Inorganic biomaterials-reinforced printable hydrogel modulating regenerative microenvironments for tissue repair

Complex tissue/organ regeneration is a well-orchestrated biological process that orchestrated by coordinate effort of neural, vascular and immune systems, accompanied with multiple cellular interaction and signals crosstalk. The beneficial pro-regenerative microenvironments are of great significance for regulating tissue-resident cell viability, migration and differentiation to direct tissue repair process. 3D bioprinting is an advanced biomanufacturing strategy that utilizes hydrogelcontaining bioinks to fabricate cell-laden scaffolds, but they face the limitations of insufficient bioactivity. Inorganic biomaterials have been recognized as effective bioactive agents owing to their tunable chemical composition, topographical architectures, and physiochemical properties, which can overcome the limitation of printable hydrogel and broaden their potential biological applications. This review primarily concentrates on the design of inorganic biomaterials-reinforced printable hydrogel for modulating regenerative microenvironments including neural, vascular, and immune regulation, and summarizes the recent progress of their applications for tissue and organ regeneration. It begins with an introduction of inorganic biomaterials augmenting the biophysical and the biochemical properties of 3D-printed hydrogel, especially highlighting the improvement of topographical cues, mechanical strength, external field responsiveness, and releasing bioactive components for regulating various tissue microenvironments. Subsequently, recent advancements of inorganic biomaterialsreinforced printable hydrogel in regenerating various tissues including musculoskeletal system, skin, and cardiac tissues are systematically reviewed. Finally, current challenges and future perspectives in the development of inorganic biomaterials-reinforced printable hydrogel are proposed. This review may offer a universal strategy for the design of novel bioinks in combination with inorganic biomaterials and printable hydrogel, which shows great potential for engineered biofabrication and complex tissue/organ regeneration.