Abstract
Bone grafting and reconstruction are still challenging in clinical practice because of the limitations of bone autografts and the drawbacks of currently approved bone substitutes. We thus developed a gene-activated bone substitute based on octacalcium phosphate and naked plasmid DNA carrying the vascular endothelial growth factor gene. This advanced combined therapy medicinal product had no cytotoxic effects in vitro, slightly decreased bone marrow mesenchymal stromal cell (MSC) doubling time, and was characterized by a prolonged level of gene construct delivery in vivo in a luciferase bioimaging assay. In the model of critically sized cranial bone defects in rabbits, the gene-activated matrix increased bone tissue formation through angiogenesis induction. After preclinical studies, we conducted an open-label non-randomized clinical trial (NCT03076138). The primary study outcome was the proportion of patients with newly formed bone tissue within the surgical area as measured by computed tomography within 6 months after surgery. The main secondary outcomes included frequencies of adverse events (AEs) and serious adverse events (SAEs) as well as the surgical failure rate. After completing the clinical trial, the patients had dental implants placed in the bone grafting area, and trephine biopsy samples were collected. In total, 20 patients with alveolar ridge atrophy (n = 16) and jaw bone defects (n = 4) were enrolled in the study. There were no AEs or SAEs during the clinical trial or the follow-up period (30 months). In all patients, newly formed tissues with a bone density of 908.13 ± 114.40 HU were detected within the zone of bone grafting. There were no significant differences between the subgroups of patients with atrophy and bone defects: 915.28 ± 125.85 and 879.56 ± 48.36 HU, respectively (p = 0.60). Histological analysis showed that the bone grafting area comprised newly formed bone tissue with some fragments of the gene-activated bone substitute partially resorbed and integrated with bone, without fibrous tissue in between. The preclinical data and clinical trial results proved the feasibility, safety, and efficacy of the investigated material for jaw bone grafting, allowing us to bring the world's first gene-activated bone substitute from bench to bedside.
Highlights
Bone tissue has significant potential for reparative regeneration
Considering the crucial role of vascular endothelial growth factor (VEGF)-A in reparative osteogenesis, the osteoconductive potential of octacalcium phosphate (OCP), and our experience in gene-therapeutic drug development and clinical translation (Deev et al, 2018), we aimed to investigate and clinically translate a gene-activated bone substitute based on an OCP scaffold and VEGFA165-carrying plasmid DNA
The mesenchymal stromal cell (MSC) doubling time increased in the OCP group compared to that in the other controls, whereas this parameter remained unchanged in the materials-free MSCs, with a solution of pDNA-VEGF and OCP/pDNA-VEGF (p > 0.05) (Figure 1)
Summary
Bone tissue has significant potential for reparative regeneration. With “osteogenic insufficiency,” this process can take a long time and often does results in incomplete bone healing, despite the use of current surgical technologies. Osteogenic insufficiency is a pathological condition associated with low activity of systemic or local osteoinductive factors and/or a lack of cambial cells in the bone lesion area; the natural course of reparative osteogenesis may not provide complete histotypic and organotypic recovery (Deev et al, 2015). Successful treatment requires restoration of the lost cambial reserve and/or osteoinductive factors, and classically involves the use of bone autografts, as the “golden standard.”. Well-known limitations and disadvantages of this approach (Baldwin et al, 2019) predetermine the development of acceptable alternatives, among which activated bone substitutes are quite promising (Deev et al, 2015) Successful treatment requires restoration of the lost cambial reserve and/or osteoinductive factors, and classically involves the use of bone autografts, as the “golden standard.” well-known limitations and disadvantages of this approach (Baldwin et al, 2019) predetermine the development of acceptable alternatives, among which activated bone substitutes are quite promising (Deev et al, 2015)
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