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
Highlights
The treatment for bone defects resulting from malignancy resection or trauma is still a long-term clinical challenge, whereas bone tissue engineering has been emerging as one hopeful alternative to surmount this problem by using cell, scaffold, bioactive molecule, and biophysical enhancement [1,2,3,4,5]
Inspired by spatiotemporal presentation cascade of morphogens during natural bone healing, we developed a hybrid hydrogel-based delivery system harnessing the macromolecule delivery feature of both GelMA hydrogel and mineral coating to optimally orchestrate the coupling of osteogenesis and angiogenesis for the vascularized bone regeneration
Taking advantage of the two materials components used in this study, we successfully achieved dual growth factor delivery with distinctive release profiles: Basic fibroblast growth factor (bFGF) was released in a "burst" pattern to promote early-stage angiogenesis, while a more durable delivery of bone morphogenetic protein-2 (BMP-2) facilitated osteogenesis
Summary
The treatment for bone defects resulting from malignancy resection or trauma is still a long-term clinical challenge, whereas bone tissue engineering has been emerging as one hopeful alternative to surmount this problem by using cell, scaffold, bioactive molecule, and biophysical enhancement [1,2,3,4,5]. Various growth factors (GFs) are present, each serving in a specified spatiotemporal pattern to orchestrate multiple biological processes during the four stages of bone healing, including inflammation stage, soft callus stage, hard callus stage, and bone remodelling stage. Various growth factor delivery systems have been developed for providing biological cues to facilitate different aspects of bone healing [7]. Bone morphogenetic proteins (BMPs) were delivered using a resorbable collagen sponge, while vascular endothelial growth factor (VEGF) was released via polymeric vehicles to enhance vascularization during bone healing [8, 9]. Novel delivery systems that meet the needs of different stages of bone healing are urgently needed to optimize the outcomes of growth factor-based bone regeneration strategies
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