Cell-bricks based injectable niche guided persistent ectopic chondrogenesis of bone marrow-derived mesenchymal stem cells and enabled nasal augmentation

Developing cartilage constructs with injectability, appropriate matrix composition and persistent cartilaginous phenotype remains an enduring challenge in cartilage repair. Bone marrow derived mesenchymal stem cells (BMSCs) have chondrogenic potential. Current approaches to drive their chondrogenic differentiation require extensive cell manipulation ex vivo and using exogenous growth factors. However, preventing hypertrophic transition of BMSCs in vivo and maintaining persistent chondrogenesis remain bottlenecks in clinical application. This study aimed to develop completely biological, injectable constructs to generate cartilage by co-transplanting chondrocyte and BMSCs. We fabricated fragmented chondrocyte macroaggregate (cell bricks) and mixed them with platelet rich plasma (PRP); BMSCs were mixed into the above constructs, allowed to clot and then subcutaneously injected into nude mice. Gross morphology observation, histological and immunohistochemical assay, immunofluorescence assay, biochemical analysis and gene expression analysis were used to compare the properties of BMSC-cell bricks-PRP complex with BMSC in PRP or BMSC/chondrocytes in PRP. The constructs of BMSCs-cell bricks-PRP that were subcutaneously injected resulted in persistent chondrogenesis with appropriate morphology, adequate central nutritional perfusion without central necrosis or ossification, and further augmented nasal dorsum without obvious contraction and deformation. We concluded that cell bricks-enriched PRP clotting provides an autologous substance derived niche for chondrogenic differentiation of BMSCs in vivo, which suggests that such an injectable, completely biological system is a suitable stem cell carrier for micro-invasive cartilage repair.