An expedited approach for sustained delivery of bone morphogenetic protein‐7 to bone defects using gene activated fragments of subcutaneous fat

Betz, Volker M.; Betz, Oliver B.; Rosin, Tom; Keller, Alexander; Thirion, Christian; Salomon, Michael; Manthey, Suzanne; Augat, Peter; Jansson, Volkmar; Müller, Peter E.; Rammelt, Stefan; Zwipp, H.

doi:10.1002/jgm.2892

Cited by 11 publications

(14 citation statements)

References 43 publications

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“…(E–H) Representative samples of rat femoral defects receiving unmodified adipose tissue. Reproduced with permission…”

Section: Expedited Ex Vivo Gene Therapymentioning

confidence: 99%

“…Another method of expedited ex vivo gene therapy for bone repair was presented by Betz et al 66,67,76,77,120 utilizing gene-activated fragments of subcutaneous fat or skeletal muscle as osteo-regenerative implants. One experiment explored the effect of directly BMP-2 transduced muscle tissue fragments on the healing of critical-size segmental defects in rat femora.…”

Section: Muscle Tissuementioning

confidence: 99%

“…Another method of expedited ex vivo gene therapy for bone repair was presented by Betz et al . utilizing gene‐activated fragments of subcutaneous fat or skeletal muscle as osteo‐regenerative implants.…”

Section: Expedited Ex Vivo Gene Therapymentioning

confidence: 99%

“…These bone repair studies were conducted utilizing a well‐established critical‐sized rat femoral bone defect model. Similar to muscle implants, the adenoviral transduction with BMP‐2 has proven to be more effective than modification with BMP‐7 cDNA …”

Section: Expedited Ex Vivo Gene Therapymentioning

confidence: 99%

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Recent advances in gene‐enhanced bone tissue engineering

Betz

Kochanek

Rammelt

et al. 2018

The Journal of Gene Medicine

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The loss of bone tissue represents a critical clinical condition that is frequently faced by surgeons. Substantial progress has been made in the area of bone research, providing insight into the biology of bone under physiological and pathological conditions, as well as tools for the stimulation of bone regeneration. The present review discusses recent advances in the field of gene-enhanced bone tissue engineering. Gene transfer strategies have emerged as highly effective tissue engineering approaches for supporting the repair of the musculoskeletal system. By contrast to treatment with recombinant proteins, genetically engineered cells can release growth factors at the site of injury over extended periods of time. Of particular interest are the expedited technologies that can be applied during a single surgical procedure in a cost-effective manner, allowing translation from bench to bedside. Several promising methods based on the intra-operative genetic manipulation of autologous cells or tissue fragments have been developed in preclinical studies. Moreover, gene therapy for bone regeneration has entered the clinical stage with clinical trials for the repair of alveolar bone. Current trends in gene-enhanced bone engineering are also discussed with respect to the movement of the field towards expedited, translational approaches. It is possible that gene-enhanced bone tissue engineering will become a clinical reality within the next few years.

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“…(E–H) Representative samples of rat femoral defects receiving unmodified adipose tissue. Reproduced with permission…”

Section: Expedited Ex Vivo Gene Therapymentioning

confidence: 99%

Section: Muscle Tissuementioning

confidence: 99%

Section: Expedited Ex Vivo Gene Therapymentioning

confidence: 99%

Section: Expedited Ex Vivo Gene Therapymentioning

confidence: 99%

See 2 more Smart Citations

Recent advances in gene‐enhanced bone tissue engineering

Betz

Kochanek

Rammelt

et al. 2018

The Journal of Gene Medicine

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“…Several efforts to produce homogeneous nanocomposites, including inorganic cement scaffolds and salt/polymer additives, still translate poorly in the repair of critical‐size bone defects . Very recent reports further reveal the lingering issues of bone malformation, e.g., incomplete bridging and irregular medullary cavities in autograft and medical‐grade scaffolds, uneven bone surfaces, and formation of multiple chambers . Therefore, addressing bone malformation still remains a grand challenge for bone regeneration of critical‐size defects by now.…”

mentioning

confidence: 99%

Ionic Colloidal Molding as a Biomimetic Scaffolding Strategy for Uniform Bone Tissue Regeneration

et al. 2017

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Inspired by the highly ordered nanostructure of bone, nanodopant composite biomaterials are gaining special attention for their ability to guide bone tissue regeneration through structural and biological cues. However, bone malformation in orthopedic surgery is a lingering issue, partly due to the high surface energy of traditional nanoparticles contributing to aggregation and inhomogeneity. Recently, carboxyl-functionalized synthetic polymers have been shown to mimic the carboxyl-rich surface motifs of non-collagenous proteins in stabilizing hydroxyapatite and directing intrafibrillar mineralization in-vitro. Based on this biomimetic approach, it is herein demonstrated that carboxyl functionalization of poly(lactic-co-glycolic acid) can achieve great material homogeneity in nanocomposites. This ionic colloidal molding method stabilizes hydroxyapatite precursors to confer even nanodopant packing, improving therapeutic outcomes in bone repair by remarkably improving mechanical properties of nanocomposites and optimizing controlled drug release, resulting in better cell in-growth and osteogenic differentiation. Lastly, better controlled biomaterial degradation significantly improved osteointegration, translating to highly regular bone formation with minimal fibrous tissue and increased bone density in rabbit radial defect models. Ionic colloidal molding is a simple yet effective approach of achieving materials homogeneity and modulating crystal nucleation, serving as an excellent biomimetic scaffolding strategy to rebuild natural bone integrity.

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Osteoinduction within adipose tissue fragments by heterodimeric bone morphogenetic Proteins‐2/6 and ‐2/7 versus homodimeric bone morphogenetic protein‐2: Therapeutic implications for bone regeneration

Betz¹,

Ren²,

Betz

et al. 2021

The Journal of Gene Medicine

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Background Fragments of subcutaneous adipose tissue that have been genetically modified to express bone morphogenetic protein‐2 (BMP‐2) regenerate large segmental osseous lesions in rodents. Gene‐activated adipose tissue can be implanted into osseous defects without prior cell extraction and cell culture. The present study aimed to explore whether the heterodimers BMP‐2/6 or BMP‐2/7 exceed the osteoinductive effect of BMP‐2 on adipose tissue. Methods In an in vitro tissue culture system, freshly harvested rat subcutaneous adipose tissue was cultivated in the presence of either BMP‐2 or BMP‐2/6 or BMP‐2/7 at a high (200 ng/ml) and low (50 ng/ml) concentration. Gene expression analysis as well as histological and immunohistochemical methods were applied to test for osteoinduction. Results A concentration of 200 ng/ml of homodimeric BMP‐2 induced osteogenic differentiation most potently, showing more calcification and a higher expression level of bone markers than both concentrations of BMP‐2/6 or ‐2/7. A concentration of 50 ng/ml of BMP‐2 was a significantly stronger osteogenic inducer than both concentrations of BMP‐2/6 and the low concentration of BMP‐2/7. The most potent heterodimeric driver of osteoinduction was BMP‐2/7 at a high concentration, demonstrating effects similar to those of BMP‐2 at a low concentration. Conclusions Homodimeric BMP‐2 evoked osteoinduction within adipose tissue more potently and at a lower concentration than heterodimeric BMP‐2/6 or BMP‐2/7. This result agrees well with the fact that it might be easier to translate adipose grafts activated by homodimeric BMP‐2 clinically. Preclinical in vivo gene transfer studies are necessary to confirm the results of the present study.

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An expedited approach for sustained delivery of bone morphogenetic protein‐7 to bone defects using gene activated fragments of subcutaneous fat

Cited by 11 publications

References 43 publications

Recent advances in gene‐enhanced bone tissue engineering

Recent advances in gene‐enhanced bone tissue engineering

Ionic Colloidal Molding as a Biomimetic Scaffolding Strategy for Uniform Bone Tissue Regeneration

Osteoinduction within adipose tissue fragments by heterodimeric bone morphogenetic Proteins‐2/6 and ‐2/7 versus homodimeric bone morphogenetic protein‐2: Therapeutic implications for bone regeneration

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