Dual microparticles programmed delivery system regulating stem cell-based cartilage regeneration by cartilage-specific matrix hydrogels

Bone marrow mesenchymal stem cells (BMSCs)-based engineered cartilage usually faces the significant challenge of endochondral ossification tendency in an ectopic environment because of the inevitable vascular infiltration during chondrogenic differentiation and developmental stages. Additionally, current scaffold-free BMSC cartilage regeneration requires a long in vitro preinduction time for chondrogenic differentiation before in vivo transplantation, which limits its application in multiple cartilage defect repair. Therefore, ideal stem cell-based cartilage regeneration needs to meet time-dependent requirements of both early chondrogenic and late anti-angiogenic microenvironments in vivo. Here, we developed a cartilage-specific matrix hydrogel (CMH) with a dual microparticle-based programmed delivery system (dM-PDs) to dynamically regulate in vivo stem cell-based cartilage regeneration without in vitro preinduction. In this study, CMH scaffolds offer a three-dimensional matrix microenvironment for tissue regeneration, while dM-PDs has an early chondrogenic induction function to promote cartilage-specific differentiation and exerts a late anti-angiogenic effect to stabilize the cartilaginous phenotype. Stem cell-based cartilage regeneration was successfully achieved by sequentially dynamic regulation in vivo by dM-PDs, in which TGFβ3-loaded microparticles effectively activated the early-stage TGFβ/Smad signaling pathway and levatinib-loaded microparticles regulated the late-stage VEGF/TIMP signaling pathway. This study demonstrates a universal stem cell-based cartilage regeneration technique for clinical cartilage defects repair.