Spatiotemporal regulation of angiogenesis/osteogenesis emulating natural bone healing cascade for vascularized bone formation

Abstract

Engineering approaches for growth factor delivery have been considerably advanced for tissue regeneration, yet most of them fail to provide a complex combination of signals emulating a natural healing cascade, which substantially limits their clinical successes. Herein, we aimed to emulate the natural bone healing cascades by coupling the processes of angiogenesis and osteogenesis with a hybrid dual growth factor delivery system to achieve vascularized bone formation. Basic fibroblast growth factor (bFGF) was loaded into methacrylate gelatin (GelMA) to mimic angiogenic signalling during the inflammation and soft callus phases of the bone healing process, while bone morphogenetic protein-2 (BMP-2) was bound onto mineral coated microparticles (MCM) to mimics osteogenic signalling in the hard callus and bone remodelling phases. An Initial high concentration of bFGF accompanied by a sustainable release of BMP-2 and inorganic ions was realized to orchestrate well-coupled osteogenic and angiogenic effects for bone regeneration. In vitro experiments indicated that the hybrid hydrogel markedly enhanced the formation of vasculature in human umbilical vein endothelial cells (HUVECs), as well as the osteogenic differentiation of mesenchymal stem cells (BMSCs). In vivo results confirmed the optimal osteogenic performance of our F/G-B/M hydrogel, which was primarily attributed to the FGF-induced vascularization. This research presents a facile and potent alternative for treating bone defects by emulating natural cascades of bone healing. Graphical Abstract

Gelatin Methacryloyl Hydrogels for Musculoskeletal Tissue Regeneration

“…Various studies have shown that the dual release of growth factors at different kinetic rates leads to successful bone tissue repair [ 80 , 81 ]. To release bFGF and BMP-2 in a spatiotemporal manner, Zhou et al designed a composite hydrogel including GelMA-bFGF and mineral and microparticles (MCM)-BMP-2 ( Figure 3 B) [ 82 ]. When bFGF molecules were rapidly released and BMP-2 released over time from composite gels, a significantly enhanced vascularized bone regeneration was observed compared to the single release system.…”

Manufacturing functional hydrogels for inducing angiogenic–osteogenic coupled progressions in hard tissue repairs: prospects and challenges

“…10), which was largely accredited to the FGF-induced bone vascularization. 92 In the case of bone damage, after the damage has occurred, immune cells (including macrophages, neutrophils, and T lymphocytes) are employed and contribute to immunomodulation and bone dynamics regulation at the site of injury. Therefore, the manipulation of immune cells is an encouraging strategy to produce a favorable osteo-immune environment for bone regeneration.…”

“…10 Schematic illustration of (A) the fabrication and (B) the application of the F-G/B-M hybrid hydrogel. 92…”

Emerging roles of growth factors in osteonecrosis of the femoral head

“…Studies have shown that FGF-2 in gelatin hydrogels can be released consistently at relatively low concentrations ( Nguyen et al, 2015 ). FGF-2 delivered via gelatin hydrogels has therapeutic potential in ischemic limb and heart injury and bone formation for fracture repair ( Nakajima et al, 2004 ; Zhou et al, 2021 ). Therefore, FGF-2 encapsulated within gelatin hydrogels offers a promising strategy for the treatment of ONFH.…”