Flexible Plasmonic Biosensors for Healthcare Monitoring: Progress and Prospects

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INTRODUCTION
Flexible biosensors have received increasing appreciations owing to their capabilities to monitor activities ranging from tissue deformation to body motions in healthcare region, 1, 2 which has also been considered as important component to develop Human Machine Interface (HMI) recently. [3][4][5] Flexible biosensors with characteristics as light weight, portability, tailorable electrical or optical performance and good compatibility, have been particularly favored in designing modern electrical and optical sensors. [6][7][8][9] The general classification of flexible biosensors includes: (1) Functional materials based sensors to detect physical adsorption of target analytes and subtle movements with sharp electric and optical signals. 10,11 (2) The sensors with specific biological recognition elements (e.g. enzyme, antibody, cell receptor or organelle) to responsively translate the change(s) of target analytes into electrical and optical signals. 12,13 For example, Gao's group developed a sensitive and non-invasive wireless immunosensing platform to monitor stress biomarker cortisol by specific recognition between labeled cortisol and antibody-modified graphene electrode. 14 Recently, there has been a considerable research fever to innovate flexible biosensor/bio-sensing system to meet the diverse demands, such as an electronic skin with integrated sensing units and circuits to fulfill functions as robots and artificial limbs, and tactile perception. 15,16 Flexible plasmonic biosensors, a group of emerging sensors by introducing responsive noble metal nanoparticles (NPs) into flexible system, have been utilized in monitoring human health, disease diagnosis and environmental pollution analysis, etc. [17][18][19][20][21][22] The "Plasmonic unit" enables sensors with some properties, such as: (1) the charge-transport properties and resistive sensitivity to strain changes, 23,24 (2) the ability to enhance fluorescence and Raman signal driven by the localized surface plasmon resonance (LSPR), 25,26 (3) the inherent optical response to target analytes, 27,28 (4) the high designability on the surface modification of noble metal nanoparticles. 29,30 Such flexible plasmonic biosensors possess the superiorities with the conformal attachment to skin and multi-sensing capabilities. However, the progress of emerging flexible plasmonic biosensors have not been systematically reviewed elsewhere. [31][32][33] Given the rapid development and promising future of this filed, we strive to offer this horizontal scan on the technical advances from the narrative of integrating "plasmonic" and "flexible" and the state of art innovations of flexible plasmonic sensing mechanism.
In addition, we also aim to give the readers a broad sense of comprehension of the flexible plasmonic biosensors for advanced healthcare applications that have been developed in last few years (Figure 1). Thus, this report will articulate from the following aspects: (1) The concept of "Plasmonic biosensors" and its design mechanism,  analysis method, the sensitivity of SERS is mostly determined by the enhancement factor (EF) and the analytical enhancement factor (AEF). 61,62 Noble metal NPs based SERS substrate can achieve optimal sensitivity through their trailable micro-nano structure, surface roughness and wetting status, and spectral matching among NPs, exciting laser as well as analytes. For instance, hydrophobic surface and rough structure of NPs assembles have been highlighted in many reports for their accurate recognition of target analytes. 63,64 Local electric fields associated excitation enhancement for plasmonic-enhanced fluorescence (PEF). The LSPR of noble metal NPs provide opportunities to improve the efficiency of absorption and emission of fluorophore (fluorescent molecules or quantum dots) via coupling with the emitters. 65,66 Thus, the bridge of molecular absorption and emission spectra between LSPR of noble metal NPs and fluorophores is promising to enhance the fluorescence signal significantly. 67,68 Additionally, the fluorophore should keep a certain distance from the noble metal NPs surface to avoid the energy attenuation (quenching) of the excited state. [69][70][71] Aggregation or shape morphing induced colorimetric sensing. Plasmonic NPs usually behave intense extinction in the visible region, accompanied by corresponding color changes. Moreover, the specification of colorimetric biosensors can be tunned to the high sensitivity of LSPR by varying the size, morphology, composition, interparticle distance as well as orientation of nanostructures. 72,73 Recently, our group have designed Au NRs etch-dependent colorimetric biosensors for sensitive tracing environmental pollutants and mycotoxins for the application in food safety. [74][75][76] Thermally activated tunneling of charge carriers resulted conductivity of ligandstabilized NPs for chemiresistors. This sensing mechanism is based on the change of resistivity (ΔR) of the film by adsorbing the analyte to the chemically sensitive Au NPs film, which exhibit high sensitivity for both liquids and gases detections. 77,78 It is noting worthy that the selection of thiols on NPs surface plays an important role in the sensitivity and selectivity of Au NPs based chemiresistors, which have been widely exercised to optimize the properties of chemiresistors. [79][80][81] Soft contact lenses is a kind of healthcare product that have been expected to integrate some above merits with high reliability and stability and minimizing irritation of the eye to maximize the user's experiences. 110 Amongst a variety of flexible substrates, polymeric substrates offer ductility with a number of popular candidates such as polydimethylsiloxane (PDMS), polyimide (PI), polyethylene terephthalate (PET), polyethylene naphthalate (PEN) as well as polyurethane (PU). 111 PDMS is the most widely practiced material for flexible substrate for its stable chemical properties, good elasticity (100-1100%) for both stretching and bending, good thermal stability, transparency and biocompatibility. More importantly, PDMS can be fabricated through the convenient processing, with trimmable surface modification and designable composition. [112][113][114] While the high strength restricts the uniaxial stretchability of PI, a robust bending performance can be achieved through structural design, thus, endowed it wide applications as cantilever and other bending based functional units in flexible biosensors. 115 Additionally, PET and PEN with good flexibility, high transmittance (>85%) have also been applied in wearable electronics for human health monitoring. 116 Paper and silk fibroin (  (Table 1b). With the assistance of template, light or heat triggered polymerization of hydrogels has been practiced as a flexible substrate for ultra-thin wearable electronics (Table 1d). 118 Speaking of scale-up fabrication for flexible substrate, lithography (such as decal transfer lithography, photo-assisted polymer transfer lithography, and maskless soft lithography) has been a popular strategy since last century (Table 1e). 129,130 The rational control for interfacial fracture and adhesive mechanics of transfer have been seen as critical measures for constructing multidimensional, large-scale as well as compatibility functional flexible substrates.

BIOSENSORS
The synergistic effect of "flexible" and "plasmonic" in biosensor   136,137 By integrating the NPs within a finite space of flexible thin-film substrate, we can not only achieve high reacting efficiency with target analytes, but also realize the detection in wide range by the controllable plasmonic coupling, therefore, lead to the high optical sensitivity. One example in this context is that, the traditional SERS detection with fixed NPs locations on substrate often result in unavailable optimal detection signal amplification. 138,139 However, the recent development of flexible SERS sensing platform can effectively settled the issue by generating tunable interparticle gap distances in response to the applied strain, which will not only endow optimal detection signal amplification but also broaden the detecting ranges with the adjustable optical spectra. [140][141][142] Moreover, the tailorable quantum tunneling property 143,144 of flexible plasmonic biosensors cannot be realized in rigid plasmonic biosensors. As for the piezoresistive flexible pressure mechanical stability, the poor environmental tolerance greatly impedes the loop sensing performance. Nevertheless, the flexible plasmonic biosensors can effectively settle these problems and exhibit high mechanical stability and detecting stability.
Additionally, the integrating types of embedding and warping plasmonic units into flexible matrix can effectively overcome the modulus mismatches. 56 For instance, most real-time analysis are conducted by acquiring continuous target analytes from skins, where the contact between the rigid detecting platform and skin will severely affect sensitivity. With this term, flexible plasmonic biosensors ensure a conformal contact with skins, with both capturing and enriching ability for target analytes from skins, saliva, or tears from the plasmonic units. (4) Bio-compatibility. Despite of the sensitivity and stability, some other factors should also been highlighted for wearable electronic/optical sensing devices to minimize irritation of human body and to maximize the user's comfort. 110 With this respect, the biodegradable and biocompatible flexible substrates provide significant advantages for the highly designable nature (Figure 3f).

The fabrication of flexible plasmonic biosensor
To date, the interests on fabrication have grown heavily on the relevant characteristics that links to the industrial scale-up process, i.e., rapid prototype, easyto-operate, cost-effective, etc. While the practical method of preparing composite materials is largely depended on the applications, we classify the fabrication broadly into the following categories: (1) Physical blending and curing. This conventional approach has an advantage with minimal requirements on the infrastructure. 149,150 Surface modification is needed on nanoparticles as necessary so that they can be uniformly dispersed in the precursors.
Lee and co-workers 55 (Figure 4b). 152 However, the technical challenges remain in achieving accurate control of the thickness and structural roughness of films, 153 which will significantly affect the conductivity and optical sensing functions. 154,155 (2) Template method. This route offers great flexibility on designing the variety of morphologies. With the assistance of anodic aluminum oxide (AAO) template (Figure   4c), the cauliflower-like 3D Au NPs-PDMS composite film was prepared. 156 Furthermore, the 3D periodic wave-shaped microribbons array of Ag NPs and poly(εcaprolactone) composite films were prepared via longitudinally stretching (Figure  4d), 142 where the stretched film exhibited a magnitude enhancement in optical signal compared with the unstretched ones. (3) Embedded co-growth. It is of great importance to maintain plasmonic activities under deformation for healthcare monitoring. 158 However, the mis-matches of physical and chemical properties between the plasmonic units and flexible substrate (for example, the Young's modulus of Au is ten times higher than that of PDMS) are likely to cause a poor interfacial adhesion. 159 Embedded co-growth is an efficient approach to solve above problems, which requires significant understanding on the chemicalphysical nature of system. One example is the mechanical interlocking structure proposed by Chen's group (Figure 4e-f), 56,159,160 which was achieved via thermalradiation-assisted Au NPs encapsulation. 56 This interlocked structures not only enhanced the stability of the flexible conductor, but also provide a pathway for acquiring on-demand and highly stable composited structures. Kim and co-worker brought another approach to obtain wearable and implantable bioelectronics with high conductivity (41,850 S cm −1 ) and good stretchability (266%) by creating microstructures during phase separation (Figure 4g). 157 The Ag-Au nanowire-rich region maintains stable electrical conduction when stretching the nanocomposite (Figure 4h), thus enable a good adaptatvity for the flexible sensors. The technical route of 'Embedded co-growth' is full of scientific charming and yet to be fully explored.

MONITORING
In the clinical practice, heart rate, blood pressure, blood glucose, etc. are standard readings to evaluate the life-sustaining functions for individuals. Particularly, the detection of blood glucose can be utilized to identify the early symptom of series diseases including diabetes, heart disease, kidney failures and blindness. 161,162 Various flexible plasmonic biosensors have already been developed to monitor human health c). When the bilayer of Au serpentine mesh and gold-doped CVD graphene provided high conductivity and mechanical reliability for stable electrical signal transfer, 173 the plasmonic units (Au NPs) acted as scattered clusters of functional materials to expose more active surface area for better electrochemical performance (Figure 5d). Feng's group 115 reported an ultrathin biosensor for noninvasive intravascular glucose monitoring via generating subcutaneous electrochemical twin channels, where Au NPs were deposited to construct "sand dune" thin films to achieve high sensitivity (130.4 mA/mM) as well as high correlation (>0.9), at clinically measured blood glucose levels.
In this work, the low density of electrochemically active defects of graphene was compensated by the doping of Au NPs and the invasive injury was inevitable due to the application of polymeric microneedles for thermally activated drug delivery.
Enzyme linked immunosorbent assay (ELIA) has also been widely applied for glucose monitoring. Wang's group developed a dual-marker biosensor chip that combined enzyme and antibody-based assays for simultaneous electrochemical measurements of insulin and glucose (Figure 5e-f), 40 where the Au and Ag NPs were sputtered on plastic PETG substrate to achieve accurate sensing. It is noting worthy that the magnitude difference between the physiological concentrations of insulin (pM) and glucose (mM), has been considered as a major challenge for integration. Thus, this work originally addressed core operational and fabrication challenges relating to two different bioassays. The obtained dual diabetes biomarker chip presented good selectivity and reproducibility, and provided a distinct point-of-care concept for multiplexed biomarker monitoring.

Surface-enhanced Raman scattering (SERS) is a flexible biosensing technology that
has attracted extensive research attentions, due to its ability to detect extremely low amount of analytes (at single molecule level) non-invasively. 176,177 Traditionally, the regulation and optimization of SERS sensing focused on tailoring the morphologies and species of noble NPs. 178,179 The incorporation of flexibility has recently leveraged the SERS detection to the conformal health monitoring. 12,[180][181][182] In these flexible SERS biosensors, plasmonic NPs play critical roles due to their irreplaceable electromagnetic enhancements, which results in sharp signal amplification for sensitive detection. [183][184][185] As a typical spectral trace analysis means, most SERS-based glucose monitoring systems are conducted in solutions with glucose extracts. The development of wearable continuous glucose monitoring with SERS detection remains challenging. Yang and coworkers delivered a continuous and sensitive monitoring platform based on reversible interaction between glucose and mercaptophenylboronic acid (Figure 5g), 174 which is promising to develop implantable devices with improved Raman enhancement and concentration-readout speeds. Katseli and co-workers developed a smartphoneaddressable e-ring via 3D printing to achieve nonenzymatic and sensitive self-testing glucose amounts in human sweat. 175 Unlike the traditional enzyme-based biosensors, the electrodeposited Au NPs film provides effective catalytic sites for sensitive glucose sensing. Furthermore, the configurable conductive plastic electrodes can act as flexible substrate to attach to skin and extract sweat analytes. Despite the rapid development of blood glucose monitoring, it remains challenging to exploit a robust noninvasive flexible plasmonic biosensor with high sensitivity.

TEMPERATURE BIOSENSORS
Temperature sensing is of significative importance in day-to-day health monitoring, environmental control to disease diagnosis as well as complex medical solutions. [186][187][188] Temperature sensing is also one of the main tactile sensing mechanisms, which can transmit the key information of the contact object, 189 such as to reflect the health status of the human body suffering from trauma and sepsis (Figure 6a). The high temperature can be clinic proof as a main symptom of disease for significant public health event, such as COVID- 19. 190, 191 However, the inadequate physical contact will easily cause inaccuracy/error on the thermal-readings, which is common in conventional rigidtemperature sensors. 192 The latest innovation trend has focused on the temperature detection on human beings in a conformal, implantable and remote manner. 193,194 Rogers's group has been devoted to non-invasive monitoring of core body temperature by using ultrathin epidermal circuits and heat flux sensors, 149,[195][196][197][198] which possess subtly and reversibly attachment onto the skin (Figure 6b-c) to accurately monitor body temperature. Their "skin-like" composed biosensors integrated with circuits, electrodes, sensors, communication modules as well as power unit exhibited effective modulus and bending stiffness for sensitive temperature monitoring.
Temperature coefficient of resistance (TCR), a core term to describe the temperature sensing properties, is defined as the relative change of resistance value per a temperature change of 1 °C, where a larger TCR value means a high sensitivity for resistance temperature detectors (RTDs). 199 The combination of conductive materials and temperature sensitive polymers can improve the temperature sensing function dramatically. 189,200 Ag NPs has been a popular candidate to build flexible temperature sensing for its highest conductivity among all metals as well as a relatively low cost.
Oh and coworker design and developed a series of Ag NPs-PET flexible temperature sensors 201 and optimize the charge transport mechanism via surface treatments (Figure   6d-e). 192 The surface treated Ag NPs was then combined with PDMS to design sensitive flexible temperature sensors based on the interparticle distance-dependent transport mechanism between Ag NPs (Figure 6f). 202

ION BIOSENSORS
The ion levels in body fluid (i.e. sweat, urine, etc.) are core indicators to reflect the electrolyte activities for human body. 204,205 Taking potassium ion (K + ) as an example, it plays vital importance in multiple biological processes (including blood pressure control, regulation of muscle contractions as well as heartbeat) as one of the most abundant physiological metal ions in the living organism. [206][207][208] From fitness and medical perspectives, the flexible wearable potentiometric ion sensors can offer irreplaceable support in diagnosing of electrolyte imbalance disorders 209 and monitoring for dehydration status of the individuals. 210 The general criteria for assessing wearable potentiometric ion sensors includes responsive time, reversibility of the electrode response, resiliency and stability, appropriate calibration protocol, contact mode (noninvasive/invasive), etc (Figure 7a). 44 Ionophore is commonly used to capture ions selectively due to its high sensitivities.
As shown in Figure 7b, the polymeric membrane for selectivity capturing K + that only K + can enter its molecular structure. 17 The chemiresistors based on the combination of plasmonic units and ionophore are effective for selective ionic biosensing. The mechanism of such chemiresistors, can be expressed by the following equation:  (Figure 7c-d), which exhibited high selectivity to K + in presence of interfering cations (such as Na + , Ca 2+ ).
Since the production of Au NPs can be comfortably scaled up by synthesizing at ambient conditions, this advantage make Au NPs an appealing candidate to be used as conductive materials. 214 However, 0D NPs have a percolation threshold that is 10-100 times higher than high aspect-ratio nanowires (NWs), which usually result in poor conductivity and charge carriers scattering in the matrix due to many NP-NP junctions. 215 Compared to AuNPs, Au NWs are more suitable for establishing percolation conductivity and require lower loading of the active materials, which is highly desired for intrinsic stretchable conductors. Cheng's group 216 reported that the vertically aligned mushroom like Au NWs can serve as stretchable and wearable ionto-electron transducers for in-situ potentiometric detection of K + in sweat. Such flexible biosensors can continuously and wirelessly collect signal data (Figure 7e-f) and performed multiple and sensitive detection of pH, Na + , and K + . The challenges in chemiresistor are the universality, reusability and multi-channel detection, because each sensing mechanism for chemiresistor strongly depends on coupling between specific receptors and ions.

GAS (VOLATILE ORGANIC COMPOUNDS) BIOSENSORS
Volatile organic compounds (VOCs) refer to a class of organic molecules with melting point lower than room temperature and boiling point between 50-260 °C. Those gas molecules closely relate to human health due to their irritant to upper respiratory tract and easily causes allergic dermatitis. VOCs often release from their origin and/or fat compartment storage into the circulatory system that can be directly detected from blood and the headspace of cells. 217,218 Recently, VOCs have been regarded as cancer biomarkers due to their manifestation and accumulation in headspace of cancer cells or blood samples, even in the exhaled breath. 42, 219-221 Among them, the exhaled breath has been wildly investigated for monitoring bodily health and disorder, for its connivence and noninvasive nature (Figure 8a). 222 However, the composition of gas exhaled from human lungs is extremely complicated as there are thousands of organic compounds, therefore, there is a timing request to improve the sensitivity and precision.
Haick et al. has identified sensing strategies for more than 1,000 major compounds from exhaled breath by the human body, known as "Nano Nose" (Figure 8b). 223 In their VOCs monitoring system, the modified Au NPs that compounded with flexible substrates, can recognize specific VOCs by the interaction between ligands and VOCs.
As a result, the resistance between NPs changed due to the capture of VOCs, further resulting in changes in electrical signals. 224 The sensitivity of Au NPs-based flexible sensors mainly comes from the tunneling mechanism between neighboring Au NPs ( Figure 8c). 225 They developed two Au NPs sensing strips which are paralleling to each other with opposite thickness gradients to overcome the resolution limitation in traditional strain (or pressure) sensors. By combining ligand modified Au NPs with selfhealable polymer substrate, they also achieved noninvasive monitoring of VOCs with high sensitivity and stability (Figure 8d). 36 The diverse route to surface functionalization of plasmonic units has been usually considered as a strength for flexible plasmonic biosensors. The case becomes quite different for flexible plasmonic VOC sensors, as the recognition of specific VOC doesn't offer much room to adjust process of fabricating sensor. However, the recent colorimetric monitoring technology for gas analytes, 226 is still challenging to achieve sensitive multiple targets detection for accurate diagnosis by rich functionalization for flexible plasmonic biosensors.
Like "Nano Nose", efficient discrimination of VOCs based on SERS, which can be acted as the "optical nose" to provide fingerprint information to detect molecule. [227][228][229] To date, several SERS substrates based gas sensors have already been developed, to overcome the limitations of traditional gas sensors, i.e., long response times and narrow sensing range. 230-232 Wang's group 34 designed a SERS substrate consisting of ZIF-8 layer and Au NPs for selectively gaseous aldehydes detection ( Fig. 8e-f). 34 It is noting worthy that the ZIF-8 channel provided enough space for capturing gaseous aldehydes via the chemical interaction between 4-ATP on Au NPs and them. Importantly, the gaseous aldehydes can be sensitively detected at ppb level via the nucleophilic addition reaction with the pre-grafted Raman-active molecule of 4-ATP. This Au NPs@ZIF-8 structures-based system provides a capability to selectively trace VOCs for monitoring cancer biomarker, which indicates strong potential in the real-world applications.

COVID-19 BIOSENSORS
The outbreak of COVID-19 has by far caused a horrible public health crisis for human being, which resulted in nearly 196 million confirmed cases and over 4 million deaths globally as of July 2021. [233][234][235] The extreme contagious of COVID-19 contributed to the ultrastrong affinity of spike protein with angiotensin-converting enzyme II (ACE2), which plentifully express on the surface of human lung cells. 236 There are desperately desire to exploit new direct viral detection method by identifying viral pathogens on-demand. 237  Li and co-workers developed a rapid nano-sensing platform (Figure 9a) for sensitive detection of SARS-CoV-2 RNA by integrating Au NPs-decorated graphene into fieldeffect transistor sensor. 242 The complementary phosphonodiamidite morpholino oligos probe on surface of Au NPs presented strong capturing capability for SARS-CoV-2 RNA by minimizing background signals. Thus, the substrate supported plasmonic biosensor exhibited extremely low limit of detection in throat swab (2.29 fM) within 2 min (Figure 9b). Panat's group innovated a biosensing platform for ultra-fast (within seconds) and fingerprinted (2.8 × 10 −15 for SARS-CoV-2 spike protein) identification of COVID-19 (Figure 9c-g). 243 In their platform, the rGO on patterned Au substrate provided plenty sites for immobilizing specific viral antigens (Figure 9e) and the integration of 3D printed Au electrode with microfluidic device further improved the detecting sensitivity and stability by signal reading with the smartphone-based user interface (Figure 9f-g). The capability of plasmonic units to convert light into located heat as known as the thermoplasmonic effect, is widely applied in controllable thermal process and photothermal therapies. 246 However, the implementation of thermoplasmonic effect into biosensing remains to be fully exploited. Qiu and co-workers provide a promising solution for COVID-19 by tactful introducing plasmonic photothermal effect of plasmonic units for elevating the in-situ hybridization efficiency (Figure 9h). 244 With this plasmonic biosensor platform, the detection limit was down to 0.22 pM and precise detection of the specific target can be achieved in a multigene mixture. Pan et al.
developed a paper-based plasmonic electrochemical sensor for rapid (within 5 min), low-cost, easy-toimplement, and quantitative monitoring COVID-19 (Figure 9i), 245 where the plasmonic NPs were functionalized with identifying units and the sensitive detection signal can be recorded by a hand-held reader. At moment, researchers and scientists are making tremendous to seek high effecient therapeutic solution to fight against Covid-19, with applying plasmonic biosensor.

MOTION BIOSENSORS
Human movements monitoring has vital potential to improve the living quality via developing the products, including prosthetic, rehabilitation and surveillance. 16,20 In principle, the motion monitoring relies on stretchable strain and pressure sensors. 247,248 Noble metal NPs (Au, Ag), especially Au/Ag NWs, often exhibit high mechanical flexibility and high conductivity which has been wildly applied in flexible motion monitoring biosensors. 249,250 Cheng's group developed series strategies to monitor human motion via Au NWs-flexible plasmonic biosensors, [251][252][253][254] such as micrometrethickness strain sensors (Fig. 10a-c) 37 , which showed high stretchability (>350%), fast response time (<22 ms) and high durability (>5000 cycles). Our group 39 reported a biofriendly untra-thin flexible biosensor based on hyperbranched polyethyleneimine (PEI)-capped Au NPs (Fig. 10d-e), to monitor both physical activities and psychological states. The PEI-Au NPs were in-situ cross-linked with polydopamine, which acted as a biofriendly and adhesive flexible substrate for the biosensor.
The surface/interfacial engineering is also critical to overcome the barrier caused by the magnitude mechanical mismatch between conductive materials (noble metal NPs) and flexible polymeric substrate (i.e., PDMS, PET). Generally, the tailorable conductivity of plasmonic units endows the flexible plasmonic biosensors unique sensing performance for motion monitoring. Chen's group brought many progresses in this term (Figure 10f-g), 255,256 one of which is the stable and stretchable Au NPs/PDMS biosensor to sensitively distinguish on-skin electromyography signal. 56 Wearable and implantable devices often show higher demands on conductivity, ductility and biocompatibility. The biocompatibility has raised significant concerns, one example is that the harm to human tissues by directly exposing them to Ag NWs, caused by the possible leach out of Ag ion from Ag nanowires. 257 Choi and co-workers 157 prepared wearable and implantable biosensors based on the complex of ultralong Au-coated Ag NWs and elastomeric poly(styrene-butadiene-styrene) (SBS, Fig. 10h-i). The wearable and implantable device was able to record electro-physiological information continuously by integrating with human skin and swine heart. In light of specific conformal and mechanical features required for motion monitoring, the research focuses in this field will be to explore more effective strategies for integrating plasmonic units with flexible substrates for higher sensitivity, conformability and robustness.

FLEXIBLE PLASMONIC BIOSENSORS FOR OTHER PURPOSES
Hyperuricemia, occurring with the rise of uric acid, can degrade life quality by causing gout, fever, and pain in the joints, as well as other chronic underlying conditions such as diabetes, high blood pressure and hyperlipidemia. The uric acid in tears and blood can provide direct information for antioxidant status in the eye and gouty arthritis, respectively, for early diagnosis. 258,259 Jeong's group reported a plasmonic Schirmer strip by integrating Au NPs with flexible cellulose nanofibers for monitoring human tear based gouty arthritis (Figure 11a). 35 The hygroscopic micro/nanopores in the cellulose nanofibers were efficient for collecting human tears and the nanogap-rich Au nano-islands created sufficient electromagnetic hot spots for sensitive detection, leading to an efficient analyzing with high sensitivity (Fig. 11b).
Nowadays, skin infection caused by bacteria poses great threats to human health.
Traditional photothermal therapy brought excessive heat that damages host cells and  Although SERS is effective pathway for health-related analytes tracing, one challenge in SERS based bio-sensor is the reliability of signal with high accuracy. From this perspective, Kim and co-workers 43 achieved high SERS reproducibility (< 6%) via growing arrays of AuNPs dressed ZnO NRs on the cellulose paper ( Fig. 11e-f), which is used to identify amniotic-fluid-mediated diseases during pregnancy. Another trend in SERS is to utilize the prominent optical properties of enormous increase in the electromagnetic (EM) in the distance between plasmonic units for developing powerful wearable sensing mechanisms. [262][263][264] Another essential requirement for SERS biosensors is to maintain the plasmonic activity when coping the mechanical deformations and vibrations with body movement. 12, 265, 266 Liu's group developed a wearable plasmonic sensor with target specificity and higher stability for monitoring the drugs amounts in the body (Figure 11g-i). 38 This work decoupled the stringent mechanical requirements that is challenging for wearable SERS biosensors, the recognition of targets in sweat can reach 'fingerprint' level.

MULTIPLEXED FLEXILE OPTICAL BIOSENSORS
The visible colorimetric detection for health monitoring provide massive conveniences for their simplicity, portability, rapidity, as well as low cost. 117,267,268 Au NPs has been used as a core component of visual biosensors due to their bright colors and environmental sensitivity, i.e. the famous "Colloidal gold test strip". 117,269 By far, researches have been concentrated on enhancing the detection sensitivity, such as NPs growth amplification, enzymatic amplification, as well as NP accumulation amplification. 269 Chen's group reported a paper-based nanobiosensor to sensitively and customized detecting of biomarkers (Figure 12a), 270 (Figure 12f-g). This soft, enclosed microfluidic system has elite feature by using microchannels to capture and re-route sweat via the sweat glands, capillary effects to enable a precise feedback with minimal requirement on samples (Figure 12h-  (2) The progress in most flexible and wearable plasmonic biosensors are still bottlenecked by the conductivity and spectrum-based physical sensing mechanism. One option is to combine plasmonic and dye color change to break through the sensitivity bottleneck of visual detection. In addition, the noble metal NPs modified by ligands usually present superior stability than dyes. can support patients and clinicians to obtain clinically feedbacks on demand.
Particularly, artificial intelligence (AI), HMI as well as machine learning are playing growing significance for offering both caregiver and clinical decision support.
In short, the abovementioned challenges in flexible plasmonic biosensors need mutual efforts from interdisciplinary experts. We expect that this review will help increase understanding the development in flexible biosensors for health monitoring, thus set a clear course for the flexible biosensor technology in future.

Notes
The authors declare no competing financial interest.

ACKNOWLEDGMENTS
We gratefully acknowledge the financial supports from the National Natural Science