Osteoinduction by microbubble‐enhanced transcutaneous sonoporation of human bone morphogenetic protein‐2

Osawa, Kenji; Okubo, Yasunori; Nakao, Kazumasa; Koyama, Noriaki; Bessho, Kazuhisa

doi:10.1002/jgm.1331

Cited by 57 publications

(44 citation statements)

References 34 publications

(34 reference statements)

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“…It is known that rhBMP-2 can induce the differentiation of non-osteogenic cell lines into osteoblastic cells, indicating that the BMP-2 gene could be transfected into C3H10T1/2 cells with an ultra-fine needle to induce the differentiation of fibroblast into osteoblast. Our previous studies demonstrated that implantation of rhBMP-2 with a carrier matrix [14], in vivo adenovirus-mediated gene transfer [15], and in vivo plasmid DNA-mediated gene transfer, such as electroporation [16], sonoporation [11], or repeat plasmid injection [17], could cause osteoinduction. However, the above techniques showed some limitations in practical usage.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous attempts have been made to overcome the relatively low transfection efficiency, including the application of electric pulses and / or ultrasonic devices. Although these techniques are efficient to some degree, using a large amount of plasmid DNA is needed to enhanced the effect [11,17]. In addition, direct injection of naked plasmid DNA into the animal or human body is associated with toxicity and immunogenicity [18].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, ultrasound-enhanced gene transfer (sonoporation) has been investigated [10]. We recently reported osteoinduction by microbubble enhanced transcutaneous sonoporation of BMP-2 plasmid DNA [11]. Although this method seems to be safer than electroporation, it also requires special equipment and it is necessary to optimize the parameter of ultrasound.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Feasibility of BMP-2 Gene Therapy Using an Ultra-Fine Needle

Osawa¹,

Okubo²,

Nakao³

et al. 2011

Targets in Gene Therapy

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Feasibility of BMP-2 Gene Therapy Using an Ultra-Fine Needle

Osawa¹,

Okubo²,

Nakao³

et al. 2011

Targets in Gene Therapy

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“…(50) Sonoporation with 75 µg BMP-2 plasmid led to radiographic bone formation in a mouse intramuscular model, although pDNA without sonoporation also led to some ectopic bone in this study. (51) Multiple cycles of injections and sonoporations were required to induce bone. (51) Electroporation similarly allows cellular internalization of pDNA after plasma membrane integrity is compromised by electrical pulses.…”

Section: Bmp9mentioning

confidence: 99%

“…(51) Multiple cycles of injections and sonoporations were required to induce bone. (51) Electroporation similarly allows cellular internalization of pDNA after plasma membrane integrity is compromised by electrical pulses. (52) Electroporation of 25 to 50 µg BMP-2/7 plasmid yielded radiopaque bone in a rat intramuscular model.…”

Section: Bmp9mentioning

confidence: 99%

Realizing the potential of gene-based molecular therapies in bone repair

Rose

Uludağ

2013

Journal of Bone and Mineral Research

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A better understanding of osteogenesis at genetic and biochemical levels is yielding new molecular entities that can modulate bone regeneration and potentially act as novel therapies in a clinical setting. These new entities are motivating alternative approaches for bone repair by utilizing DNA-derived expression systems, as well as RNA-based regulatory molecules controlling the fate of cells involved in osteogenesis. These sophisticated mediators of osteogenesis, however, pose unique delivery challenges that are not obvious in deployment of conventional therapeutic agents. Viral and nonviral delivery systems are actively pursued in preclinical animal models to realize the potential of the gene-based medicines. This article will summarize promising bone-inducing molecular agents on the horizon as well as provide a critical review of delivery systems employed for their administration. Special attention was paid to synthetic (nonviral) delivery systems because they are more likely to be adopted for clinical testing because of safety considerations. We present a comparative analysis of dose-response relationships, as well as pharmacokinetic and pharmacodynamic features of various approaches, with the purpose of clearly defining the current frontier in the field. We conclude with the authors' perspective on the future of genebased therapy of bone defects, articulating promising research avenues to advance the field of clinical bone repair. © 2013 American Society for Bone and Mineral Research. KEY WORDS: OSTEOGENESIS; BIOENGINEERING; MOLECULAR PATHWAYS; GENE-BASED THERAPYClinical Need for New Bone-Regeneration Strategies N early 2.2 million bone grafts are performed worldwide annually (1) and up to 20% of fractures are hampered by impaired healing. (2) The economic impact of nonunions is enormous, with the cost of spinal fusions alone reaching $20 billion annually. (3) The gold standard for repair of large segmental defects remains autologous grafts, where bone harvested from a non-weight-bearing site, usually the iliac crest, is used to repair defects. Bone grafts, however, are limited in several aspects, including potency of the grafts and the physiological detriment resulting from harvest surgery. Allografts are alternatively employed, where donor tissue is used to repair the defect, but the risk of disease transmission is always a concern. Allografts are extensively processed to reduce this risk, but osteopotency of the graft could be decreased in this way. (4) Demineralized bone matrix derived from decalcified bone can similarly act as a substitute; its potency, however, is variable and depends on the processing conditions. Synthetic scaffolds have been used to provide a hospitable environment for new bone formation. Scaffolds have been constructed from the organic (collagen) and inorganic (hydroxyapatite [HA]) components of bone, but such scaffolds are incapable of inducing osteogenesis on their own and they are more suitable for smaller defects.Osteogenic proteins are frequently employed to render ost...

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Nonviral gene transfer strategies to promote bone regeneration

2013

J Biomedical Materials Res

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Despite the inherent ability of bone to regenerate itself, there are a number of clinical situations in which complete bone regeneration fails to occur. In view of shortcomings of conventional treatment, gene therapy may have a place in cases of critical-size bone loss that cannot be properly treated with current medical or surgical treatment. The purpose of this review is to provide an overview of gene therapy in general, nonviral techniques of gene transfer including physical and chemical methods, RNA-based therapy, therapeutic genes to be transferred for bone regeneration, route of application including ex vivo application, and direct gene therapy approaches to regenerate bone.

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Osteoinduction by microbubble‐enhanced transcutaneous sonoporation of human bone morphogenetic protein‐2

Abstract: These results suggest the possibility of the effective clinical use of human BMP-2 gene therapy using transcutaneous sonoporation, and should facilitate clinical applications of BMP-2 gene therapy.

Cited by 57 publications

References 34 publications

Feasibility of BMP-2 Gene Therapy Using an Ultra-Fine Needle

Feasibility of BMP-2 Gene Therapy Using an Ultra-Fine Needle

Realizing the potential of gene-based molecular therapies in bone repair

Nonviral gene transfer strategies to promote bone regeneration

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