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World's First Clinical Case of Gene-Activated Bone Substitute Application.

ABSTRACT: Treatment of patients with large bone defects is a complex clinical problem. We have initiated the first clinical study of a gene-activated bone substitute composed of the collagen-hydroxyapatite scaffold and plasmid DNA encoding vascular endothelial growth factor. The first patient with two nonunions of previously reconstructed mandible was enrolled into the study. Scar tissues were excised; bone defects (5-14?mm) between the mandibular fragments and nonvascularized rib-bone autograft were filled in with the gene-activated bone substitute. No adverse events were observed during 12 months of follow-up. In 3 months, the average density of newly formed tissues within the implantation zone was 402.21 ± 84.40 and 447.68 ± 106.75 HU in the frontal and distal regions, respectively, which correlated with the density of spongy bone. Complete distal bone defect repair with vestibular and lingual cortical plates formation was observed in 6 and 12 months after surgery; thereby the posterior nonunion was successfully eliminated. However, there was partial resorption of the proximal edge of the autograft entailed to relapse of the anterior nonunion. Thus, the first clinical data on the safety and efficacy of the gene-activated bone substitute were obtained. Given a high complexity of the clinical situation the treatment, results might be considered as promising. NCT02293031.

SUBMITTER: Bozo IY

PROVIDER: S-EPMC5116519 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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World's First Clinical Case of Gene-Activated Bone Substitute Application.

Bozo I Y IY Deev R V RV Drobyshev A Y AY Isaev A A AA Eremin I I II

Case reports in dentistry 20161107

Treatment of patients with large bone defects is a complex clinical problem. We have initiated the first clinical study of a gene-activated bone substitute composed of the collagen-hydroxyapatite scaffold and plasmid DNA encoding vascular endothelial growth factor. The first patient with two nonunions of previously reconstructed mandible was enrolled into the study. Scar tissues were excised; bone defects (5-14 mm) between the mandibular fragments and nonvascularized rib-bone autograft were fill ...[more]

PMID: 27891264

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Project description: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.

Project description:Background: The autograft is still considered the gold standard for the treatment of bone defects. However, given the significant morbidity of the donor site with which it has been associated, alternative substitutes for bone grafts have been developed. In the present study, a bone substitute composed of CaP biphasic bioceramics obtained from shark teeth was used (BIOFAST-VET). Objective: The objective of this study is to evaluate the efficacy of a marine bioapatite in the veterinary clinical field using it as a bone-grafting scaffold in dogs and cats. Methods: The biomaterial was randomly distributed in 6 veterinary clinical centers in Spain and was used in 24 cases (20 dogs and 4 cats) including 14 fractures, 9 arthrodesis, and 1 bone cyst. Grains between 500 and 2,000 μm were used. Inclusion and exclusion criteria were established. The time of consolidation and functional recovery were quantitatively and qualitatively assessed. For this, a follow-up was carried out at 2, 4, 8, and 12 weeks, included radiographic images, physical examination and sharing the feedback with the owners. Results: Nineteen cases completed the study (18 dogs and 1 cat; 11 fractures, 7 arthrodesis, and 1 bone cyst). The remaining five were excluded because they did not complete the radiographic follow-up (three cats and two dogs), being three arthrodesis and two fractures. In 18 of 19 cases, the use of the biomaterial was successful; the remaining one failed due to causes not related to the biomaterial. There were no systemic or local adverse reactions. Eighteen patients had a good functional recovery. The average consolidation time was 5.94 weeks in dogs with fractures and arthrodesis, not finding statistically significant differences between sex, weight, and procedure. Conclusions: This biomaterial is presented as a very suitable candidate for orthopedic surgery in the veterinary field. Preliminary results showed that its use reduces consolidation time in dogs with fractures and arthrodesis. In addition, no adverse systemic or local reactions have been observed derived from its use.

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World's First Clinical Case of Gene-Activated Bone Substitute Application.

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World's First Clinical Case of Gene-Activated Bone Substitute Application.

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