Tendon healing affects the multiscale mechanical, structural and compositional response of tendon to quasi-static tensile loading

Tendon experiences a variety of multiscale changes to its extracellular matrix during mechanical loading at the fascicle, fibre and fibril levels. For example, tensile loading of tendon increases its stiffness, with organization of collagen fibres, and increases cell strain in the direction of loading. Although applied macroscale strains correlate to cell and nuclear strains in uninjured tendon, the multiscale response during tendon healing remains unknown and may affect cell mechanosensing and response. Therefore, this study evaluated multiscale structure–function mechanisms in response to quasi-static tensile loading in uninjured and healing tendons. We found that tendon healing affected the macroscale mechanical and structural response to mechanical loading, evidenced by decreases in strain stiffening and collagen fibre realignment. At the micro- and nanoscales, healing resulted in increased collagen fibre disorganization, nuclear disorganization, decreased change in nuclear aspect ratio with loading, and decreased indentation modulus compared to uninjured tendons. Taken together, this work supports a new concept of nuclear strain transfer attenuation during tendon healing and identifies several multiscale properties that may contribute. Our work also provides benchmarks for the biomechanical microenvironments that tendon cells may experience following cell delivery therapies.