Adaptive Hyaluronic Acid Hydrogels for Regenerative Wound Healing: From Microenvironment Sensing to ECM Reprogramming and Precise Tissue Regeneration

ABSTRACT

Impaired wound healing is primarily influenced by oxidative stress, aberrant enzyme activity, and disruption of the extracellular matrix (ECM), conditions that conventional dressings inadequately address. In contrast, adaptive hyaluronic acid (HA) hydrogels have emerged as a promising platform due to their inherent bioactivity and structural tunability. This review elucidates recent advancements in stimulus‐responsive HA hydrogels, with a particular emphasis on the translation of pH, reactive oxygen species (ROS), enzymatic activity, and mechanical stimuli into network remodeling and controlled therapeutic release. Exemplary systems, such as Schiff base‐based pH‐responsive hydrogels, disulfide‐crosslinked ROS‐responsive platforms, and matrices sensitive to matrix metalloproteinases (MMPs), illustrate how structure–function relationships facilitate precise regulation of inflammation, angiogenesis, and tissue repair. Furthermore, we explore how these materials orchestrate biochemical signaling, matrix mechanics, and dynamic structural adaptation to influence ECM remodeling and cellular behavior. Finally, we outline emerging strategies, including spatiotemporal regulation, multi‐signal integration, and AI‐assisted design, to address existing challenges in predictability and clinical translation. This review provides a design‐oriented perspective for developing next‐generation adaptive hydrogels for precise regenerative medicine.

Adaptive hyaluronic acid hydrogels integrate microenvironment sensing, ECM reprogramming, and spatiotemporal regulation to enable intelligent regenerative interfaces for precise wound healing and functional tissue reconstruction.

1. Introduction

Wound healing is a complex, multiscale biological process characterized by dynamic evolution [1]. This process encompasses the regulation of inflammation, cell migration and proliferation, angiogenesis, and the remodeling of the ECM [2]. Conventional treatment approaches predominantly focus on infection control, the application of physical barriers, and the maintenance of a moist environment, with the primary aim of facilitating wound closure [3, 4]. However, rapid closure does not equate to functional regeneration [5]. In the context of chronic wounds, passive protection strategies often face challenges in adapting to the dynamic local microenvironment [6]. High levels of ROS, abnormal pH, and imbalanced MMPs sustain inflammation and disrupt the extracellular matrix, significantly hindering tissue regeneration [7]. Emerging research increasingly suggests that the fundamental aspect of wound healing is rooted in the reconstruction of the microenvironment, rather than simply covering the wound [8]. The focus of this field is transitioning from “passive sealing” to “active regulation of regeneration” [9]. This new paradigm underscores the importance of dynamic sensing, signaling regulation, and the synergy of tissue regeneration [10]. Consequently, there is a pressing need to develop novel materials that are safe, controllable, and biofunctional.

Future regenerative materials are required to concurrently offer structural support, modulate biological signals, and adapt to environmental conditions [11]. Bioactive platforms that can emulate the functions of the ECM have emerged as a focal point of research [12]. HA, an essential part of the natural ECM, offers structural support and biological regulation, making it highly beneficial for regenerative medicine [13]. Unlike traditional inert substances, HA can influence cell adhesion and migration by interacting with receptors like CD44 [14]. This interaction facilitates fibroblast activation and angiogenesis while also engaging in the regulation of inflammatory processes [15]. Consequently, the material transitions from a passive carrier to an active regulatory interface. The molecular structure of HA demonstrates significant modifiability [16]. Its molecular backbone allows for dynamic crosslinking, responsiveness to stimuli, and the integration of functional modules [17]. This design flexibility serves as an engineering foundation for the development of adaptive regenerative systems [18]. By utilizing ECM biomimicry and structural programmability, HA hydrogels are transitioning from traditional scaffolds to “adaptive regenerative interfaces” [19]. This concept highlights the synergy between material structure, microenvironmental signals, and cell fate, shifting wound healing from passive coverage to active regeneration.

This paper proposes a three‐tier regulatory framework encompassing “material‐microenvironment‐cell fate.” This framework offers a novel theoretical perspective for reinterpreting the functional role of adaptive HA hydrogels in regenerative wound healing. Within this framework, the material surpasses its traditional role as a passive scaffold by actively sensing local physiological signals and engaging in microenvironmental reprogramming. Consequently, material responses are translated into the regulation of cellular behavior, ultimately influencing the trajectories of tissue regeneration. This review begins by outlining the fundamental design principles of adaptive HA hydrogels and their ECM‐mimetic properties (Figure 1). It focuses on elucidating the response mechanisms to key stimuli, including pH, ROS, enzymes, and mechanical signals. Subsequently, it describes the regulatory pathways within the regenerative microenvironment across two dimensions: ECM remodeling and immune modulation. The paper further highlights the critical role of multiscale signal integration in achieving precise tissue repair. Finally, it envisions future directions for adaptive regenerative interfaces by integrating AI‐assisted design with multimodal feedback systems. This framework offers a comprehensive theoretical structure and practical design logic for the development of next‐generation intelligent regenerative materials.

FIGURE 1.

Schematic diagram illustrating the mechanism of action of HA hydrogels in wound healing.

2. Structure–Function Design of Adaptive HA Hydrogels

2.1. Dynamic Covalent Networks Balancing Reversibility and Stability

Dynamic covalent bonds are the core design principle underlying adaptive HA hydrogels [20, 21]. The key lies in network restructuring driven by reversible bonding [21]. Unlike permanently crosslinked systems, dynamic covalent bonds have the capacity to continuously break and reform under physiological conditions [22]. This characteristic endows materials with time‐dependent and environment‐responsive properties [23]. Exemplary systems include Schiff bases, borate esters, and disulfide bonds [24]. These bonds exhibit responsiveness to variations in pH, redox states, and local metabolic signals, facilitating the synergistic regulation of both structure and function [25, 26]. Dynamic crosslinking advances HA hydrogels toward mimicking the dynamic behavior of natural ECMs [27, 28]. This network undergoes continuous remodeling in response to microenvironmental changes, while maintaining a balance between mechanical stability and biological activity [29, 30]. Such a strategy imparts materials with essential properties including self‐healing, injectability, and remodelability [31]. Upon structural damage, the crosslinks rapidly reestablish, thereby enhancing long‐term adaptability in complex wound environments [32]. Furthermore, dynamic rearrangement facilitates cell migration and ECM deposition by alleviating the structural constraints typically imposed by rigid scaffolds [33]. Notably, the performance of these networks strongly depends on the specific bond chemistry: Schiff base bonds show rapid exchange kinetics but limited stability under physiological conditions, whereas hydrazone bonds provide enhanced stability at the expense of slower responsiveness; disulfide‐based linkages offer redox sensitivity but may undergo premature cleavage in highly oxidative environments. These distinctions highlight an inherent trade‐off between responsiveness and structural stability, underscoring the need for application‐specific design of dynamic covalent networks.

2.2. Supramolecular Interactions Enhancing Network Adaptability

In addition to dynamic covalent bonds, supramolecular interactions present a crucial strategy for the development of adaptive HA hydrogels [34]. This method uses reversible noncovalent interactions, including host‐guest recognition, hydrogen bonding, electrostatic, and hydrophobic interactions, for network crosslinking [35, 36]. In contrast to traditional covalent crosslinking, supramolecular networks demonstrate enhanced dynamism and reconfigurability [37]. These networks can swiftly rearrange and restore structural integrity when environmental changes [38]. This adaptable architecture allows for cell migration, nutrient diffusion, and ECM deposition, thereby improving the material's biocompatibility [39]. Furthermore, the synergy of multiple weak interactions can lead to the formation of hierarchical structures, enabling functional regulation across molecular to macroscopic scales [40]. Consequently, supramolecularly crosslinked hydrogels transition from passive scaffolds to adaptive soft interfaces that can interact with the tissue microenvironment. Nonetheless, their functionality is intrinsically limited by the relatively weak interaction strength of noncovalent bonds, potentially undermining mechanical stability and long‐term integrity under physiological conditions. This limitation underscores a fundamental trade‐off, wherein the enhancement of dynamic responsiveness frequently comes at the cost of mechanical robustness, thereby emphasizing the necessity for rational design strategies to balance these competing requirements.

2.3. Hierarchical Structures Integrating Stability and Responsiveness

Hierarchical crosslinked networks constitute the structural basis for adaptive HA hydrogels, ensuring both stability and responsiveness [41, 42]. This method combines permanent covalent crosslinks, dynamic reversible bonds, and supramolecular interactions to create a network system with multiscale control. Permanent crosslinks establish a stable backbone, ensuring overall mechanical integrity [43]. Conversely, dynamic crosslinks enable reversible restructuring, allowing structures to adapt to microenvironmental changes [44, 45]. Weak interactions offer rapid response pathways, enhancing the material's sensitivity to external stimuli [46]. The synergistic regulation among hierarchical crosslinks enables the hydrogel to undergo localized structural rearrangement while maintaining macroscopic stability. Consequently, the hierarchical network precisely adjusts pore structure and viscoelasticity, enhancing conditions for cell migration, nutrient transport, and ECM deposition [47, 48]. At the same time, different crosslinking interfaces influence molecular diffusion routes, enabling more controlled and gradual drug release rates. This programming strategy converts HA hydrogels from basic support materials into advanced biomaterials with structural control and functional feedback [49]. Nevertheless, the heightened structural complexity inherent in these systems presents significant challenges in terms of precise control, reproducibility, and large‐scale fabrication. Consequently, attaining an optimal equilibrium among stability, responsiveness, and manufacturability necessitates meticulous adjustment of the interaction between permanent and dynamic crosslinks.

3. Microenvironment Sensing and Signal Translation in Adaptive HA Hydrogels

The wound microenvironment is defined by a complex interplay of dynamic biochemical and physical signals [50]. Fluctuations in pH, ROS levels, enzymatic activity, and mechanical stress collaboratively influence processes such as inflammation, ECM remodeling, and tissue regeneration (Figure 2). Consequently, adaptive HA hydrogels are engineered to detect these signals and convert them into structural and functional responses. Table 1 presents a systematic overview of representative stimulus types, responsive chemistries, and typical regenerative functions.

FIGURE 2.

Adaptive HA hydrogels sense pathological microenvironmental cues (pH, ROS, enzymes, and mechanical stress) and translate them into dynamic network remodeling and controlled bioactive release, thereby modulating ECM and inflammation to promote tissue regeneration.

TABLE 1.

Applications of hyaluronic acid hydrogels in wound healing.

Irritant	Responsive chemistry / design	Biological function	Application/Disease model	Therapeutic outcome	References
pH Response	Schiff bases	Enables self‐healing, injectability, and stress dissipation	Infected wound	Improves structural stability and accelerates tissue repair	[51]
pH Response	Schiff bases	Regulates inflammation, promotes cell migration, and enhances angiogenesis under diabetic wound conditions	Diabetic wounds	Accelerated diabetic wound closure with reduced inflammatory cytokine expression and enhanced collagen deposition	[52]
pH Response	Hydrazones	Promotes hemostasis, cell migration, and angiogenesis	Traumatic wounds	Accelerated wound closure and enhanced tissue regeneration	[53]
pH Response	Hydrazones	Regulates ROS levels, protects encapsulated cells, and maintains a moist bioactive environment for tissue repair	Chronic wounds	Accelerates chronic wound healing by reducing oxidative stress, enhancing cell survival, and promoting tissue regeneration	[54]
pH Response	Hydrazones	Enables antibacterial activity and regulates the wound microenvironment	Chronic wounds	Promotes infected wound healing and tissue regeneration	[55]
ROS Response	Sulfide	Eliminates bacteria and alleviates oxidative inflammation	Diabetic wounds	Promotes infected wound healing and tissue regeneration	[56]
ROS Response	Sulfide	Scavenges ROS and reprograms M1 macrophages toward M2 phenotype	Burn wounds	Accelerates angiogenesis and infected wound healing	[57]
ROS Response	Disulfide	Reduces oxidative stress and promotes angiogenesis/collagen regeneration	Diabetic wounds	Accelerates diabetic wound healing and tissue remodeling	[58]
ROS Response	Disulfide	Reduces inflammation and promotes macrophage M2 polarization	Diabetic wounds	Accelerates diabetic wound healing and collagen regeneration	[59]
ROS Response	Selenium bonds	Reduces inflammation and promotes angiogenesis	Diabetic wounds	Accelerates infected diabetic wound healing and tissue regeneration	[60]
ROS Response	Phenylboronic acid	Reduces oxidative stress and inflammatory cytokine expression	Traumatic wounds	Accelerates corneal epithelial wound healing and suppresses scar formation	[61]
ROS Response	Phenylboronic acid	Reduces oxidative stress, suppresses inflammation, and promotes angiogenesis	Diabetic wounds	Accelerates diabetic wound healing and tissue regeneration	[62]
Enzyme Response	MMPs	Suppresses excessive extracellular matrix degradation and modulates inflammation	Chronic wounds	Promotes tissue remodeling and accelerates chronic wound healing	[63]
Enzyme Response	MMP‐9	Promotes collagen remodeling, angiogenesis, and fibroblast proliferation	Diabetic wounds	Accelerates diabetic wound closure and tissue regeneration	[64]
Enzyme Response	MMPs	Reduces inflammation and promotes cell proliferation and angiogenesis	Chronic wounds	Accelerates wound closure and enhances tissue regeneration	[65]
Mechanical Microenvironment Response	Possessing super‐expansion and elastic mechanical properties	Facilitates cell infiltration, nutrient transport, and tissue remodeling	Diabetic wounds	Promotes faster wound healing and improves tissue regeneration	[66]
Mechanical Microenvironment Response	Rigidity and Mechanical Stress	Enhances cell adhesion, mechanotransduction, and tissue support	Infected wound	Accelerates tissue regeneration and improves wound stability	[67]

3.1. pH‐Responsive Systems Controlling Network Dissociation

Wounds typically have an acidic environment, which is associated with ongoing inflammation, bacterial growth, and delayed healing [68]. In response to these conditions, pH‐responsive HA hydrogels regulate cellular behavior by converting acidity fluctuations into dynamic structural transitions, thereby modulating local biochemical conditions [69]. Schiff base bonds are highly sensitive to slight changes in pH. They break rapidly and reversibly, triggering a burst release, making them suitable for early‐stage infected wounds. Hydrazone bonds are more stable. They hydrolyze more slowly, enabling sustained release and maintaining structural integrity, making them suitable for chronic wounds. Under stable pH, the network stays intact for mechanical support. When pH changes, dynamic bonds cleave and recombine, causing structural relaxation and controlled release of active molecules. For example, acid‐triggered network dissociation and silver ion release are achieved through the rapid, reversible cleavage of Schiff base bonds [70] (Figure 3A). Low cross‐linking leads to rapid swelling and burst release, while high cross‐linking maintains the structure and enables controlled release. Similarly, pH‐triggered rearrangement of Schiff bases significantly boosts eugenol release efficiency (from 37.6% to 82.1%), thereby enhancing its ability to intervene in the biofilm environment [71] (Figure 3B). Furthermore, a hyaluronic acid hydrogel based on a palmitoyl‐linked crosslink triggers the release of metformin in response to pH changes, thereby regulating macrophage polarization and fibroblast behavior to promote ECM remodeling in diabetic wounds [72] (Figure 3C). Another type of HA composite hydrogel releases acetylacetone via hydrazone bond cleavage, thereby regulating ROS, inflammation, and angiogenesis and promoting the healing of diabetic wounds [73] (Figure 3D). Collectively, these dynamic networks emulate ECM adaptability by linking structural responsiveness with microenvironmental modulation, transforming HA hydrogels from passive carriers into adaptive regenerative interfaces.

FIGURE 3.

Preparation of HA hydrogel copolymers containing pH‐responsive groups. (A) Schematic diagram of hydrogel production; Copyright 2024, ACS. (B) Schematic of preparing AHA‐CMCS essential oil hydrogel; Copyright 2024, Elsevier. (C) Schematic illustration of the HA–COL hydrogel and its application as a dressing on a full‐thickness wound model in diabetic BALB/c mice; Copyright 2025, Elsevier BV. (D) Preparation of GHD hydrogel for diabetic wound healing; Copyright 2022, RSC.

3.2. ROS‐Responsive Systems Regulating Redox Balance

Chronic wounds exhibit elevated ROS levels, which induce oxidative stress and impair cell survival, inflammation regulation, and tissue regeneration [74]. To address this, HA hydrogels are engineered with oxidation‐sensitive motifs (sulfide, disulfide, selenium bonds, or phenylboronic acid) to enable dynamic redox modulation and regulate cellular behavior [75]. Sulfide systems undergo gradual oxidation, resulting in sustained release. Disulfide bonds are more prone to breaking, allowing for rapid release. Selenium bonds exhibit higher sensitivity and lower bond energy, enabling rapid responses. The phenylboronic acid system, on the other hand, is selective toward hydrogen peroxide, allowing for more precise control. These structures enable the hydrogels to selectively respond to localized oxidative environments. When ROS levels increase, these sensitive bonds oxidize, leading to network relaxation or degradation, releasing functional molecules, and altering the microenvironment. For example, When disulfide bonds break under ROS conditions, the GC‐HA@ZIF‐8@Cur hydrogel releases curcumin and Zn^{2 +}, thereby modulating inflammation, oxidative stress, and angiogenesis and significantly promoting the healing of diabetic wounds [76] (Figure 4A). Similarly, HA@Cur@Ag hydrogels release curcumin liposomes and Ag⁺ through the cleavage of disulfide bonds, thereby regulating oxidative stress, inflammation, and angiogenesis, and accelerating diabetic wound healing by inhibiting the TNF/NF‐κB pathway [77] (Figure 4B). Another type of SCSH‐Gel hydrogel utilizes selenide bond cleavage to release CeO₂ nanoenzymes, which effectively scavenge ROS, thereby regulating macrophage polarization, suppressing inflammation, and promoting tissue regeneration [78] (Figure 4C). Furthermore, HA‐PBA/PVA/TA/MoB₂NSs hydrogels release MoB₂ nanozymes during the oxidation of phenylboronic acid, enhancing antioxidant activity and achieving highly effective anti‐inflammatory and antibacterial effects as well as accelerated healing of infected diabetic wounds [79] (Figure 4D). These ROS‐responsive dynamic networks emulate ECM adaptability by coupling structural transformation with redox microenvironment regulation. This enables HA hydrogels to evolve from passive carriers into adaptive regenerative interfaces.

FIGURE 4.

Preparation of HA hydrogel copolymers containing ROS‐responsive groups. (A) Schematic illustration of ROS‐triggered hydrophilic switching synergized with pH‐responsive nano system and its therapeutic mechanism for diabetic wound healing; Copyright 2024, ACS. (B) Synthesis and evaluation of HA@Cur@Ag hydrogel for diabetic wound healing; Copyright 2023, WILEY. (C) Schematic of current study: (a) Preparation of Se‐CeO₂. (b) “Ce³⁺–Se⁴⁺–Ce⁴⁺ electron transfer chain” model. (c) Preparation of SCSH‐Gel. (d), (e) SCSH‐Gel combined with SMF to achieve precise on‐demand regulation of ROS scavenging rate for tissue repair; Copyright 2026, WILEY (D) The preparation method and structural diagram of HPTM and its primary mechanism in infected diabetic wound healing; Copyright 2026, Elsevier.

3.3. Enzyme‐Responsive Systems Enabling Selective Degradation

Chronic wounds exhibit abnormal enzyme activity, particularly excessive MMPs, disrupting ECM balance and hindering tissue repair [80]. To address this, enzyme‐responsive HA hydrogels are designed to couple enzymatic activity with matrix remodeling dynamics, thereby modulating the wound microenvironment and enabling feedback regulation of cell–matrix interactions [81]. This methodology integrates MMP peptide sequences or enzymatically degradable crosslinking structures, thereby enabling the materials to selectively respond to changes in the local enzymatic profile. Upon exposure to MMP activity, the crosslinks gradually dissociate, leading to network relaxation and restructuring. This process facilitates the release of bioactive molecules and generates space for cellular migration. For example, MMP‐responsive HA hydrogels incorporating MMP‐cleavable peptides enabled pathological enzyme‐triggered degradation and sustained DFO release, thereby stabilizing HIF‐1α expression, promoting VEGF‐mediated angiogenesis, and significantly accelerating diabetic wound healing compared with nonresponsive hydrogels [82] (Figure 5A). In a separate study, the OE‐G@D hydrogel enabled glucose, ROS, and MMP‐9 responsive drug release through dual‐crosslinked networks, thereby reducing inflammation, promoting angiogenesis, and accelerating diabetic wound healing [83] (Figure 5B). Additionally, the collagen‐binding HA/DS‐SILY system reduced MMP‐1/13‐mediated collagen degradation, regulated collagen fibril organization, and improved tensile strength, ultimately decreasing scar formation and promoting regenerative wound healing [84] (Figure 5C). Another category of Ad‐HA‐AMP hydrogels used HA host–guest supramolecular networks and MMP/ROS‐cleavable cyclic linkers to release antimicrobial peptides only under infected conditions, thereby improving antibacterial efficacy, reducing AMP cytotoxicity, and accelerating infected diabetic wound healing [85] (Figure 5D). Overall, enzyme‐triggered degradation synchronizes material renewal with ECM remodeling, enabling dynamic structural adaptation in response to pathological enzymatic signals. This mechanism supports adaptive cell–matrix interactions and provides a basis for precision regulation of the wound microenvironment.

FIGURE 5.

Preparation of HA hydrogel copolymers containing Enzyme‐responsive groups. (A) Schematic illustration of the construction of MMP‐cleavable hydrogel; Copyright 2022, Elsevier. (B) The design strategy of the OE‐G@D hydrogel and mechanism of DFU healing promoted by the hydrogel; Copyright 2025, Elsevier. (C) Representative Mason Trichrome stained microscopic sections of healed incisions in rats at 21 days. Arrows indicate the outer limit of the granulation tissue area with no treatment (NT), HA excipient (HA), and peptidoglycan‐treated wounds (DS‐SILY). In each group, note the marked differences in collagen organization and maturity in the granulation tissue area; Copyright 2011, PLS (D) Schematic illustration of the injectable sHG with the precisely controlled release of AMP in response to bacterial infection for diabetic chronic wound healing; Copyright 2023, ACS.

3.4. Mechanoresponsive Systems Modulating Cellular Behavior

During wound healing, matrix stiffness and mechanical stress continuously change, directly affecting cell migration, proliferation, and differentiation [86]. Mechanoresponsive HA hydrogels regulate these processes through adaptive tuning of viscoelasticity and dynamic crosslinking, enabling structural reconfiguration under mechanical stimulation [43]. Changes in matrix mechanics influence integrin‐mediated focal adhesion formation and downstream mechanotransduction pathways, including FAK, Src, RhoA/ROCK, and YAP/TAZ signaling. These pathways regulate cytoskeletal tension, cellular spreading, macrophage polarization, angiogenesis, and ECM remodeling. Unlike rigid matrices that may induce fibrosis, dynamically adaptable hydrogels maintain balanced mechanobiological signaling favorable for regenerative healing. For instance, the CHC hydrogel patch enhanced mechanical strength, tissue adhesion, and biocompatibility through the synergistic incorporation of gallol‐conjugated chitosan, HA, and Ca^{2 +}, thereby reducing inflammation and improving wound sealing and tissue regeneration in vivo [87] (Figure 6A). The HDiE hydrogel system combined HAMA microspheres with induced EMSCs to promote angiogenesis, collagen deposition, and ECM remodeling, thereby significantly accelerating wound closure and tissue regeneration in vivo [88] (Figure 6B). In diabetic models, the DMN@TCH/DFO microneedle system enabled sequential antibacterial and pro‐angiogenic therapy through rapid TCH release and sustained DFO delivery, thereby enhancing angiogenesis, collagen deposition, and diabetic wound healing [89] (Figure 6C). Additionally, the HG‐CB@R hydrogel system achieved blood‐triggered mechanical reinforcement through Fe^{3 +}–bisphosphonate coordination and rapid blood absorption, thereby accelerating thrombosis, reducing inflammation, and significantly improving hemorrhagic wound healing [90] (Figure 6D). As a result, mechanoresponsive design transforms HA hydrogels from static scaffolds into adaptive interfaces capable of interacting with the tissue's mechanical environment. These systems regulate cellular responses through mechanical microenvironment adaptation, where viscoelastic properties and structural dynamics determine mechanotransduction outcomes.

FIGURE 6.

Preparation of HA hydrogel copolymers containing Mechanical Microenvironment‐Response groups. (A) Synthesis and the chemical structure of CHI‐G; Copyright 2025, Elsevier. (B) Preparation of Hyaluronic Acid‐Methacrylate Hydrogels; Copyright 2025, Elsevier. (C) Schematic of the fabrication of the double‐layer drug‐loaded microneedle and its accelerated healing of diabetic wounds by resisting bacteria, reducing inflammation, and promoting angiogenesis and collagen regeneration; Copyright 2023, RSC (D) Schematic illustration of the hemostatic mechanism of HG‐CB@R hydrogel; Copyright 2023, Elsevier.

4. ECM Modulation and Cell–Matrix Interaction by Adaptive HA Hydrogels

Traditional wound dressings are mainly seen as passive supports, primarily offering physical protection and coverage [91]. However, with advancements in regenerative medicine, this perception is undergoing a transformation. The ECM is recognized as a dynamic system that regulates cellular behavior and influences tissue regeneration through combined mechanical and biochemical signals [92]. In this context, adaptive HA hydrogels have been proposed as programmable regenerative interfaces that enable spatiotemporal regulation through dynamic structural adaptation, controlled signal presentation, and multi‐stimulus responsiveness [19]. These materials transcend mere spatial support, actively engaging in the remodeling of the microenvironment, regulating cell fate, and directing tissue renewal. The core of this approach lies in emulating the structural and signaling characteristics of natural ECM, achieving continuous structural renewal through dynamic crosslinking and signal modulation [93]. As a result, a long‐term, controllable interactive relationship is established between the material and the tissue, offering a novel material paradigm for precision regeneration.

4.1. Structural Mimicry Reproducing ECM Architecture

HA hydrogels demonstrate highly hydrated characteristics, forming three‐dimensional network structures analogous to the natural ECM [94]. This water‐rich milieu, coupled with flexible molecular chains, reduces resistance to cell migration and facilitates the efficient exchange of nutrients and metabolic byproducts [95]. Additionally, HA molecules play a role in cell recognition and signaling, providing biomimetic functions beyond just structurally mimicking the ECM. By modulating the crosslink density, pore architecture, and viscoelastic properties, microenvironments conducive to cell growth and tissue regeneration can be created [96]. This ECM‐inspired design gives the material “soft adaptive matrix” properties, allowing it to remain structurally stable while being dynamically adaptable. Thus, the flexible microenvironment enhances cell adhesion, migration, and proliferation, promotes organized tissue formation, and serves as a vital foundation for regenerative interfaces.

4.2. Signal Integration Regulating Cell–Matrix Interactions

ECM signal regulation arises from the integration of receptor‐mediated Signaling, matrix mechanics, and biochemical cues. Within this framework, HA regulates cellular signaling by engaging receptors such as CD44, which play a central role in inflammation control and tissue regeneration [97]. HA‐CD44 interactions can shift macrophages from an active inflammatory state to a reparative one [98]. Additionally, HA is involved in cell migration, cytoskeletal reorganization, and matrix remodeling, which collectively support the formation of organized tissue structures [99]. HA hydrogels can alter cell adhesion molecule expression and local mechanical sensing, affecting cellular behavior [100]. The continuous dynamic interaction between the matrix and cells imparts feedback regulation characteristics to the regenerative process. Integrating multisource signals in the matrix, HA hydrogels minimize dependence on single growth factors, improving regeneration stability. Consequently, ECM signaling transforms HA hydrogels from passive scaffolds into instructive matrices with the capability to guide cellular processes.

4.3. Dynamic Remodeling Coordinating Degradation and Regeneration

The natural ECM constantly balances degradation and reconstruction, a renewal process vital for tissue repair [101]. HA hydrogels mimic this behavior by using dynamic crosslinking and controlled degradation, enabling the material's structure to gradually remodel alongside regeneration. Reversible bonds enable network reorganization in response to external stimuli or cellular traction, promoting cell migration, matrix deposition, and tissue reconstruction [102]. Degradation rates can be adjusted through molecular structure to align the material's renewal with the natural ECM remodeling process. This approach minimizes interference from long‐term residual materials. Continuous structural remodeling creates “dynamic reciprocity” between the material and tissue, strengthening the two‐way regulatory relationship between cells and the matrix. Consequently, HA hydrogels have evolved from static scaffolds into dynamically regulated matrices that enable controllable degradation, structural reconfiguration, and feedback interactions with surrounding cells, thereby actively participating in regenerative processes in a spatiotemporal manner. These hydrogels facilitate the systematic development of tissue architecture and enhance functional recovery.

4.4. Immune–Matrix Interaction Regulating Tissue Regeneration

ECM reprogramming involves the coordinated modulation of immune signaling, matrix structure, and biochemical cues, collectively reshaping the regenerative microenvironment [103]. In the process of wound healing, adaptive HA hydrogels play a crucial role in modulating macrophage polarization via CD44‐mediated signaling pathways. Additionally, they exert influence over broader immune networks, encompassing complement activation, neutrophil recruitment, dendritic cell maturation, and modulation of T‐cell‐mediated immune responses [104, 105, 106]. The surface chemistry of hydrogels, along with their degradation products and dynamic viscoelastic properties, can significantly influence complement pathways that are crucial for early immune recognition, the amplification of inflammatory responses, and the integration of biomaterials. Concurrently, the regulation of ROS levels, cytokine gradients, and matrix permeability plays a pivotal role in modulating neutrophil infiltration and the resolution of inflammation, thereby mitigating excessive protease release and subsequent tissue damage. During the later stages of regeneration, matrix remodeling and biochemical signaling further affect dendritic cell activation and T‐cell responses, which are essential for achieving immune tolerance and ensuring long‐term tissue integration. Notably, the immune regulation facilitated by adaptive HA hydrogels is governed by an interplay of biochemical signals and matrix mechanics, wherein factors such as stiffness, viscoelasticity, and degradation kinetics collectively impact immune cell adhesion, migration, and mechanotransduction. By integrating ROS, pH, enzymatic activity, and mechanical signals, adaptive HA hydrogels serve as immune‐instructive matrices that can direct immune specificity, ECM remodeling, and functional tissue regeneration.

5. Functional Tissue Regeneration Enabled by Adaptive HA Hydrogels

Effective tissue regeneration requires materials that actively manage the regenerative process over time and space, not just provide passive support [107]. Adaptive HA hydrogels form regenerative interfaces by integrating ECM‐like structures that respond to the microenvironment [16]. In this framework, material structure, signal delivery, and cellular behavior work together to regulate and make the regenerative process more predictable and controllable. As a result, HA hydrogels not only facilitate the reconstruction of tissue structures but also modulate essential regenerative signaling networks. Angiogenesis, neurorepair, and the regulation of stem cell fate are identified as fundamental aspects for achieving functional regeneration and serve as critical metrics for assessing the efficacy of adaptive regenerative materials.

5.1. Angiogenesis Regulation Promoting Vascular Formation

Angiogenesis is crucial for tissue regeneration, impacting oxygen supply, nutrient delivery, and immune response [108]. HA hydrogels function as programmable delivery platforms, facilitating the stable incorporation and spatiotemporal release of proangiogenic factors such as VEGF [109]. The hydrogels' dynamic crosslinking networks modulate release rates to maintain local signaling at levels ideal for inducing vascular sprouting and maturation [43]. The high water content of HA hydrogels reduces cell migration resistance, promoting endothelial cell alignment, lumen formation, and vascular network expansion. Concurrently, the adjustable stiffness and pore architecture of the matrix influence cellular mechanosensing, thereby modulating vascular branching patterns and ensuring structural stability. Throughout the stages of regeneration, the dynamic network undergoes continuous remodeling, directing the progressive maturation of vascular architecture [110]. Consequently, HA hydrogels act as vascular‐instructive matrices that regulate endothelial alignment and angiogenic signaling, promoting tissue‐like vascular reconstruction.

5.2. Neural Regeneration Guiding Axonal Growth

Neural repair is heavily impacted by the extracellular matrix's microenvironment, including its mechanical properties, structure, and local signaling [111]. HA, an essential part of the nervous system's natural ECM, shows excellent biocompatibility and supports neural growth and axonal guidance. Adaptive HA hydrogels provide a stable environment with dynamic networks, ensuring optimal neuron adhesion for migration, differentiation, and synapse formation. Flexible viscoelastic matrices reduce mechanical stress, optimizing neural mechanosensory responses to improve neural network reconstruction and recovery [112]. Simultaneously, localized signal delivery works synergistically with matrix structure formation, providing spatial and directional cues essential for axonal growth. During regeneration, dynamic network reconfiguration enables the material to act as a neuro‐instructive interface that guides axonal growth and neural network reconstruction. This transformation facilitates the systematic reconnection of neural structures.

5.3. Stem Cell Regulation Guiding Differentiation

Stem cell fate is influenced by the substrate's mechanical properties and ECM architecture, both key factors in the regenerative microenvironment [113]. HA hydrogels possess the ability to modulate the mechanical stimuli experienced by cells through modifications in their viscoelastic properties, crosslink density, and network dynamics [96]. These alterations can significantly influence cellular processes, including proliferation, migration, and differentiation pathways. Cells detect matrix stiffness and topology via mechanotransduction, influencing cytoskeletal tension and gene expression [114]. The dynamic nature of these networks allows cells to continuously remodel their surrounding microenvironment, establishing a feedback‐regulated mechanism that mimics the natural ECM. This adaptability permits stem cell behavior to undergo phased and plastic changes. The combination of structural features and biochemical cues forms a stem cell niche that guides differentiation and maintains tissue renewal. Consequently, HA hydrogels have transitioned into stem‐fate instructive matrices that regulate differentiation through matrix mechanics, structural cues, and dynamic cell–matrix interactions, enabling spatiotemporal control of tissue regeneration.

6. Spatiotemporal Regulation and Multi‐Signal Coordination in Adaptive HA Hydrogels

Traditional wound dressing materials have predominantly concentrated on single‐stimulus responses or single‐stage repair processes [115]. In contrast, genuine tissue regeneration is characterized by distinct temporal and spatial partitioning [116]. The inflammatory, proliferative, and remodeling phases each exhibit significant differences in signal type, intensity, and duration. As a result, adaptive HA hydrogels are evolving from responsive materials into programmable regenerative interfaces, with spatiotemporal control enabled by dynamic network adaptation and multi‐signal responsiveness. The fundamental principle underlying this shift is the attainment of spatiotemporal control over signals through advanced structural engineering. This approach allows materials to adapt their functions during regeneration, guiding tissue repair to better mimic natural physiological processes.

6.1. Temporal Regulation Aligning With Healing Stages

Wound healing constitutes a multifaceted and dynamic process delineated by distinct temporal phases: the inflammatory, proliferative, and remodeling stages [117]. Traditional materials with a singular release profile often fail to address the intricate requirements of tissue regeneration. Recently, adaptive HA hydrogels have shown the capability to time‐regulate regeneration through dynamic crosslinking and multistage degradation. These materials are capable of dynamically adjusting their functional outputs in response to changes in the microenvironment. For example, hierarchical or dual‐crosslinked structures facilitate staged delivery, enabling an initial rapid release followed by a sustained release [43]. ROS‐responsive elements specifically facilitate the release of antioxidant or antibacterial agents during the inflammatory phase [118]. Conversely, enzyme‐degradable structures are instrumental in promoting the release of growth factors and facilitating ECM remodeling during the proliferation or remodeling phases [119]. This time‐sequenced functionality supports phase‐specific intervention, facilitates ECM remodeling, and improves overall healing efficiency, providing a practical framework for temporally guided regenerative design.

6.2. Spatial Control Through Gradient Structures

Real wounds demonstrate considerable spatial heterogeneity, characterized by varying regenerative requirements across different regions. Cell migration and epithelialization dominate at the wound edges, while the center often faces hypoxia and ongoing inflammation [120]. In contrast, deeper tissues depend on vascular reconstruction and matrix remodeling [121]. As a result, the regulation of spatial gradients emerges as a pivotal strategy for adaptive HA hydrogels to facilitate precise regeneration. Through the incorporation of stiffness gradients, these materials facilitate directed cell migration and promote organized cellular alignment. Additionally, variations in pore size and network density enhance the diffusion of oxygen and nutrients, thereby improving local metabolic conditions. Furthermore, the spatially encoded delivery of growth factors supports the systematic development of vascular networks. Simultaneously, advanced manufacturing techniques, such as 3D printing and microfluidics, offer novel tools for multiscale structural programming, enabling the creation of regenerative microdomains with distinctly defined functional zones [122]. Collectively, this spatial encoding strategy transforms HA hydrogels from uniform scaffolds into dynamic interfaces capable of guiding tissue formation through localized functional optimization.

6.3. Multi‐Signal Integration Enabling Selective Activation

The regenerative microenvironment is governed by multiple dynamic signals, including pH fluctuations, ROS levels, enzymatic activity, and mechanical stress [123]. Single‐stimulus responses often lack sufficient specificity, highlighting the importance of multi‐signal responsiveness in adaptive HA hydrogels. By integrating pH, ROS, enzyme, and mechanical triggers, these systems enable condition‐dependent activation rather than continuous release, thereby improving targeting precision and reducing off‐target effects. For instance, pH/ROS dual‐responsive networks selectively release antioxidants or antimicrobial agents in inflamed regions while remaining stable in healthy tissues [124]. Enzyme‐sensitive crosslinking structures further restrict drug release to areas with elevated MMP expression, enhancing spatial selectivity [125]. In addition, mechanically responsive modules facilitate localized network rearrangement in response to cellular traction or matrix stress, promoting tissue renewal [126]. Collectively, the integration of multidimensional signals allows hydrogels to achieve selective and on‐demand functional activation, providing an effective strategy for targeted regulation of complex regenerative environments.

6.4. System‐Level Coordination in Regenerative Processes

Through the incorporation of temporal control, spatial structuring, and multi‐signal responsiveness, adaptive HA hydrogels transition from passive materials to active regenerative systems with the capability to coordinate tissue repair. In this context, the material's structure encodes functional logic, wherein crosslinking topologies and responsive modules delineate system behavior. Microenvironmental signals, including pH, ROS, enzymatic activity, and mechanical forces, serve as inputs, while cellular responses and tissue reconstruction manifest as outputs [127]. This system‐level organization facilitates predefined regenerative pathways and phased regulation, thereby enabling coordinated and condition‐dependent interventions throughout the healing process. As a result, these materials operate as bio‐programmatic systems, incorporating integrated signal processing, feedback regulation, and adaptive structural control. This provides a conceptual foundation for the design of advanced regenerative interfaces.

6.5. AI‐Assisted Design and Closed‐Loop Regulation

Regeneration's spatio‐temporal programmability involves complex parameters with nonlinear interactions among crosslinking structures, mechanical traits, degradation rates, and biological reactions. Conventional methodologies for material design, which rely on experiential knowledge, encounter difficulties in achieving precise optimization [128]. As a result, AI is increasingly recognized as a vital instrument in the predictive design of adaptive HA hydrogels. Recent research has illustrated the potential of AI‐assisted biomaterial design by employing machine learning to predict hydrogel behavior and elucidate structure–property relationships. For instance, Leng et al. constructed a fully connected neural network model, trained on discrete fiber‐network datasets, to forecast the mechanical behavior of fibrin‐based biopolymer gels. This approach facilitates efficient multiscale simulation of gel mechanics and alleviates the computational demands typically associated with traditional finite‐element modeling [129]. In a similar vein, methodologies such as graph neural networks and Bayesian optimization have been employed to forecast drug‐release kinetics and assess biomaterial performance within responsive hydrogel systems, thus minimizing the reliance on experimental trial‐and‐error procedures [130]. Nonetheless, contemporary AI‐assisted methodologies are significantly constrained by the limitations of existing datasets, inadequate biological complexity, and the lack of standardization across experimental platforms. The majority of current models depend on small‐scale datasets derived from simplified in vitro conditions, which can result in overfitting and reduced generalizability within complex in vivo regenerative contexts. Furthermore, the absence of comprehensive biomaterial databases and standardized characterization protocols further impedes the predictive reliability of AI‐driven models. Consequently, future research should prioritize the integration of large‐scale experimental datasets, multi‐omics analyses, real‐time biosensing, and digital‐twin modeling to develop more robust predictive frameworks for adaptive regenerative systems. By embedding AI into the design process, material development is shifting from a trial‐and‐error methodology to a goal‐oriented reverse engineering approach, thereby enhancing HA hydrogels with predictable and controllable regenerative properties.

7. Future Outlook

7.1. Current Research

In recent years, adaptive HA hydrogels have transitioned from traditional structural scaffolds to sophisticated regenerative interfaces with the capability to sense microenvironments and dynamically modulate cellular responses. This review systematically examines significant advancements in adaptive HA hydrogels, focusing on a three‐tier regulatory framework comprising “material‐microenvironment‐cell fate.” It highlights key developments in the design of dynamic covalent networks, multi‐signal response mechanisms, and ECM reprogramming. These materials, through their responsiveness to diverse stimuli including pH, reactive oxygen species, enzymatic activity, and mechanical signals, enable precise regulation within intricate wound environments. This capability significantly contributes to the resolution of inflammation, the promotion of angiogenesis, and the restoration of tissue functionality. Furthermore, the integration of spatiotemporal programming elevates material design from merely responding to a single stimulus to facilitating a comprehensive regulation of the regenerative process. This advancement transforms hydrogels from basic therapeutic carriers into sophisticated, controllable regenerative interfaces. When integrated with AI‐assisted design and intelligent closed‐loop systems, adaptive HA hydrogels are increasingly being developed into “programmable regenerative platforms.” This advancement signifies a new phase in regenerative materials research, transitioning from passive response mechanisms to active regulatory functions.

7.2. Challenges and Shortcomings

Despite advancements in adaptive HA hydrogels, their clinical application faces challenges [131]. The incorporation of dynamic crosslinking networks, multifunctional responsive modules, and hierarchical architectures frequently enhances structural complexity, resulting in batch‐to‐batch variability and challenges in scalable manufacturing. During the transition from laboratory‐scale preparation to industrial production, minor variations in polymer molecular weight, degree of substitution, crosslinking density, reaction temperature, or solvent conditions can significantly impact the viscoelasticity, degradation kinetics, injectability, and release behavior of hydrogels. Furthermore, ensuring uniform distribution of bioactive agents and consistent responsiveness during large‐scale fabrication and prolonged storage poses significant challenges. Sterilization procedures, transportation conditions, and storage environments may further compromise network stability and biological performance. Critically, the long‐term biosafety of degradation products remains inadequately understood. While HA is inherently biocompatible, the inclusion of dynamic covalent linkers, ROS‐responsive motifs, nanozymes, and embedded therapeutic agents may produce bioactive intermediates or metabolites during extended degradation. This process has the potential to induce chronic inflammation, oxidative imbalance, or unanticipated immune responses [132]. Consequently, it is imperative for future research to prioritize the development of standardized synthesis protocols, scalable manufacturing technologies, and real‐time quality control systems. These systems should integrate rheological characterization, structural analysis, and automated process monitoring to enhance reproducibility, ensure manufacturing consistency, and improve translational reliability.

In addition, adaptive hydrogels frequently operate through simultaneous responses to multiple stimuli, including pH, ROS, enzymes, and mechanical stress. However, the potential signal interference or crosstalk among these dynamic pathways remains poorly characterized in vivo. Such nonlinear interactions may alter release behavior, disrupt feedback regulation, or reduce response specificity under complex pathological conditions. Current studies still largely rely on static endpoint evaluation and simplified animal models, which are insufficient to capture the spatiotemporal evolution of regenerative microenvironments. Future research should integrate multi‐omics analysis, real‐time imaging, wearable sensing, and AI‐assisted digital modeling to establish predictive frameworks capable of monitoring and simulating material–tissue interactions in vivo. These strategies may provide a foundation for the development of intelligent closed‐loop regenerative systems with higher precision, predictability, and translational potential.

7.3. Future Outlook

Future advancements in the development of adaptive HA hydrogels are anticipated to prioritize intelligent, personalized, and systematic design approaches. AI‐driven reverse design is increasingly utilized for the optimization of materials with specific functions, facilitating the prediction of crosslinking topology, mechanical properties, and release behavior by correlating target performance with structural parameters. For instance, existing studies have employed supervised learning to establish structure–property relationships, enabling the prediction of the mechanical properties of polymer hydrogels based on their composition and crosslinking density [133]. Nonetheless, these methodologies are still heavily dependent on limited datasets and simplified models. There is a pressing need to further integrate systematic experimental validation and complex biological environments to enhance their predictive accuracy and potential for application. This will enable precise regulation of regenerative pathways. Concurrently, the integration of multimodal sensing and wearable technologies is poised to propel hydrogels toward the development of closed‐loop regenerative systems [134]. These systems are distinguished by their capabilities for real‐time monitoring and dynamic intervention, thereby facilitating a comprehensive approach to diagnosis and treatment. Furthermore, the deep integration of spatial structural encoding with temporal dimension programming has the potential to endow materials with decision‐making capabilities akin to those found in biological systems. This integration enables the development of programmable and adaptive features within the regeneration process. By combining food‐derived biomaterials with environmentally sustainable manufacturing strategies, future regenerative platforms are poised to achieve significant breakthroughs in safety, sustainability, and clinical scalability. In summary, the field of regenerative medicine is evolving from a phase predominantly focused on materials to one that is increasingly driven by biological programming. In this context, adaptive HA hydrogels are emerging as a pivotal link between materials science and precision regenerative therapy.

8. Conclusion

Adaptive HA hydrogels are catalyzing a transformative shift in wound healing research, transitioning from passive coverage to the active regulation of regeneration. Utilizing dynamic covalent networks, supramolecular crosslinking, and multi‐signal response strategies, these materials are capable of sensing complex microenvironments and facilitating real‐time structural and functional remodeling. This capability positions them as crucial agents in the regulation of inflammation, reprogramming of the ECM, and the recovery of tissue functionality. This review systematically examines the latest advancements in adaptive HA hydrogels within the framework of a three‐tier regulatory model: “material–microenvironment–cell fate.” It highlights developments in microenvironment sensing, targeted delivery, and spatiotemporal programming. Furthermore, it introduces the notion of “adaptive regeneration programming,” which elevates material design to a regenerative system with logical decision‐making capabilities. By integrating AI‐assisted design, multimodal sensing, and food‐derived biomaterials, future regenerative platforms are anticipated to progress from passive responders to intelligent interfaces with predictive and closed‐loop regulatory functions. Regenerative medicine is progressively advancing toward bio‐programming and systematization, with adaptive HA hydrogels positioned to play a crucial role in bridging materials science, precision medicine, and clinical translation. This advancement offers novel theoretical foundations and design trajectories for the development of next‐generation intelligent regenerative therapies.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.