cyclic bending and stretching. Some sensing components cannot be restored to their original state and as a result, there is a deterioration in the sensing performance. For example, the strong binding between some aptamers and analytes, [17] the decomposition of DNase after interacting with the targets, [116] degradation of Prussian blue and ferrocene during a redox reaction, [153] will result in gradual dysfunction of sensors. The transducing interface between the sensor and the skin also easily deteriorates during long-term usage arising from physical movement. Though it is quite difficult to realize longterm monitoring, some researchers also reported sensors with more than 20 days of usage. [154]

Reliability and Accuracy Issues for High-Sensing Performance
The high demand for sensing performances such as reliability, accuracy, stability, ultralow detection limit, wide detection range, and high linearity are also challenging for epidermal sensors. The performances are usually restricted by the sampling method, sensing principle, anti-interfering capabilities, materials, and engineering methods. Simultaneously achieving all these is usually quite challenging. Sometimes, there is a trade-off among some of these parameters, such as the trade-off between sensing range and sensitivity.
Generally, samples obtained through invasive or minimally invasive methods are quite small, which poses a great challenge to the reliability and accuracy of sensing. For example, the amounts of tears, sweat, and ISF are usually minute. To increase the sample amount, pre-exercise is usually needed for sweat monitoring. However, in some conditions, these strategies are not applicable, for example, in wet environments or for some inactive or immobile elderly users and the disabled. To address this issue, some strategies such as reverse iontophoresis, [155] microfluidics, [91] and swelling hydrogels [156] are reported to help with sampling. [91] swelling hydrogels [156] are reported to facilitate biofluid sampling.
As for reliability, another question is how to avoid the influences from pH, temperature, or batch-to-batch differences. [90] The concentration of the sweat may vary under different temperatures or evaporation speeds. This will induce doubts about how much the correlation is between the concentrations of sweat and blood analytes. The individual differences also lead to fluctuations in the amount of ISF extraction. pH can influence the sensing performance as well. To meet this end, some researchers successfully used calibration methods to eliminate this. [66,90] Moreover, how to reduce the interferences of human-body movement and environment on the sensing performance is also important for reliability. The movement-induced stress may influence the transducing interface, the structure or conformation of the sensing materials, and the electrical performance of sensing circuits and electrodes. Thus, it is necessary to make the whole device conformable and strain-insensitive or take precautions to avoid these factors.
Anti-interference and anti-biofouling are also key factors for reliable sensing. Generally, there are numerous other background elements in biofluids and the concentration of the targeted analyte is relatively small. The responsive non-target elements can easily cause unreliability. The biofouling may cause dysfunction of the sensor. Thus, for some sensors, a selectively permeable membrane is introduced to block the interfering chemicals and reduce the possibility of bio-fouling. [66] However, for big biomolecule monitoring, the interference or bio-fouling may be challenging, especially in a complex biofluid environment.

Safety, Non-Irritation, Miniaturization, Conformable Issues
With prolonged interface with the human skin, safety, biocompatibility, and irritation can sometimes be an issue. The biocompatibility, irritation, and safety of some materials in sensors are far from being thoroughly investigated. The non-gas permeability of substrates may also irritate during long-term use. Because of the rigidity and bulkiness of some electronic chips, batteries, and wireless modules, the final systems are sometimes bulky and not conformable, which may cause an adverse user experience.

Costs and Scalability Issues
To commercialize epidermal sensors for chronic disease management, especially for the elderly and low-income patients, one important factor is the cost. However, some materials of the building blocks of sensors are expensive and some fabrication processes are difficult to be mass produced or may require the use of expensive facilities. To reduce fabrication and production costs, paper or plastic-based substrates and printing strategies can be utilized as well as other low-cost methods such as screen printing and ink-jet printing.

Promising Future Directions
Considering the challenges and required features of chronic disease monitoring, several directions may be significant and can result in great breakthroughs. The first one is to develop long-term robust reliable monitoring systems by implementing robust interfacing strategies, recyclable transducing principles, stable materials, and reliable sampling and sensing methodologies. To realize a robust on-body tissue-sensor interface, adhesives with high bonding strength and stimuli-triggered easy detachment and soft conformable devices with all soft stretchable materials can be utilized. Some recyclable transducing, physical sensing mechanisms (e.g., optoelectronic mechanisms) are good candidates. Recyclable biochemical sensing can be realized either by using recycling receptor-target recognition (e.g., using molecular imprinting technology or dynamically balanced receptor-target bonding and debonding) or by resetting sensors through the stimuli-triggered release of targets. Besides, considerations must be taken seriously to ensure all the functional layers including receptors and conductors are stable during usage. Thus, functional materials that can withstand the physical strain (e.g., using stretchable functional materials), temperature variation, or biochemical interference should be chosen.
The second direction is to develop highly integrated multifunctional systems, through integrating multi-sensors to monitor multiple symptoms and complications, integrating signal management, sensors, AI, and software into a systematic platform, and integrating sensors and on-demand therapies for a closed-loop smart chronic disease management. For example, to systematically manage diabetes, smart multifunctional sensing platforms are expected through monitoring both glucose concentration and related complications and biomarkers (e.g., diabetic ketoacidosis, hyperglycemia, and hyperketonemia monitoring through monitoring the pH and ketones of blood), insulin concentration, and even providing alerts and suggested actions through big data.
The last direction is to develop high-performance sensors that can perform under challenging conditions such as in a wet environment, a wide range of ambient temperatures, and under highly challenging biomechanical situations such as during physical exercise or when epidermal sensors are subjected to physical contact. For example, underwater sensors can be developed by utilizing waterproof and special microfluidic designs that can collect biofluids but expel water. Motion-resilient sensors can be realized by using strain-isolated design or strain-insensitive materials (e.g., stretchable materials or structural engineering with serpentine and buckling designs).