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

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.