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. A gradient multi-tissue construct incorporating tissue-specific bioinks and stem cells is developed by 3D cell-printing technology. This construct generates integrated fibrocartilaginous gradient matrices in vitro and promotes reconstruction of gradient TBIs and shoulder function recovery in translational rat RC tear model. This complicated regeneration process is consecutively monitored by multispectral near-infrared fluorescence imaging coupled with tissue-specific bioimaging agents. [Display omitted] •A biomimetic cellular TBI scaffold was 3D bioprinted with dECM bioinks.•A gradient multi-tissue construct was implanted for RC repair in vivo.•Targeted NIR fluorescence imaging facilitated real-time monitoring of TBI regeneration.•The scaffolds had therapeutic contribution on gradient TBI regeneration and functional recovery.