Bioorthogonal Click Chemistry Bioinks Advance 3D Bioprinting for Osteochondral Regeneration and Osteoarthritis Therapy

Osteoarthritis (OA) is a debilitating, progressive joint disease causing significant damage to cartilage and subchondral bone, leading to chronic pain and disability. Current therapeutic approaches, such as systemic drug administration and intraarticular injections, primarily offer palliative relief rather than curative regeneration of osteochondral defects. While hydrogels incorporating biologics and small molecules have shown promise in preclinical studies, their clinical translation has been hampered by inadequate patient benefits, often due to issues with stability, targeting, and rapid clearance. This gap underscores the critical need for advanced regenerative biomaterials capable of sustained delivery and effective tissue repair.

This translational review systematically examines the fundamental concepts, challenges, and future prospects of bioorthogonal click chemistry in developing engineered bioinks for 3D bioprinting. It specifically focuses on their application in osteochondral regeneration and osteoarthritis therapy, addressing a recognized gap in the literature that lacks a dedicated focus on this intersection. The review explores how click chemistry, characterized by its rapid, spontaneous, and bioorthogonal reactions, can overcome limitations associated with traditional crosslinkers in bioink formulation, which often compromise cytocompatibility, biodegradability, and biomechanical properties. It synthesizes information on various polymer types and crosslinking mechanisms, highlighting the advantages of click chemistry in optimizing bioink characteristics for tissue engineering.

The review identifies bioorthogonal click chemistry as a transformative strategy for engineering advanced bioinks, overcoming critical limitations of conventional methods in osteoarthritis and osteochondral repair. Traditional crosslinkers often compromise the intrinsic properties of bioinks, leading to reduced cell viability and suboptimal biomechanical performance. In contrast, click reactions enable the formation of bioinks with superior characteristics due to their inherent efficiency and biocompatibility.

Click chemistry strategies significantly enhance bioink properties by favoring optimal gelation time, controlled degradation rates, and improved cell viability, making them highly suitable for complex 3D bioprinting applications.

This approach allows for precise control over the bioink's microenvironment, crucial for supporting cell proliferation, differentiation, and extracellular matrix production in regenerative applications. The review details how these reactions facilitate the incorporation of bioactive small molecules, proteins, and peptides without compromising their integrity or the bioink's structural and biological functions. By leveraging bioorthogonal reactions, the resulting bioinks exhibit enhanced cytocompatibility and tunable biomechanical properties, which are essential for mimicking native osteochondral tissue and promoting effective regeneration. This advancement addresses the need for biomaterials that can withstand the dynamic joint environment while actively supporting tissue repair.