BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry
Abstract
:1. Introduction
2. BMPs in Bone Tissue Healing
3. rhBMP-2 Delivery in Protein Form
4. BMP-2 Gene Delivery
4.1. Ex Vivo BMP-2 Gene Delivery
4.1.1. Cells for Ex Vivo BMP-2 Gene Delivery
4.1.2. Viral Vectors for Ex Vivo BMP-2 Gene Delivery
4.1.3. Non-Viral Vectors for Ex Vivo BMP-2 Gene Delivery
4.1.4. Bone Regeneration via Ex Vivo BMP-2 Gene Delivery
4.1.5. Dental Application via Ex Vivo BMP-2 Gene Delivery
4.2. In Vivo BMP-2 Gene Delivery
4.2.1. Viral Vectors for In Vivo BMP-2 Gene Delivery
4.2.2. Non-Viral Vectors for In Vivo BMP-2 Gene Delivery
4.2.3. Bone Regeneration through In Vivo BMP-2 Gene Delivery
4.3. Complementary Strategies of In Vivo and Ex Vivo BMP-2 Gene Delivery
4.4. Combined Approaches Improving Bone Regeneration
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Delivery Type | Advantages | Disadvantages |
---|---|---|
ex vivo | Gene transfer is limited to the target cell population and not to other cells or tissues | Expensive and time-consuming process |
Can use gene transfer to genetically modify stem cells, e.g., embryonic stem cells and iPSCs [29,30] | Complicated manipulation including cell harvesting, cell expansion and transfection | |
High efficacy | The outcome can be influenced by the carrier cells [31,32] | |
Low quantity of vectors is necessary for desired therapeutic effects | ||
Minimal immune recognition of the gene vectors [33] | ||
in vivo | Simple process via direct injection into the site or intravenous administration | Low efficacy |
Avoids complicated process related to cells | High quantity of vectors is necessary for desired therapeutic effects | |
Relatively low cost | Induction of immune reaction due to direct exposure of vectors | |
Difficult to target the cell population of interest | ||
Vector system is potentially toxic [34] |
Type of Vectors | Advantages | Disadvantages |
---|---|---|
Viral vectors | High gene transduction efficiency | Difficult to manufacture, produced in low virus titers |
Transgene expression can be controlled by virus (transient expression or persistent expression) | Immune reactions to virus [56] | |
Can target specific cell types such as dividing cells or non-dividing cells [33,57] | Limitation in packaging capacity e.g., 4.5 kb for AAV vectors [33,57] | |
Safety concerns e.g., insertion mutagenesis [58] | ||
Non-viral vectors | Simple manufacturing | Low in vivo gene transduction efficiency [57] |
Low cost | High quantity for therapeutic effects | |
Low immunogenicity | Cannot target specific cell types | |
High packaging capacity | Toxicity related to materials [34] |
References | Cells | Vectors | Transgene | Carrier | Model | Results |
---|---|---|---|---|---|---|
Lee et al. 2001,2002 [36,37] | Muscle-derived cells | Adenovirus | BMP-2 | Collagen sponge | Mouse calvarial defect | Mouse calvarial defects treated with BMP-2-producing muscle cells had >85% closure within two weeks and 95–100% closure within four weeks. |
Blum et al. 2003 [68] | MSCs | Adenovirus Retrovirus Cationic lipid | BMP-2 | Titanium mesh scaffold | Rat calvarial defect | All viral and non-viral vectors carrying the BMP-2 gene were effective in bone regeneration. However, adenoviral vectors resulted in slightly significantly increased amounts of newly formed bone compared to those achieved with other vectors and the control group. |
Hirata et al. 2003 [51] | Skin fibroblasts | Adenovirus | BMP-2 or Runx2 | PDLLGA /gelatin sponge | Rat calvarial defect | AdBMP-2-transplanted skin fibroblasts were effective on new bone formation. However, cells with AdRunx2 were insufficient in inducing bone repair. |
Park et al. 2003 [35] | BMSCs | Adenovirus Liposome | BMP-2 | Collagen sponge | Rat mandibular defect | Both liposome-mediated and adenoviral BMP-2 gene transfer to BMSCs successfully achieved the healing of critical-size bone defects in rats. |
Gafni et al. 2004 [63] | MSCs | AAV | BMP-2 | Collagen sponge | Mouse calvarial defect | AAV-BMP-2 with a tetracycline-sensitive promotor was effective in regulation of bone formation by gene therapy. |
Hu et al. 2007 [40] | Fibroblasts | Adenovirus | BMP-2 | Gelatin sponge, HA disc | Rat calvarial defect | Lyophilized AdBMP-2 in a gelatin sponge was more effective than the free form of adBMP-2 in rat calvarial defects. |
Koh et al. 2008 [76] | Fibroblasts | Adenovirus | BMP-2/7 | Gelatin sponge | Mouse calvarial defect | AdBMP-2/7-transduced cells were more effective in healing cranial defects than were cells individually transduced with AdBMP-2 or BMP7. |
Tang et al. 2008 [74] | BMSCs | Liposome/Plasmid | BMP-2 | Coral hydroxyapatite matrix | Rat mandibular defect osteoporotic model | Autogenous cells transfected with pBMP-2 promoted bone formation in osteoporotic rats. |
Steinhardt et al. 2008 [43] | BMSCs | Adenovirus | BMP-2 | Collagen sponge | Mouse mandibular defect | Application of genetically engineered BMP-2-producing BMSCs into a mandibular defect led to tissue regeneration at the defect site. |
Wang et al. 2009 [69] | Skin fibroblasts | Retrovirus | BMP-2 | Gelatin sponge | Rat calvarial defect | Autologous BMP-2-modified skin fibroblasts successfully led to bone regeneration in rat calvarial defects. Fibroblasts could be effectively used in ex vivo gene therapy for local bone repair. |
Chang et al. 2009 [44] | BMSCs | Adenovirus | BMP-2 | Gelatin/ tricalcium phosphate ceramic/ glutaraldehyde biopolymer | Rat calvarial defect | AdBMP-2-transfected cells with the gelatin/tricalcium phosphate ceramic/glutaraldehyde biopolymer strongly enhanced the bone healing of critical-size bicortical craniofacial defects. |
Shin et al. 2010 [55] | Human gingival fibroblasts (HGF) | Adenovirus | BMP-2 | Collagen matrix | Rat calvarial defect | AdBMP-2-transfected HGF promoted osseous healing of calvarial defects compared with that achieved in the other groups. |
Chuang et al. 2010 [64] | Human MSCs | Baculovirus | BMP-2 | PLGA scaffolds | Rat calvarial defect | Although a baculovirus was effective for BMP-2 gene transfer into cells, the use of hMSCs could not overcome the immunological barrier in rats. |
Kroczek et al. 2010 [77] | BMSCs | Plasmid-liposome | BMP-2 | Direct injection with an aqueous solution of osteoinductive substances | Minipig distraction osteogenesis | BMP-2 expression was maximal in the pBMP-2 group although bone regeneration was not significantly enhanced in the pBMP-2 group compared to that in the rhBMP-2 and rhBMP-7 groups. |
Xia et al. 2011 [78] | BMSCs | Adenovirus | BMP-2 Nell-1 | Beta-tricalcium phosphate | Rabbit maxillary sinus graft | BMP-2 and Nell-1 genes showed a synergistic effect on osteogenic differentiation of BMSCs and promoted new bone formation and maturation in a rabbit maxillary sinus model. |
Lin et al. 2012 [46] | BMSCs | Baculovirus | BMP-2 VEGF | Disc-shaped PLGA scaffolds | Rabbit calvarial defect | Baculoviral vectors were effective in BMSCs for sustained BMP-2/VEGF expression and the repair of critical-size calvarial defects. |
He et al. 2013 [82] | MSCs EPCs | Adenovirus | BMP-2 | Injectable and porous nano calcium sulfate/alginate | Rat calvarial defect | The combination of BMP-2 gene-modified MSCs and EPCs in injectable scaffolds increased new bone and vascular formation. |
Park et al. 2013 [45] | BMSCs | Adenovirus | BMP-2 | Collagen gel | Rat calvarial defect | Dual delivery of autologous AdBMP-2-transfected BMSCs and rhPDGF-BB enhanced both the quality and quantity of new bone formation. |
Jhin et al. 2013 [79] | BMSCs | Adenovirus | BMP-2 | Deproteinized bovine bone mineral | Rabbit maxillary sinus Dental implant placement | BMSCs with AdBMP-2 transfection resulted in earlier bone healing with increased amounts in the maxillary sinus defects when dental implants were simultaneously placed. |
Jin et al. 2014 [83] | BMSCs | PEI-alginate/Plasmid | BMP-2 | Cell sheet | Rat calvarial defect | PEI-al nanocomposites as a carrier for pBMP-2 gene delivery to BMSCs was effective. Bone regeneration was slightly enhanced by BMP-2- producing BMSCs compared to that in the control group. |
Liao et al. 2014 [47] | ASCs | Baculovirus | BMP-2/miR-148b | Disc-shaped poly (L-lactide-co-glycolide) (PLGA) scaffolds | Mouse calvarial defect | Co-transduction of hASCs with BMP-2/miR-148b via baculovirus vectors enhanced and prolonged BMP-2 expression and synergistically promoted bone regeneration. |
Park et al. 2015 [39] | PDLSCs | Adenovirus | BMP-2 | HA particle with collagen gel | Beagle peri-implantitis defect | PDLSCs transfected by AdBMP-2 produced significantly greater amounts of new bone in peri-implantitis defects than those produced in other groups. |
Keeney et al. 2016 [54] | Skull-derived osteoblasts | Cationic amine polymer/Plasmid | BMP-2 | PLGA | Mouse calvarial defect | Skull-derived osteoblasts transfected by pBMP-2 led to substantially accelerated bone repair as early as two weeks, which continued to progress over 12 weeks. |
Yi et al. 2016 [52] | Human PDLSCs | Adenovirus | BMP-2 | Block-type biphasic calcium phosphate | Rat calvarial defect | hPDLSCs showed an inhibitory action on BMP-2-induced osteogenic differentiation. hPDLSCs-transfected AdBMP-2 produced lower amounts of newly formed bone than did hPDLSCs with rhBMP-2 protein. |
Xu et al. 2016 [38] | ASCs | Adenovirus | BMP-2 | Beta-tricalcium phosphate | Beagle peri-implantitis defect | ASCs transfected by adenoviral BMP-2 produced significant amounts of new bone formation and re-osseointegration compared to those in control groups. |
Vural et al. 2017 [84] | BMSCs | Liposome/Plasmid | BMP-2 | Gelatin sponge | Rat calvarial defect | pBMP-2 gene delivery in BMSCs effectively led to bone regeneration in rat calvarial defects. |
Park et al. 2018 [32] | BMSCs | Adenovirus | BMP-2 | Collagen gel | Rat calvarial defect Diabetic model | In diabetic animals, BMP-2 gene therapy using diabetic cells was more effective in new bone formation than was BMP-2 gene therapy using non-diabetic cells. |
References | Administration | Vector | Transgene | Model | Results |
---|---|---|---|---|---|
Alden et al. 2000 [87] | Direct injection | Adenovirus | BMP-2 BMP9 | Rat mandible defect | Significant bone healing was observed in the BMP gene transfer group. |
Ashinoff et al. 2004 [100] | Direct injection | Adenovirus | BMP-2 | Rat distraction osteogenesis | Local injection of AdBMP-2 increased bone regeneration during distraction osteogenesis. |
Chew et al. 2011 [97] | Gelatin microparticle | Triacrylate/ amine polymer/ Plasmid | BMP-2 | Rat calvarial defect | Triacrylate/amine gelatin effectively slowed the degradation rate compared to that of naked pDNA. |
Zhang et al. 2011 [28] | Fibronectin/apatite | Plasmid | BMP-2 | Rat calvarial defect | Bone formation in the pBMP-2 with fibronectin/hydroxyapatite group was enhanced compared to that in the control group. |
Wu et al. 2012 [93] | Electroporation | Plasmid | BMP-2 BMP-2/ VEGF | Rabbit distraction osteogenesis | pBMP-2/VEGF gene transfer with electroporation was effective for bone regeneration relative to the control. |
Liu et al. 2012 [104] | Muscle tissue | Adenovirus | BMP-2 | Rat calvarial defect | The amount of new bone in muscle tissue transduced with AdBMP-2 was more than twice that in the control. |
Ben Arav et al. 2012 [89] | Bone allograft | AAV | BMP-2 | Mouse calvarial defect | Self-complementary-rAAV-BMP-2-coated allografts were more effective for bone regeneration than were single strand-rAAV-BMP-2-coated allografts, the effects of which were not significantly different from those of autografts or uncoated allografts. |
Qiao et al. 2013 [100] | PLGA nanoparticle | PEI nanoparticles encapsulated by PLGA/plasmid | BMP-2 | Rat calvarial defect | pBMP-2 gene delivery using a PLGA nanoparticle delivery system was effective for producing BMP-2 cDNA and new bone formation. |
Kolk et al. 2016 [102] | Poly(d, l-lactide) (PDLLA)-coated titanium disc | PEI/plasmid | BMP-2 | Rat mandibular defect | pBMP-2 gene delivery using a copolymer was successful for controlling new bone formation with an inverse dose dependency. |
Xie et al. 2017 [88] | Direct injection | Plasmid | BMP-2/VEGF | Rabbit distraction osteogenesis | The direct injection of pBMP-2/VEGF promoted bone formation in the distraction gap with the upregulation of TGF-β1 expression. |
Li et al. 2017 [98] | Injectable thermosensitive hydrogel scaffold | Chitosan/plasmid | BMP-2 | Rat calvarial defect Dog mandibular defect | An injectable chitosan-based thermosensitive hydrogel scaffold (CS/CSn-GP) enhanced new bone formation in rat calvarial defects and bony defect healing in beagle dogs. |
Zhu et al. 2017 [103] | Electrospun PLGA nanofibrous scaffold | Adenovirus | BMP-2 | Rat calvarial defect | A lyophilized PLGA nanofibrous scaffold efficiently released functional AdBMP-2 to transduce local cells, resulting in hBMP-2 secretion and promoting new bone formation in vivo. |
Kawai et al. 2017 [94] | Electroporation | Plasmid | BMP-2/7 | Rat periodontal tissue | The mineral apposition rate of the alveolar bone following BMP-2/7 gene transfer was significantly higher than that in the control group. |
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Park, S.-Y.; Kim, K.-H.; Kim, S.; Lee, Y.-M.; Seol, Y.-J. BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry. Pharmaceutics 2019, 11, 393. https://doi.org/10.3390/pharmaceutics11080393
Park S-Y, Kim K-H, Kim S, Lee Y-M, Seol Y-J. BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry. Pharmaceutics. 2019; 11(8):393. https://doi.org/10.3390/pharmaceutics11080393
Chicago/Turabian StylePark, Shin-Young, Kyoung-Hwa Kim, Sungtae Kim, Yong-Moo Lee, and Yang-Jo Seol. 2019. "BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry" Pharmaceutics 11, no. 8: 393. https://doi.org/10.3390/pharmaceutics11080393
APA StylePark, S.-Y., Kim, K.-H., Kim, S., Lee, Y.-M., & Seol, Y.-J. (2019). BMP-2 Gene Delivery-Based Bone Regeneration in Dentistry. Pharmaceutics, 11(8), 393. https://doi.org/10.3390/pharmaceutics11080393