Biological activation of bone‐related biomaterials by recombinant adeno‐associated virus vector

Nasu, Tomonori; Ito, Hiromu; Tsutsumi, Ryosuke; Kitaori, Toshiyuki; Takemoto, Mitsuru; Schwarz, Edward M.; Nakamura, Takashi

doi:10.1002/jor.20860

Cited by 12 publications

(13 citation statements)

References 43 publications

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“…This suggests that both direct and in‐direct vector application may be equally as effective in inducing repair. Other groups have successfully demonstrated long‐term bioactivity of adenoviral vectors when incorporated with hydroxyapatite (Hu et al , ) and for adeno‐associated virus when freeze‐dried on to cortical bone allograft (Ito et al , ) and on to hydroxyapatite, tri‐calcium phosphate and titanium alloy (Nasu et al , ). In future work, we plan to assess longer term bioactivity of our vector after lyophilizing to MBCP.…”

Section: Discussionmentioning

confidence: 99%

A doxycycline inducible, adenoviral bone morphogenetic protein-2 gene delivery system to bone

Bara

Dresing

Zeiter

et al. 2017

J Tissue Eng Regen Med

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We report the novel use of a tuneable, non-integrating viral gene delivery system to bone that can be combined with clinically approved biomaterials in an 'off-the-shelf' manner. Specifically, a doxycycline inducible Tet-on adenoviral vector (AdTetBMP-2) in combination with mesenchymal stromal cells (MSCs), fibrin and a biphasic calcium phosphate ceramic (MBCP®) was used to repair large bone defects in nude rats. Bone morphogenetic protein-2 (BMP-2) transgene expression could be effectively tuned by modification of the doxycycline concentration. The effect of adenoviral BMP-2 gene delivery upon bone healing was investigated in vivo in 4 mm critically sized, internally fixated, femoral defects. MSCs were transduced either by direct application of AdTetBMP-2 or by pre-coating MBCP granules with the virus. Radiological assessment scores post-mortem were significantly improved upon delivery of AdTetBMP-2. In AdTetBMP-2 groups, histological analysis revealed significantly more newly formed bone at the defect site compared with controls. Newly formed bone was vascularized and fully integrated with nascent tissue and implanted biomaterial. Improvement in healing outcome was achieved using both methods of vector delivery (direct application vs. pre-coating MCBP). Adenoviral delivery of BMP-2 enhanced bone regeneration achieved by the transplantation of MSCs, fibrin and MBCP in vivo. Importantly, our in vitro and in vivo data suggest that this can be achieved with relatively low (ng/ml) levels of the growth factor. Our model and novel gene delivery system may provide a powerful standardized tool for the optimization of growth factor delivery and release for the healing of large bone defects.

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Section: Discussionmentioning

confidence: 99%

A doxycycline inducible, adenoviral bone morphogenetic protein-2 gene delivery system to bone

Bara

Dresing

Zeiter

et al. 2017

J Tissue Eng Regen Med

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“…Adenoviral vectors are efficient, can be produced in high titres, achieve high levels of expression following transduction, and can transfer genes to both dividing and nondividing cells [33]. In this study, rASCs were transfected with a replication defective adenovirus-mediated BMP2 gene [32,34,35]. Further research will focus on the use of AAV in our group.…”

Section: Discussionmentioning

confidence: 99%

Enhanced bone formation in large segmental radial defects by combining adipose-derived stem cells expressing bone morphogenetic protein 2 with nHA/RHLC/PLA scaffold

Dong

Jiang³

et al. 2010

International Orthopaedics (SICOT)

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In this study, rabbit adipose-derived stem cells (rASCs) were isolated, cultured in vitro, and transfected with recombinant adenovirus vector containing human bone morphogenetic protein 2 (Ad-hBMP2). These cells were combined with a nano-hydroxyapatite/recombinant humanlike collagen/poly(lactic acid) scaffold (nHA/RHLC/PLA) to fabricate a new biocomposite (hBMP2/rASCs-nHA/RHLC/ PLA, group 1) and cultured in osteogenic medium. Nontransfected rASCs mixed with nHA/RHLC/PLA (rASCsnHA/RHLC/PLA, group 2) and nHA/RHLC/PLA scaffold alone (group 3) served as controls. Scanning electron microscope (SEM) demonstrated integration of rASCs with the nHA/RHLC/PLA scaffold. Quantitative real-time RT-PCR analyses of collagen I, osteonectin, and osteopontin cDNA expression indicated that the osteogenic potency of rASCs was enhanced by transfection with Ad-hBMP2. After in vitro culture for seven days, three groups were implanted into 15-mm length critical-sized segmental radial defects in rabbits. After 12 weeks, radiographic and histological analyses were performed. In group 1, the medullary cavity was recanalised, bone was rebuilt and moulding was finished, the bone contour had begun to remodel and scaffold was degraded completely. In contrast, bone defects were not repaired in groups 2 or 3. Furthermore, the scaffold degradation rate in group 1 was significantly higher than in groups 2 or 3. In summary, after transduction with Ad-hBMP2, the osteogenesis of rASCs was enhanced; a new biocomposite created with these cells induced repair of a critical bone defect in vivo in a relatively short time.

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“…42,43 An rAAV coating strategy has been also involved for biological activation of bone-related biomaterials. 74,75 Nasu et al 74 lyophilized rAAV-lacZ and rAAV-BMP-2 (serotype 2) in hydroxyapatite, b-tricalcium phosphate (b-TCP), and titanium (Ti) alloy. When implanted in rat muscles, a higher b-galactosidase activity and significant induction of bone formation were observed when rAAV-lacZ and rAAV-BMP-2 were immobilized into hydroxyapatite scaffolds.…”

Section: Raav Gene Transfer In Cartilagementioning

confidence: 99%

Recent tissue engineering-based advances for effective rAAV-mediated gene transfer in the musculoskeletal system

Rey‐Rico

Cucchiarini

2016

Bioengineered

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Musculoskeletal tissues are diverse and significantly different in their ability to repair upon injury. Current treatments often fail to reproduce the natural functions of the native tissue, leading to an imperfect healing. Gene therapy might improve the repair of tissues by providing a temporarily and spatially defined expression of the therapeutic gene(s) at the site of the injury. Several gene transfer vehicles have been developed to modify various human cells and tissues from musculoskeletal system among which the non-pathogenic, effective, and relatively safe recombinant adeno-associated viral (rAAV) vectors that have emerged as the preferred gene delivery system to treat human disorders. Adapting tissue engineering platforms to gene transfer approaches mediated by rAAV vectors is an attractive tool to circumvent both the limitations of the current therapeutic options to promote an effective healing of the tissue and the natural obstacles from these clinically adapted vectors to achieve an efficient and durable gene expression of the therapeutic sequences within the lesions.

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Biological activation of bone‐related biomaterials by recombinant adeno‐associated virus vector

Cited by 12 publications

References 43 publications

A doxycycline inducible, adenoviral bone morphogenetic protein-2 gene delivery system to bone

A doxycycline inducible, adenoviral bone morphogenetic protein-2 gene delivery system to bone

Enhanced bone formation in large segmental radial defects by combining adipose-derived stem cells expressing bone morphogenetic protein 2 with nHA/RHLC/PLA scaffold

Recent tissue engineering-based advances for effective rAAV-mediated gene transfer in the musculoskeletal system

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