Tensile Stimulation in Biorelevant Culture Conditions Enhances MSC and TPSC Tenogenesis on Aligned Electrospun Scaffolds

Tendon injuries affect millions each year, yet effective repair remains limited by the tissue's avascular nature and complex mechanobiology. An anisotropic electrospun scaffold functionalized with GDF‐7‐loaded mesoporous silica nanoparticles (MSNs) is developed to address these challenges. GDF‐7 is efficiently encapsulated (99.9%) in MSNs and incorporated into aligned poly(ε‐caprolactone) (PCL) fibers, achieving controlled release over 46 days following non‐Fickian kinetics. MSN incorporation initially reduces scaffold stiffness and tensile strength; however, dynamic bioreactor culture of human mesenchymal stromal cell (MSCs) and porcine tendon progenitor stem cell (TPSCs) seeded scaffolds, under physiological axial strain, enhances cell alignment, proliferation, and extracellular matrix deposition. Culture under physiological oxygen (2%) conditions further promotes cell viability, proliferation, and tenogenic gene expression. Notably, the combination of topographical guidance, mechanical loading, and physoxia synergistically enhances the expression of terminal tenogenic markers, such as tenomodulin (Tnmd), in both MSCs and TPSCs, as evidenced by increased protein levels detected via immunofluorescence and elevated gene expression confirmed by RT‐qPCR analysis. This integration of topographical, biochemical, and mechanical cues in a tissue engineering approach supports tendon‐specific lineage commitment, offering a promising strategy for functional tendon regeneration.