Abstract
The presence of insufficient bone volume remains a major clinical problem for dental implant placement to restore the oral function. Gene-transduced stem cells provide a promising approach for inducing bone regeneration and enhancing osseointegration in dental implants with tissue engineering technology. Our previous studies have demonstrated that the hypoxia-inducible factor-1α (HIF-1α) promotes osteogenesis in rat bone mesenchymal stem cells (BMSCs). In this study, the function of HIF-1α was validated for the first time in a preclinical large animal canine model in term of its ability to promote new bone formation in defects around implants as well as the osseointegration between tissue-engineered bone and dental implants. A lentiviral vector was constructed with the constitutively active form of HIF-1α (cHIF). The ectopic bone formation was evaluated in nude mice. The therapeutic potential of HIF-1α-overexpressing canine BMSCs in bone repair was evaluated in mesi-implant defects of immediate post-extraction implants in the canine mandible. HIF-1α mediated canine BMSCs significantly promoted new bone formation both subcutaneously and in mesi-implant defects, including increased bone volume, bone mineral density, trabecular thickness, and trabecular bone volume fraction. Furthermore, osseointegration was significantly enhanced by HIF-1α-overexpressing canine BMSCs. This study provides an important experimental evidence in a preclinical large animal model concerning to the potential applications of HIF-1α in promoting new bone formation as well as the osseointegration of immediate implantation for oral function restoration.
Highlights
The immediate dental implant possesses several advantages over the delayed implant, including agonistic bone resorption postextraction, reduced time required to make dentures, and immediate satisfaction with the aesthetics and function, especially at locations of formerly missing teeth [1]
Under an optimal multiplicity of infection (MOI = 7), Bone mesenchymal stem cells (BMSCs) were transduced by Lenti-GFP, Lenti-HIF, and Lenti-constitutively active form of HIF-1a (cHIF)
The percentage of remnant scaffold area was 42.75%62.62% of the total area per 1006 field, 38.16%61.92%, 34.2163.14%, and 25.82%61.98% in the Calcium-magnesium phosphate cement (CMPC), GFP, HIF, and cHIF groups, respectively (Figure 3C). These results demonstrate that constitutively active hypoxia-inducible factor-1a (HIF-1a) in BMSCs increases bone formation when incorporated with CMPC scaffolds
Summary
The immediate dental implant possesses several advantages over the delayed implant, including agonistic bone resorption postextraction, reduced time required to make dentures, and immediate satisfaction with the aesthetics and function, especially at locations of formerly missing teeth [1]. The main challenge of immediate post-extraction implants is significant alveolar bone loss (height or width of alveoli) owing to periodontal disease, traumatic injury, congenital abnormalities, tumors, or physiological bone resorption. Due to autologous bone grafts limited clinical applications [2,3], gene-enhanced tissue engineering method is attempted to promote bone repair and tissue regeneration, especially for challenging defect sites, where spontaneous repair is not achievable [4]. The combination of stem cell and gene therapies could be an optimal clinical strategy for tissue replacement/repair, where BMSCs are genetically modified to express higher levels of some specific factors. Growth factor-overexpressing stem cells have the potential to accelerate osteogenesis and angiogenesis in bone defects with tissue engineering technology; these growth factors include bone morphogenic protein (BMP), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor [7,8]
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