Bioactive scaffolds integrated with micro-precise spatiotemporal delivery and in vivo degradation tracking for complex tissue regeneration

Three-dimensional (3D) printing has evolved to incorporate controlled delivery systems to guide the regeneration of complex tissues, with limited clinical translation. The challenges include the limited precision in spatiotemporal delivery and poorly understood <i>in vivo</i> scaffold degradation rates. Here, we report auspicious preclinical outcomes in the functional regeneration of temporomandibular joint (TMJ) discs of mini-pigs. TMJ disc has been an extremely challenging target for regenerative engineering given the uniquely heterogeneous matrix distribution and region-variant anisotropic orientation. We optimally implemented advanced 3D printing technologies with micro-precise spatiotemporal delivery to build anatomically correct, bioactive scaffolds with native-like regionally variant microstructure and mechanical properties. We also applied quantum dots (QDs) labeling of scaffolds to enable non-invasive <i>in vivo</i> degradation tracking. In mini-pigs, the scaffold implantation upon discectomy has successfully led to <i>in-situ</i> regeneration of TMJ discs by 3 months, exhibiting native-like heterogeneity and multi-scale mechanical properties without any sign of cartilage damage. In addition, our non-invasive imaging resulted in reliable <i>in vivo</i> tracking of scaffold degradation, exhibiting notably different degradation rates between individual animals. Our findings suggest a significant translational potential of our cell-free, bioactive scaffolds equipped with non-invasive tracking modality for in-situ tissue engineering of TMJ discs.