Chitosan-based hydrogels for chronic wound healing: From multifunctional modification to microenvironment regulation...

The management of chronic wounds remains a critical challenge in biomedical research owing to their complex pathophysiology and unmet clinical needs. As a naturally derived cationic polysaccharide, chitosan exhibits exceptional biocompatibility, biodegradability, antimicrobial efficacy, and tissue-repair capabilities, making it an ideal building block for advanced wound care. When crosslinked into a three-dimensional hydrogel network that retains water effectively and mimics the extracellular matrix, this biomaterial provides an ideal platform for chronic wound management. Consequently, recent research has increasingly focused on functional chitosan-based hydrogel systems, with strategies such as chemical modification and stimuli-responsive design intensively explored to precisely regulate the wound microenvironment and accelerate tissue regeneration. This review is organized around three core objectives: (i) multifunctional modification, (ii) microenvironment regulation, and (iii) clinical translation. It systematically summarizes the pathophysiological characteristics of chronic wounds, outlines methods for preparing chitosan-based hydrogels, and comprehensively discusses their applications in chronic wound repair. Particular emphasis is placed on emerging functionalization strategies, such as incorporating TCM active ingredients, loading nanozymes and single-atom enzymes, and designing multi-stimuli-responsive systems. It provides a critical discussion of clinical translation, highlighting current challenges and realistic future perspectives to guide the rational design and development of high-performance chitosan-based hydrogels for chronic wound therapy.