The Use of Bone Morphogenetic Protein Gene Therapy in Craniofacial Bone Repair

Alden, Tord D.; Beres, Elisa J.; Laurent, Jeffrey S.; Engh, Johnathan A.; Das, Subinoy; London, Scott D.; Jane, John A.; Hudson, Sarah B.; Helm, Gregory A.

doi:10.1097/00001665-200011010-00005

Cited by 83 publications

(32 citation statements)

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“…However, limitations exist with these reconstructive approaches including lack of predictability and ability to achieve volumetric bone changes beyond the benvelopeQ of the alveolus. Advances in the field of tissue engineering and biomimetics offer significant potential to regenerate craniofacial structures using biologic mediators and matrices that mimic the tissueTs original formative processes [13,14]. In this study, in vivo gene therapy was used to deliver BMP-7 to promote osteogenesis and osseointegration.…”

Section: Discussionmentioning

confidence: 99%

BMP gene delivery for alveolar bone engineering at dental implant defects

et al. 2005

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A challenge in the tissue engineering of alveolar bone surrounding oral or dental implants is achieving the targeted and sustained delivery of growth-promoting molecules at the osteotomy site. Bone morphogenetic protein-7 (BMP-7) has demonstrated the ability to stimulate bone regeneration in multiple skeletal sites, including the craniofacial complex. This study evaluates in vivo gene delivery of BMP-7 for bone tissue engineering around titanium dental implants. The maxillary first molar teeth of 44 Sprague-Dawley rats were extracted and allowed to heal for a period of 1 month. Large osteotomy defects were created in the edentulous ridge areas followed by the placement of dental implant fixtures. Recombinant adenoviral vectors encoding either the BMP-7 or the luciferase gene were delivered to the osseous defects using a collagen matrix. The kinetics of the gene expression was measured using in vivo bioluminescence optical imaging, while bone regeneration was evaluated under light and scanning electron microscopy. The results revealed sustained, targeted transgene expression for up to 10 days at the osteotomy sites with nearly undetectable levels by 35 days. Treatment of dental implant fixtures with Ad/BMP-7 resulted in enhancement of alveolar bone defect fill, coronal new bone formation, and new bone-to-implant contact. In vivo gene therapy of BMP-7 offers potential for alveolar bone engineering applications.

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Section: Discussionmentioning

confidence: 99%

BMP gene delivery for alveolar bone engineering at dental implant defects

et al. 2005

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“…Many viral carriers showed an attenuated response (32) or are ineffective in animals with intact immune systems. (33)(34)(35)(36)(37)(38)(39)(40)(41) Immunosuppression of normal animals can restore the efficacy of viral therapy, (42) (Table 1), which recognizes the preference of practitioners in the field. Nonviral methods, including use of naked pDNA and physical delivery methods (Fig.…”

Section: Pdna Delivery For Bone Induction and Functional Outcomesmentioning

confidence: 99%

“…Bone induction via endochondral ossification was observed in hindlimb muscle of immunocompetent rats (101,102) Viral particles delivered on hydroxyapatite scaffold to the back muscles of immunocompetent rats led to bone formation (103) Bone formation in thigh muscle after delivery of a tetracycline-sensitive expression system was observed in mice only when a tetracycline analogue was administered (153) Orthotopic AV Increased regeneration in a mandibular distraction osteogenesis model in rats (154) Increased bone regeneration in an osteoporotic fracture model in tibia of sheep (155) Bone formation or increased regeneration was observed in several defect models, including a critical-size mandibular defect, (33) critical-size nasal defect in athymic nude mice, (156) rib defect in horses, (157) metatarsal defect in horses, (158) and femoral critical-size defect in rats (159) Injected AVs led to partial regeneration of critical-size calvarial defects in rats, with a more vigorous response when particles were delivered in a gelatin scaffold (117) Healing of iliac crest critical-size defects in sheep was delayed compared with no treatment when viral particles were injected to injury site (160) Bone formation was observed in a dental model in immunocompetent dogs (107) Enhanced cartilage and subchondral bone was observed in femur condyle defect in immunocompetent ponies (161) Delaying administration of viral particles improved healing of femur critical-size defects in rats (162) …”

Section: Aavmentioning

confidence: 99%

“…(58) The broadly effective carrier 25 kDa polyethylenimine (PEI25) has been employed to deliver BMP-4 plasmid (200 µg) in a poly (lactic-co-glycolic) acid implant for regeneration of a rat criticalsize skull defect. (59) Bone formation was observed around defect (33) and healing of spinal arthrodesis model in athymic nude mice (168) TGFb Orthotopic AV Increased epiphyseal thickness was observed after injection of viral particles into the humerus of rats (169) …”

Section: Delivery With Synthetic Carriersmentioning

confidence: 99%

“…(42) AV delivered in a collagen sponge to calf muscle led to bone in immunocompetent rats but not when AV particles were injected without the sponge (41) Bone formation in the calf muscle of rats was observed only with immunosuppression (38)(39)(40) Bone induction in quadriceps was stronger in athymic nude rats compared with immunocompetent rats (32) AV delivery to soleus muscle of rats resulted in bone only when ischemic degeneration was induced via muscle grafting. Bone was not observed without grafting (152) AAV Bone induction via endochondral ossification was observed in hindlimb muscle of immunocompetent rats (101,102) Viral particles delivered on hydroxyapatite scaffold to the back muscles of immunocompetent rats led to bone formation (103) Bone formation in thigh muscle after delivery of a tetracycline-sensitive expression system was observed in mice only when a tetracycline analogue was administered (153) Orthotopic AV Increased regeneration in a mandibular distraction osteogenesis model in rats (154) Increased bone regeneration in an osteoporotic fracture model in tibia of sheep (155) Bone formation or increased regeneration was observed in several defect models, including a critical-size mandibular defect, (33) critical-size nasal defect in athymic nude mice, (156) rib defect in horses, (157) metatarsal defect in horses, (158) and femoral critical-size defect in rats (159) Injected AVs led to partial regeneration of critical-size calvarial defects in rats, with a more vigorous response when particles were delivered in a gelatin scaffold (117) Healing of iliac crest critical-size defects in sheep was delayed compared with no treatment when viral particles were injected to injury site (160) Bone formation was observed in a dental model in immunocompetent dogs (107) Enhanced cartilage and subchondral bone was observed in femur condyle defect in immunocompetent ponies (161) Delaying administration of viral particles improved healing of femur critical-size defects in rats (162) AAV Bone formation in femur defects in immunocompromised rats, but addition of human mesenchymal stem cells did not improve the outcome (163) BMP4 Ectopic AV Bone induction in hindlimb muscle, (164) calf muscle, (34) and quadriceps (35) of athymic nude rats Bone formation in the thigh muscle was observed in athymic nude rats but not in immunocompetent rats (36) Ectopic AAV Bone formation in hindlimb muscle of immunocompetent rats (104) Orthotopic AV Enhanced bone formation around implants in femur defects in ovariectomized rabbits (165) RV Increased callus size and enhanced healing in a femur fracture model in immunocompetent rats (166) BMP6 Ectopic AV Bone formation in quadriceps in athymic nude mice, (35) in thigh muscle of various immunocompetent rat strains, (36,37) and in calf muscle of nude athymic rats (34) Orthotopic AV En...…”

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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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