PMID- 33614609 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210223 IS - 2296-4185 (Print) IS - 2296-4185 (Electronic) IS - 2296-4185 (Linking) VI - 9 DP - 2021 TI - Bringing a Gene-Activated Bone Substitute Into Clinical Practice: From Bench to Bedside. PG - 599300 LID - 10.3389/fbioe.2021.599300 [doi] LID - 599300 AB - 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. CI - Copyright (c) 2021 Bozo, Drobyshev, Redko, Komlev, Isaev and Deev. FAU - Bozo, Ilia Y AU - Bozo IY AD - Department of Maxillofacial Surgery, A. I. Burnazyan Federal Medical Biophysical Center, Federal Medical Biological Agency of Russia, Moscow, Russia. AD - Histograft, LLC, Moscow, Russia. FAU - Drobyshev, Alexey Y AU - Drobyshev AY AD - Department of Maxillofacial and Plastic Surgery, A. I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia. FAU - Redko, Nikolay A AU - Redko NA AD - Department of Maxillofacial and Plastic Surgery, A. I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia. FAU - Komlev, Vladimir S AU - Komlev VS AD - A. A. Baikov Institute of Metallurgy and Materials Science, Russian Academy of Sciences, Moscow, Russia. FAU - Isaev, Artur A AU - Isaev AA AD - Human Stem Cells Institute, Moscow, Russia. FAU - Deev, Roman V AU - Deev RV AD - Human Stem Cells Institute, Moscow, Russia. AD - Department of Pathology, I. I. Mechnikov North-Western State Medical University, Saint Petersburg, Russia. LA - eng PT - Journal Article DEP - 20210204 PL - Switzerland TA - Front Bioeng Biotechnol JT - Frontiers in bioengineering and biotechnology JID - 101632513 PMC - PMC7889956 OTO - NOTNLM OT - bone substitute OT - clinical trial OT - gene-activated matrix OT - octacalcium phosphate OT - osteogenesis OT - plasmid DNA OT - vascular endothelial growth factor COIS- The clinical trial, as part of registering a gene-activated bone substitute for clinical use, was carried out under Russian Ministry of Healthcare regulations. Based on an official report examination performed by an expert government institution, market authorization was granted in 2019. The clinical trial and registration process were funded by Histograft LLC. IB, AI, and RD are co-owners of the company. In addition, IB and RD are Histograft employees who participated in the development of the clinical study design in cooperation with the principal investigator (AD); no CRO companies are required for bone substitute registration in the Russian Federation. IB, AI, and RD were not involved in the clinical data collection, analysis, or official report writing. For manuscript writing, all the results were transferred from a clinical trial official report submitted to the Ministry of Healthcare. Additional follow-up data were collected by AD and NR and were analyzed together with IB and RD. The investigated bone substitute is covered by a patent application "Methods of producing optimized gene-activated materials," US 20190224379A1, patent applicant - Histograft, LLC; inventors: RD, AI, IB, and VK. EDAT- 2021/02/23 06:00 MHDA- 2021/02/23 06:01 PMCR- 2021/01/01 CRDT- 2021/02/22 05:57 PHST- 2020/08/26 00:00 [received] PHST- 2021/01/11 00:00 [accepted] PHST- 2021/02/22 05:57 [entrez] PHST- 2021/02/23 06:00 [pubmed] PHST- 2021/02/23 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fbioe.2021.599300 [doi] PST - epublish SO - Front Bioeng Biotechnol. 2021 Feb 4;9:599300. doi: 10.3389/fbioe.2021.599300. eCollection 2021.