Microbial hyaluronic acid production by integrating molecular structure, biological function, purification, and application

Hyaluronic acid (HA) is a valuable biopolymer with rapidly growing demand due to its extensive utilization in medical and pharmaceutical applications, encompassing osteoarthritis therapy, ophthalmology procedures, and wound healing. Traditionally, commercial HA has been extracted from animal tissues, including rooster combs and bovine synovial fluid; however, concerns over environmental safety, contamination risk, low extraction rates, and supply chain limitations have induced the development of microbial production strategies. In recent years, significant progress has been observed in microbial HA production by both wild-type and genetically modified strains via the fermentation process. HA production by microbial methods has been growing due to bioprocess optimization, including the refinement of fermentation medium and process conditions. This allows for optimizing carbon, nitrogen, and mineral supplies, as well as regulating temperature, agitation, aeration, and pH levels. This review paper provides a summary of HA structure, biological function, metabolic synthesis, and its application. Also, comprehensive review of the most recent advanced technologies for HA production, utilizing both wild-type and genetically modified strains, was conducted alongside purification and characterization methods. At the end, this review made recommendations to address bottlenecks in HA fermentation as future research, including process optimization using artificial intelligence (AI), strain modification via the CRISPR method, design of novel bioreactors, renewable raw materials utilization, and advanced purification strategies.