3D Printed Gene-activated Octacalcium Phosphate Implants for Large Bone Defects Engineering

Бозо, И Я; Деев, Р. В.; Smirnov, Igor; Fedotov, A. Yu.; Попов, В. К.; Миронов, А. Н.; Mironova, Olga A.; Gerasimenko, Alexander Yu.; Komlev, V. S.

doi:10.18063/ijb.v6i3.275

Cited by 22 publications

(7 citation statements)

References 29 publications

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“…In addition, the above‐mentioned bioactive substances are not suitable for high‐temperature printing (SLS and FDM) or stents requiring high‐temperature post‐treatment. Fortunately, loading bioactive substances in the 3D printed scaffolds after AM is considered as a solution to the above limitations, for example, the good developments of loading genes, [ 274,275 ] drugs [ 276 ] and proteins [ 277 ] have been made in bone regeneration.…”

Section: Future Prospectsmentioning

confidence: 99%

Recent Developments of Biomaterials for Additive Manufacturing of Bone Scaffolds

Zhang

et al. 2020

Adv Healthcare Materials

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Recent years have witnessed surging demand for bone repair/regeneration implants due to the increasing number of bone defects caused by trauma, cancer, infection, and arthritis worldwide. In addition to bone autografts and allografts, biomaterial substitutes have been widely used in clinical practice. Personalized implants with precise and personalized control of shape, porosity, composition, surface chemistry, and mechanical properties will greatly facilitate the regeneration of bone tissue and satiate the clinical needs. Additive manufacturing (AM) techniques, also known as 3D printing, are drawing fast growing attention in the fabrication of implants or scaffolding materials due to their capability of manufacturing complex and irregularly shaped scaffolds in repairing bone defects in clinical practice. This review aims to provide a comprehensive overview of recent progress in the development of materials and techniques used in the additive manufacturing of bone scaffolds. In addition, clinical application, pre-clinical trials and future prospects of AM based bone implants are also summarized and discussed.

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Section: Future Prospectsmentioning

confidence: 99%

Recent Developments of Biomaterials for Additive Manufacturing of Bone Scaffolds

Zhang

et al. 2020

Adv Healthcare Materials

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“…We have previously demonstrated that an OCP-based bone substitute could improve reparative osteogenesis in vivo (Komlev et al, 2014 ; Bozo et al, 2020 ). However, a lack of osteoinductive capacities has been observed in experimental studies, which could explain why a significant part of the newly formed tissues in the biopsy samples was presented by fibrous tissue in the clinical study.…”

Section: Discussionmentioning

confidence: 99%

Bringing a Gene-Activated Bone Substitute Into Clinical Practice: From Bench to Bedside

Бозо

Drobyshev

Redko

et al. 2021

Front. Bioeng. Biotechnol.

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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.

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“…Then, an nHA-collagen scaffold has been reported to accelerate bone regeneration with sustained localized delivery of angiogenic (pVEGF) and osteogenic (pBMP2) genes [42]. Moreover, the potential clinical usefulness of 3D printed GAM based on octacalcium phosphate (OCP) and pVEGF has been shown in the regeneration of large bone defects [43]. Therefore, many challenges in establishing GAM-based bone engineering need to be overcome by further investigating both the target genes in a nanoball and the biodegradable matrices.…”

Section: Discussionmentioning

confidence: 99%

Gene-Activated Matrix with Self-Assembly Anionic Nano-Device Containing Plasmid DNAs for Rat Cranial Bone Augmentation

et al. 2021

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We have developed nanoballs, a biocompatible self-assembly nano-vector based on electrostatic interactions that arrange anionic macromolecules to polymeric nanomaterials to create nucleic acid carriers. Nanoballs exhibit low cytotoxicity and high transfection efficiently in vivo. This study investigated whether a gene-activated matrix (GAM) composed of nanoballs containing plasmid (p) DNAs encoding bone morphogenetic protein 4 (pBMP4) could promote bone augmentation with a small amount of DNA compared to that composed of naked pDNAs. We prepared nanoballs (BMP4-nanoballs) constructed with pBMP4 and dendrigraft poly-L-lysine (DGL, a cationic polymer) coated by γ-polyglutamic acid (γ-PGA; an anionic polymer), and determined their biological functions in vitro and in vivo. Next, GAMs were manufactured by mixing nanoballs with 2% atelocollagen and β-tricalcium phosphate (β-TCP) granules and lyophilizing them for bone augmentation. The GAMs were then transplanted to rat cranial bone surfaces under the periosteum. From the initial stage, infiltrated macrophages and mesenchymal progenitor cells took up the nanoballs, and their anti-inflammatory and osteoblastic differentiations were promoted over time. Subsequently, bone augmentation was clearly recognized for up to 8 weeks in transplanted GAMs containing BMP4-nanoballs. Notably, only 1 μg of BMP4-nanoballs induced a sufficient volume of new bone, while 1000 μg of naked pDNAs were required to induce the same level of bone augmentation. These data suggest that applying this anionic vector to the appropriate matrices can facilitate GAM-based bone engineering.

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3D Printed Gene-activated Octacalcium Phosphate Implants for Large Bone Defects Engineering

Cited by 22 publications

References 29 publications

Recent Developments of Biomaterials for Additive Manufacturing of Bone Scaffolds

Recent Developments of Biomaterials for Additive Manufacturing of Bone Scaffolds

Bringing a Gene-Activated Bone Substitute Into Clinical Practice: From Bench to Bedside

Gene-Activated Matrix with Self-Assembly Anionic Nano-Device Containing Plasmid DNAs for Rat Cranial Bone Augmentation

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