Recent Advances in Chitosan-Based Hydrogels for Flexible Wearable Sensors

Abstract

Flexible wearable sensors show great potential for applications in wearable devices, remote health monitoring, artificial intelligence, soft robotics, and artificial skin due to their stretchability, bendability, thinness and portability, and excellent electrical properties. Hydrogels have tunable mechanical properties, excellent biocompatibility, and flexibility, making them attractive candidates for wearable flexible sensors. Among them, tremendous efforts have focused on the advancement of chitosan-based hydrogels (CS-Gels) to realize multifunctional wearable sensing by modifying hydrogel networks with additives/nanofillers/functional groups. Recently, remarkable progress has been made in flexible wearable sensors. Herein, this review summarizes recent advances in CS-Gels wearable sensors for applications such as human motion monitoring, health monitoring, human-machine interface and soft robotics. Representative synthesis methods and strategies for CS-Gels are briefly described, the problems and deficiencies of CS-Gels for wearable sensors are discussed. Finally, the possible opportunities and challenges for the future development of CS-Gels flexible wearable devices are proposed.

1. Introduction

Flexible wearable sensors are receiving increasing attention for their great potential in personalized health monitoring, human-machine interfaces, clinical diagnosis, soft robotics, and electronic skin [1,2,3]. Wearable sensors can convert external mechanical stimuli into easily detectable electrical signals with portability, high flexibility, fast response, and good compliance. Thin, lightweight, and portable flexible sensors facilitate the monitoring of health and exercise information, which is conducive to the timely detection, prevention, or rehabilitation of diseases. Currently, flexible wearable sensors have made remarkable progress and have been widely used for the detection of pulse, motion, temperature and biochemical parameters [4,5,6]. However, there are still many problems to be solved in the development of flexible wearable sensors. The conductive functional materials for flexible sensors mainly include carbon-based nanomaterials, liquid metals, and conductive polymers. Most of the conductive functional materials have complicated preparation processes, which increase the manufacturing cost of flexible sensors. In recent decades, many efforts have been made in designing high-performance electronic sensing materials [7,8,9,10]. In this regard, hydrogel-based flexible wearable sensing materials are ideal candidates for the fabrication of wearable sensors by easily tuning the mechanical properties, electrical conductivity, network structure, and biochemical properties of hydrogels.

Chitosan (CS) is the only alkaline polysaccharide present in nature, which is deacetylated from chitin, and has attracted great interest in the biomedical field due to biocompatibility, non-toxicity, biodegradability, antimicrobial ability and safety. Notably, the large number of hydroxyl and amino groups in the molecular structure of chitosan can lead to the development of physical/chemical crosslinked CS-Gels in different fields. The main physical interactions that form CS-Gels mainly include molecular entanglement, van der Walls forces, electrostatic forces, hydrogen bonds, interpolymer complexes, ionic and hydrophobic linkages [11,12]. However, physically crosslinked CS-Gels also pose some problems, such as lack of elastic modulus, tensile strength, and toughness. Moreover, a variety of chemical interactions can occur between the -OH and -NH₂ groups on CS and the function groups in the chemical crosslinkers. Among them, crosslinking agents are molecules with at least two reactive groups that allow for the formation of bridges between polymer chains. Currently, the most common chemical crosslinkers for the manufacture of CS-Gels are dialdehydes (e.g., glutaraldehyde, acetaldehyde) and epoxides (e.g., epichlorohydrin, ethylene glycol diglycidyl ether, genipin) [13,14,15]. The physicochemical structure and mechanical properties of physically crosslinked CS-Gels can be easily tuned by modifying parameters such as the type and concentration of CS crosslinking agents. In addition, CS-Gels also exhibit unique porous structures, high capacitance and flexibility and are considered as promising materials for developing flexible wearable sensors. Over the past few years, many reinforcing substances, such as metal nanomaterials, carbon-based materials, and polymers, have been incorporated into CS, and the resulting CS-Gels have significantly improved in flexible wearable sensors [16,17,18].

Recently, with the increasing popularity of CS-based materials, many excellent reviews have been published on the subject. However, most of them focus on the fields of biomedicine, adsorbents, environmental remediation and food engineering [19,20,21,22]. Thus, a comprehensive and undated review of CS-Gels based flexible wearable sensors is still lacking. Herein, this article reviews the research on the application of CS-Gels in flexible wearable sensors. Firstly, the chemical structure and physicochemical properties of CS-Gels are introduced, and the synthetic strategies and design principles of CS-Gels for wearable sensors are summarized. The research and application of flexible wearable sensors based on CS-Gels in different fields are mainly discussed. Finally, the challenges and development directions of CS-Gels based flexible wearable sensors are summarized and prospected.

2. Structure and Properties of CS

Chitosan is the product of N-deacetylation of chitin, which is the most basic and important derivative of chitin. Chitin, also called β-(1,4)-2-acetamido-2-deoxy-D-glucose, widely exists in the shells of crustaceans such as shrimps, carbs and insects, as well as in the cell walls of fungi and algae. Chitin and chitosan have been intensively used in many fields including biomedical materials, food additives, environmental protection, agriculture, cosmetics, medical treatment and drug development due to their biodegradability, biocompatibility and antibacterial abilities [23,24,25,26]. The annual biosynthesis of chitin on earth amounts to billions of tons, and it is a natural polymer compound whose output is second only to cellulose in production. Chitin, chitosan and cellulose have similar chemical structures, with fiber being hydroxyl at the C2 position, and chitin and chitosan are replaced by an acetylamino and amino group at the C2, respectively [27,28]. They are all polymers of six-carbon sugars with a molecular weight of more than one million. The sources and chemical structures of chitin and chitosan are shown in Figure 1.

The amino group in the molecular structure of CS is more reactive than the acetylamino group in the chitin molecule, which gives CS unique properties and enables chemical modification. CS exhibits a double helix structure with a helical pitch of 0.515 nm, and six sugar residues form a helical plane [27]. The amino groups, hydroxyl groups and N-acetylamino groups on the molecular chain of CS involved in the formation of intramolecular and intermolecular hydrogen bonds, forming the secondary structure of CS macromolecules. CS molecules are more likely to form crystalline regions because of the large number of hydrogen bonds, thus having high crystallinity and good physical and mechanical properties such as adsorption, film-forming, fiber-forming and moisturizing [29,30,31,32].

3. Design and Preparation of CS Hydrogels

Polymer hydrogels are highly water-swellable three-dimensional (3D) crosslinked networks that can rapidly swell in water and retain a large volume of water without dissolving in this swollen state [33,34]. The amount of water absorbed is closely related to the crosslinking density, the higher the degree of crosslinking, the lower the water absorption. This property of polymer hydrogels is similar to biological soft tissues, showing good physicochemical and biological properties, has wide application prospects in the controlled release of drugs, bioadhesion and biodegradable materials [35,36]. Chitosan acidic aqueous solution will immediately form a hydrogel when it encounters an alkaline environment, which is greatly affected by environmental pH. Therefore, the conventional preparation methods of CS hydrogels include physical crosslinking, chemical crosslinking and radiation crosslinking. In addition, the electrochemical deposition method developed in recent years for the preparation of CS gels has the characteristics of simple, rapid, non-polluting, reversible and controllable process, and is an economical and green new method for preparing chitosan gel [37,38,39,40].

3.1. Physically Crosslinked CS Hydrogels

Physically crosslinked hydrogels are mainly formed by crosslinking 3D network structures by physical interactions such as intermolecular entanglement, hydrogen bonds, hydrophobic interaction, van der Waals forces, coordination bonds, and ionic bonds [41,42,43,44]. Physically crosslinked hydrogels can be regarded as reversible hydrogels, and changes in physical states, such ionic strength, pH, temperature, stress, and solutes, could disrupt the structure of gels. Smart hydrogels with good biocompatibility and environmental responsiveness could be obtained under mild experimental conditions, which has become one of the current research hotspots [45,46,47].

Physically crosslinked hydrogels are generally prepared by the following methods: (1) Freeze-thaw cycles: hydrogels are prepared by microcrystals formed by repeated freeze-thaw processes [48,49]. (2) Ionic action: the principle of which is to use the electrostatic action of ions to form hydrogels. This method aggregates polyvalent ions with opposite charges in a polyelectrolyte solution to form a hydrogel [50,51]. The polycationic effect of CS and polyanionic polymers such as polyacrylic acid and alginate form hydrogels through electrostatic attraction between anions and cations. (3) Hydrogen bonding: the most common crosslinking method in physically crosslinked hydrogels [52,53,54]. The formed hydrogels are usually reversible, and hydrogen bonds are easily destroyed in salt solutions. (4) Hydrophobic interaction: when the polarity of the polymer solution changes, it will affect the hydrophobic interaction between molecular chains [55,56]. When this physical interaction increased, it can promote the self-assembly of molecules to form a gel. The solvent has a great dependence on hydrophobic interactions and affect the degree of crosslinking of polymer chains. Wearable strain sensors were prepared by dynamic physical crosslinking of polyacrylic acid, CS, and graphene oxide in a mixed solvent of water and glycerol [57], as shown in Figure 2a. The physical crosslinked CS gel had high stretchability (over 1000%), anti-freeze (use temperature range −20~70 °C), and excellent sensing performance (response time 40 ms).

Self-healing hydrogels can be obtained by using the physical interaction between two polysaccharide chains of soluble pectin and CS (Figure 2b) [58]. Cryo-SEM revealed the presence of nanogels in the crosslinked matrix (Figure 2c). Due to the dynamic interaction between the pectin chains and the CS nanogels, the formed networks dissociated under the applied shear, allowing the hydrogel to flow. When the applied shear was removed, the storage modulus of the hydrogel can be quickly and fully recovered. The Young’s modulus of the hydrogels increased with increasing CS gel content (Figure 2d) indicating that higher crosslinking led to higher strength of the hydrogel.

3.2. Chemically Crosslinked CS Hydrogels

The chemical crosslinking method refers to the CS molecular chains involved in network through covalent bonds in the presence of crosslinking agents. Usually, glutaraldehyde (GA) [59,60,61], epichlorohydrin [62,63], formaldehyde [64,65], and genipin [14,66,67,68], are used as chemical crosslinking agents to form new covalent bonds at the crosslinking sites, so the chemical crosslinking process is generally irreversible and has good stability. Chemical crosslinking is an important method for preparing CS gels because it enhances the physical and mechanical properties of CS. The CS molecular chain contains a large number of hydrophilic groups, especially the amino group at the C2 position is often used as a crosslinking point, which can chemically interact with the functional groups on the crosslinking agent to form a crosslinking network [69,70]. To date, dialdehyde, especially glutaraldehyde (GA), are the most studied and prevalent crosslinkers for chemically modified chitosan. Dialdehyde formyl groups react with amino groups in CS to form covalent imine bonds. The semi-interpenetrating polymer network (IPN) hydrogel was prepared by crosslinking chitosan-polyvinylpyrrolidone with GA, and the gel showed good pH responsiveness [71]. In the presence of GA, crosslinked chitosan gels grafted with aminopropylsilane graphene oxide (GO) were prepared by sol-gel in acidic medium. The gel has high surface active sites and low swelling properties [72]. Khapre et al. modified chitosan with aniline in the presence of formaldehyde, and then further crosslinked chitosan with alginate using GA to obtain biocomposite gels [59]. Bilal et al. used 2.0% (v/v) GA to functionalize for 3 h in order to produce a fungal laccase-chitosan biocatalyst. This study demonstrates the efficient binding of laccase on the biopolymer network of glutaraldehyde-crosslinked chitosan, thereby enhancing the storage stability and substrate oxidation potential of the material [15].

The chemical reaction conditions using aldehyde groups and chitosan amino groups are mild and do not require the introduction of other auxiliary molecules such as reducing agents. However, the drawback of dialdehydes (GA, glyoxal, etc.) as crosslinkers is their high level of cytotoxicity and carcinogenic effects. The natural biological crosslinking agent genipin is an iridoid compound because its biological toxicity is much lower than other small organic molecules (formaldehyde, GA, etc.), and it is often used as a chemical crosslinking agent instead of aldehydes [73,74]. The biotoxicity of chitosan hydrogels can be greatly reduced. As a water-soluble bifunctional crosslinker, it reacts rapidly with chitosan to generate blue, fluorescent hydrogels. Under acidic and neutral conditions, genipin and chitosan are linked by amides and tertiary amines to form a crosslinked structure [75], as shown in Figure 3a. Delmar et al. studied genipin-crosslinked chitosan hydrogels and found that pH and crosslinking time significantly affected the properties of chitosan hydrogels (Figure 3b) [76]. Changing the pH in the range of 4.00–5.50 significantly affected the reaction, resulting in different appearance and properties of the hydrogel (Figure 3c). Increasing the pH by 1.5 units resulted in a fourfold reduction in gel time and a more than tenfold equilibrium swelling. The swelling ability of the hydrogel was significantly pH dependent, which was attributed to the degree of protonation of CS and the inability of protonated CS to react with genipin. Tavares et al. investigated the effect of deacetylation degrees (DD, 83, 94 and 96%) on the properties of chitosan-genipin crosslinked gels. Using dynamic rheological tests, they confirmed that CS gel strength depends on frequency and temperature. The higher DD of CS, the lower the gelation temperature and the stronger the gel network structure. In addition, the high DD of CS is easier to crosslink with genipin, which can significantly improve the mechanical properties of the gel [66]. Nasrabadi et al. modeled two chitosan polymer sequences and six monomer units crosslinked by genipin [77]. The formation mechanism of genipin-crosslinked chitosan (GSC) was studied by calculating activation enthalpy and activation Gibbs free energy. The results suggested that H₂O molecules were involved in the formation of the gel by substituting secondary amide bonds for the ester functional group of genipin through a tetrahedral intermediate (SN2 mechanism). Comparing the GCS model with a simple model of one polymer chain showed that the GCS model had more negative binding energies and stronger hydrogen bonds than the simple model. Muhammad Ubaid et al. prepared and optimized chitosan hydrogel membranes containing metformin using different concentrations of genipin as a crosslinker [14]. The gel membranes exhibited significant pH-sensitive behavior. The presence of hydrogen and ionic bonds between chitosan and genipin ensures that the drug is intact in the matrix system. The obtained hydrogels can be used for drug delivery. The ninhydrin assay allows for the measurement of the cross-linkage of the genipin crosslinked chitosan network and determination of the appropriate crosslinker concentration for gels used for swelling and thermomechanical analysis. Using a combined analysis of the modified Arrhenius and William Landel Ferry theories, Whitehead et al. determined the glass transition temperature range of −68 to −8 °C for genipin-crosslinked chitosan networks (40~60%, w/w solids), providing important guidance for the design and control of targeted delivery systems for biologically active compounds [78].

3.3. Irradiation-Crosslinked CS Hydrogels

The radiation crosslinking method refers to the gelation of CS by the interaction between molecular chains to form a crosslinked network structure under the action of high-energy light source such as ultraviolet rays, electron beams, γ-rays, etc. Irradiation can cause crosslinking and gel formation when the polysaccharide solution at the high concentration. Huh et al., introduced methacrylate groups on the CS molecular chain to obtain methacrylated hexanoyl glycol chitosan (M-HGC), and irradiated them with UV light at 220–260 nm [79]. It was found that there was a significant change at 15 min under UV irradiation and the signal of double-bonded peaks almost disappeared after 30 min and formed a gel, indicating that the crosslinking of C=C occurred under light irradiation. N-(2-hydroxyethyl)prop-2-enamide (HEPE) was grafted onto CS by reversible addition–fragmentation chain transfer (RAFT) radical polymerization under γ-ray irradiation, and the amino group need not be protected during the reaction. The drug was attached to the polymer by generating a Shiff base with the amino group of CS, and the product can self-assemble to form nanomicelles with pH and temperature sensitivity (Figure 4a) [80]. Nasef et al. crosslinked polyvinyl alcohol (PVA) and chitosan under γ-ray irradiation. The study showed that the dissolution rate of the composite hydrogel film decreased significantly with increasing radiation dose, which can be used as an elastic biomaterial for artificial skin [81]. Chan et al. prepared chitosan (CS)/corncob (CC) biocomposite gels by electron beam irradiation membrane [82]. When radiation was exposed to the biocomposite membrane, the free radicals generated by the radiolysis of water may attack CC to form CC radicals. These CC radicals may then attack long CS chains to form new CS-CC bonds (Figure 4b). The induced crosslinking of CS/CC increased after electron beam irradiation. Compared with the unirradiated biocomposite films, the irradiated CS/CC biocomposite films showed better thermal stability and biodegradability.

3.4. Electrodeposited CS Hydrogels

CS is a weak electrolyte with specific pH responsiveness, and it is also the only natural cationic polymer that can be deposited to form hydrogels by electric field-induced deposition [83,84,85]. When the pH is less than its pKa (about 6.3), the protonation of the chitosan amino group leads to the dissolution of CS in cationic form; when the pH is close to or greater than its pKa, the amino group is deprotonated and precipitated. After applying an electric field, the H⁺ in the solution undergoes a reduction reaction at the cathode, causing the pH of the cathode surface to rise, inducing deprotonation of CS molecules and precipitation from the solution to form a CS gel. The CS gel film can be easily washed out by acid and could also be preserved after being crosslinked by a crosslinking agent. Compared with physical and chemical crosslinking methods, the preparation of CS hydrogels by electrodeposition shows unique advantages, such as simple operation, mild reaction, no need to add other chemical reagents, and can be carried out in the aqueous phase [86,87,88]. Recently, Yan et al. fabricated a vascular-like structured CS hydrogel with a diameter of about 0.4 mm by a templated electrodeposition process stimulated with an oscillating electrical signal (Figure 5) [89]. The method spatially and temporally controls the internal multilayer structure of the hydrogel by using pulsed electrical signals (ON-OFF model), with short interruptions (OFF steps) forming tight boundaries between each individual layer. The work provides a very promising self-assembly technique for constructing hydrogel coatings and artificial blood vessel regeneration. Yang et al. used electrodeposition-induced covalent crosslinking of CS and epichlorohydrin to obtain CS-based hydrogel contact lenses [90]. The electrodeposited hydrogel exhibits favorable optical properties, mechanical properties, and biocompatibility. The geometry of CS hydrogel could be simply tailored by electrode templates, the properties can be tuned by electrical signal and electrochemical crosslinking. In addition, the use of electrodeposition to print 3D CS hydrogels has received considerable attention for biomedical applications. Noriko Taira et al. performed 3D chitosan/gelatin hydrogel bioprinting by electrodeposition with a needle-shaped device [86]. This 3D design approach allows us to rapidly electrodeposit large hydrogels into several shapes, which holds promise for future tissue engineering, drug delivery, and on-chip applications.

4. Synthesis and Modification of CS-Based Hydrogels for Flexile Wearable Sensors

CS is highly permeable to water and anions, easily adheres to negatively charged surfaces, aggregates with polyanionic compounds, and chelated metal cations, and has been widely used as a biosensor [91]. CS-Gels can be prepared by chemically or physically crosslinking to form composites. Chemical crosslinking provides excellent gel properties, stabilities and mechanical properties through covalent bonding with the addition of crosslinkers. The amino and hydroxyl groups of CS molecular chains could be chemically modified to immobilize sensing compounds such as enzymes, conductive polymers, or stimulus-responsive polymers for sensing applications. Physically crosslinked hydrogels are achieved through non-covalent bonding (e.g., electrostatic interactions, hydrogen bonds, ionic hydrogelation, and hydrophobic interactions) without the addition of crosslinking agents. The non-covalent bonds are easily broken under physiological conditions, thus providing good biodegradability for the hydrogels [92]. In recent years, CS-Gels sensors have been cleverly designed and widely used for real-time and efficient monitoring of physiological signals or target biomolecules, which demonstrates their potential applications in the field of flexible wearable sensors [93,94,95]. In this context, a large number of CS-based composite hydrogel sensors have been established, including pressure and strain sensors. The synthesis and application of CS-based hydrogels for flexible wearable sensors are shown in Figure 6, and the comparison of CS-based hydrogel materials, synthesis strategies and applications reported in related work is summarized in

Table 1. Summary of synthesis strategies and applications of CS-Gels wearable sensors.

CS-Based Hydrogel Materials	Role/Function of CS	Sensing Types	Conductivity	Stretchability	Applications	Ref.
CS/AMPS/PAAm a	Electrostatic interaction; improved the mechanical properties	Strain sensor	0.0848 S/cm	2839%	Human motion and physiological signal monitoring	[17]
CS/PA/PAAm b	Polymerization; anti-freezing and moisturizing properties	Strain sensor	0.041 S/cm	1266%	Electrocardiography (ECG) signal detection	[96]
CCDHG c	Hydrogen bonding and reversible dynamic bonding; bio-availability and applicability	Triboelectric nanogenerator	─	185%	Monitoring the health condition of Parkinson’s disease (PD) patients	[97]
P(SBMA-co-AAc)/CS-Cit d	Electrostatic interaction and hydrogen bonding; self-healing and self-adhesive	Strain sensor	0.11 S/cm	800%	Human motion detection and health monitoring	[98]
CS/P(AA-co-SS)/NaCl e	Hydrogen bonds, electrostatic interactions, and hydrophobic domains; high elasticity	Strain sensor	4.5 S/m	620%	Detect various movements of the human body	[99]
PAAm @CS	Ion coordination; self-healing and self-adhesive	Strain sensor	1.7 mS/cm	636%	Electronic skin and human activity monitoring	[100]
CS/PAA f	Ionic interaction; high deformability, self-healing and anti-freezing	Self-healable and strain sensor	4.58–5.76 S/m	1190–1550%	Detect the conventional motion signals of human body	[101]

^a AMPS, 2-acrylamido-2-methylpropane sulfonic acid; PAAm, polyacrylamide; ^b PA, phytic acid; ^c CCDHG, catechol-chitosan-diatom hydrogel triboelectric nanogenerator; ^d P(SBMA-co-AAc)/CS-Cit, poly(sulfobetaine-co-acrylic acid)/chitosan-citrate; ^e CS/P(AA-co-SS)/NaCl, chitosan/poly(acrylic acid-sodium p-styrene sulfonate)/sodium chloride; ^f PAA, polyacrylic acid.

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4.1. CS/Carbon-Based Nanomaterial Composite Hydrogel Sensors

Carbon-based nanomaterials, such as carbon nanotubes (CNTs), graphene, graphene oxide, fullerenes, carbon nanoparticles, play an important role in building 3D conducting networks in polymer matrices due to their high electrical conductivity, high stability, and excellent surface-to-volume ratio. By introducing carbon-based nanomaterials into hydrogel matrices, not only electron transport pathways through π-conjugated structures are established, but also the mechanical properties of hydrogels are significantly improved owing to their abundant surface functionalization and hydrophobic associations [102]. Pirahmadi et al. prepared polyvinyl alcohol/chitosan (PVA/CS) hydrogel networks (water content 90 wt%) with physical crosslinking by the freeze-thaw method and used to mechanically enhance the mechanical properties of the composite hydrogels by introducing high modulus CNTs [103]. The PVA/CS-Gels containing 0.25 wt% CNT showed electrical conductivity greater than 9 mS/cm and 260% improved shape memory behavior of the hydrogels for potential use in soft smart robots, flexible wearable electronics, and smart sensors and actuators. Figure 7a demonstrated the use of glucose oxidase/CS/CNTs hydrogel extraction and analysis for cystic fibrosis and blood glucose monitoring [104]. The CS/CNTs hydrogel wearable sensing platform incorporates an electrochemically enhanced iontophoretic interface (Figure 7b). This interface can extract sufficient sweat volume and deliver it to the sensor surface for robust analysis. Furthermore, the use of programming the interface to periodically induce sweating of various secretions can be used for cystic fibrosis diagnosis and real-time monitoring of blood/sweat glucose (Figure 7c,e).

4.2. CS-Based Double-Network Hydrogel Sensors

Double-network (DN) hydrogels are two interpenetrating crosslinked polymer networks prepared based on physical or chemical crosslinking, and the mechanical properties of hydrogels can be improved by the DN structure. DN hydrogels are mainly composed of a rigid network and a flexible network, where the rigid network is used to dissipate energy during deformation and increase the strength of the gel, while the flexible network is used to enhance the tensile properties of the gel [105,106]. The synergistic effect of the two networks effectively enhances the pressure conduction and dispersion and endows the hydrogel with excellent mechanical properties. Recently, a novel DN chitosan hydrogel has been developed by introducing dynamic crosslinked networks into the chitosan network. Figure 8a shows the flexible polyacrylamide (PAAm) network composed of dynamically crosslinked chitosan (CS) and doped polyaniline (PANI) via hydrogen bonding between hydroxyl, amide and aniline groups to form DN [18]. The obtained hydrogels exhibited a dense network interpenetrating structure, which facilitates the mechanical properties and conductivity improvement (Figure 8b). At a strain of 600%, the hysteresis loop of the PANI/CS DN hydrogel was significantly enlarged with increasing CS content (Figure 8c). It is suggested that CS doping acts as a “sacrificial bond” that contributes to energy dissipation. As the strain continues to increase, the dynamic crosslinking in the PANI/CS DN hydrogel was broken to release mechanical energy. When the dissipation energy was increased to 0.99 MJ/m3, the dissipation coefficient of the hydrogel reached 52.94% (Figure 8d). The hydrogel sensor has good stability and reproducibility under different strains (Figure 8e). This DN-structured CS hydrogel exhibits excellent mechanical properties, amazing electrical conductivity, and good freezing resistance, and shows excellent sensitivity in detecting stretching and bending as well as human activities. Zhao et al. designed and prepared non-expandable DN hydrogels by adding CS to poly(acrylic acid-2-methoxyethyl acrylate)-Fe3+ [P(AA-MEA)-Fe] network (Figure 8f) [107]. Due to the non-covalent physical crosslinking of CS, the prepared hydrogels showed excellent mechanical flexibility and mechanical strength (Figure 8g) with tensile, toughness, and recovery capacities of 1199%, 2.01 MJ/m³, and 97.22%, respectively. Due to the introduction of CS, the hydrogel exhibited excellent non-swelling properties in water (pH = 1, 4 and 7), saline, seawater and organic solvents (dodecane, n-hexane and chloroform) (Figure 8h). After immersion in deionized water for 7 days, the hydrogel still achieved a mechanical strength of 0.467 MPa and an elongation of 1072%. The strain sensitivity of the hydrogel sensor increases rapidly with increasing tensile stain, showing the remarkable strain sensitivity of the hydrogel (Figure 8i). Such hydrogel-based flexible sensors can satisfy the periodic real-time signals of human motion monitoring underwater (e.g., joint movements and electronic skin contact). Sahoo et al. constructed DN hydrogels by the synergistic interaction between CS, tetraethylene glycol (TEG) and polyacrylic acid (PAA). The hydrogels possess abundant hydroxyl functional groups and can self-adhere to various materials with up to 90–95% self-healing properties. Owing to the dynamic crosslinking nature of the polymer, the obtained DN hydrogels exhibit tunable mechanical properties and have potential applications in real-time soft human motion sensors [108].

4.3. CS-Based Ion-Conducting Hydrogel Sensors

Ion conduction is a key process for achieving physiological signal transmission in biological systems [109]. Under the electric field, the free ions in the ion-conducting hydrogels are directionally transported, which is similar to the signaling principle in living organisms, allowing for the exchange of information with the surrounding environmental tissues through diffusion. Ion-conducting hydrogels avoid the conversion between electron and ion signals, and have low interface impedance with tissues, which have low impedance at the interface with tissue and great biocompatibility, making them ideal materials for wearable and implantable flexible devices [110,111]. Recently, Li et al., inspired by the adhesion of natural mussels, in situ polymerized acrylamide (AM) in a CS matrix to prepare a hydrogel (PAM@CS), and then introduced plant polyphenol tannins acid (TA) into the system with Fe³⁺ as a redox agent for ultrafast polymerization, and prepared ion-conductive composite hydrogels PAM@CS/TA-Fe within 1 min at 60 °C (Figure 9a) [100]. PAM@CS hydrogel is ionically conductive and show good sensing properties in detecting joint motion and subtle physiological signals such as articulation and alcohol consumption. Inspired by the human tongue sensing mechanism, Khan et al. synthesized supramolecular ionic hydrogels by first copolymerizing acrylic acid (AA) and acrylamide (AM) with CS in the presence of NaCl electrolyte to form CS/poly(AM-co-AA) 3D network structure [112]. Then, the secretory protein mucin was added, N,N,N′,N′-tetramethylethylenediamine (TEMED) was used as a promoter and ammonium persulfate (APS) as an initiator to form an artificial bioelectronic tongue (E-tongue) (Figure 9b) for the detection of astringent and bitter substances. Figure 9c shows a schematic diagram of the sensing mechanism of E-tongue in contact with astringent or bitter substances. In this case, mucin plays a crucial role in the detection of target analytes. The electronic tongue, which contains mucin as secreted protein and NaCl as ion transport electrolyte, exhibited excellent sensitivity of 0.2 and 0.12 wt%⁻¹, and a wide detection range of 29.3 mM-0.59 μM and 63.8 mM-6.38 μM, respectively. In addition, the sensitivity of the electronic tongue is not affected at −5 °C, which is suitable for subzero temperature environments (Figure 9d). This work provides a promising approach for the development of flexible, curable artificial bioelectronic tongues with potential applications in food taste detection and humanoid robotics.

4.4. Three-Dimensional Printed CS Hydrogel Sensors

Three-dimensional (3D) printing technology is based on digital models to create 3D functional devices with complex geometries in a later-by-layer fashion. Moreover, 3D printing has changed the concept of free-form construction and end-user customization and is considered as a next-generation tool for wearable sensors due to its easy-to-use, rapid manufacturing capabilities. This additive manufacturing technique allows for complex geometries to be printed precisely into desired microstructures, enabling on-demand customization of 3D wearable biomedical electronics. Currently, 3D printing-based technologies for the development of wearable sensors such as glucose sensors, artificial skin, sweat sensors, tactile sensors, microfluidic biosensors, strain sensors, pressure sensors, wearable oximeters are attracting great interest in the field of healthcare [113,114,115,116]. Hao et al. used CS prepared under alkaline conditions for rapid 3D printing of composite multifunctional hydrogels [117]. Figure 10a shows a schematic diagram of 3D printing using CS hydrogel ink. The CS hydrogel can not only print uninterruptedly at room temperature without clogging the nozzle, but also has a stable shape retention during printing. Some graphics (e.g., squares) can be designed by CAD and then rendered by a 3D printer (Figure 10b). The 3D printed-CS hydrogel exhibited high sensitivity, stability and repeatability when used for temperature detection (Figure 10c–d). Darabi et al. developed a conductive self-healing CS hydrogel with pressure-sensitive properties, and the 3D printing process is shown in Figure 10e [118]. The dynamic ionic interaction between the carboxyl group of poly(acrylic acid) and iron ions contributes to the self-healing abilities. The application of CS-Gels in human motion detection (e.g., finger bending and relaxation resistance changes) and their good 3D printing properties reveal their practical potential (Figure 10f).

It should be noted that 3D printing technology still has many limitations, such as the lack of fine processing conditions, high requirements for raw materials, post-processing compatibility, anisotropic mechanical strength, lack of corresponding standards and complete product technology chain. However, with the development of 3D printing technology, miniaturization/integration, customization, higher resolution, and lower cost biomedical sensors will continue to innovate for the foreseeable future.

5. Problems and Challenges

CS hydrogel sensors have great prospects in the field of flexible sensing due to their excellent flexibility, stretchability, and biocompatibility. Flexible sensors designed with CS hydrogels as sensitive materials show great application potential in biomedicine, wearable electronics, health monitoring, etc. Although CS hydrogel-based sensors have many advantages, they still have shortcomings, such as insufficient stability in harsh environments, water evaporation in high-temperature and dry environments, and moisture condensation in low-temperature environments, which make the use of CS hydrogel-based sensors more stringent [119,120,121]. At present, the commonly used solution is to use glutaraldehyde, epichlorohydrin, genipin, CaCl₂ aqueous solution, etc. to crosslink the hydrogel to effectively prevent the evaporation of water molecules. In addition, combined water is more difficult to form crystals than free water, and its average molecular motion ability is lower than that of free water molecules, so it is difficult to transfer freely at low temperatures, thus hindering the growth of ice crystals [59,122]. The CaCl₂ aqueous solution firmly fixes the water molecules in the polymer network through the strong coordination bonds between H₂O-Ca²⁺, thus endowing the hydrogel with anti-freeze and moisturizing properties.

The operating range is an important parameter that needs to be considered in the practical application of CS hydrogel sensors. When the CS hydrogel sensor undergoes a large degree of deformation, the response baseline drift usually occurs, which seriously affects the accuracy of the CS hydrogel sensor. Therefore, addressing the sensitivity to a single variable is the key to improving the performance of flexible CS hydrogel sensors. The large operating range puts higher requirements on the tensile properties and fatigue resistance of CS hydrogels, which need to be optimized according to actual needs. Electrode corrosion also often affects the performance of CS hydrogel sensors. Due to the long-term application of voltage on the electrodes, the surface of the sensor is prone to corrosion and accumulation of reaction products, which seriously affects the performance and service life of the CS hydrogel sensor. In addition, insufficient air permeability is also a major problem for CS hydrogel sensors. Despite the good biocompatibility of CS hydrogel materials, long-term adhesion to the skin surface can prevent the skin from breathing, resulting in inflammation. Therefore, the realization of CS hydrogels as flexible wearable devices is still full of opportunities and challenges in the fields of human motion monitoring, human-machine interface, and health monitoring.

6. Conclusions and Outlook

In recent years, the application prospects of flexible sensors in fields including wearable devices, medical electronics, implantable devices, and electronic skin have attracted the extensive attention of researchers. Hydrogel materials have mechanical properties that are similar to biological tissues and that are biocompatible, making them one of the ideal materials for application in flexible sensing devices. Many CS-Gels have been developed for flexible wearable sensing devices in different working environments. This review provides a comprehensive summary of the development of CS-Gels flexible wearable sensors in recent years. In terms of materials, the development of various carbon nanomaterials and metal nanomaterials has laid the foundation for the fabrication of flexible CS-Gels sensors with advanced performance. From the perspective of preparation technology, various printing processes are becoming more and more mature, especially the development of 3D printing, which has shown great vitality in advanced manufacturing. Although great progress has been made in the application of CS-Gels in flexible wearable devices, there are still huge opportunities and challenges for their preparation, functionality and practical applications. The influence of CS-Gels network structure on sensing performance still needs to be studied in depth. It is necessary to develop new methods for the synthesis and processing of CS-Gels and to precisely construct the hydrogel network structure. By revealing the relationship between the hydrogel structure and performance, the effect of improving the sensing performance of CS-Gels is achieved. At present, the detection function of CS-Gels sensors is relatively simple and realizing multi-dimensional signal monitoring can effectively promote the practical application of CS-Gels sensors. In addition to stress-strain signals, changes in physiological parameters such as temperature, humidity, and pH within the human body can also effectively reflect changes in human health status. Therefore, the development of CS-Gels sensors with fast response rate, high sensitivity, and wide detection range for signals such temperature, humidity, and pH has important application prospects in the field of smart wearable and implantable devices.