Abstract
Bone fracture repair is a multifaceted, coordinated physiological process that requires new bone formation and resorption, eventually returning the fractured bone to its original state. Currently, a variety of different approaches are pursued to accelerate the repair of defective bones, which include the use of 'gold standard' autologous bone grafts. However, such grafts may not be readily available, and procedural complications may result in undesired outcomes. Considering the ease of use and tremendous customization potentials, synthetic materials may become a more suitable alternative of bone grafts. In this study, we examined the osteogenic potential of guanosine 5′-diphosphate-crosslinked chitosan scaffolds with the incorporation of hydroxyapatite, with or without pyrophosphatase activity, both in vitro and in vivo. First, scaffolds embedded with cells were characterized for cell morphology, viability, and attachment. The cell-laden scaffolds were found to significantly enhance proliferation for up to threefold, double alkaline phosphatase activity and osterix expression, and increase calcium phosphate deposits in vitro. Next, chitosan scaffolds were implanted at the fracture site in a mouse model of intramedullary rod-fixed tibial fracture. Our results showed increased callus formation at the fracture site with the scaffold carrying both hydroxyapatite and pyrophosphatase in comparison to the control scaffolds lacking both pyrophosphatase and hydroxyapatite, or pyrophosphatase alone. These results indicate that the pyrophosphatase-hydroxyapatite composite scaffold has a promising capacity to facilitate bone fracture healing.
Highlights
Bone fracture repair is a multifaceted, coordinated physiological process that requires new bone formation and resorption, eventually returning the fractured bone to its original state
We demonstrated that the addition of the enzyme pyrophosphatase (PPase) to the scaffold breaks down P Pi into two phosphate ions, and as such the scaffold can be modified to act as a reservoir for these ions essential for extracellular matrix (ECM) mineralization in vitro and in vivo
The proof of concept for a 3D bone scaffold was attained through pre-osteoblast cell encapsulation studies, which led to identifying the CS75HAP as the most pro-osteogenic scaffold
Summary
Bone fracture repair is a multifaceted, coordinated physiological process that requires new bone formation and resorption, eventually returning the fractured bone to its original state. Despite all the beneficial properties, chitosan’s relatively weak mechanical properties may fall short for bone repair applications To address this issue, linear chitosan chains are cross-linked by purine nucleotides, and biominerals HA and β-TCP are added to form b iocomposites[22,23,24]. Purine nucleotides can act as ligands for P2X receptors, which may, in turn, stimulate the differentiation of human mesenchymal stem cells (MSCs) to osteoblasts[26,27,28,29] and promote skeletal tissue d evelopment[30,31] These studies indicate that the use of purine nucleotides to crosslink chitosan may have beneficial effects on bone fracture healing
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