3D cell-printing of gradient multi-tissue interfaces for rotator cuff regeneration

Owing to the prevalence of rotator cuff(RC)injuries and suboptimal healing outcome,rapid and functional regeneration of the tendon-bone interface(TBI)after RC repair continues to be a major clinical challenge.Given the essential role of the RC in shoulder movement,the engineering of biomimetic multi-tissue constructs presents an opportunity for complex TBI reconstruction after RC repair.Here,we propose a gradient cell-laden multi-tissue construct combined with compositional gradient TBI-specific bioinks via 3D cell-printing technology.In vitro studies demonstrated the capability of a gradient scaffold system in zone-specific inducibility and multi-tissue formation mimicking TBI.The regenerative performance of the gradient scaffold on RC regeneration was determined using a rat RC repair model.In particular,we adopted nondestructive,consecutive,and tissue-targeted near-infrared fluorescence imaging to visualize the direct anatomical change and the intricate RC regeneration progression in real time in vivo.Furthermore,the 3D cell-printed implant promotes effective restoration of shoulder locomotion function and accelerates TBI healing in vivo.In summary,this study identifies the therapeutic contribution of cell-printed constructs towards functional RC regeneration,demonstrating the translational potential of biomimetic gradient constructs for the clinical repair of multi-tissue interfaces.