Advances in Composite Stimuli-Responsive Hydrogels for Wound Healing: Mechanisms and Applications

Abstract

Stimuli-responsive hydrogels have emerged as a promising class of biomaterials for advanced wound healing applications, offering dynamic and controllable responses to the wound microenvironment. These hydrogels are designed to respond to specific stimuli, such as pH, temperature, light, and enzyme activity, enabling precise regulation of drug release, antimicrobial activity, and tissue regeneration. Composite stimuli-responsive hydrogels, by integrating multiple response mechanisms and functions, show potential for addressing the diverse needs of wound healing. This review explores the biological mechanisms of wound healing, the design and classification of composite stimuli-responsive hydrogels, and the key fabrication strategies employed to optimise their properties. Despite their immense potential, unresolved challenges such as biocompatibility, long-term stability, and scalability continue to limit their translation into clinical practice. Future research will focus on integrating hydrogels with smart wearable devices, AI-driven personalised medicine, and 3D bioprinting technologies to develop next-generation wound care solutions. With continuous advancements in biomaterials science and bioengineering, stimuli-responsive hydrogels hold great promise for revolutionising wound management.

Keywords: antibacterial hydrogels; bioactive agents; biomedical applications; composite hydrogels; controlled drug release; smart biomaterials; stimuli-responsive hydrogels; wound healing.

Figure 1

Schematic illustration of stimuli-responsive mechanisms and therapeutic functions of composite hydrogels in wound healing.

Figure 2

Schematic illustration of the four stages of wound healing: (a) hemostasis—blood clot formation and vessel constriction; (b) inflammation—infiltration of immune cells for pathogen clearance; (c) proliferation—fibroblast activation, collagen deposition, angiogenesis, and re-epithelialisation; and (d) remodelling—collagen remodelling and scar tissue formation.

Figure 3

Schematic illustration of the preparation of pH-responsive RPC/PB hydrogel fabricated from PB and RPC: (a) synthetic route for the preparation of the RPC conjugate, (b) schematic illustration of the fabrication process of RPC/PB hydrogels, and (c) SEM images of PB hydrogel and RPC/PB hydrogels with varying RPC content. Reproduced from [72], licensed under CC BY 4.0.

Figure 4

Glucose and MMP-9 dual-responsive, shape-self-adaptive hydrogels for chronic diabetic wound treatment: (A) preparation of GMs@Cel (celecoxib-loaded gelatin microspheres), (B) fabrication and characteristics of CBP/GMs@Cel&INS hydrogel, and (C) treatment of chronic diabetic wounds with CBP/GMs@Cel&INS hydrogel via dual-responsive system. Reproduced from [117] with permission from Elsevier.

Figure 5

(a) Schematic diagram of the fabrication of PMT-C@PhM hydrogel for wound healing. (b) ROS (H₂O₂, OH⁻, ${\mathrm{O}}_2^{-}$) scavenging efficiency of the hydrogels (n = 3). Statistical significance is indicated as follows: * $p<0.05$, ** $p<0.01$, *** $p<0.001$, **** $p<0.0001$. Adapted from [128] with permission from Elsevier.