Bioorthogonal Click Chemistry Engineered Bioinks for 3D Bioprinting in Osteochondral Regeneration and Osteoarthritis Therapy: A Translational Review.

Osteoarthritis (OA) is a rapidly growing joint disease worldwide, and its chronic and progressive form can cause damage to the cartilage and subchondral bone, resulting in physical and economic suffering for affected individuals. So far, potential therapeutic approaches, such as systematic drug administration and intraarticular injections, have been used to treat OA and regenerate osteochondral defects, but they are palliative rather than curative. Thus, hydrogels with biologics (matrix-degrading enzyme inhibitors) and small molecules (growth factors, anti-inflammatory molecules) show promising results in preclinical studies but have failed in clinical practice due to inadequate patient benefits. Recently, bioinks have gained significant attention as regenerative biomaterials in tissue engineering due to their ability to contain cells and bioactive small molecules, such as proteins, peptides, and growth factors. Bioinks are developed using various polymers with crosslinkers. The crosslinkers play a crucial role in the formation of bioinks, which can be natural or synthetic (ionic, chemical, photo, etc.). However, extensive usage of crosslinkers limits the clinical application of bioinks due to compromising the ideal properties of bioinks, such as cytocompatibility, biodegradability, and biomechanical properties. Therefore, the potential solution to this problem is utilizing the click chemistry approach. The click chemistry strategy can achieve efficient bio-inks without compromising their intrinsic and optimal characteristics, as click reactions are rapid, spontaneous, and bioorthogonal, favoring the gelation time, rate of degradation, and cell viability. A few reports have delivered thorough information on click chemistry-induced hydrogels and bioinks for bone regeneration, but they are not specific to osteochondral regeneration. This review addresses this gap by exploring the fundamental concepts, challenges, and prospects of click chemistry, specifically its distinct click reactions, in developing bioinks and 3D bioprinting scaffolds for OA treatment and osteochondral regeneration. Furthermore, it addresses regulatory and clinical hurdles tied to bioink translation, providing an integrative overview of translational bioinks and tissue engineering strategies for cartilage and osteochondral regeneration.