Hyaluronic Acid-based Hydrogels as Anti-inflammatory Drug Delivery Platforms for Osteoarthritis: Design Strategies, Mechanisms, and Translational Perspectives.

Osteoarthritis (OA) is a clinical problem that remains difficult to treat because few therapeutic options can support sustained cartilage repair. Hyaluronic acid (HA) hydrogels have been advanced as multifunctional drug delivery systems and tissue engineering scaffolds because they are biocompatible and can be designed to possess specific physicochemical properties. This review article makes four major contributions. First, it proposes a framework for classifying HA crosslinking techniques, including covalent, click/enzymatic, and supramolecular chemistry. Second, it proposes a chemistry-to-function framework that shows how HA structure is related to critical properties, such as drug release, chondrogenesis, and immunomodulation. Third, this article synthesizes preclinical studies that illustrate how multifunctional HA hydrogels can support cartilage repair. Fourth, this article proposes a framework for translating HA hydrogels to the clinic that considers issues, such as manufacturing scale-up and emerging technologies, such as 3D printing and AI. Despite such advancements, there are several hurdles to be overcome for translation. These hurdles include a lack of standardization in cross-linking and characterization, an incomplete understanding of long-term immune response, and difficulties with reproducibility in manufacturing. These hurdles need to be addressed to bridge the gap between preclinical and clinical success. The review aims to provide an overview for the rational design and translation of HA-based hydrogels for OA therapy.