Biological tendon regeneration, are we almost there or is it still a stretch?

Tendon injuries are a major clinical challenge, affecting millions worldwide and often resulting in impaired mobility, chronic pain, and high rates of re-injury. The adult tendon’s poor vascularity and low cellularity limit its regenerative capacity, frequently leading to disorganized repair and fibrotic scar formation rather than functional tissue regeneration. Current therapeutic approaches, including orthobiologics and mesenchymal stromal/stem cells (MSCs), offer only modest benefits due to issues such as donor variability, short-lived effects, and poor reproducibility. Moreover, MSCs are often driven toward fibrotic or non-tenogenic lineages within the injury microenvironment, further hindering effective repair.

Recent advances in stem cell biology have enabled the generation of induced pluripotent stem cell (iPSC)-derived tenocytes (iTenocytes), which show promise as a scalable, lineage-committed, and potentially hypoimmunogenic cell source. These cells can be integrated with engineered biomaterials, such as bioresorbable 3D-printed scaffolds, to enhance structural support, guide tissue organization, and promote host-mediated repair. Mimicking developmental signaling pathways has improved tenogenic differentiation, but challenges remain in optimizing maturation stages and minimizing off-target lineage formation. Moving forward, combining iTenocytes with mechanically robust, cell-laden scaffolds and precise biomechanical cues may enable scarless tendon regeneration and full functional recovery, addressing a longstanding unmet clinical need in musculoskeletal medicine.