Injectable hydrogel scaffold incorporating microspheres containing cobalt‐doped bioactive glass for bone healing

• Published in: Journal of biomedical materials research. Part A 2024-12, Vol.112 (12), p.2225-2242
• Main Authors: Ghiasi Tabari, Parmida, Sattari, Amirmohammad, Mashhadi Keshtiban, Mohsen, Karkuki Osguei, Nushin, Hardy, John G., Samadikuchaksaraei, Ali
• Format: Article
• Language: English
• Subjects: Alginates; Alginic acid; Angiogenesis; Animals; Bioglass; Biological activity; Biomimetics; Bone healing; Bone Regeneration - drug effects; Calcium chloride; Cbfa-1 protein; Cell proliferation; Cobalt; Cobalt - chemistry; Cobalt - pharmacology; Collagen (type I); Endothelial cells; Gelatin; Gene expression; Genes; Glass - chemistry; Healing; Hominids; Humans; Hydrogels; Hydrogels - chemistry; Hydrogels - pharmacology; In vivo methods and tests; Injections; Male; Microfluidics; Microspheres; Mineralization; Osteogenesis; Osteogenesis - drug effects; Physicochemical properties; Rats; Rats, Sprague-Dawley; Scaffolds; Silk fibroin; Tissue Scaffolds - chemistry; Vascular endothelial growth factor; Wound Healing - drug effects
• ISSN: 1549-3296; 1552-4965; 1552-4965
• DOI: 10.1002/jbm.a.37773

Injectable in situ‐forming scaffolds that induce both angiogenesis and osteogenesis have been proven to be promising for bone healing applications. Here, we report the synthesis of an injectable hydrogel containing cobalt‐doped bioactive glass (BG)‐loaded microspheres. Silk fibroin (SF)/gelatin microspheres containing BG particles were fabricated through microfluidics. The microspheres were mixed in an injectable alginate solution, which formed an in situ hydrogel by adding CaCl2. The hydrogel was evaluated for its physicochemical properties, in vitro interactions with osteoblast‐like and endothelial cells, and bone healing potential in a rat model of calvarial defect. The microspheres were well‐dispersed in the hydrogel and formed pores of >100 μm. The hydrogel displayed shear‐thinning behavior and modulated the cobalt release so that the optimal cobalt concentration for angiogenic stimulation, cell proliferation, and deposition of mineralized matrix was only achieved by the scaffold that contained BG doped with 5% wt/wt cobalt (A‐S‐G5Co). In the scaffold containing higher cobalt content, a reduced biomimetic mineralization on the surface was observed. The gene expression study indicated an upregulation of the osteogenic genes of COL1A1, ALPL, OCN, and RUNX2 and angiogenic genes of HIF1A and VEGF at different time points in the cells cultured with the A‐S‐G5Co. Finally, the in vivo study demonstrated that A‐S‐G5Co significantly promoted both angiogenesis and osteogenesis and improved bone healing after 12 weeks of follow‐up. These results show that incorporation of SF/gelatin microspheres containing cobalt‐doped BG in an injectable in situ‐forming scaffold can effectively enhance its bone healing potential through promotion of angiogenesis and osteogenesis. Injectable in situ‐forming hydrogel scaffolds containing cobalt‐doped bioactive glass‐loaded silk fibroin/gelatin microspheres. The microspheres are fabricated through microfluidics and the scaffold promotes bone healing by enhancing angiogenesis and osteogenesis, as confirmed by in vitro gene expression and in vivo rat model studies.