Dynamic covalent design of oxidized hyaluronic acid hydrogels: Tailoring programmable biofunctions toward clinical translation in regenerative medicine.

Oxidized hyaluronic acid (OHA)-based hydrogels, fabricated via aldehyde-mediated dynamic covalent bonds (e.g., Schiff bases, hydrazones, and boronate esters), exhibit excellent biocompatibility, tunable degradation profiles, and stimuli-responsive behavior to physiological cues. Exploiting these attributes, OHA hydrogels have been extensively applied in wound healing, bone regeneration, and stimuli-responsive drug delivery, positioning them as promising platforms for regenerative medicine. However, their clinical translation is impeded by three key challenges: (i) temporal mismatch between mechanical stability and degradation kinetics, (ii) batch-to-batch inconsistency during scalable manufacturing processes, and (iii) biosafety concerns associated with metabolic byproducts of dynamic bond formation. To comprehensively map interdisciplinary advancements, this review conducts a systematic analysis of 181 peer reviewed publications (2008-2025) using bibliometric mapping and thematic clustering. We elucidate key advancements in molecular engineering strategies, dynamic crosslinking chemistries, multicomponent network design, and multifunctionality optimization, with emphasis on stimuli-responsiveness, mechanical reinforcement, and immunomodulatory effects. This review positions OHA hydrogels as intelligent, adaptive biomaterials with significant translational potential. A clinical translation roadmap is proposed, addressing stability-function trade-offs and standardizing GMP-compliant manufacturing to align with dynamic pathological microenvironments.