Engineering bioactive citrate-based hydrogels for wound repair: From structure-function design to microenvironmental regulation

Abstract

Chronic non-healing wounds, characterized by a complex microenvironment of persistent infection, chronic inflammation, and defective angiogenesis, pose a significant hurdle to regenerative medicine. Citrate-based chemistry has emerged as a sophisticated platform for engineering bio-instructive materials due to its versatile crosslinking chemistry and intrinsic metabolic bioactivity. This review provides a comprehensive appraisal of hydrogels constructed from citrate-based polymers (PC hydrogels) as a high-performance therapeutic toolkit for wound orchestration. Guided by the biological imperatives of the skin-healing cascade, we delineate the network construction mechanisms and structure-function relationships of PC hydrogels, together with the molecular mechanisms underlying their regulation of the wound microenvironment. On this basis, a modular classification of PC hydrogels is proposed. It encompasses seven functional paradigms including antimicrobial, antioxidant, and pro-angiogenic activities, with a critical focus on their structure-property-function relationships. Finally, we identify the existing bottlenecks in clinical translation and offer strategic perspectives on next-generation PC platforms, emphasizing precision design, mechanistic elucidation through multi-omics, and standardized manufacturing. This work aims to catalyze the development of intelligent, translation-ready PC wound dressings for complex tissue repair.