Recent advances in biomaterials and cell engineering as tools and combinations for tendon regeneration

Tendons are highly aligned and strong tissues that transmit force between bone and muscle via specialized tissue-tissue interfaces. Tendons are especially resilient to high tensile forces but are commonly injured by excessive mechanical stress. Tendon injury is a large unmet clinical burden that can affect patients of all ages, with seven million new cases reported worldwide annually. Despite current surgical and biological interventions, tendon healing is often associated with dysregulated cellular responses, resulting in inflammation, fibrosis, altered extracellular matrix organization, and impaired mechanical performance. Advanced biomaterials and engineered cells can act synergistically by programming cells to sense, respond to, and remodel the injured tendon microenvironment, enabling the control of complex tissue dynamics that ultimately result in the formation of healthy and mechanically stable tendon tissue. This review describes recent engineering and biological advances that can be utilized to enhance tendon healing, emphasizing biomaterials, engineered cells, and cell-derived therapeutic strategies. We first outline current clinical tendon repair strategies and then describe key biological processes underlying tendon development and injury, highlighting cells and pathways that become dysfunctional in chronic inflammation, aging, and metabolic disease. Next, we discuss biomaterial-based platforms that can support and stimulate tendon repair, including engineered nanofibers and hydrogels as tendon-mimetic scaffolds or controlled delivery systems for bioactive payloads. Then, we review advances in cell engineering, including immune modulation, genetic augmentation of endogenous repair programs, directed tenogenic programming, and programmable synthetic control systems. Finally, we consider the therapeutic potential of extracellular vesicles and their integration with advanced scaffold systems. By highlighting these emerging approaches, we aim to define the current state of the field to aid in the development of next-generation solutions to improve the therapeutic landscape for advanced tendon tissue regeneration and repair.