A Review of Functional Hydrogels for Flexible Chemical Sensors

Hydrogels have drawn considerable attention in the field of flexible chemical sensors due to their unique 3D structure, high permeability, ion‐conductivity, and tissue‐like mechanical properties. These structures and properties allow them to be functionalized into diverse sensing components and respond to chemical signals in complex environments. Herein, an overview of functional hydrogel‐based flexible chemical sensors is provided. First, the representative hydrogel materials are introduced and the operating principles for flexible chemical sensors are discussed. Then, state‐of‐the‐art functional hydrogel‐based flexible chemical sensing applications are highlighted including gas sensors, humidity sensors, pH sensors, glucose sensors, wound monitoring, and others. Finally, major challenges and opportunities in this field are provided.


Introduction
As an important component in health monitoring applications, chemical sensing is essential for real-time monitoring of human physiological information and environmental quality at the molecular level, not only for medical diagnosis, but also for preventive medicine. [1]However, traditional rigid chemical sensors DOI: 10.1002/adsr.202300021 have restrictions on practical applications, greatly affecting user comfort and mobility, as well as reducing the possibility of integration with emerging interaction approaches (e.g., augmented reality, virtual reality, and personalized medicine) in the future.Flexible chemical sensors change the way that human interacts with the external environment, in the context of "metaverse," [2] due to their promising properties such as lightness, thinness, excellent stretchability, and clinical-grade accuracy. [3]So far, flexible chemical sensors have seen widespread applications in healthcare, [4] security, [5] environmental monitoring, [6] food safety, [7] and agriculture. [8]remendous efforts have been made to improve the performance of flexible chemical sensors by developing innovative materials and device structures.Advanced materials including carbon-based materials (e.g., carbon nanotubes, graphene, and carbon dots), [1a,9] transition metal compounds (e.g., MnO 2 , MoS 2 , and Ti 3 C 2 T x MXene), [10] and hydrogels [11] have been developed to manufacture flexible chemical sensors because of their great mechanical, electrical, and chemical properties.Among them, hydrogels have emerged as one of the most ideal building blocks of flexible chemical sensors, especially in wearable applications due to their excellent biocompatibility as well as tissuelike chemical, mechanical, and biological properties. [12]Hydrogels consist of 3D cross-linking polymer networks whose interstices are filled with abundant water.These networks can swell in water and retain water as well as allow penetration of ions and molecules, while the high-water content of hydrogels can provide a moist and ion-rich environment.On the microcosmic level, the polymer chains are enriched with one or more functional groups, e.g., amine, acylamino, carboxy, and hydroxy. [13]hese functional groups can be further modified to endow hydrogels with desirable mechanical strength, conductivity, and stimulus responsivity. [14]On the macroscopical level, hydrogels exhibit favorable soft and flexible nature (withstanding even more than tenfold stretchability). [15]s the materials chemistry improves by leaps and bounds and the understanding of sensing mechanisms deepens, there are increasing efforts in the functionalization of hydrogels to expand the detecting species and enhance the sensing performance.Advanced processing technologies endow hydrogels with new properties (e.g., conductivity, antifreezing, and self-healing). [16]This is mainly done by designing cross-linking structures (e.g., interpenetrating polymer networks), [17] or hosting novel structures (e.g., nanoparticles, nanowires, and nanosheets) of conventional  [23,133] Copyright 2004, 2023, Elsevier.Reproduced with permission. [88,99]Copyright 2011, 2022, Royal Society of Chemistry.15b,69,128b] Copyright 2016, 2020, 2022, American Chemical Society.91a] Copyright 2008, The Authors, published by Multidisciplinary Digital Publishing Institute.Reproduced with permission. [132]Copyright 2018, Wiley-VCH.96b] Copyright 2021, The Authors, published by Walter de Gruyter.Reproduced under the terms of CC-BY-NC license. [131]Copyright 2020, The Authors, published by American Association for the Advancement of Science.chemical sensing materials. [18]Functional hydrogel-based flexible chemical sensors have experienced extensive development in the last two decades (Figure 1).14a,22] However, none of them summarizes functional hydrogel-based chemical sensors for environmental and human health monitoring at the molecular level.To this end, this work aims to provide a comprehensive review of functional hydrogel-based flexible chemical sensors and to suggest possibilities for future exciting developments.After a detailed introduction of hydrogel materials and operating principles of functional hydrogel-based chemical sensors, the latest applications such as gas sensors, humidity sensors, pH sensors, glucose sensors, wound monitoring, and others are presented in detail.The report concludes with a critical reflection on the current challenges and pertain-ing solutions associated with functional hydrogel-based chemical sensors.

Hydrogel Materials
Hydrogels can be classified inseveral ways, e.g., sources of polymer, types of cross-linking, and methods of preparation. [24]erein, we categorize them by the sources of polymer, namely, natural hydrogels, synthetic hydrogels, and functional hydrogels (Figure 2).Their unique chemical, biological, and physical properties are utilized to enhance sensing capability.
19a] This section presents natural hydrogels for flexible chemical sensors represented by cellulose, alginate, and chitosan.
Cellulose is the most abundant and ubiquitous polymeric raw material on the earth and is an important green renewable resource of linear polysaccharide material consisting of repeating -(1,4)-linked D-glucose units (Figure 2a). [31]It is mainly isolated and extracted from plants (e.g., wood, flax, and cotton), or produced by bacteria (e.g., Acetobacter, Sarcina ventriculi, and Agrobacterium).Cellulose has desirable mechanical properties, excellent thermal stability, structural stability, biocompatibility, and biodegradability.19c] Among them, cellulose-based hydrogels can be combined with diverse functional materials, including metal or metal oxide nanomaterials, carbon nanomaterials, and conducting polymers, to achieve composite with desired sensing capabilities. [31]For instance, Ruiz-Palomero et al. utilized carboxylated nanocellulose as a carrier for S,N-codoped graphene quantum dots (S,N-GQDs) to detect 2,4,5-trichlorophenol.The results showed that the incorporation of GQDs into hydrogels significantly enhanced the fluorescence intensity compared to pristine GQD solutions due to the interactions between the dots and carboxyl groups, where the interactions stabilized the GQDs and prevented their aggregation. [32]lginates are salts refined from brown seaweed, consisting of -L-glutamine and 1,4-linked -D-mannuronic acid (Figure 2b). [26]The gelation process and physical linkage of common alginate-based hydrogels are through the exchange of Na + with divalent cations, such as Ca 2+ , Sr 2+ , and Ba 2+ . [33]The cross-linking mechanisms between different divalent metal ions and sodium alginate vary, which may lead to significant discrepancies in the structures and characteristics of the resulting hydrogels. [34]The rich and tunable physical and chemical properties of alginate-based hydrogels, e.g., biocompatibility, biodegradability, and swellability, make them attractive for wearable and implantable chemical sensors. [35]For instance, Tamayol et al. fabricated alginate-based hydrogel fibers equipped with pHresponsive beads for long-term monitoring of wound pH levels.It should be noted that continuous measurement of wound pH is important for wound management because it reflects the current state of healing.Thanks to the excellent flexibility of the asprepared alginate-based hydrogel, the assembled pH-responsive microfibers could maintain conformal contact with the skin.Meanwhile, the hydrogel provided a biocompatible interface with the wound site to prevent adverse effects from pH-responsive beads. [36]hitosan is a natural polysaccharide derived from the deacetylation of chitin which is the main component of the exoskeleton of crustacean.It consists of randomly distributed -(1,4)-linked D-glucosamine and N-acetyl-D-glucosamine units with a degree of polymerization ranging from 500 to 5000 (Figure 2c). [37]Its biodegradability, biocompatibility, and nontoxicity have attracted immense interest in potential medical and sensor applications. [38]19a] In addition, the amine and hydroxyl groups on the chains can be modified to immobilize the sensing materials. [39]Owing to its outstanding adsorption capacity, chitosan-based hydrogels have been widely used for the detection and monitoring of heavy metal ions.For example, Gogoi et al. introduced chitosan-based carbon dot-rooted agarose hydrogel films as a hybrid solid sensing platform for the detection of heavy metal ions.The fabrication of this solid sensing platform focused on simple electrostatic interactions between NH 3 + groups in carbon dots and OH − groups in agarose.The strip of hydrogel film was simply immersed in a solution of heavy metal ions, such as Cr 6+ , Pb 2+ , Mn 2+ , and then displayed a color change upon exposure.The concentration of heavy metal examples can be quantified by the UV-visible reflectance spectrum. [40]

Synthetic Hydrogels
The first observation of synthetic hydrogels dates back to the 1960s, when Otto Wichterle and Drahoslav Lím cross-linked hydroxyethyl methacrylate with ethylene dimethacrylate. [41]This was an incredible discovery, as it meant that people could synthesize polymer with water absorption/retention capabilities and superior biocompatibility even though they do not possess any inherent biological activity. [42]Synthetic hydrogels are becoming increasingly important in various applications, e.g., point-of-care assays, medical products, and biosensors, as they can be manipulated to yield desirable physical and chemical properties, similar to their natural counterparts. [43]They have also attracted extensive interest in flexible chemical sensors, typical examples includ polyacrylamide (PAAm), [44] polyvinyl alcohol (PVA), [18b,45] polyethylene glycol (PEG), [46] and their substituted derivatives.
PAAm is a water-soluble linear polymer made from acrylamide or a mixture of acrylamide and acrylic acid.Since its structure contains an amide group that readily forms hydrogen bonds with other polymers or functional groups, it can be grafted or cross-linked to obtain a variety of functionalized hydrogels with branched or networked structures (Figure 2d). [28]6a,44b,47] For instance, He et al. constructed a conductive MXene-cellulose nanocrystals-tamarind gum-PAAm hydrogel consisting of ionically cross-linked tamarind gum network and UV photoinitiated cross-linked PAAm network.The asprepared sensor can stably indicate the change of humidity. [47]AAm hydrogels can also be employed as sensing materials in pH sensors [48] and glucose sensors [49] by ionic intensity tracking.
PVA is synthesized by the partial or complete hydrolysis of polyvinyl acetate group, rather than by polymerization of its structural monomer (vinyl alcohol), resulting in a hydrophilic synthetic polymer with semicrystalline, serrated structure, and excellent mechanical properties (Figure 2e). [29]11a] Due to their unique mechanical properties, biocompatibility, and biodegradability, PVA-based hydrogels have emerged as promising materials to manufacture wearable chemical sensors in recent years. [50]or instance, a bendable/wearable ethanol sensor had been successfully fabricated with a limit of detection (LOD) of 9.17 ppm by using PVA as coating material. [51]14a,52] For example, Pan et al. reported a conducting PVA-based hydrogel as smart ionic skin for humidity sensing.The sensing mechanism of the ionic skin could be attributed to the hydrolytic ionization and the swelling effect of PVA. [53]EG is a polar macromolecule consisting of repeating ethylene oxide units (Figure 2f). [30]It is suitable for medical products and sensor applications owing to its unique biological properties such as nontoxicity, biocompatibility, and biodegradability. [54]he cross-linking process of PEG-based hydrogels relies on connecting two or more polymer chains through chemical reactions.It benefits PEG-based hydrogel devices because the 3D structure of the cross-linked network increases the mechanical strength of the material, providing greater durability for applications with complex handling steps or harsh environmental conditions. [55]or example, Yao et al. introduced cellulose nanocrystals into PEG to fabricate flexible and responsive chiral nematic films with uniform helical structures.The resulting sensor exhibited a reversible smooth color change between green and transparent as the humidity varying from 30% to 100%, accompanied by a reversible swelling and shrinking.The mechanical strength and thermal stability of the sensors were further enhanced due to the incorporation of PEG. [56]

Functional Hydrogels
Although the key features of virgin hydrogels enable them as promising materials for sensor applications, their drawbacks, such as heterogeneity and network chain termination/entanglement, are also obvious, which can affect their mechanical properties, the diffusion rate of analytes, and the transmission rate of signals. [57]Therefore, their mechanical strength, adsorption/resolution kinetics, and sensitivity still need to be optimized.It has sparked widespread interest in constructing hybrid hydrogels by combining functional materials to improve the properties of sensors and address existing issues. [58]57c,58c] When exposed to external stimuli, the sensing material undergoes physical/chemical changes that modulate interactions between polymer chains and analytes. [59]n addition, functional hydrogels combined with conductive materials are endowed with high electrical conductivity, a fundamental property of electronics.The conductivity of hydrogels can be enhanced by doping salts, polyelectrolytes, or other conducting compositions, [45,60] including inorganic salts, [16b] gold nanoparticles, [61] silver nanoparticles, [62] magnetic nanoparticles, [63] carbon nanotubes, [64] and conducting polymers. [65]Meanwhile, other monomers can be added to improve the physical-chemical properties of the hydrogels during polymerization.For example, PAAm is one of the most commonly used substrates for tough and stretchable conductive hydrogels, and many vinyl monomers (e.g., 2-hydroxyethyl methacrylate, sodium p-styrenesulfonate, acrylic acid) have been selected to copolymerize with AAm to improve biocompatibility, flexibility, adhesion, and electrical conductivity of PAAm-based hydrogels. [66]

Operating Principles of Hydrogel Chemical Sensors
Hydrogels can exploit their special characteristics, such as hygroscopicity, swellability, and excellent permeability to construct flexible chemical sensors. [67]Typically, hydrogel chemical sensors accept inputs via analytes diffusion and then convert them into quantifiable outputs.The output signals are usually expressed in the form of volumetric, [44b] colorimetric, [17c] chemomechanical, [68] electrical, [69] and optical [70] changes.Based on the visualization of the signals, and the role played by hydrogels in chemical sensors, herein we discuss three operating principles: 1) volume/color change; 2) signal transduction; and 3) bidirectional exchange (Figure 3).For volume/color change and signal transduction, the signal occurs directly within the hydrogel body (Figure 3a,b), while for bidirectional exchange, the hydrogel acts as an interface between the biological system and the chemical sensing components (Figure 3c).

Volume/Color Change
14b,44b] Changes in the composition and structure of polymer chains or networks cause increases/decreases in the volume of hydrogels, which can be visually observed (Figure 3a,I top). [75]For example, polyelectrolyte hydrogels have collapsed or extended polymer chains resulting in a macroscopic expansion or contraction in response to inputs such as pH and ions. [68,76]74a] Hydrogels can also serve as hosts for microorganisms (e.g., Saccharomyces cerevisiae), creating living composites by exploiting genetic networks.Cell proliferation results in a controllable increase in composite volume, allowing sensors or medical devices to respond to the specific analytes, e.g., D-glucose, L-histidine, found in biological environments (Figure 3a,II). [71]nother type is the color change-based hydrogel in which indicators are embedded for the detection of chemical and biochemical signals (Figure 3a,I bottom). [77]Indicators are evenly distributed in hydrogel through reswelling form.17c,78] When receiving a chemical signal, the indicator responds rapidly to achieve a smooth transition of color. [56]Koh et al. proposed a mechanically compliant and biocompatible wearable microfluidic patch to collect and analyze sweat during exercise.A cobalt (II) chloride-containing poly(hydroxyethyl methacrylate) hydrogel coating was embedded in the serpentine-shaped channel.Among them, cobalt (II) chloride was responsive to sweat, while the hydrogel coating facilitated sweat sampling and flow.When sweat entered the sensor, the color of channel changed from deep blue to light purple as the chelation of cobalt (II) and water.The color change provides quantitative information on sweat rate and volume. [70]Furthermore, the injection of mixed indicators into hydrogels provides a reliable route to develop multifunctional chemical sensors. [79]Siripongpreda et al. utilized reswelling properties to disperse pH indicators, a mixture of GOx, and KI solution in cellulose-based hydrogel.17b] It can be concluded that volume/color change operation is simple yet effective, but not applicable to high-precision analysis.52a]

Signal Transduction
The signal transduction of hydrogel-based chemical sensors is mainly achieved through the conversion of chemical signals into electrical or optical signals and then Examples include II) living Saccharomyces cerevisiae embedded in PAAm hydrogel as a glucose sensor, and III) carboxymethyl cellulose/bacterial cellulose matrix host pH indicators and glucose oxidase enzyme (GOx) as a sweat sensor.Reproduced under the terms of the CC-BY-NC license. [71]Copyright 2020, The Authors, published by American Association for the Advancement of Science.17b] Copyright 2021, Elsevier.b) Signal transduction.Examples include II) GOx-loaded hemin/G-boronate-polyaniline hydrogel for the detection of glucose, and III) Imprinted asymmetric microlens arrays of PAAm hydrogels as a glucose sensor.Reproduced with permission. [72]Copyright 2018, Wiley-VCH.46a] Copyright 2019, Elsevier.c) Hydrogels serve as tissue/device interface that are permeable to chemical analytes.Examples include II) glucose-responsive fluorescence dye immobilized with PEG hydrogel for continuous monitoring of blood glucose concentration in vivo, and III) PAAm hydrogel-based artificial tongue used for astringency perception.46b] Copyright 2021, Wiley-VCH.Reproduced under the terms of the CC-BY-NC license. [73]Copyright 2020, The Authors, published by American Association for the Advancement of Science.
outputting.The hydrogel can be functionalized with corresponding stimulus-responsive sensing components that are determined by the target analytes (Figure 3b,I). [82]Various active elements (e.g., carbon-based, [83] metal-based, [61,84] and conducting polymer [65,85] ) have been integrated with hydrogels to monitor chemical analytes.16b,87] For instance, Bai et al. synthesized graphene oxide/polypyrrole hydrogels by in situ chemical polymerization.The resistance of the as-prepared sensor increases rapidly when exposed to an ammonia atmosphere, which is related to the dedoping of the conductive polymer by ammonia. [88]The electrical changes of functional hydrogelbased chemical sensors can also be manifested in variance of capacitance [89] and dielectric properties. [90]In addition, functional hydrogels are widely used to fabricate electrochemical sensors which is an important branch of chemical sensors.19a,82,91] For example, Zhong et al. developed a novel nanofibrous hydrogel with remarkable enzyme-like activity that can be used as an "ink" to print flexible electrochemical devices (Figure 3b,II).The as-prepared electrochemical sensor is highly sensitive to glucose. [72]onversion of chemical signals to optical signals (e.g., fluorescence, phosphorescence, transmittance/reflectance) [92] typically involves pre-crosslinking the luminescent material, such as porphyrin conjugate, thioflavin, and metal-organic frameworks (MOFs), with hydrogels that emit light of a specific intensity. [93]lternatively, the sensing components are integrated with the hydrogel to change the transmittance/reflectance intensity in response to stimulation by chemical analytes. [81,94]For instance, Gao et al. reported an agarose hydrogel-based fluorescent sensor composed of Zr-MOF, UiO-66-NH 2 , and rhodamine.This sensor can successfully detect phosphate with a low LOD of 2.0 μm.93c] As another example, Elsherif et al. demonstrated a glucose-responsive hydrogel-based optical fiber via photopolymerization.6a,b] Photonic crystals have a periodic dielectric structure that selectively modulates electromagnetic waves at specific frequencies according to Bragg's law.When attached to a stimulus-responsive hydrogel, the Bragg diffraction of the sensor varies in response to an external stimulus.The diffraction intensity of the 2D photonic crystal array provides an excellent responsivity to the change of analyte concentration. [95]

Bidirectional Exchange
Hydrogel is an ideal interface between chemical sensors and biological tissues due to its soft, biocompatibility, permeability, and ionic properties (Figure 3c,I).11b,12c,22b] The high permeability of hydrogels enables efficient bidirectional exchange of target analytes, where the hydrogels serve as substrates of chemical sensors.
12b,20] As mentioned previously, this is ascribed to the water-rich 3D crosslinked networks of hydrogels, which facilities the diffusion of analytes.11a,96] The tunable optical/electrical properties of functionalized hydrogels have significant implications for the development of high-performance implantable/wearable chemical sensors.For example, Sawayama et al. reported a wireless implantable device that incorporated a glucose-responsive fluorescent dye into a four-arm PEG hydrogel for measuring glucose concentrations in rat and pig models (Figure 3c,II).The hydrogel was mounted on top of light-emitting diodes and photodiodes for excitation and fluorescence detection, respectively.The hydrogel effectively mitigated the foreign body response and inhibited the formation of fibrous capsules, thereby minimizing the diffusion hysteresis in sensing.46b] Another example is that Liu et al. encapsulated genetically engineered bacteria in a hybrid tough, stretchable hydrogel-elastomer.The encapsulated bacteria with programmed genetic circuitry can reflect green fluorescent protein in response to different chemicals.The tough hydrogel matrix allowed the diffusion of water, nutrients, and chemicals into the lumen to be recognized by bacteria and prevented bacteria from leaking into the environment (Figure 3c,III). [73]

Applications
The development of flexible chemical sensors is driven by the monitoring of chemical analytes that are crucial indicators of human health and potential hazardous in the environment.Benefiting from their impressive properties, i.e., biocompatibility, high permeability, and tailorable mechanical and electrical properties, functional hydrogels have seen numerous applications as highperformance flexible chemical sensors.In this section, representative examples are discussed and summarized, including gas sensors, humidity sensors, pH sensors, glucose sensors, wound monitoring, and others.

Gas Sensors
Gas monitoring can be used to determine the levels of specific gases present in the environment, which plays an imperative role in environmental/health monitoring and industrial process gas analysis.For instance, NO 2 is a highly oxidized volatile gas that can affect the human immune, respiratory, and nervous systems.It greatly increases the risk of pneumonia, asthma, and neurological disorders if the concentration exceeds 1 ppm. [97]n addition, gas sensing is essential for monitoring human activities in which respiration involves changes in gas compositions and concentrations (e.g., O 2 , CO 2 , and H 2 O). [98]Flexible gas sensors can be employed for respiratory monitoring, industrial production, and other applications requiring deformable structures.Hydrogels are inherently stretchable and therefore have excellent adaptability, making them ideal for the development of flexible gas sensors.In the following part, we review flexible/stretchable hydrogel-based gas sensors for environment monitoring and wearable applications.
Regarding environmental gas (e.g., NO x and NH 3 ) monitoring, an important sensing mechanism is the diffusion of analytes into the hydrogel to participate in the electrode reaction and influence the charge transfer process. [61,99]91b] For example, a CaCl 2 -functionalized PAAm/carrageenan double network hydrogel was developed as a NO 2 sensor by a salt permeation strategy.Porous PAAm/carrageenan hydrogels were fabricated by a one-pot polymerization method and then immersed in CaCl 2 solutions to allow complete salt penetration (Figure 4a,b).When the sensor was exposed to different concentrations of NO 2 atmosphere, the current recorded by the external source meter changed significantly.In addition, the as-fabricated sensor was able to operate under large mechanical strains.87b] To continuously monitor gas concentrations under larger tensile strains, Wu et al. developed a flexible, ultrastretchable, and transparent sensor for simultaneous detection of NO 2 and NH 3 .The increased toughness was achieved by forming a double network of polymer chains.The as-prepared sensor exhibited high selectivity, sensitivity (78.5 ppm −1 ), linearity, and exceptionally low theoretical LOD (1.2 ppb) owing to the interaction between NO 2 and functional groups of the hydrogel (Figure 4e).The signal output was in the form of resistance which caused by the hindering effect of NO 2 on freemoving ions in the hydrogel (Figure 4f).15a] Other developed functional hydrogel-based flexible gas sensors have been demonstrated for the monitoring of NH 3 , [6c,88,91a,100] CO 2 , [101] NO 2 , [15b,99,102] O 2 , [91b,98a,c] trimethylamine, [19e,96a] and methanol vapor. [103]The signal output is mainly through colorimetric, [96a,101b] optical, [32,93a] and electrochemical, [91b,98a] forms.
98b] For instance, a flexible/swellable hydrogel-based chemical sensor was fabricated to monitor changes in the concentration of oxygen molecules, based on colorimetric methods.The color-changing hydrogel was formed by rapid cross-linking of the polyamine porphyrin conjugate and the 4-arm star PEG-NH 2 polymer/N-hydroxysuccinimide-PEG (SVA-PEG) at room temperature.Herein, the polyamine porphyrin conjugate is the sensing material with a green-dominated fluorescence emission in an oxygen-rich environment and a red-dominated phosphorescence emission in a low oxygenation level, realizing the "traffic light"-like change.The SVA-PEG and the 4-arm PEG dendrimers enable hydrogel to swell and absorb wound exudate (Figure 5a).The as-prepared PEG hydrogel showed a porous structure with a diameter of about 5 μm after swelling to the maximum volume, enhancing the permeation of oxygen molecules (Figure 5b-d).In addition, the colorchanging hydrogel-based oxygen sensor can maintain sufficient skin-adhesive properties (Figure 5e).The hydrogel exhibited accurate "stoplight" response to oxygen over its dynamic range from green to red, even in the presence of highly disturbed tissue auto-fluorescence (Figure 5f,g).98a] These results present newmaterial solutions for developing flexible, self-adhesive, and self-healable gas sensors with desirable performance.

Humidity Sensors
44a,105] Research on hydrogel-based humidity sensors is flourishing because the conductivity of functional hydrogel is directly related to the water content, while the adsorption/desorption of moisture inevitably leads to a change in conductivity. [53,106]17a,89] The sensing mechanism of hydrogel-based humidity sensors is mainly attributed to the swelling/deswelling effect in which the hydrophilic groups in the hydrogel matrix are stimulated by water. [47,107]Wu et al. reported a double-network glycol/glycerolbased hydrogel for humidity sensors.With the relative humidity rising from minimum to maximum, the concentration of polymer chains decreases as the ionic solubility of polymer chains increases.Furthermore,the free water molecules weaken the interference of the polymer chains, therefore reducing the resistance and improving the sensing capability. [13]Zeng et al. developed a double network hydrogels with high transparency, viscosity, and flexibility by physical and chemical cross-linking of starch and in situ radical polymerization of acrylamide from the abundant biomass.The starch-based hydrogel had a porous structure after freeze-drying, which is consistent with the fact that the hydrogel can retain a substantial amount of water (Figure 6a).Moreover, the addition of PAAm improved the mechanical performance of  [87b] Copyright 2022, Wiley-VCH.e-g) Stretchable NO 2 sensor based on PAAm/carrageenan double network hydrogels.15a] Copyright 2019, American Chemical Society.93a] Copyright 2022, Wiley-VCH.
the as-prepared hydrogels by creating a covalently cross-linked network and forming extra hydrogen bonds between the ─OH of the starch and ─NH 2 of the polymer chains, which can withstand variedying degrees of compression, stretching, and twisting (Figure 6b).The as-assembled hydrogel-based sensor exhibited remarkable accuracy in detecting ambient humidity fluctuations (between 35% and 97% RH) and a broad spectrum of deformations.The device also showed fluctuating conductance curve when exposed to irregular human exhalation (Figure 6c).It is suggested that the as-prepared sensor can effectively track changes in breath length and intensity and help identify respiratory issues. [104] addition, the ultrathin structures can enhance flexibility and sensing performance by increasing the specific surface area. [89,108]For example, a PAAm/carrageenan film with a thickness as low as 54.6 μm was used to fabricate a highperformance, stretchable, transparent, and low-cost humidity sensor (Figure 6d).As shown in Figure 6e, the responsivity of the hydrogel thin film-based humidity sensor increased with decreasing film thickness over a wide RH range.This is because the specific surface area of the hydrogel was enhanced by filming, which increased the contact area between the hydrogel and the water molecules, thereby improving the responsiveness to humidity (Figure 6f).And there was better sensing performance  [104] Copyright 2021, Elsevier.d) Scheme illustration of PAAm/carrageenan hydrogel preparation.e) Time-dependent response of humidity sensors with different film thicknesses when exposed to different RH.f) Relationship between RH and time.g) Dynamic response curves for different RH at different tensile strains.h) Dynamic response curves of the sensor to irregular human exhalation, inset is the photograph of the humidity sensor integrated with a mask.44a] Copyright 2022, The authors, published by SpringerOpen.
under high strains due to the exposure of a larger specific surface area (Figure 6g).Finally, the humidity sensor was tightly affixed to the inside of a face mask and applied to track respiratory behavior.44a]

pH Sensors
pH sensors have been investigated extensively over the past few decades because pH is an important parameter that is frequently tracked and regulated in industry and the environment. [110]110c,112] In addition, hydrogels can be functionalized by well-developed pH indicators and conductive materials to improve sensing performance. [71,113]H-responsive hydrogels are comprised of main-chain polymers featuring weakly acidic or alkaline groups that become more ionized in acidic or basic surroundings, respectively. [114]ichter et al. published an extensive, comprehensive, and intricate review on this topic in 2008.110b] To date, various cross-linking methods and conductive materials have been utilized to develop functional hydrogel-based pH sensors with high flexibility and conductivity. [79,115]For instance, a pH-sensitive poly(3,4ethylenedioxythiophene) polystyrene sulfonate/hydrophilic polyurethanes (PEDOT:PSS/HPU) hydrogel was prepared by solution casting.It responded to pH changes in solution by swelling/deswelling, resulting in fluctuating current signal output.PEDOT:PSS dispersions are colloidal particles with a diameter range from 20 to 80 nm and swell when exposed to water.These colloidal particles consist of short chains of PEDOT and long chains of PSS, where the PSS polymer chains are negatively charged and used to balance the positive charge of the PEDOT segments (Figure 7a).The as-prepared PEDOT:PSS/HPU hydrogel exhibited high flexibility and stretchability (Figure 7b).In addition, the resulting hydrogel films exhibit excellent stability and promising pH sensitivity, and can withstand extreme deformations, including twisting, bending, and stretching for 400 cycles, without significant degradation in sensing performance (Figure 7c-e). [109]As another example, Lee et al. demonstrated a wearable pH sensor employing MXene as the conductive agent and polyacrylic acid/PVA hydrogel as the pH-responsive material for muscle fatigue monitoring.The obtained sensor can effectively bind to human skin and firmly maintain its adhesion (Figure 7f).The electromechanical signals during exercise were recorded by a Bluetooth device to determine the pH change in sweat (Figure 7g).The results showed that the pH value of sweat decreased as the muscles became exhausted.110c,116]

Glucose Sensors
46b,92,118] However, traditional sampling methods usually suffer from finger pricking, limiting long-term monitoring application.39b,119a] Electrochemical analysis is one of the most widely used methods in functional hydrogel-based flexible chemical sensors for glucose monitoring due to its easy integration, simple operation mode, and wide detection range.For example, Liang et al. fabricated a flexible electrochemical glucose sensor based on quaternized chitosan/oxidized dextran hydrogel.The hydrophilic network of the as-prepared hydrogels enabled the infiltration and enrichment of glucose, thus increasing the contact area between glucose and GOx, and broadening the detection range.The sensor was assembled on a flexible three-electrode screen-printed chip (Figure 8a,b), and the signal output was in the form of current.The anode current increased correspondingly in a stepwise manner when different concentrations of glucose solution were added sequentially to the electrolyte, indicating that the as-assembled functional hydrogel-based flexible chemical sensor has high sensitivity and fast response for glucose (Figure 8c). [117]n addition, PBA and Concanavalin A can reversibly bind to glucose, leading to an increase in the distance of polymer chains, thereby changing the optical/electrical properties of hydrogel. [92]or instance, Yetisen et al. designed a hydrogel optical fiber made of poly(acrylamide-co-polyethylene glycol diacrylate) core and calcium alginate cladding for continuous glucose monitoring.When glucose penetrated the fiber core and reacted with PBA, the osmotic pressure of the hydrogel increased and resulted in a change in the network density (Figure 8d).The asprepared hydrogel fiber is flexible and biocompatible, and can be injected into epidermis (Figure 8e).The glucose content is derived by detecting the refractive index variations of the fiber (Figure 8f). [94]

Wound Monitoring
Wound healing is a complex process.Wound monitoring plays a pivotal role in clinical and public health care, especially in patients with diabetes who may suffer from infections due to improper wound management. [122]Traditional gauze bandages are popular in wound healing due to their low cost and excellent air permeability, but they are uncomfortable for a long time wearing because of the need for repetitive uncovering for inspection and dressing replacement. [123]21a,120] Among them, functional hydrogel based-chemical sensors have attracted extensive attentions due to their intrinsic flexibility, excellent biocompatibility, sensitivity to wound exudate components, and ability to integrate with drug delivery, etc. [36,124] They can respond to the variations of wound exudate compositions in real-time by colorimetric or signal transduction, [47,78b,90] and achieve drug delivery by exploiting the structure changes under stimulation. [125]For instance, a multifunctional wound dressing was established for dynamic monitoring of pH and glucose in the wound area, and for promoting wound healing (Figure 9a).The as-integrated patch was highly transparent to help observe the status of wound, and outputted the accurate pH value and glucose contents in electrochemical signals. [120]As another example, Liang et al. proposed a The electrical response of printed pH sensors to both ascending and descending pH changes.Reproduced with permission. [109]Copyright 2018, Wiley-VCH.f) Photograph of squat exercise pose.The inset schematic shows the M-hydrogel sensor exposed to human sweat during exercise.g) Measured pH value during exercise.18b] Copyright 2021, Wiley-VCH.
dual pH and glucose responsive hydrogel based on the dynamic bonding of Schiff bases and phenylboronate for the release of metformin.Here, the Schiff base serves as pH-sensitive material, while the PBA is responsive to glucose.125a] In addition, taking advantage of the liquid properties of hydrogel, Wang et al. utilized 3D printing technology to prepare smart wound dressing for on-demand treatment.The hydrogels were formed by radical polymerization of quaternary ammonium-type chitosan and acrylamide monomers (HACC-PAAm), obtaining a highly cross-linked 3D network structure (Figure 9b).The asprepared hydrogels had strong adhesion and stretching properties and could follow the motions of human fingers (Figure 9c),  [117] Copyright 2020, Elsevier.d) Structural composition of the glucose-sensitive fiber core cladded with calcium alginate, and quantified the concentration of glucose molecules by measuring the variation in the intensity of the output light.e) The implantation of hydrogel optical fibers in porcine tissue.f) Transmitted light intensity across the hydrogel fiber measured in different glucose concentrations.Reproduced with permission. [94]Copyright 2017, The Authors, published by Wiley-VCH.
which is crucial for long-term usage.Meanwhile, the transparent hydrogel facilitated colorimetric sensing.Figure 9d shows the linear relationship between color intensity of hydrogels and pH value, and the inset are the corresponding photographs of the as-prepared hydrogel under different pH.The results show that the hydrogels have excellent specificity and sensitivity in response to H + while monitoring the wound state.Furthermore, the as-prepared wound monitors promoted wound healing in mice (Figure 9e), attributing to a reduction of underlying inflammation and promotion of nearby tissue growth (Figure 9fg). [121]Table 1 provides a summary of recently reported functional hydrogel-based chemical sensors for wound monitoring.

Others
Other applications of flexible chemical sensors for detecting ions (e.g., Na + , K + , Hg 2+ , Cu 2+ ), [6b,96a,128] alcohol, [69] DNA, [129] pesticide, [130] astringency perception, [131] and living cells [132] have also been developed with functional hydrogels.For example, a skin-like hydrogel elastomer-based electrochemical sensor has been fabricated by employing PAAm/calcium alginate hydrogels as a substrate to achieve conformal contact with skin, while thermoplastic polyurethane (TPU) film as an interlayer to bridge the hydrogels and conductive ink.The hydrogel precursor solution was prepared by crosslinking acrylamide with N, N'methylenebis-acrylamide and calcium sulfate, which was then carefully casted onto the oxygen plasma-treated side of the TPU film to form stretchable and tough hydrogels.The as-prepared hydrogel-TPU hybrid had a tensile strength of up to 1100% strain and a Young's modulus of 0.37 MPa similar to that of skin.In addition, the assembled electrochemical sensor demonstrated high sensitivity (58.14 mV −1 pH for pH, 58.89 mV decade −1 for Na + , and 59.11 mV decade −1 for K + ), excellent specificity and reproducibility for detecting electrolytes in sweat. [133]For chlorpyrifos pesticide monitoring, Yan et al. embedded the fluorescent indicators, namely gold nanoclusters@zeolite-like imidazole framework (AuNCs@ZIF) composites, in double network hydrogels (glutaraldehyde cross-linked bovine serum albumin and Ca(II)mediated alginate) to fabricate a flexible chemical sensor.Here, the ZIF framework is an ideal structure to achieve aggregationinduced emission through steric confinement effect, while the hydrogels worked as a host to improve the sensitivity by stabilizing the fluorescent signal and providing antifouling properties.Fluorescence images of hydrogels were converted into data information using a homemade portable device consisting of a 3D printed accessory and a smartphone.The device exhibited excellent linearity over the concentration range of ≈0.5-10 000 ng mL −1 of chlorpyrifos and a low LOD of 0.2 ng mL −1 . [130]

Conclusions and Perspectives
The advantageous physical and chemical properties of functional hydrogel include intrinsic softness, three-dimensional  [121] Copyright 2022, Elsevier.
nanostructure, excellent permeability, swellability, conductivity, and biocompatibility/biodegradability, and large-scale industrial accessibility, all of which provide strong benefits for the development of high-performance flexible chemical sensors.In this review, we first introduce common polymers for functional hydrogel-based chemical sensors, such as natural hydrogels, synthetic hydrogels, and functional hydrogels.Subsequently, we summarize three operating principles of functional hydrogel-based flexible chemical sensors, including 1) volume/color change, 2) signal transduction, and 3) bidirectional exchange according to the role played by hydrogels in chemical sensing process.We then present recent advances in functional hydrogel-based flexible chemical sensors toward environmental and human health monitoring, with a focus on gas sensors, humidity sensors, pH sensors, glucose sensors, wound monitoring, and others.Despite the great progress in this field, there are still challenges.We outline several remaining challenges with pertinent solutions below.

Sensing Performance
106b] For example, MOFs hydrogels are reliable fluorescent sensing platforms for chemical sensing owing to their solid framework structure, rich porosity, and versatility. [134]58c,135] However, hydrogels are not yet ideal candidates for high-performance commercial sensors due to their limited electrical conductivity, mechanical strength, and fatigue resistance.In this case, the introduction of diverse functional components to modulate the physical and chemical properties of hydrogels is a fascinating strategy to improve the measurement capabilities in real-life situations.12a,b] Further studies should combine experimental analysis, theoretical calculations, and macroscopic modeling to better understand the interactions of hydrogels with other functional components to reduce the burden of development while improving sensor performance.Another important fact is that the existing hydrogels are mostly used as coatings or hosts in a passive manner, rather than in an active, responsive function. [86]Therefore, the development of all-hydrogel flexible chemical sensors, which is possible to truly realize tissue-like devices, can be considered in the future by developing actively responsive hydrogels.

Manufacturing Strategy
57b] Future flexible chemical sensors require high precision and small size for wearable and implantable applications.However, hydrogels are difficult to be patterned into high-resolution structures by conventional techniques owing to their high-water content.22a] Recent study by Zhong et al.  shows that the hydrogels responding to shear stress can rapidly switch between sol and gel states, facile to fabricate different patterns. [72]Lithography, e.g., imprint lithography, photolithography, and flow lithography, is another fascinating strategy for fabricating hydrogel devices at the microscale.However, the pattern obtained by lithography is relatively simple since the crosslinked hydrogel may need to be removed from the mold.34b,96a] There is also a need to improve existing processes and develop new manufacturing strategies in synergy with the development of materials.

System Integration
The ultimate goal of functional hydrogel-based flexible chemical sensors is to achieve closed-loop sensing systems that can be deployed in real-life situations, where their power supply, data analysis, communication, and management should be considered.Therefore, the robust integration of functional hydrogels with bioelectronic devices and biological tissues is another challenge in this field.Liquid environments and wet substrates prevent hydrogel from adhering to target surfaces and lead to device failure.Recently, progress has been made in the interfacial adhesion properties of hydrogels, such as mussel-inspired selfadhesive hydrogels, [138] Janus hydrogels for bioadhesion to wet surfaces, [139] and hydrogels with strong adhesion in both aqueous and oily environments. [140]Catechol groups are capable of forming covalent and noncovalent bonds with a variety of materials.Therefore, functionalization of hydrogels with catecholcontaining compounds, such as polydopamine, tannic acid, and tea polyphenols, is an important strategy to improve self-adhesive properties. [141]In addition, the establishment of effective interfacial bonding of hydrogels to target surfaces is a promising research direction.This can be achieved by modulating the synergistic interaction between hydrophilic and hydrophobic polymer chains and by removing the interfacial liquid layer. [140]In the future, the enhanced adhesion properties will provide reliable and conformal contact of integrated functional hydrogel-based flexible chemical sensors with tissues, thus enabling high device stability and signal fidelity.In addition, in laboratory research, most hydrogel-based chemical sensors focus on detection of single analyte and require external power source.Therefore, rational design to fabricate multifunctional and self-powered chemical sensing systems with capability of monitoring multiple analytes is expected.To achieve this goal, novel functional materials, transduction mechanisms, and integration methods need to be further explored in the future.

Long-Term Stability
Despite the great progress in hydrogel-based wearable and implantable electronics, there remains an urgent need for future research to improve the chronic stability and the biocompatibility of hydrogels due to dehydration and the impact of foreign body reactions and damages.Water volatilization caused by high temperatures and dry conditions will affect the mechanical properties of hydrogels, severely limiting their service life and application scenarios.The construction of anti-drying hydrogels by adding hygroscopic salts or water-retaining agents is a promising material solution for applications exposed to air. [13,142]2b,143] A promising solution is to construct functional hydrogels with interpenetrating network structures and sufficient dynamic noncovalent bonds by controlling the cross-linking approaches and synthesis steps.98a] Moreover, the lighter and thinner structural designs should be targeted for better mechanical compliance, which can effectively facilitate long-term, and real-time health monitoring imperceptibly.For the tradeoff of mechanical compliance and robustness, innovative materials design is necessary. [3,144]Last but not least, for on-skin applications, permeable hydrogels enable long-term health monitoring and should be further developed. [145]

Commercialization
The advent of hydrogels offers great market prospects for healthcare, pharmaceuticals, etc.At present, many hydrogel-based drugs and wound dressings have been successfully commercialized, such as Advil for fast pain relief, Gaviscon for acid reflux, Kaltostat, and Helix3-cm for wound dressing.A few commercial drugs have utilized the basic chemical sensing ability of hydrogel, which is essentially based on structural expansion caused by glucose level, pH value, and ionic strength, to achieve controlled drug release.42a] For commercialization of hydrogel chemical sensing and therapeutics, an important direction is the development of smart hydrogels to monitor wound healing status (e.g., glucose levels and pH) in real-time for targeted drug release.11a,22a] The raw materials, processing methods, biocompatibility, sensing reliability, and cost-effectiveness of hydrogel flexible chemical sensors need to be further validated for their transition from the lab to the factory.
Besides the aforementioned challenges, there is a great need for extensive interdisciplinary teamwork of experts in mechanics, microelectronics, computing, clinic, and medicine to translate functional hydrogel-based flexible chemical sensors from laboratory prototypes to real-life commodities.It is expected that, after addressing these issues and together with the combined multidisciplinary efforts, functional hydrogel-based chemical sensors will expedite the development of soft bioelectronics toward smart diagnostics and therapeutics.

Figure 1 .
Figure 1.Representative examples of functional hydrogel-based flexible chemical sensors over the last two decades.Reproduced with permission.[23,133]Copyright 2004, 2023, Elsevier.Reproduced with permission.[88,99]Copyright 2011, 2022, Royal Society of Chemistry.Reproduced with permission.[15b,69,128b]Copyright 2016, 2020, 2022, American Chemical Society.Reproduced under the terms of CC-BY-NC license.[91a]Copyright 2008, The Authors, published by Multidisciplinary Digital Publishing Institute.Reproduced with permission.[132]Copyright 2018, Wiley-VCH.Reproduced under the terms of CC-BY-NC license.[96b]Copyright 2021, The Authors, published by Walter de Gruyter.Reproduced under the terms of CC-BY-NC license.[131]Copyright 2020, The Authors, published by American Association for the Advancement of Science.

Figure 3 .
Figure 3. Operating principles of functionalized hydrogel in chemical sensors.a) Ambient input for hydrogel detection with volume/color change.Examples include II) living Saccharomyces cerevisiae embedded in PAAm hydrogel as a glucose sensor, and III) carboxymethyl cellulose/bacterial cellulose matrix host pH indicators and glucose oxidase enzyme (GOx) as a sweat sensor.Reproduced under the terms of the CC-BY-NC license.[71]Copyright 2020, The Authors, published by American Association for the Advancement of Science.Reproduced with permission.[17b]Copyright 2021, Elsevier.b) Signal transduction.Examples include II) GOx-loaded hemin/G-boronate-polyaniline hydrogel for the detection of glucose, and III) Imprinted asymmetric microlens arrays of PAAm hydrogels as a glucose sensor.Reproduced with permission.[72]Copyright 2018, Wiley-VCH.Reproduced with permission.[46a]Copyright 2019, Elsevier.c) Hydrogels serve as tissue/device interface that are permeable to chemical analytes.Examples include II) glucose-responsive fluorescence dye immobilized with PEG hydrogel for continuous monitoring of blood glucose concentration in vivo, and III) PAAm hydrogel-based artificial tongue used for astringency perception.Reproduced with permission.[46b]Copyright 2021, Wiley-VCH.Reproduced under the terms of the CC-BY-NC license.[73]Copyright 2020, The Authors, published by American Association for the Advancement of Science.

Figure 5 .
Figure 5. Flexible/swellable gas sensors from functional hydrogels.a) Schematic of the one-pot synthesis of a swellable oxygensensing hydrogel.Inset are photographs of the as-prepared hydrogel under different oxygen concentrations.b) SEM image of blank hydrogel.c) SEM image of hydrogels containing polyamine porphyrins.d) Pore size distribution of hydrogel with and without polyamine porphyrins (p < 0.0001).e) Photograph of hydrogel adhering to tissue.f) Quantitative luminescence photography of a dual-emissive conjugate.g) Derive normalized oxygen calibration scaled from the Stern-Volmer relationship.Reproduced with permission.[93a]Copyright 2022, Wiley-VCH.

Figure 6 .
Figure 6.Flexible/stretchable humidity sensors from functional hydrogels.a) SEM image of freeze-dried starch hydrogel.b) Photographs of twisting hydrogel.c) Real-time response of the starch hydrogel-based humidity sensor to irregular human exhalation.Reproduced with permission.[104]Copyright 2021, Elsevier.d) Scheme illustration of PAAm/carrageenan hydrogel preparation.e) Time-dependent response of humidity sensors with different film thicknesses when exposed to different RH.f) Relationship between RH and time.g) Dynamic response curves for different RH at different tensile strains.h) Dynamic response curves of the sensor to irregular human exhalation, inset is the photograph of the humidity sensor integrated with a mask.Reproduced according to the terms of the C-CBY license.[44a]Copyright 2022, The authors, published by SpringerOpen.

Figure 7 .
Figure 7. Flexible/stretchable pH sensors from functional hydrogels.a) Schematic illustration of the impact of pH on molecular structure of PEDOT:PSS.b) Flexible fully swollen PEDOT:PSS/HPU hydrogels wrapped around a 4 mm glass.c) The swelling behavior of the PEDOT:PSS/HPU hydrogels in Milli-Q water after 1 week and 2 months.d) Correlation between resistance and pH of the solution for PEDOT:PSS/HPU hydrogels.e)The electrical response of printed pH sensors to both ascending and descending pH changes.Reproduced with permission.[109]Copyright 2018, Wiley-VCH.f) Photograph of squat exercise pose.The inset schematic shows the M-hydrogel sensor exposed to human sweat during exercise.g) Measured pH value during exercise.Reproduced with permission.[18b]Copyright 2021, Wiley-VCH.

Figure 8 .
Figure 8. Flexible/bendable pH sensors from functional hydrogels.a) Schematic illustration of constructing a glucose sensor on a screen-printed circuit.b) Photograph of the constructed glucose sensor.c) Response of the flexible sensor to the repeated addition of 4 and 8 mm glucose in the electrolyte at 0.6 V. Reproduced with permission.[117]Copyright 2020, Elsevier.d) Structural composition of the glucose-sensitive fiber core cladded with calcium alginate, and quantified the concentration of glucose molecules by measuring the variation in the intensity of the output light.e) The implantation of hydrogel optical fibers in porcine tissue.f) Transmitted light intensity across the hydrogel fiber measured in different glucose concentrations.Reproduced with permission.[94]Copyright 2017, The Authors, published by Wiley-VCH.

Figure 9 .
Figure9.Flexible/stretchable wound dressing from functional hydrogel.a) Schematic illustration of constructing multifunctional wound dressing for wound closure, bacteriostasis, and wound infection monitoring.Reproduced with permission.[120]Copyright 2022, Wiley-VCH.b) SEM image of HACC-PAAm hydrogels.c) Photograph of HACC-PAAm hydrogels adhere in finger.d) The relationship between color intensity and pH value, inset are the photographs of HACC-PAAm hydrogel under different pH values.e) Photographs of skin wound in different days.f) Wound area in different days.g) Epithelium thickness in different days.Reproduced with permission.[121]Copyright 2022, Elsevier.

Table 1 .
Applications of hydrogel-based flexible chemical sensors for wound monitoring.