Microcarriers containing “Hypoxia-engine” for simultaneous enhanced osteogenesis and angiogenesis

Abstract

Currently, most practiced strategies for accelerating bone healing are introducing osteoinductive factors such as growth factors, osteogenic pharmaceuticals, and inorganic ions. However, uncontrollable side effects such as hematoma limit their clinical applications. Inspired by the crowded subway, a kind of novel hierarchically porous and hollow microcarriers containing multicellular spheroids and adhesive cells are developed to not only avoid the utilization of osteoinductive factors but also promote the regeneration of vascular bone tissues. The hierarchically porous and hollow structures are formed based on a new hierarchical pore forming mechanism called “centripetal force-driven multistage separation”, where the diameters of macropores and micropores are 241 μm and 13 μm. Multicellular spheroids in the microcarriers serve as the “Hypoxia-engine” to produce the hypoxia-inducible factor (HIF-1α) to significantly increase the expression of osteogenic and angiogenic factors. Adhesive cells in the microcarriers proliferate to facilitate the development of new bones. After being implanted, the microcarriers containing “Hypoxia-engine” accelerate the regeneration of vascular alveolar bone tissues. The neogenerated alveolar bones well integrated with the healthy bones due to the hierarchical pore structure. Imageological, histological, immunohistochemical, and biomechanical evaluation prove that the treatment efficacy of microcarriers containing “Hypoxia-engine” generally reaches that of the standard clinical grafts (Geistlich Bio-Oss®).