Abstract
Purpose: Cartilage and subchondral bone, the two integrated parts of a joint, contain different cells and extracellular matrix. Thus it is still a daunting challenge to regenerate these two parts at the same time to achieve joint repair. To tackle this challenge, we developed new biomaterials to simultaneously regenerate these two parts for joint repair. Methods: Specifically, we chemically generated a composite composed of two well-connected layers with each layer being a unique hydrogel phase. One layer was called bone regenerating hydrogel (BRH) and another was termed cartilage-regenerating hydrogel (CRH). The BRH and CRH were formed by photo-crosslinking of gelatin methacryloyl (GelMA) and hyaluronic acid methacrylate (HAMA) in the presence of a photo-crosslinkable nano-box, isocyanatoethyl acrylate (AOI)-modified β-cyclodextrin (β-CD-AOI2), respectively. Both layers were seeded with mesenchymal stem cells (MSCs). The nano-boxes in BRH and CRH were loaded with melatonin and kartogenin through hydrophobic interaction, which could induce the MSCs to differentiate into osteoblasts and chondrocytes, respectively. Both in vitro and in vivo studies were carried out to evaluate the differentiation of MSCs into osteoblasts and chondrocytes for the regeneration of bone and cartilage tissues. Results: The BRH and CRH were found to induce the differentiation of MSCs into osteoblasts and chondrocytes, respectively, due to the controlled release of the corresponding differentiation inducers from the nano-boxes in them. The BRH-CRH biphasic hydrogel could be in situ formed in the joint defect model with BRH and CRH located in the subchondral bone and cartilage defect area, respectively. The inducers were then found to be released from the nano-boxes in BRH and CRH, and induce the stem cell differentiation to regenerate bone and cartilage tissue in the subchondral bone and cartilage defect area, respectively, leading to successful joint repair within 12 weeks. Conclusions: This work demonstrates a new strategy for controllable phase/site-specific release of differentiation inducers for simultaneous subchondral bone and cartilage regeneration in osteochondral repair.
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