Bioadhesive hydrogels as immunomodulatory interfaces for chronic wound healing: from microenvironmental regulation mechanism to engineering strategies

Abstract

Abstract Chronic wounds represent a major and growing clinical burden, particularly among aging populations and individuals with diabetes, in whom persistent inflammation and immune dysregulation delay normal tissue repair. Addressing this challenge requires functional materials that do more than passively cover the wound and instead actively regulate the wound microenvironment. Advances in hydrogel chemistry and bioengineering have enabled the development of bioadhesive interfaces that maintain stable contact with wound tissue while modulating immune and regenerative responses. In this Review, we present bioadhesive hydrogels as immunomodulatory interfaces rather than simple wound coverings and systematically examine their mechanisms of action, including the reduction of microbial and inflammatory stimuli; modulation of macrophage polarization; regulation of NF-κB-, NLRP3-, and STAT-associated signaling; and control of mechanobiological signaling at the material–tissue interface. Through these mechanisms, bioadhesive hydrogels can alleviate excessive inflammation and support a regenerative microenvironment that promotes angiogenesis, re-epithelialization, and extracellular matrix remodeling. We classify the engineering approaches used to achieve these functions into four complementary strategies. Structural and protective hydrogels stabilize the wound and protect it from contamination and mechanical disruption. Bioactive and regenerative systems deliver therapeutic molecules or cells to regulate inflammation and promote repair. Externally activated platforms provide spatiotemporal control over therapeutic activity, whereas sensing-integrated systems monitor wound conditions and support adaptive or closed-loop treatment. We also discuss major translational barriers, including unstable adhesion under exudative and mechanically dynamic conditions, limited long-term safety data, insufficient standardization, manufacturing challenges, and unclear regulatory pathways. Future progress will require disease-specific material design, clinically relevant validation, and the reliable integration of sensing and therapeutic functions.