Property-tailoring chemical modifications of hyaluronic acid for regenerative medicine applications

Hyaluronic acid (HA) as well as HA-based materials are widely applied in regenerative medicine due to their good biocompatibility, bioactivity and amenability to chemical modifications. Although the reactive sites and associated reaction types of HA have been summarized previously to guide chemical modification and synthesis of HA-based materials, the relationship between chemical modifications and HA-based material properties has not yet been discussed. In this review, the key properties of HA-based materials required for regenerative medicine in various tissues and organs including skin, bone, cartilage, heart and cornea are summarized and various chemical modification strategies aimed at achieving these properties are discussed. Versatile HA-based materials can be tailored through crosslinking and conjugation, as well as regulating the internal bonding types and degrees of modification. We also provide a comparative analysis of commonly used HA-based materials modification methods and discuss their practical advantages, limitations, and the current status of clinical translation. Even with significant progress already achieved, there is still a long way to go in precisely fine-tuning chemical modifications, balancing functionality and practicality, as well as in understanding their interactions with the diverse array of cells and tissues in vivo. This review bridges tissue-specific property demands with chemical design strategies. We believe that this demand-driven framework provides a practical and accessible guide for researchers intending to design HA-based materials with targeted regenerative capabilities. STATEMENT OF SIGNIFICANCE: This review critically examines hyaluronic acid (HA) and HA-based materials in regenerative medicine applications, focusing on the key properties required for applications in specific tissues such as skin, bone, cartilage, heart, and cornea, as well as the associated chemical modification strategies. While design strategies for HA-based materials have been studied in the past, the relationship between chemical modifications and the resulting material properties remains under-explored. This review thus addresses this gap by systematically categorizing various chemical modification strategies that have been tailored to different material property requirements, providing a comparative analysis of commonly used chemical modification methods, and discussing current clinical challenges and future directions of HA-based materials. By linking material properties to chemical modification strategies, this review thus provides a comprehensive guide for researchers and offers valuable insights for advancing the applications of HA-based materials in regenerative medicine.