Molecular recognition-directed site-specific release of stem cell differentiation inducers for enhanced joint repair

The remarkable difference in cell type and matrix composition between two connected parts of a joint (cartilage and subchondral bone) makes it challenging to simultaneously regenerate both parts for joint repair. Thus we chemically designed a biphasic hydrogel made of two well-bonded shape-tunable hydrogel phases, termed bone-regenerating hydrogel (BRH) and cartilage-regenerating hydrogel (CRH). The BRH and CRH, encapsulating stem cells, were produced by photo-crosslinking bone and cartilage matrix-mimicking biopolymers and a nanobox (β-cyclodextrin) in situ in the subchondral bone defect and cartilage defect, respectively. The nanoboxes in BRH and CRH were loaded with osteogenic and chondrogenic differentiation inducers (melatonin and kartogenin) by host-guest interactions, respectively. Such interactions directed the sustained phase- and defect site-specific release of the inducers and subsequent site-specific stem cell differentiation into cartilage and bone forming cells for joint repair. The strategy opens up a new chemical approach to biomaterials with phase-specific drug release for tissue repair.