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Injectable gel systems, for the purpose of bone defect reconstruction, have many advantages, such as controlled flowability, adaptability to the defect site, and increased handling properties when compared to the conventionally used autologous graft, scaffolds, hydroxyapatite blocks, etc. In this work, nanohydroxyapatite (nHAp) incorporated chitin-poly(ε-caprolactone) (PCL) based injectable composite microgels has been developed by a simple regeneration technique for bone defect repair. The prepared microgel systems were characterized using scanning electron microscope (SEM), Fourier transformed infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The composite microgel, with the incorporation of nHAp, showed an increased elastic modulus and thermal stability and had shear-thinning behavior proving the injectability of the system. The protein adsorption, cytocompatibility, and migration of rabbit adipose derived mesenchymal stem cells (rASCs) were also studied. Chitin-PCL-nHAp microgel elicited an early osteogenic differentiation compared to control gel. The immunofluorescence studies confirmed the elevated expression of osteogenic-specific markers such as alkaline phosphatase, osteopontin, and osteocalcin in chitin-PCL-nHAp microgels. Thus, chitin-PCL-nHAp microgel could be a promising injectable system for regeneration of bone defects which are, even in deeper planes, irregularly shaped and complex in nature.

Cryogels have recently gained interest in the field of tissue engineering as they inherently possess an interconnected macroporous structure. Considered to be suitable for scaffold cryogel fabrication, methacrylated gelatin (GelMA) is a modified form of gelatin valued for its ability to retain cell adhesion site. Bioglass nanoparticles have also attracted attention in the field due to their osteoinductive and osteoconductive behavior. Here, we prepare methacrylated gelatin cryogel with varying concentration of bioglass nanoparticles to study its potential for bone regeneration. We demonstrate that an increase in bioglass concentration in cryogel leads to improved mechanical property and augmented osteogenic differentiation of mesenchymal cells during in vitro testing. Furthermore, in vivo testing in mice cranial defect model shows that highest concentration of bioglass nanoparticles (2.5 w/w %) incorporated in GelMA cryogel induces the most bone formation compared to the other tested groups, as studied by micro-CT and histology. The in vitro and in vivo results highlight the potential of bioglass nanoparticles incorporated in GelMA cryogel for bone regeneration.

For craniofacial bone regeneration, shear-thinning injectable hydrogels are favored over conventional scaffolds because of their improved defect margin adaptability, easier handling, and ability to be injected manually into deeper tissues. The most accepted method, after autografting, is the use of recombinant human bone morphogenetic protein-2 (BMP-2); however, complications such as interindividual variations, edema, and poor cost-efficiency in supraphysiological doses have been reported. The endogenous synthesis of BMP-2 is desirable, and a molecule which induces this is fibroblast growth factor-18 (FGF-18) because it can upregulate the BMP-2 expression  by supressing noggin. We developed a chitin-poly(lactide-co-glycolide) (PLGA) composite hydrogel by regeneration chemistry and then incorporated CaSO and FGF-18 for this purpose. Rheologically, a 7-fold increase in the elastic modulus was observed in the CaSO-incorporated chitin-PLGA hydrogels as compared to the chitin-PLGA hydrogel. Shear-thinning Herschel-Bulkley fluid nature was observed for both hydrogels. Chitin-PLGA/CaSO gel showed sustained release of FGF-18. In vitro osteogenic differentiation showed an enhanced alkaline phosphatase (ALP) expression in the FGF-18-containing chitin-PLGA/CaSO gel when compared to cells alone. Further, it was confirmed by studying the expression of osteogenic genes [RUNX2, ALP, BMP-2, osteocalcin (OCN), and osteopontin (OPN)], immunofluorescence staining of BMP-2, OCN, and OPN, and alizarin red S staining. Incorporation of FGF-18 in the hydrogel increased the endothelial cell migration. Further, the regeneration potential of the prepared hydrogels was tested in vivo, and longitudinal live animal μ-CT was performed. FGF-18-loaded chitin-PLGA/CaSO showed early and almost complete bone healing in comparison with chitin-PLGA/CaSO, chitin-PLGA/FGF-18, chitin-PLGA, and sham control systems, as confirmed by hematoxylin and eosin and osteoid tetrachrome stainings. This shows that the CaSO and FGF-18-incorporated hydrogel is a potential candidate for craniofacial bone defect regeneration.

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An injectable strontium ranelate nanoparticle-loaded composite gel provides a required environment for chondrogenesis, supplemented with the controlled release of strontium ranelate.

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