Self-Healing Hydrogels Based on Different Driving Forces and Their Applications

Mengru Wang; Qiang Ma; Xiao Chang; Jiale Li; Zetao He; Guohe Xu; Ruihui Dai

doi:10.7536/PC20250711

Progress in Chemistry ›› 2026, Vol. 38 ›› Issue (6) : 1126-1143 DOI: 10.7536/PC20250711

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Self-Healing Hydrogels Based on Different Driving Forces and Their Applications

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Abstract

Hydrogel is a three-dimensional cross-linked network capable of absorbing and retaining large amounts of water. Furthermore， it exhibits good biocompatibility and excellent chemical and physical properties. Therefore， hydrogels became a representative of soft materials. However， traditional hydrogels have shortcomings such as easy damage and short lifespan， which limit their development. Recently， self-healing hydrogels have been developed rapidly due to they can restore the damage without destroying their own functions， thereby prolongingtheir service life. In this review， the research status of self-healing hydrogels with different driving forces are reviewed. The self-healing hydrogels constructed by single driving forces and multiple driving forces， respectively. Among them， single driving forces include reversible non-covalent bonds and dynamic covalent bonds. Reversible non-covalent bonds encompass hydrogen bonds， hydrophobic interactions， metal coordination interactions， host-guest interactions and electrostatic interactions. Dynamic covalent bonds include imine bonds， boronic ester bonds and hydrazone bonds. The application of self-healing hydrogels in wound dressings， drug delivery， tissue engineering， sensors， and 3D printing are also discussed. Finally， some problems in the performance optimization of self-healing hydrogels（such as cumbersome experimental procedures， poor mechanical properties， poor antifreeze performance， and scientific issues related to mechanism research and clinical transformation）and their development are prospected.

Contents

1 Introduction

2 Different drivers of self-healing hydrogels

2.1 Reversible non-covalent bonds

2.2 Dynamic covalent bond

2.3 Multiple driving force

3 Application of self-healing hydrogels

3.1 Wound dressing

3.2 Drug delivery

3.3 Tissue engineering

3.4 Sensor

3.5 3D printing

4 Conclusion and outlook

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Keywords

hydrogels / self-healing / noncovalent dynamic interaction / dynamic covalent bond / applications

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Mengru Wang, Qiang Ma, Xiao Chang, Jiale Li, Zetao He, Guohe Xu, Ruihui Dai. Self-Healing Hydrogels Based on Different Driving Forces and Their Applications. Progress in Chemistry, 2026, 38(6): 1126-1143 DOI:10.7536/PC20250711

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1 Introduction

Hydrogels are three-dimensional network materials formed through physical or chemical crosslinking. Their excellent biocompatibility, physicochemical properties, and water retention capacity make them a representative class of rapidly developing soft materials.^[1-2]. Since Wichterle et al.^[3]applied hydrogels to biology in the 1960s, their applications have developed rapidly. With deeper research into hydrogels, their applications have become increasingly widespread.^[4]. However, during long-term use of traditional hydrogels, mechanical motion can damage their intact structure, reducing their effectiveness and lifespan. Inspired by the self-healing and self-recovery mechanisms widely existing in natural systems, recent studies have introduced self-healing mechanisms into polymer materials. For instance, the preparation of self-healing hydrogels has improved the performance of traditional hydrogels and expanded their practical application directions.^[5-6].

Relying on their intrinsic properties, self-healing hydrogels can repair fractured gel structures, significantly addressing the short lifespan defect of traditional hydrogels^[7]. In 1999, Jiang et al.^[8]designed chitosan-based hydrogels with self-healing capabilities for bulk conformal films featuring high laser damage thresholds and potential reversibility during the damage process. Since then, self-healing hydrogels have entered the public eye. Due to their excellent biocompatibility, self-healing properties, and biodegradability, self-healing hydrogels are widely applied across various fields.

Although research on self-healing hydrogels has yielded significant results and numerous review articles exist, most discussions focus on the types and applications of dynamic bonding interactions (such as hydrogen bonds, ionic coordination, and dynamic covalent bonds), essentially remaining at the level of listing and elaborating on bond types. Consequently, current research still lacks an in-depth analysis of how these microscopic interactions act as driving forces to actively guide molecular chain motion and reconstruct the three-dimensional network, ultimately driving the macroscopic self-healing process. The driving mechanisms of this process, healing kinetics (rate), and performance reconstruction effects (such as mechanical property recovery) are key to designing various functionalized self-healing hydrogels, yet they have been overlooked in previous reviews.

Therefore, this article aims to reorganize the research progress of self-healing hydrogels starting from the essential source of "driving forces." No longer limited to a brief introduction of dynamic bonds, it focuses on discussing the following content: how driving forces of different natures (such as reversible non-covalent bonds and dynamic covalent bonds) trigger and regulate the interfacial healing process; how these driving forces determine the evolution laws of the mechanical properties (such as strength, toughness, and modulus) of hydrogels before and after healing. At the same time, it details the application of self-healing hydrogels in wound dressings^[9], drug delivery^[10], marine fisheries^[11], sensors^[12], and 3D printing^[13]and other fields. Finally, an outlook is provided on the development of self-healing hydrogels regarding performance optimization (such as simplifying experimental steps, improving mechanical properties, antifreeze capabilities, as well as scientific issues like mechanism research and clinical translation).

2 Different driving forces of self-healing hydrogels

Although self-healing hydrogels possess strong self-repair capabilities, the key to their function lies in the carefully designed dynamic interactions within the material. Therefore, deeply understanding the different driving forces that endow hydrogels with self-healing abilities is the foundation for designing and optimizing multifunctional self-healing hydrogels. During the self-repair process of self-healing hydrogels, different types exhibit different driving forces, for example: reversible non-covalent bonds include hydrogen bonds^[14], hydrophobic interactions^[15], metal coordination interactions^[16], host-guest interactions^[17], and electrostatic interactions^[18]; dynamic covalent bonds include imine bonds^[19-20], boronate ester bonds^[21], and acylhydrazone bonds^[22]. Meanwhile, self-healing hydrogels can also achieve the simultaneous action of multiple driving forces to promote self-healing^[23]. Furthermore, some of the aforementioned driving forces can be accelerated by external stimuli, such as pH^[24], temperature^[25], conductivity^[26], light^[27], and electricity^[28]and other stimuli. In the spontaneous self-healing process of self-healing hydrogels without external stimuli, a relatively long healing time is usually required^[29]. In contrast, the healing process under external stimulation requires significantly less time, which can effectively improve healing efficiency^[30].

2.1 Reversible non-covalent bonds

2.1.1 Hydrogen bond

Hydrogen bonding is a common physical interaction generated by the attractive force between a hydrogen atom and a highly electronegative atom, such as oxygen (O), fluorine (F), or nitrogen (N). In common self-healing hydrogels, polymer segments driven by hydrogen bonds generally contain abundant functional groups such as hydroxyl, carboxyl, and amide groups. When the hydrogel is damaged, hydrogen bonds break under external stimuli; the free groups generated at the fracture surface can re-form hydrogen bonds, reassembling the broken hydrogel to achieve recombination and self-repair. The self-healing mechanism is asshown in Figure 1(a). Hydrogen bonds are the most commonly used reversible non-covalent bonds driving self-healing hydrogels to achieve self-healing properties^[31]. Hydrogen bonds endow hydrogels with rapid self-healing capabilities, but their inherent limitations are also evident: single hydrogen bond networks often have limited mechanical strength, the recovery rate of mechanical properties after healing is generally low, and their stability is poor, making them susceptible to interference from environmental factors such as moisture, temperature, and ionic strength. Therefore, hydrogels relying solely on hydrogen bonds are mostly suitable for application scenarios with low mechanical performance requirements but needing rapid self-healing, such as certain flexible sensors or wearable devices. To improve this limitation, researchers' design strategies have shifted from constructing single hydrogen bond networks to developing hydrogen bond synergistic enhancement systems.

Ji et al.^[32]Polymerized hydroxyethyl acrylamide (HEAA) in a LiCl cryoprotectant/water (Cryo/water) solution to prepare fully physically crosslinked PHEAA-Cryo-LiCl organohydrogels based on multiple intramolecular and intermolecular hydrogen bonds. Intramolecular hydrogen bonds form between polyhydroxyethyl acrylamide chains, while intermolecular hydrogen bonds form between hydroxyethyl acrylamide and the cryoprotectant. When the hydrogel is cut, a large number of hydrogen bonds at the fracture surface are broken. Upon contact of the fractured surfaces, exposed hydroxyl and amide groups re-form new hydrogen bonds with neighboring groups. This dynamic process of recombination after fracture is the core mechanism driving hydrogen bond-mediated self-healing of the hydrogel. Experimental results show that the PHEAA-Cryo-LiCl organohydrogel can initially support a mass of 200 g; after self-healing, due to the relatively weak newly formed hydrogen bond network, it can only support 50 g. However, as healing time increases, the hydrogen bond network continuously optimizes, and both fracture stress and strain gradually increase from 28 kPa and 65% to 37.5 kPa and 125%. Therefore, hydrogen bond interactions are the primary driving force promoting hydrogel self-healing, asFigure 2shown. Meanwhile, LiCl and the cryoprotectant impart good conductivity and antifreeze properties to the organohydrogel, respectively, enabling simple hydrogen bond-driven self-healing hydrogels to demonstrate application potential in fields such as flexible electronics and extreme environment sensing.

Chen et al.^[33]prepared magnetic hydrogels with self-healing capabilities based on polyvinyl alcohol (PVA) and Fe₃O₄. A large number of hydroxyl groups exist in the PVA chains, and the hydrogel exhibits excellent self-healing performance through reversible hydrogen bonds between these hydroxyl groups. Experimental results show that when the strain increased from 5% to 200% at a certain point in time, the gel network collapsed. When subjected to a strain of 5%,G′ andG″ recovered to their original values. This recovery behavior can be repeated for at least 4 cycles, which fully demonstrates that the PVA hydrogen bond network possesses rapid and reversible breakage-recombination capabilities, reflecting its self-healing nature. In experiments investigating the effect of magnetic force on self-healing properties, it was found that when the content of Fe₃O₄ particles increased from 2.5% to 5%, the tensile strength after self-healing reached its maximum. The results indicate that low content of nanoparticles can serve as effective physical crosslinking points, synergistically enhancing the mechanical strength of the gel with the hydrogen bond network without affecting the recombination of hydrogen bonds in the hydrogel. When the Fe₃O₄ particle content exceeds 5%, the Fe₃O₄ particles inhibit the binding of free hydroxyl groups via hydrogen bonds; a large number of particles occupy the internal space, hindering the reformation of new hydrogen bonds on the fractured surface. Therefore, when the Fe₃O₄ particle content is 5%, the hydrogel exhibits optimal self-healing strength and efficiency, indicating that magnetic force exerts a significant regulatory effect on hydrogen bonds, thereby influencing the self-healing performance of the hydrogel. In composite self-healing hydrogels, the synergy between fillers and dynamic bonds (such as hydrogen bonds) achieves a balance between functionality and self-healing. This conclusion provides important guidance for designing high-performance multifunctional self-healing materials.

2.1.2 Hydrophobic interactions

Hydrophobic interactions refer to the aggregation of hydrophobic monomers in an aqueous medium. When the reaction begins, hydrophobic microdomains act as physical crosslinking points with sufficient toughness. These crosslinking points connect with other polymer chains, causing hydrophilic polymer chains to crosslink and form a macroscopic three-dimensional gel network, generating self-healing hydrogels containing hydrophobic associations.^[34]. The self-healing mechanism of this type of self-healing hydrogel is that hydrophobic groups attached to short chains in the network are pulled out by hydrophobic microdomains during deformation; after the external force is removed, the extracted free hydrophobic groups spontaneously enter the hydrophobic microdomains and re-associate, asFigure 1(b)shown, thereby driving the hydrogel to achieve self-repair to its initial state within a relatively short time.^[35].

The most significant advantage of hydrophobic interactions lies in their ability to form strong and robust physical crosslinks. Compared to hydrogen bonds, hydrophobic microdomains possess higher binding energy, typically endowing hydrogels with superior mechanical strength and toughness. Meanwhile, since the nature of the interaction is non-polar, its stability is less susceptible to interference from water molecules, ions, or pH changes in the environment, demonstrating good reliability especially under physiological or humid conditions. However, its limitations are equally prominent: pure hydrophobic association may exhibit slow kinetics in aqueous environments at room temperature, and overly robust hydrophobic microdomains may reduce chain segment mobility, which is instead detrimental to molecular diffusion and reconstruction across fracture surfaces, thereby affecting self-healing efficiency. Therefore, the key to design often lies in regulating the balance between the strength and kinetics of hydrophobic interactions.

Sarmah et al.^[36]synthesized a bio-based self-healing hydrogel based on acrylamide (AM) and starch, asFigure 3shows. The surfactant used was sodium dodecylbenzenesulfonate (SDBS), the hydrophilic monomer was AM, and the hydrophobic monomer was stearyl methacrylate (SMA). Due to its reversibly physically cross-linked network structure, after cutting the hydrogel in half and placing it at room temperature, the reversible strong hydrophobic interactions between the alkyl groups of the fractured SMA chains and the SDBS micelles can rapidly rebuild during deformation without any external stimulus, allowing them to reconnect within 20 minutes, demonstrating the hydrogel's self-healing capability. Starch-containing hydrogels chemically cross-linked with PAM cannot self-heal after damage; however, the hydrogel synthesized in this experiment still exhibits significant self-healing ability even after the addition of a large amount of starch. Therefore, this starch network contributes nothing to the self-healing performance of the hydrogel and cannot fully recover after damage, indicating that the driving force promoting hydrogel self-healing is the reversible strong hydrophobic interactions of reversible non-covalent physical cross-linking.

2.1.3 Metal coordination interactions

Metal coordination interactions are dynamic and reversible interactions formed between transition metal ions with vacant orbitals and functional groups acting as ligands with lone pair electrons. Depending on the specific ligands and metal ions, their bond energies vary but are typically far higher than those of hydrogen bonds, hydrophobic interactions, and electrostatic interactions, being comparable to or even higher than certain host-guest interactions. Metal ion coordination bonds are the most effective reversible non-covalent bonds for driving self-healing in gels. When a hydrogel is damaged, these metal ion coordination bonds break; upon re-contact of the fractured surfaces, they can be re-recognized and reconstructed based on their reversibility, thereby driving the self-healing of the hydrogel, asshown in Figure 1(c).

The prominent advantages of metal coordination interactions lie in their tunable bonding strength and rich stimulus responsiveness. Many metal coordination bonds exhibit sensitive responses to pH, light, electric fields, or competitive ligands, offering possibilities for developing smart self-healing systems regulated by external fields. However, their application faces significant challenges: certain metal ions may possess biological toxicity, limiting their direct use in biomedical fields; the stability of coordination bonds is susceptible to interference from environmental pH, ionic strength, and competitive ligands; furthermore, excessively strong coordination interactions may lead to overly stable bonding, thereby inhibiting the dynamic reconstruction processes required for self-healing. Therefore, designing biocompatible coordination systems is one of the key directions.

Shen et al.^[37]prepared self-healing hydrogels (HIDs) based on hyaluronic acid, dopamine, imidazole, and metal ions. The hydrogel contains a dual cross-linked network and metal-ion coordination interactions. Among them, Fe³⁺and Cu²⁺form metal coordination bonds with hyaluronic acid-dopamine (HA-DOPA), respectively, serving as the driving force for hydrogel self-healing. When the hydrogel is damaged, the coordination bonds can rapidly break to dissipate energy; when the fractured surfaces come into contact, metal ions and catechol groups can quickly re-recognize and coordinate, driving the reconstruction of the polymer network, enabling the hydrogel to achieve instant self-healing within 7–8 seconds. Furthermore, the hydrogel exhibits excellent comprehensive performance: it possesses a tensile strength of up to 25 kPa and a compressive strength of 12 kPa, directly demonstrating the superior mechanical properties of the metal-coordinated cross-linked network. Meanwhile, the inherent strong adhesive characteristics of catechol groups enable the hydrogel to maintain a skin adhesion force of 6 kPa. Therefore, this combination of properties makes it highly valuable for applications in injectable tissue engineering scaffolds, strongly adhesive wound dressings, and drug-loaded delivery systems.

Our research group^[38]constructed a double-network self-healing hydrogel (PAA/Ce hydrogel) based on polyacrylic acid/cerium ions (PAA/Ce ions), utilizing metal coordination interactions between metal ions and carboxyl groups to drive hydrogel self-healing. First, traditional crosslinkers (N,N'-methylenebisacrylamide, MBA) were used for covalent crosslinking to maintain macroscopic shape and mechanical properties; subsequently, further physical crosslinking was achieved through ionic interactions between carboxyl groups within the hydrogel network and cerium ions. When the hydrogel is damaged, the reformation of ionic interactions drives the hydrogel to heal, asFigure 4(a)shows. Experiments demonstrate that the healing efficiency of PAA/Ce hydrogels can reach 80%, and the healed hydrogels can even be stretched to approximately 560% of their original length, asFigure 4(b)shows, proving the ability of metal coordination bonds to drive hydrogel self-healing.

2.1.4 Subject-object interaction

Host-guest interaction refers to the interaction between host and guest compounds within supramolecular materials under selective complementarity. Host-guest interactions are universal and reversible, making them suitable for preparing supramolecular materials. Common macrocyclic host molecules include crown ethers, cyclodextrins, pillararenes^[39], as well as cucurbiturils. When the material is damaged, external forces or molecular motion at the interface disrupts the equilibrium, prompting the dissociation of binding units; once the fractured surfaces come into contact, exposed host and guest molecules can rapidly reconstruct the cross-linked network through fast molecular recognition and complexation, thereby driving self-healing. Therefore, supramolecular materials composed of host and guest polymers can leverage their own reversibility to enable self-healing properties in hydrogels, asFigure 1(d)shows.

The most prominent advantages of host-guest interactions lie in their excellent selectivity and structural designability. Through precise selection or modification of host and guest units, specific assembly regarding binding strength, kinetic rates, and stimulus-response types can be achieved, thereby constructing intelligent materials with complex functions. Furthermore, many classic host-guest systems (such as cyclodextrin inclusion complexes) exhibit good biocompatibility and environmental friendliness. However, this system also faces challenges: the synthesis and modification of host and guest molecules can be complex and costly; the binding force of a single host-guest interaction is sometimes insufficient to meet demands for high mechanical strength; and in complex biological fluids, competitive interference from endogenous molecules may occur, affecting stability and function in vivo. Therefore, these challenges can be addressed through innovative design and the realization of multifunctionality.

Sadeghi et al.^[40]prepared ALG-DOP/β-CDsD/Ag nanocomposite hydrogels based on β-cyclodextrin dimers (β-CDsD), dopamine-modified alginate (ALG-DOP), and Ag nanoparticles, asFigure 5shows. Among them, β-CDsD with acceptable biocompatibility serves as the host, while ALG-DOP acts as the guest polymer. The host-guest interactions formed between β-CDsD and ALG-DOP promote hydrogel self-healing. Optical image results show that scratches on the surface (140 μm) gradually faded after 120 s, indicating that a large number of host-guest interactions at the fracture site continuously break and recombine, driving the macroscopic re-interlacing of the polymer network. After 300 s, the scratches completely disappeared, indicating that the host-guest interaction-driven hydrogel successfully self-healed. Meanwhile, the incorporation of Ag nanoparticles increased the antibacterial activity of the hydrogel, endowing it with additional biomedical value. Therefore, this hydrogel achieves synergy between host-guest interaction-driven self-healing capability and Ag nanoparticle-provided antibacterial function, making it have clear application prospects in fields such as smart drug delivery systems and antibacterial dressings.

Zhu et al.^[41]constructed self-healing hydrogels based on star-shaped [Ad-(PNIPAM-Ad)₄] and linear [Ad-(PNIPAM-βCD)₂] thermosensitive poly(N-isopropylacrylamide) (PNIPAM). Among them, the star-shaped [Ad-(PNIPAM-Ad)₄] thermosensitive PNIPAM serves as the host, while the linear [Ad-(PNIPAM-βCD)₂] thermosensitive PNIPAM acts as the guest. The reversible host-guest assembly enables rapid self-repair of microcracks, serving as the core driving force for hydrogel self-healing. When the hydrogel is damaged causing bond rupture, exposed Ad and βCD groups at the interface spontaneously seek and recognize new group molecules, reconstructing new bonds to drive the reassembly of the hydrogel network, thereby achieving self-healing. Meanwhile, this hydrogel exhibits temperature-responsive characteristics. When encountering large open wounds, it can first absorb water and swell at low temperatures to close the wound, allowing free group molecules to assemble into new bonds forming a network structure. Subsequently, upon heating, the gel contracts to restore its original shape, realizing hydrogel self-healing. The excellent self-healing capability and temperature responsiveness of this hydrogel hold great application prospects in fields such as wound dressings, electronic skin, wearable biosensors, and humanoid robots, capable of withstanding extensive human movement.

2.1.5 Electrostatic interaction

Electrostatic interactions are electrostatic attractions between molecules with opposite charges, causing them to bind together, asshown in Figure 1(e). When the hydrogel is damaged, the electrostatic crosslinks at the fracture surface dissociate. When the fractured surfaces come into contact, free counterions migrate and diffuse, rapidly re-mediating charged sites to form new ion pairs. This rapid "dissociation-reassociation" cycle enables hydrogels dominated by electrostatic interactions to achieve self-healing within a relatively short time^[42].

The most significant advantages of electrostatic interactions lie in their rapid dynamic response and the ease of constructing conductive pathways. Due to the high migration rate of ions, hydrogels based on electrostatic crosslinking can often achieve self-healing within seconds or even instantaneously, which is crucial for applications requiring immediate functional recovery. Meanwhile, free ions within the system or introduced conductive components (such as MXenes and conductive polymers) can naturally form ionic or electronic conduction pathways, endowing the materials with inherent excellent conductivity. However, pure electrostatic crosslinked networks also possess inherent limitations: their bonding strength is typically weak, resulting in generally low mechanical properties of the hydrogels; furthermore, their stability is highly dependent on the environment, making them prone to failure due to charge screening under extreme pH or high ionic strength conditions. Therefore, these limitations can be improved by constructing systems that synergize with electrostatic interactions.

Wang et al.^[43]conductive self-healing hydrogel (PCHM-Zn) prepared based on polyacrylic acid (PAA), chitosan (CS), and Ti₃C₂T x (MXene), asFigure 6shows, using quantitative metal ions and phytic acid (PHA) as key modifiers. Among them, phytate ions and metal ions promote hydrogel self-healing through electrostatic interactions. During the corresponding cutting/healing process, when the hydrogel sample is completely severed, circuit interruption occurs. When the two separated parts are physically contacted, it can be visually observed that the self-healing hydrogel sample lights up the bulb again with the same brightness. After the cross-sections contact, free metal ions and carboxylate groups at the interface recognize and reconstruct under ionic interactions, driving the synchronous assembly of the internal hydrogel structure, demonstrating good self-healing performance. The hydrogel can obtain identifiable, stable, and repeatable signals from strains of 10%~500% and frequencies of 0.4~2.0 Hz. Meanwhile, the response and recovery times of the PCHM-Zn hydrogel are 0.2 ms and 0.34 ms, respectively. Notably, even under a large strain of 500%, no resistance hysteresis was observed, indicating that its conductive network avoids irreversible damage under the buffering protection of dynamic ionic crosslinking, achieving conductive stability. This provides insights for developing a new generation of flexible electronic skins and wearable sensors capable of adapting to severe deformation and self-restoring function after damage.

2.2 Dynamic covalent bonds

2.2.1 Imine bond

Imine bonds are dynamic covalent bonds formed by the condensation of active carbonyl compounds with amines or amine derivatives^[44]. After being broken, they can autonomously recombine the fractured bonds to restore their network structure, asshown in Figure 7(a). Therefore, imine bonds are the most commonly used dynamic covalent bonds to drive hydrogel self-healing. Imine bonds are pH-sensitive; they can break and regenerate under weakly acidic conditions and exhibit good stability under neutral to weakly alkaline conditions. Thus, the self-healing property of hydrogels can be controlled by adjusting the pH. Natural polymer materials contain relatively abundant amino groups (such as chitosan, gelatin, and collagen). Chitosan is the most widely applied, forming imine bonds with aldehyde groups to optimize performance^[45].

The most significant advantages of imine bonds lie in their excellent bonding strength and clear stimulus responsiveness. As dynamic covalent bonds, imine bonds possess bond energies significantly higher than physical interactions such as hydrogen bonds, providing a robust covalent cross-linked skeleton for hydrogels and endowing them with superior mechanical strength and structural stability. Meanwhile, the formation and cleavage of imine bonds are highly sensitive to pH, offering inherent advantages for designing smart responsive drug delivery systems and on-demand degradable tissue engineering scaffolds. However, imine bonds also face several challenges: their dynamic exchange rates are typically slower than non-covalent interactions, with self-healing times often measured in hours; certain aldehyde components may exhibit cytotoxicity, necessitating careful selection of biocompatible precursors. Therefore, utilizing natural polymers to construct biocompatible systems and building multiple imine bond networks have become pathways to breakthroughs.

Lin et al.^[46]Self-healing hydrogels (CHEDA) were prepared based on chitin nanofibers (CH NFs) and alginate dialdehyde (ADA). The imine bonds formed by the crosslinking of aldehyde groups in ADA and amino groups in CH NFs promote the self-healing of the hydrogel. Through rheological recovery tests, when a high strain of 1000% is applied,G″ is higher thanG′, indicating the collapse of the hydrogel crosslinked network. Subsequently, upon applying a 1% strain,G″ andG′ values rapidly recover even after five alternating repeated cycles, dynamically driving the breakage and regeneration of the covalent network, demonstrating the excellent self-healing behavior of CHEDA hydrogels. Furthermore, CHEDA hydrogels exhibit pH responsiveness. Under acidic conditions, the structure of the hydrogel is disrupted; however, when the environment shifts to alkaline conditions, the broken imine bonds within the hydrogel recombine, restoring the gelation of the hydrogel.

Park et al.^[47]based onN-carboxyethyl chitosan (CEC), oxidized dextran (OD), and collagen (COL), CEC-OD/COL-GP composite hydrogels were designed and prepared. Genipin (GP) was used as a crosslinking agent, asFigure 8shown. The hydrogel possesses self-healing, adhesive, injectable, and biocompatible properties. Imine bonds are formed between the primary amines of CEC and the aldehyde groups of OD, as well as between the primary amines of COL and the aldehyde groups of OD; these dual imine bonds serve as the driving force for hydrogel self-healing. When the hydrogel is damaged, the breaking of imine bonds effectively dissipates energy; upon contact of the fractured surfaces under physiological conditions, aldehyde and amino groups can spontaneously re-react, driving the formation of new imine bonds and thereby achieving autonomous network repair. This process enables the hydrogel to exhibit effective self-healing within 30 minutes and recover 92% of its compressive modulus within 2 hours, demonstrating high-efficiency self-healing capability. Coupled with excellent biocompatibility, it shows great potential in the fields of injectable tissue engineering scaffolds and smart wound dressings.

Ding et al.^[48]prepared a self-healing hydrogel based on acrylamide-modified chitosan (AMCS) and oxidized alginate (ADA). The imine bonds formed between the amine groups in AMCS and the aldehyde groups in ADA promote hydrogel self-healing. Experimental observations showed that two semicircular hydrogels combined into one after 2 hours of self-healing, forming a complete circular hydrogel without any cracks, driven by the reversible breaking and recombination of imine bonds. The self-healed hydrogel could be stretched, demonstrating excellent self-healing capability. Under high-amplitude force (strain = 1000%, frequency = 1.0 Hz),G′ value decreased from 69.6 Pa to 21.5~30.7 Pa, lower thanG″ (31.4~38.5 Pa), indicating that dynamic imine bonds in the hydrogel network broke to dissipate energy. When the amplitude returned to 10% strain, the aldehyde and amino groups at the fracture site reacted again under the drive of molecular thermal motion to form new imine bonds, thereby driving the reconstruction of the covalent cross-linked network,G′ recovered rapidly, demonstrating excellent recoverability driven by dynamic covalent bonds.

2.2.2 Borate ester bond

The boronate ester bond is formed by the coordination of a boronic acid group and dihydroxyl groups, asshown in Figure 7(b). During the rearrangement process following the cleavage of boronate ester bonds, free boronic acid and dihydroxyl groups are generated; these then re-form boronate ester bonds with newly adjacent acids and dihydroxyl groups during diffusion, thereby completing recognition and reorganization.^[49]. Boronate ester bonds are also pH-sensitive; they can break and regenerate under weakly acidic conditions while exhibiting good stability under neutral to weakly alkaline conditions. Therefore, regulating pH can control the cleavage of boronate ester bonds, thereby driving hydrogel self-healing. Dynamic boronate ester bonds possess high reactivity, reversibility, and pH responsiveness, which can be leveraged to enhance the self-healing properties of hydrogels. Thus, the prominent advantages of boronate ester bonds lie in their highly tunable dynamics and precise pH responsiveness. Furthermore, many materials containing boronate ester bonds exhibit excellent biocompatibility and glucose responsiveness, providing a core foundation for developing next-generation diabetes management devices (such as smart insulin delivery systems). However, this system also faces challenges: the long-term stability of boronate ester bonds in pure aqueous environments, particularly their sensitivity to hydrolysis, may limit their application in long-term implantation scenarios. In response to these characteristics and challenges, researchers' strategies primarily focus on optimizing bonding stability and expanding multifunctionality.

Wang et al.^[50]Based on copolymer C₅PEG and alginate grafted with phenylboronic acid (Alg-PBA), a self-healing hydrogel with adjustable transparency (P-C₅PEG) was prepared, asshown in Figure 9. The boronic acid groups on C₅PEG and Alg-PBA form boronate ester bonds, serving as the driving force for promoting hydrogel self-healing. When two P-C₅PEG hydrogels of different colors are brought close together, a large number of free boronic acids and diols at the interface spontaneously recognize and reconstruct, driving the formation of new boronate ester bonds, causing the hydrogels to rapidly fuse within 10 min into a complete gel. Cyclic strain sweep tests conducted between 0.1% and 1000% shear strain showed that the gel network of P-C₅PEG disintegrated at 100~200 s; after reducing the shear strain to 0.1% at 200~300 s, P-C₅PEG rapidly recovered its original network structure with no significant loss in mechanical strength, demonstrating excellent self-healing capability and reversibility.

Jing et al.^[51]A multifunctional hydrogel (P-LP-PMX-CA-L) for treating diabetes was constructed based on phenylboronic acid-modified flaxseed gum (LG-PBA), polyvinyl alcohol (PVA), polydopamine-coated MXene (PMX), L-ascorbic acid 2-phosphate trisodium salt strips (L), and chlorogenic acid (CA), utilizing dynamic boronate ester bonds between PVA and LG-PBA as the driving force for self-healing. Cutting experiments were performed on the hydrogel; after 30 minutes, the healed hydrogel was stretched, and it was observed that the contact area of the cut hydrogel was completely healed and very tight. Step-strain experiments were conducted,G' andG" rapidly recovered, indicating that the hydrogel possesses self-healing capabilities. Furthermore, the incorporation of MXene endowed the hydrogel with good electrical conductivity, facilitating the transmission of electrical signals in biological tissues and promoting wound healing.

Zhang et al.^[52]A biomass-based double-network hydrogel electrolyte (PSBGL) was synthesized based on peach gum polysaccharide (PGP) and sisal nanofiber composites (SgC). Borax served as a crosslinker between PGP and SgC, forming reversible borate ester bonds by crosslinking with the —OH groups on the molecular chains of SgC and PGP, acting as the driving force for hydrogel self-healing. Experiments demonstrated that after the PSBGL bio-based hydrogel was cut, free boric acid and dihydroxyl groups at the contact interface recombined and reorganized, driving the internal network structure to generate new borate ester bonds, enabling the hydrogel to exhibit a rapid self-healing time of 1 s at 25 °C. After immersing the circuit containing the PSBGL bio-based hydrogel electrolyte in liquid nitrogen for 15 s, the LED maintained its brightness, indicating good conductivity at extremely low temperatures. Therefore, the PSBGL bio-based hydrogel electrolyte, featuring rapid self-healing and low-temperature stability, can be applied in flexible supercapacitors, providing strong support for performance optimization of related devices and holding promise for further development and innovative applications of flexible supercapacitor technology.

2.2.3 acylhydrazone bond

The acylhydrazone bond is a dynamic covalent bond obtained through the condensation reaction of aldehyde groups and acylhydrazides, which can also undergo hydrolysis and exchange reactions^[53]. The acylhydrazone bond is pH-sensitive; it can break and regenerate under weakly acidic conditions and exhibits good stability under neutral to weakly alkaline conditions. Therefore, the breaking of acylhydrazone bonds can also be controlled by adjusting the pH to drive hydrogel self-healing, asshown in Figure 7(c). This dynamic covalent bond endows the hydrogel with excellent self-healing properties^[54]. In most cases, molecules containing acylhydrazone bonds simultaneously possess biocompatibility, holding significant application potential in biological and biomedical fields. Therefore, the core advantage of the acylhydrazone bond system lies in the synergy between its exceptional biocompatibility and precise pH responsiveness. However, this bond also faces specific challenges: the self-healing rate of acylhydrazone bonds is relatively slow, and their long-term stability is relatively poor in prolonged physiological environments, especially in the presence of abundant competing amine groups. Consequently, researchers primarily advance frontier studies through meticulous molecular design and function-oriented system construction.

Wang et al.^[55]Injectable chondroitin sulfate composite hydrogels were prepared based on aldehyde-modified chondroitin sulfate (ChS-CHO) and hydrazide-modified chondroitin sulfate (ChS-ADH), asFigure 10shows. The acylhydrazone bonds formed between the aldehyde groups of ChS-CHO and the acylhydrazide groups of ChS-ADH serve as the driving force for promoting hydrogel self-healing. Experimental results indicate that after an intact hydrogel is cut in half, dyed with different colors, and placed together, a large number of acylhydrazide and aldehyde groups at the interface continuously undergo a "hydrolysis-condensation" dynamic equilibrium mediated by water molecules. This drives the mutual diffusion of polymer chains and the reformation of the cross-linked network, enabling the hydrogel to heal completely within 3 hours, demonstrating its excellent self-healing capability. A major advantage of acylhydrazone bonds lies in their high sensitivity to pH. Under weakly acidic conditions, their formation rate and stability reach optimal levels, making the gelation and self-healing behavior of this hydrogel function as an intelligent response mechanism. This exhibits unique application prospects in the fields of targeted drug delivery and smart wound dressings.

Zhang et al.^[56]A self-healing hyaluronic acid-based hydrogel with enhanced strength was prepared based on aldehyde-modified sodium hyaluronate (AMHA) and 3,3′-dithiobis(propionohydrazide) (DTP). Dynamic acylhydrazone bonds formed between the aldehyde groups of AMHA and the hydrazide groups of DTP drive the self-healing of the hydrogel. When the hydrogel was cut in half and the cut interfaces were immediately brought into contact, the crack gradually became blurred after 6 hours and completely merged into an integrated hydrogel disk capable of withstanding tensile force perpendicular to the contact surface. This intuitively demonstrates that, driven by the dynamic reversible reaction of acylhydrazone bonds, a covalent cross-linked network with sufficient strength formed at the repair interface, indicating that the hydrogel possesses excellent self-healing capability. Evaluated dynamically through rheological tests, the hydrogel maintained its stable network structure under low strain; when the strain increased from 10% to 2000%,G′ decreased from approximately 880 Pa to approximately 134 Pa, falling belowG″, primarily due to the rupture of a large number of acylhydrazone bonds. When the strain was reduced to 10%,G′ increased again and approached its original value, indicating that acylhydrazone bonds rapidly reorganized under equilibrium driving forces to restore the hydrogel network, thereby exhibiting excellent self-healing performance.

2.3 Multiple Driving Forces

The binding of reversible non-covalent bonds is based on intermolecular physical forces with relatively low bond energy, which results in lower activation energy required for their breakage and recombination, thereby typically exhibiting excellent self-healing properties. The advantages lie in rapid response, high reversibility, and good adaptability to biological environments, making them particularly suitable for applications requiring immediate functional recovery, such as instantaneous damage repair in flexible sensors or enhanced daily durability in wearable devices. Compared to reversible non-covalent bonds like hydrogen bonds and hydrophobic interactions, the greatest advantage of dynamic covalent bonds is the high degree of mechanical property recovery and strong network stability after healing. However, the cost of this advantage is usually longer self-healing times and dependence on specific environmental conditions (such as pH and humidity). For example, compared to metal coordination bonds, dynamic covalent bonds generally avoid potential metal ion biotoxicity issues and offer easier control over biosafety, but they may be slightly inferior in self-healing rate and diversity of response to stimuli such as external electric fields. Therefore, the most cutting-edge design strategy currently does not isolate the pursuit of the extreme performance of a single bond type, but rather focuses on constructing synergistic networks of dynamic covalent and non-covalent bonds. Dual driving forces mean that at least two types of driving forces act together during the hydrogel self-healing process, such as reversible covalent bonds and dynamic covalent bonds, multiple types of non-covalent bonds, or multiple types of dynamic covalent bonds. Multiple driving forces can achieve high self-healing efficiency, reduce self-healing time, and enhance overall performance.

Palungan et al.^[57]prepared self-healing hydrogel wound dressings based on polyvinyl alcohol (PVA), carboxymethyl chitosan (CmChi), andS-nitrosoglutathione (GSNO). Among them, polyvinyl alcohol (PVA) is rich in abundant hydroxyl groups, while carboxymethyl chitosan (CmChi) contains amino groups. Hydroxyl and amino groups can form hydrogen bonds, promoting hydrogel self-healing. Given the low bond energy and weak interaction force of hydrogen bonds, borax was added to react with polyvinyl alcohol to generate borate ester bonds, constructing a double-network self-healing hydrogel. Hydrogen bonds and borate ester bonds serve as the dual driving forces for hydrogel self-healing, asshown in Figure 11(a). After cutting the hydrogel in half, the two halves were brought into contact for 1 h without any external stimulation. Through dynamic breaking and reformation, hydrogen bonds and borate ester bonds rapidly formed initial connections at the moment of cross-section contact. Their synergistic effect drove the healing of the hydrogel, which could be stretched to 100% of its original length, demonstrating excellent self-healing performance. GSNO converts to glutathione (GSH), spontaneously releasing NO; this gas molecule has been proven to effectively promote angiogenesis and accelerate wound closure. Incorporating GSNO into wound dressings holds promise for promoting effective wound healing. It works synergistically with the dual driving forces, jointly pioneering new directions for smart wound dressings.

Zhang et al.^[58]prepared a dual dynamic bond-crosslinked self-healing hydrogel (PBBT hydrogel) based on Bletilla striata polysaccharide (BSP), tannic acid, and polyvinyl alcohol. In this system, BSP forms hydrogen bonds with both tannic acid and polyvinyl alcohol, while polyvinyl alcohol also forms hydrogen bonds with tannic acid. Upon the addition of borax, borate ester bonds are formed with tannic acid. Both hydrogen bonds and borate ester bonds serve as driving forces promoting the self-healing of the hydrogel, asshown in Figure 11(b). Through macroscopic self-healing tests and rheological experiments, four separate PBBT hydrogel pieces stained with different colors were used. At the fracture interface, a large number of free groups underwent molecular recognition and reorganization, driving polymer chains to mutually diffuse and reform the crosslinked network. This enabled the PBBT hydrogel to rapidly heal into an intact network structure without external intervention. Furthermore, when the hydrogel was subjected to a strain increased by 200%, resulting inG' dropping belowG"", indicating that the network structure was damaged. Subsequently, whenG' recovered to its initial value, the material was able to self-recover to its original state after three cycles, demonstrating efficient self-healing properties. Hydrogen bonds and borate ester bonds jointly drive the rapid self-healing of the PBBT hydrogel. Adding HCl (0.1 mol/L) to the PBBT hydrogel changed the pH, causing the borate ester bonds to dissociate in the acidic environment, thereby destroying the gel's network structure. Subsequently, upon further introduction of NaOH (0.1 mol/L), the hydrogel restored its solid state through the reorganization of borate ester bonds. Therefore, the PBBT hydrogel exhibits excellent pH-responsive characteristics.

Gu et al.^[59]Cationic latex self-healing hydrogels (CL-HA) were synthesized via in situ polymerization of monomeric acrylamide (AAm) and hexadecyl methacrylate (HMA) in an aqueous cationic latex solution. In this work, HMA was adsorbed by the cationic latex through hydrophobic interactions in the presence of a surfactant. Furthermore, since cationic groups are bonded to the surface of the colloidal particles, anionic sulfate radicals dissociated by potassium persulfate (KPS) in the presence of the accelerator (TMEDA) are adsorbed onto the colloidal particles to undergo electrostatic interactions, asshown in Figure 12(a). Among these, hydrophobic association and ionic interactions act synergistically to drive the self-healing of the hydrogel. This study conducted loading-unloading tests with different recovery times to evaluate the self-recovery capability of the hydrogel. When the second cycle was performed immediately after the first cycle, the second cycle was almost elastic; the longer the time, the more completely these two types of dynamic bonds were reconstructed, driving a higher recovery rate of the hydrogel. Therefore, CL-HA hydrogels exhibit good self-recovery, and as the resting time increases, the recovery rate of dissipated energy also increases accordingly.

Wang et al.^[60]prepared self-healing hydrogels based on oxidized sodium alginate (OSA) with different aldehyde contents and quaternized chitosan (QCS). Sodium alginate (SA) with different ratios of β-d-mannuronic acid (M) to α-l-guluronic acid (G) (M/G = 1:2, 1:1, and 2:1) was oxidized by periodate to form OSA with varying aldehyde contents. The electrostatic interaction between the positively charged quaternary ammonium groups of QCS and the negatively charged carboxylate groups of OSA, along with the dynamic imine bonds formed in situ via Schiff base reactions between the amino groups of QCS and the aldehyde groups of OSA, serve as the dual driving forces for the self-healing of this hydrogel, asshown in Figure 12(b). Self-healing phenomena were observed macroscopically and rheological behavior was tested by placing two small sample pieces in contact: the electrostatic attraction between oppositely charged QCS and OSA, acting as a rapid and reversible physical interaction, is responsible for achieving initial and fast interfacial adhesion; while the dynamic imine bonds formed between the amino groups of QCS and the aldehyde groups of OSA, acting as strong dynamic covalent bonds, impart lasting mechanical stability. This dual-driving-force synergistic mechanism drives the hydrogel to self-heal into a single piece after 0.5 h; the hydrogel'sG′ values decreased significantly from approximately 266, 229, and 153 Pa to about 20, 30, and 18 Pa, respectively, indicating that the network structure of the hydrogel was destroyed. When the hydrogel was exposed to low strain (0.1%), itsG′ value immediately recovered to the initial value, demonstrating that the hydrogel possesses excellent self-healing properties. Furthermore, the formed hydrogel exhibits high thermal stability and a denser network structure, has the lowest equilibrium swelling ratio, and can effectively control the release of curcumin, providing insights for the development of high-performance intelligent drug delivery systems.

Zhu et al.^[61]prepared an OSA-PAM-Fe₃O₄-CNCS ionogel based on acrylamide (AM), cellulose nanocrystals (CNCs), oxidized sodium alginate (OSA), and Fe₃O₄. This ionogel possesses the characteristic of immediate self-healing. Fe₃O₄ was introduced into the gel precursor, where carboxyl groups on the OSA chains and exposed Fe₃O₄ surface Fe³⁺ ions form ionic coordination bonds, while polyacrylamide (PAM) and OSA generate acylhydrazone bonds. For the first time, metal coordination bonds and acylhydrazone bonds were combined to jointly promote hydrogel self-healing, asshown in Figure 12(c). After cutting the gel into two parts, the dynamic bonds break and dissociate in the severed region. When the damaged surfaces come into contact, both types of dynamic bonds simultaneously undergo reversible dissociation and recombination; thus, the damaged area can self-heal, jointly driving rapid interfacial repair and recovery of mechanical properties, demonstrating the self-healing performance of the hydrogel. Moreover, experiments show that the strength of this self-healing ionogel is more than 10 times that of previous ones, exhibiting good mechanical and electrochemical properties.

Yang et al.^[62]prepared multi-stimuli-responsive ionically conductive hydrogels using acrylic acid (AA), N-isopropylacrylamide (NIPAM), carboxymethyl chitosan (CMCS), TEMPO-oxidized cellulose nanocrystals (TCNCs), and FeCl₃as raw materials. Hydrogen bonds between CMCS, TCNCs, and poly(AA/NIPAM) polymer chains, metal coordination bonds formed between Fe³⁺and the carboxylic acid units of CMCS and AA ligands, along with hydrophobic associations among NIPAM groups, collectively drive the self-healing of the hydrogel. The hydrogel was cut into three pieces at room temperature and immediately reconnected by bringing their fresh surfaces into contact for 15 s using tweezers; various free functional group molecules at the interface re-recognized and reconstructed, jointly driving the hydrogel to self-heal. Results indicate that the hydrogel possesses excellent and rapid self-healing capabilities. Experiments show that the ionic conductivity of the hydrogel gradually increases as the temperature rises from 25 °C to 75 °C, demonstrating its temperature responsiveness. When the pH value increases from 2.0 to 4.0, the swelling ratio of the hydrogel decreases, and then significantly increases as the pH further rises to 12.0, exhibiting outstanding pH responsiveness. A novel natural antibacterial ionically conductive hydrogel (PCNAT-Fe₃) was meticulously developed, possessing excellent flexibility, fatigue resistance, self-recovery capability, and temperature/pH responsive properties.

3 Application of self-healing hydrogels

Self-healing hydrogels are soft materials with a three-dimensional network structure, possessing biocompatibility and tunable physicochemical properties^[63]. They possess a wide variety of different driving forces, laying a solid material foundation for the transition of self-healing hydrogels from concept to practical application. Based on these unique self-healing mechanisms and biocompatibility, self-healing hydrogels demonstrate immense application potential in frontier fields such as biomedicine and flexible electronics.

3.1 Wound dressing

When skin is injured, it compromises the surrounding antimicrobial system, exposing the body to infections from various bacteria, fungi, and microorganisms in the external environment.^[64]. Once a wound becomes severely infected due to lack of timely protection, it can accelerate the condition, delay healing, and even endanger other organs in the body.^[65]. Traditional hydrogel wound dressings, when damaged, allow external bacteria to penetrate the gel interior, causing further harm to the wound. Self-healing hydrogels overcome the limitations of traditional hydrogels by leveraging their inherent properties to reduce dressing change frequency and accelerate wound treatment. Consequently, self-healing hydrogels are most widely applied as wound dressings, addressing the issue of secondary injury caused by traditional dressings while also improving upon the defects of traditional hydrogels, such as susceptibility to damage and short lifespan.

Fathi et al.^[66]prepared self-healing hydrogels (ZCS5-ZDAS5) based on zwitterionic chitosan and dialdehyde starch (ZCS and ZDAS) to deliver silybin (SM) and levofloxacin (LEV) for burn treatment. The preparation process is asshown in Figure 13(a). The imine bonds between the amine groups of chitosan and the aldehyde groups of starch, along with the electrostatic interactions between the cations and anions present in the zwitterionic groups, jointly drive the self-healing of the hydrogel. Without requiring any external stimuli or mechanical assistance, the ZCS5-ZDAS5 hydrogel seamlessly connects two pieces of hydrogel of different colors but identical composition. During the initial contact, electrostatic interactions drive the onset of self-healing through rapid ion pairing; simultaneously, dynamic imine bonds undergo reversible Schiff base reactions at the interface, where free amine and aldehyde groups engage in molecular recognition to reconstruct the covalent cross-linked network. After merging, the hydrogel can support its own weight, demonstrating its self-healing capability. Due to the inherent hydrophilicity of LEV, a considerable amount of the drug was released compared to SM, resulting in a higher drug release rate for LEV. Both demonstrated their capacity as drug delivery agents. The drug-loaded hydrogel effectively reduced inflammation, increased granulation tissue formation, and accelerated wound healing. Consequently, the ZCS5-ZDAS5 hydrogel shows great potential in promoting the healing of third-degree burn wounds.

Feng et al.^[67]An injectable and self-healing hydrogel (CSGO) was prepared based on a mixed solution of chitosan (CS) and graphene oxide (GO). The non-covalent bonds between chitosan and graphene oxide include electrostatic interactions and hydrogen bonds, achieving self-healing properties through reversible breaking and reformation. Due to the low bond energy of these non-covalent bonds, when the strain increases from 0.5% to 500%, the bonds within the hydrogel network are broken, thereby dissipating energy and preventing irreversible damage to the material. Conversely, once the strain returns to 0.5%, these dynamic bonds rapidly reorganize, restoring the hydrogel network. Although there is slight mechanical loss during the recovery process, consistent results were observed across four alternating cyclic tests, demonstrating the excellent self-healing behavior of the CSGO hydrogel. Owing to its superior absorption capacity, CSGO exhibits good hemostatic performance, facilitating the concentration of red blood cells and platelets, thus promoting blood coagulation and achieving rapid hemostasis. This makes it highly promising as a hemostatic agent in the biomedical field.

Lu et al.^[68]PDA@LA hydrogels were constructed by introducing polydopamine nanoparticles (PDA-NPs) into LA hydrogels formed by the polymerization of lipoic acid (LA), which feature a high density of dynamically cross-linked bonds. The high density of hydrogen bonds effectively dissipates energy through preferential breakage when the material is damaged, preventing the propagation of macroscopic cracks. Upon contact of the fractured surfaces, rapid dynamic reorganization allows the cut LA hydrogel to recover to its uncut state after 10 minutes of self-healing. The introduced PDA-NPs, with their surfaces rich in catechol groups, further enhance the hydrogen bond density of the system. Furthermore, when heated above 40 °C under near-infrared (NIR) laser irradiation, the hydrogel kills approximately 100% of Escherichia coli and Staphylococcus aureus, thereby resisting wound infection. Consequently, this adhesive, highly self-healing, and NIR photothermal antibacterial PDA@LA hydrogel demonstrates significant potential for application in wound dressings.

3.2 Drug delivery

Self-healing hydrogel structures resemble the natural extracellular matrix, can encapsulate cells, and achieve self-healing in vivo, making them a new generation of injectable carriers for targeted drug delivery. Relying on their own reorganization, self-healing hydrogels can accurately deliver high concentrations of drugs or cells to required locations, avoiding the unnecessary burst release or delivery failure associated with ordinary hydrogels. Therefore, self-healing hydrogels can serve as carriers for drug release, delivering medications to accelerate the healing of injuries and diseases.^[69].

Quadrado et al.^[70]based on carboxymethyl chitosan (CMCHT) and aldehyde-functionalized hydroxyethyl cellulose (HEC-Ald) to form an in situ self-healing hydrogel (HEC-Ald/CMCHT), which promotes hydrogel self-healing through imine bonds between aldehyde and amine groups, asshown in Figure 13(b). The self-healing ability of the HEC-Ald/CMCHT hydrogel was evaluated via step-strain rheological experiments. The hydrogel was subjected to sequential strain variations from 1% to 250%, with measurements taken within 3-minute intervalsG' andG". At low strain (1%),G' exceededG", indicating an intact network structure. Increasing the strain to 250% causedG" to exceedG', disrupting the internal hydrogel network and breaking bonds, indicating interruption of the hydrogel network. When restored to 1% strain, the aldehyde and amine groups re-recognized and reformed imine bonds,G' andG" immediately recovered to their original values, indicating that imine bonds drove the gel to restore its network structure. Repeating the entire cycle yielded identical results twice, further confirming the reversibility of the internal network of the HEC-Ald/CMCHT hydrogel. HEC-Ald was synthesized via acetal functional groups followed by acid deprotection, making it highly sensitive to pH. As the pH of the release medium decreases, reversible hydrolysis of imine bonds occurs, leading to network swelling or even partial dissociation, thereby accelerating the release rate of vanillin, which confirms the pH-responsive drug release capability of the HEC-Ald/CMCHT hydrogel. Therefore, the HEC-Ald/CMCHT hydrogel holds promise as a pH-sensitive drug carrier.

Liu et al.^[71]Composite self-healing hydrogels were prepared based on self-repairing oxidized branched starch polysaccharide (OPL) and carboxymethylated chitosan (CMCS) as a curcumin-loaded exosome delivery system. The aldehyde groups of OPL and the amine groups of CMCS form imine bonds, promoting hydrogel self-healing. Two hydrogels of different colors were sheared and spliced together; free aldehyde and amine groups at the interface could re-recognize and connect. After 15 minutes of contact, the reversibility of the imine bonds drove complete healing of the hydrogel, which could also withstand some stretching, demonstrating its self-healing property. Other experimental results indicated that curcumin and exosomes possess strong ROS scavenging activity, mitigating oxidative stress, with Exo@Cur exhibiting the optimal antioxidant response. Simultaneously, they promote angiogenesis, supporting distal flap survival and tissue regeneration. This self-healing hydrogel provides a new strategy for flap transplant protection, reducing necrosis and holding broad potential for clinical application.

3.3 Tissue Engineering

Biodegradable self-healing hydrogels are the most attractive materials for tissue repair. The water retention capacity and network structure of self-healing hydrogels resemble the extracellular matrix; most importantly, they can adapt to high-intensity stretching and reorganize themselves after internal structural rupture, making them ideal scaffolds for tissue engineering applications. When designing self-healing hydrogels for different tissues, various factors can be incorporated into the hydrogel network to enhance their repair efficacy while meeting the required performance criteria.

Kim et al.^[72]successfully synthesized a novel hyaluronic acid-based hydrogel based on hyaluronic acid-calcium complexes (HA@Ca) and sodium alginate (NaAlg). The phosphorus and carboxylate sites of HA@Ca and the carboxyl sites of NaAlg promote hydrogel self-healing through metal coordination bonds mediated by Ca ions provided by HA@Ca. When high and low stresses were applied to the hydrogel in cyclic repetition, the gel remained stable under low shear strain (1%),G′ was higher thanG″. Under high shear strain (40%),G′ was less thanG″, indicating bond rupture within the gel. After removal of the high stress, free carboxyl groups and Ca ions achieved rapid recognition and reconstruction, driving the recovery of the gel material's properties within seconds, demonstrating the self-healing nature of the hydrogel. In vitro cell experiments with RNA sequencing analysis indicated that the hydrogel regulates chondrogenesis in a biphasic manner (hyaline or calcified) depending on stress relaxation characteristics and phosphate composition. These results suggest that the proposed stress-relaxing HA-based hydrogel with biphasic chondrogenesis (hyaline or calcified) is a promising material for cartilage regeneration.

Geng et al.^[73]A dual-gas-mediated self-healing injectable hydrogel (DNRS) was prepared by combining thiol-modified hyaluronic acid (HA-SH) with a dual-gas-mediated crosslinker via a metal-free double orthogonal click reaction. The rupture and reorganization of the hydrogel network structure may be primarily driven by hydrophobic interactions within DNRS, where the host is the DNRS copolymer and the guest is HA-SH, asshown in Figure 13(c). In step-strain oscillatory rheology, the hydrogel rapidly recovered after three cycles of step strain from 0.5% to 200%, demonstrating that following structural damage and bond breakage within the hydrogel, the hydrophobic interactions between DNRS copolymers and HA-SH can spontaneously reassemble without external stimuli, driving the hydrogel to complete self-healing. The hydrogel decomposes on demand by consuming excess nitric oxide (NO) and releasing therapeutic hydrogen sulfide (H₂S), thereby leading to the restoration of endogenous gases, alleviation of inflammation, and polarization of macrophages to the M₂phenotype. Furthermore, the hydrogel can inhibit osteoclastogenesis and enhance osteogenesis, significantly alleviating the clinical symptoms of collagen-induced arthritis and promoting the repair of bone erosion.

3.4 Sensor

Sensors are devices that convert changes in external environmental parameters into electrical signal outputs and are widely used in all aspects of life. Self-healing hydrogel sensors, owing to their self-healing characteristics, possess superior stretchability, can adhere tightly to object surfaces, integrate with human skin, and achieve real-time and continuous monitoring of vital physiological signals.^[74], such as temperature^[75], humidity^[76], pressure^[77], and deformation^[78], have attracted widespread attention in fields such as wearable devices^[79], health monitoring^[80], electronic skin^[81], and intelligent sensor systems^[82]. The combination of self-healing capability with the mechanical and chemical properties mimicking skin can endow sensors with attractive comprehensive performance, including excellent biocompatibility, superior conformability, significant reliability, and long service life.^[83]. Therefore, self-healing hydrogels are considered ideal matrix materials for fabricating sensors.

Li et al.^[84]constructed a self-healing hydrogel (CMC/PDA-3) based on carboxymethyl cellulose (CMC) and dopamine (DA). The amide groups generated by the amidation reaction between the carboxyl groups of CMC and the amino groups of DA form non-covalent dynamic hydrogen bonds with the hydroxyl groups in PDA, an oxidative self-polymerization compound of DA, driving the self-healing of the hydrogel. The design mechanism is asshown in Figure 13(d). Through mechanical property and rheological analyses, it was found that after damage to the hydrogel, the preferential fracture of hydrogen bonds effectively dissipates energy. During the repair process, the rapid recombination of these hydrogen bonds achieves the initial connection of the hydrogel, ultimately driving the gel to complete self-healing (3 h-98.37%). Conductivity and sensitivity tests using the CMC/PDA-3 hydrogel show that the conductivity characteristics of the hydrogel can self-recover and remain at the same level during repeated trials; the self-healing ability driven by the dynamic network structure also directly ensures the recoverability of its conductive function. Finally, by observing changes in the hydrogel's resistance, it can respond in real-time to human movement; therefore, this self-healing hydrogel can serve as a sensor to detect various body movements in real-time (even throat vocalization and pulse beating).

Wang et al.^[85]designed a multifunctional polyacrylamide (PAAm)/poly(ethylene glycol) methacrylate (PEG)/hydrolyzed keratin/MXene conductive hydrogel (PPHM hydrogel) as a high-performance therapeutic integrated sensor. MXenes are two-dimensional (2D) materials composed of early transition metal carbides/nitrides^[86]. The hydroxyl groups on the MXene surface and the amino groups in the PAAm chains form hydrogen bonds with the hydroxyl groups in the PEG chains, serving as the driving force for hydrogel self-healing. When the hydrogel was connected to a circuit and cut into two separate parts with a blade, the internal network structure was destroyed, causing hydrogen bond rupture and extinguishing the LED bulb. When the two separate parts were laminated with tweezers and electrified, a large number of free hydroxyl and amino groups at the hydrogel contact interface rapidly recognized and reconstructed each other, driving the hydrogel to self-heal and causing the LED light to illuminate again, verifying the superior self-healing capability and conductivity of the composite hydrogel. This multifunctional hydrogel sensor holds great potential for advanced applications, including smart wound dressings, bionic electronic skin, flexible robotics, human-machine interaction at low temperatures, and integrated devices for diagnosis and therapy in highly complex environments.

3.5 3D Printing

3D printing (3DP), also known as additive manufacturing technologies (AM), is a technique for fabricating solid parts by accumulating materials layer by layer based on 3D CAD data. In bioprinting, bioinks refer to specialized living cells and hydrogel biomaterials that provide structural and mechanical support for the cells.^[87]. The ultimate goal of bioprinting is to design and develop three-dimensional human structures that match natural tissues, repairing tissue defects and restoring the structure and function of organs.^[88]. Self-healing hydrogels, as ink materials suitable for 3D bioprinting, resemble the extracellular matrix (ECM) and can promote cell adhesion and migration, as well as matrix remodeling in a 3D environment, which is essential for the normal development of functional tissues.^[89].

Zhao et al.^[90]prepared a conductive self-healing composite hydrogel using PVA-borax and ZnFe₂O₄/multi-walled carbon nanotubes (MCNT)/polypyrrole (PPy). PVA-borax forms borate ester bonds, and numerous hydrogen bonds exist between PPy and PVA, enhancing the self-healing ability, asshown in Figure 13(e). After the hydrogel fractured, reorganization was achieved within 10 minutes. Herein, hydrogen bonds, acting as transient and reversible physical crosslinks, endowed the network with rapid reconstruction capability; meanwhile, the dynamic borate ester bonds formed between PVA and borax served as a class of stimulus-responsive covalent crosslinks, which not only enhanced the mechanical strength of the network but also dominated the deep repair process of the macroscopic fracture surface. Experiments demonstrated that the synergistic effect of hydrogen bonds and borate ester bonds drove the self-healing of the hydrogel. Furthermore, the ability of the dynamic crosslinked network in the composite hydrogel to effectively dissipate energy through bond breakage and recombination under stress endowed it with high stretchability (approximately 800%), good conductivity (0.3465 S/m), and good magnetism (4.10 emu/g). The biocompatibility and easy reshaping characteristics of the composite hydrogel also contribute to making it an excellent candidate for 3D printing technology of human organs.

Zhu et al.^[91]Prepared a two-component hydrogel (OS-CS hydrogel) based on oxidized starch (OS) and chitosan (CS). The amino groups in CS form imine bonds and electrostatic interactions with the active carbonyl and carboxyl groups in OS, respectively, serving as driving forces to promote hydrogel self-healing. In self-healing experiments, two pieces of hydrogel of different colors were cut and placed together; after standing for 0.5 h, ionic pairing, i.e., electrostatic interactions, rapidly formed between the amino groups on the chitosan chains and the carboxyl groups on the oxidized starch chains. Meanwhile, dynamic covalent imine bonds formed between the amino groups of chitosan and the aldehyde groups of oxidized starch. Ultimately, an intact hydrogel was formed, demonstrating that imine bonds and electrostatic interactions jointly drive the self-healing of this hydrogel. Furthermore, the hydrogel exhibits stable pH responsiveness, which is essentially due to the dynamic characteristics of the imine bonds. In an acidic microenvironment, the imine bonds are prone to protonation and reversible hydrolysis, leading to network swelling or even partial dissociation, thereby creating channels for rapid diffusion of drug molecules; whereas under physiological neutral conditions, the imine bonds remain stable, achieving slow and sustained drug release. Overall, this study provides an innovative approach for designing 3D-printed biopolymer hydrogels with excellent printability and mechanical properties.

4 Conclusion and Outlook

In recent years, self-healing hydrogels have achieved rapid development by leveraging their ability to reassemble after rupture, thereby overcoming drawbacks such as the short lifespan of traditional hydrogels. With deepening research, self-healing hydrogels have advanced from relying on a single driving force to utilizing multiple synergistic driving forces; a summary of these different driving forces is presented inTable 1as shown. Currently, multifunctional self-healing hydrogels have been realized and are widely applied in fields such as wound dressings, drug delivery, tissue engineering, sensors, and 3D printing.

However, self-healing hydrogels still have limitations and face numerous challenges, mainly including the following aspects. (1) The preparation process of some self-healing hydrogels is complex. (2) Some prepared self-healing hydrogels exhibit low mechanical properties. (3) The high water content of self-healing hydrogels results in poor sensitivity at low temperatures. (4) Scientific issues regarding the synergistic mechanism of multiple driving forces: Although many literature sources describe multiple driving forces, they fail to investigate deeper questions such as how they work synergistically and whether competitive relationships exist. (5) The fundamental reasons for the difference between in vitro and in vivo self-healing performance: Materials often demonstrate excellent self-healing properties under simple in vitro conditions (e.g., buffer solutions); however, why does their self-healing efficiency significantly decline in the complex biological in vivo environment? The causes leading to this phenomenon warrant investigation. (6) Biocompatibility in clinical translation. All these factors are unfavorable to the development of self-healing hydrogels.

Therefore, in subsequent development processes, improvements can be researched in the following aspects. (1) Explore more biopolymers with multiple functional groups, such as pectin, cationic guar gum (CG), β-cyclodextrin (β-CD), and Platycodon grandiflorus polysaccharide (PGP). Under conditions of equivalent performance, leveraging the multi-functional group characteristics of raw materials allows for the preparation of self-healing hydrogels using smaller quantities of materials. Simultaneously, accelerated self-healing can be achieved through reversible non-covalent bonds, dynamic covalent bonds, and external stimuli, simplifying preparation steps. (2) Utilize nanofibers, nanoparticles, and ionic bonding as reinforcement measures to enhance the mechanical elasticity of hydrogels. (3) By enhancing the antifreeze performance of hydrogels, antifreeze solutes can be directly introduced into the hydrogel matrix, including salts (lithium chloride (LiCl), sodium chloride, etc.), alcohols (ethylene glycol, glycerol, etc.), ionic liquids, and biomass antifreeze agents (proline, betaine, phytic acid (PA), etc.)^[92]. Additives can form one or more types of interactions with water molecules, such as strong hydration and hydrogen bonding, thereby weakening the hydrogen bonds between water molecules and inhibiting crystallization. Even at low temperatures, antifreeze properties provide hydrogels with good stretchability and sensitivity. (4) Adopt a method combining molecular dynamics models with a series of characterization techniques (such as in-situ infrared spectroscopy and Raman spectroscopy) to visualize the evolution process of dynamic bonds at the atomic-molecular level. Furthermore, through ingenious experimental design, systematically alter the composition and proportion of multiple driving forces to construct quantitative relationships for different compositions, thereby identifying key dominant driving forces and synergistic effects. Drawing on synergy theory, analyze the nonlinear interactions between various driving forces to reveal the essence of synergistic enhancement, providing precise theoretical guidance for material design. (5) The in vivo environment is a living system filled with dynamic balance and regulated by neurohumoral mechanisms. In vitro testing environments cannot simulate this complexity, leading to discrepancies between in vivo and in vitro self-healing. Therefore, an in vitro testing model mimicking the in vivo microenvironment can be designed, such as by introducing protein solutions, specific enzymes, or stimuli simulating dynamic mechanics, to replicate real in vivo conditions. Subsequently, advanced in vivo imaging techniques (such as near-infrared II region imaging and bioluminescence imaging) can be used to monitor implanted materials in real-time and non-destructively, intuitively revealing the self-healing behavior of materials within living organisms. (6) First, regarding the selection of raw materials, choose high-purity natural polymers, which requires us to explore more natural and harmless polymer raw materials, such as antimicrobial peptides^[93]and polysaccharides^[94-95]. Additionally, easily degradable synthetic polymers can be designed so that after the hydrogel performs its function within the body, it can be excreted via degradation, reducing harm to the human body. During the synthesis of hydrogels, appropriate sterilization methods should be employed, such as filtration sterilization (suitable for flowable precursor solutions), ethylene oxide sterilization (with attention to residual gas removal), or low-temperature plasma sterilization. Most importantly, biocompatibility testing must be conducted prior to use to establish a more precise biocompatibility evaluation system capable of better predicting clinical outcomes, which can accelerate the market entry of safe and effective hydrogel products.

Finally, it is hoped that through the diversity of materials and preparation methods, self-healing hydrogels with simple processes and excellent performance can be prepared to meet different environmental needs and solve various problems in future development.

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Funding

National Natural Science Foundation of China(22008054)

Basic Scientific Research Funds for Universities Affiliated to Hebei Province of China(KY2022056)

Basic Scientific Research Funds for Universities Affiliated to Hebei Province of China(KY2024016)

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Cite this article

1 Introduction

2 Different driving forces of self-healing hydrogels

2.1 Reversible non-covalent bonds

2.1.1 Hydrogen bond

2.1.2 Hydrophobic interactions

2.1.3 Metal coordination interactions

2.1.4 Subject-object interaction

2.1.5 Electrostatic interaction

2.2 Dynamic covalent bonds

2.2.1 Imine bond

2.2.2 Borate ester bond

2.2.3 acylhydrazone bond

2.3 Multiple Driving Forces

3 Application of self-healing hydrogels

3.1 Wound dressing

3.2 Drug delivery

3.3 Tissue Engineering

3.4 Sensor

3.5 3D Printing

4 Conclusion and Outlook

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