Remotely-activatable extracellular matrix-mimetic hydrogel promotes physiological bone mineralization for enhanced cranial defect healing

The biomineralization of calcium ions and phosphate ions in the extracellular matrix (ECM) is a key event in bone regeneration, and it’s of therapeutic significance to develop biomaterials capable of mimicking the physiological biomineralization process, which is especially desirable in cranial defect repairing. For this purpose, we design a composite remotely-activatable ECM-mimetic chitosan/collagen-based hydrogel incorporated with mesenchymal stem cell (MSC)-membrane-coated black phosphorus (BP), which is a photothermal material with versatile utility. Here, the MSC membrane-coated BP nanosheets could induce mild photothermal effect under near-infrared (NIR) light to stimulate the osteoblast recruitment via activating the heat shock proteins (HSPs)-mediated matrix metalloproteinase (MMP) and ERK-Wnt/β-catenin-RUNX2 axis. Meanwhile, the thermal decomposition of BP would release phosphate ions into the surrounding medium to attract calcium ions to form hydroxyapatite in the ECM in an in-situ manner, which is beneficial for osteoblast migration and osteogenic differentiation. After the implantation in to the cranial defect site on Sprague Dawley (SD) rats, it was evidently observed that the hydrogel treatment substantially enhanced the local bone density and promoted new bone formation. Overall, the ECM-mimetic BP-incorporated hydrogel could enhance osteoblast migration/differentiation and stimulate the biomineralization process under remote NIR activation to promote bone healing, which offers new opportunities for repairing cranial defect in the clinics.