Microfluidic-engineered hyaluronic acid multifunctional materials: From precision microstructure fabricating to programmable biomedical functions.

Progress in clinical requirements creates high demands for advanced biomedical materials. As a natural linear anionic polysaccharide, hyaluronic acid (HA) exhibits favorable properties such as outstanding biocompatibility, non-immunogenicity, enzyme-triggered degradation and CD44-targeting ability, attracting widespread interest in tissue engineering, drug delivery and organ chip. However, due to the wide particle size distributions, the inability to construct complex microarchitectures, and common toxic organic solvent residues, the traditional fabrication methods severely obstruct the performance of HA materials. Moreover, these drawbacks prevent HA materials from meeting rigorous biomedical standards and restrict the clinical application in precision medicine. What's more, microfluidic technology can overcome the above manufacturing limitations, enabling the fabrication of highly monodisperse HA materials with distinct microstructures to support co-loading and spatiotemporally controlled release of multiple therapeutics. While existing reviews cover HA biomaterials, general microfluidic fabrication, and its biomedical applications, a systematic framework integrating microfluidic engineering with HA properties remains absent. To fill this gap, this review establishes an integrated design framework for microfluidic-engineered HA materials, bridging processing parameters, precise microstructural control and programmable biomedical functions. This work summaries microfluidic configurations and operating parameters, discusses HA modification and crosslinking strategies adapted to microfluidic processes, analyses structure-function relationships, and describes typical biomedical applications. Moreover, the critical challenges involving clinical translation, large-scale production and artificial intelligence-assisted optimization are also highlighted. In conclusion, this work establishes a systematic guideline for developing microfluidic engineered HA materials, offering theoretical support to basic research and industrial translation.