Biomaterials strategies to balance inflammation and tenogenesis for tendon repair

Adult tendon tissue demonstrates a limited regenerative capacity, and the natural repair process leaves fibrotic scar tissue with inferior mechanical properties. Surgical treatment is insufficient to provide the mechanical, structural, and biochemical environment necessary to restore functional tissue. While numerous strategies including biodegradable scaffolds, bioactive factor delivery, and cell-based therapies have been investigated, most studies have focused exclusively on either suppressing inflammation or promoting tenogenesis, which includes tenocyte proliferation, ECM production, and tissue formation. New biomaterials-based approaches represent an opportunity to more effectively balance the two processes and improve regenerative outcomes from tendon injuries. Biomaterials applications that have been explored for tendon regeneration include formation of biodegradable scaffolds presenting topographical, mechanical, and/or immunomodulatory cues conducive to tendon repair; delivery of immunomodulatory or tenogenic biomolecules; and delivery of therapeutic cells such as tenocytes and stem cells. In this review, we provide the biological context for the challenges in tendon repair, discuss biomaterials approaches to modulate the immune and regenerative environment during the healing process, and consider the future development of comprehensive biomaterials-based strategies that can better restore the function of injured tendon. STATEMENT OF SIGNIFICANCE: Current strategies for tendon repair focus on suppressing inflammation or enhancing tenogenesis. Evidence indicates that regulated inflammation is beneficial to tendon healing and that excessive tissue remodeling can cause fibrosis. Thus, it is necessary to adopt an approach that balances the benefits of regulated inflammation and tenogenesis. By reviewing potential treatments involving biodegradable scaffolds, biological cues, and therapeutic cells, we contrast how each strategy promotes or suppresses specific repair steps to improve the healing outcome, and highlight the advantages of a comprehensive approach that facilitates the clearance of necrotic tissue and recruitment of cells during the inflammatory stage, followed by ECM synthesis and organization in the proliferative and remodeling stages with the goal of restoring function to the tendon.