Engineering Multiscale Scaffold‐Free Mimetic Environments Within Microfibrous Scaffolds Enhances Tendon Regeneration

Promoting self‐organized regeneration, rather than nonfunctional repair, has emerged as a leading strategy for treating soft tissue injuries. Tissue self‐organization typically occurs in scaffold‐free environments; however, scaffolds can offer long‐range support, which is often essential for healing extensive injuries. In this study, we develop a balanced therapeutic strategy to facilitate the regeneration of completely ruptured Achilles tendons. Scaffold‐free mimetic effects, including surface modifications and the creation of fiber‐free void spaces at three scales ranging from 100 μm to several millimeters, are integrated into microfibrous polycaprolactone scaffolds. Modifications to scaffold architecture and surgical techniques are also developed to facilitate the tissue‐assisted dynamic removal of scaffolds from the injury site. We show that these modifications reduce immune infiltration, improve the alignment of regenerated tendon fibers, and enhance the restoration of gait patterns through a synergistic effect between the scaffolds and the regenerating tissue. Our findings highlight the potential of creating scaffold‐free mimetic environments within scaffolds to promote soft tissue regeneration.