GelMA-based bioactive hydrogel scaffolds with multiple bone defect repair functions: therapeutic strategies and recent advances

Abstract Currently, the clinical treatment of critical bone defects attributed to various causes remains a great challenge, and repairing these defects with synthetic bone substitutes is the most common strategy. In general, tissue engineering materials that mimic the structural, mechanical and biological properties of natural bone have been extensively applied to fill bone defects and promote in situ bone regeneration. Hydrogels with extracellular matrix (ECM)-like properties are common tissue engineering materials, among which methacrylate-based gelatin (GelMA) hydrogels are widely used because of their tunable mechanical properties, excellent photocrosslinking capability and good biocompatibility. Owing to their lack of osteogenic activity, however, GelMA hydrogels are combined with other types of materials with osteogenic activities to improve the osteogenic capability of the current composites. There are three main aspects to consider when enhancing the bone regenerative performance of composite materials: osteoconductivity, vascularization and osteoinduction. Bioceramics, bioglass, biomimetic scaffolds, inorganic ions, bionic periosteum, growth factors and two-dimensional (2D) nanomaterials have been applied in various combinations to achieve enhanced osteogenic and bone regeneration activities. Three-dimensional (3D)-bioprinted scaffolds are a popular research topic in bone tissue engineering (BTE), and printed and customized scaffolds are suitable for restoring large irregular bone defects due to their shape and structural tunability, enhanced mechanical properties, and good biocompatibility. Herein, the recent progress in research on GelMA-based composite hydrogel scaffolds as multifunctional platforms for restoring critical bone defects in plastic or orthopedic clinics is systematically reviewed and summarized. These strategies pave the way for the design of biomimetic bone substitutes for effective bone reconstruction with good biosafety. Graphical Abstract This review provides novel insights into the development and current trends of research on GelMA-based hydrogels as effective bone tissue engineering (BTE) scaffolds for correcting bone defects, and these contents are summarized and emphasized from various perspectives (osteoconductivity, vascularization, osteoinduction and 3D-bioprinting). In addition, advantages and deficiencies of GelMA-based bone substitutes used for bone regeneration are put forward, and corresponding improvement measures are presented prior to their clinical application in near future (created with BioRender.com).