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PDGF-B gene therapy accelerates bone engineering and oral implant osseointegration.

Chang PC, Seol YJ, Cirelli JA, Pellegrini G, Jin Q, Franco LM, Goldstein SA, Chandler LA, Sosnowski B, Giannobile WV - Gene Ther. (2009)

Bottom Line: Furthermore, a panel of local and systemic safety assessments was performed.No significant dissemination of the vector construct or alteration of systemic parameters was noted.In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.

ABSTRACT
Platelet-derived growth factor-BB (PDGF-BB) stimulates repair of healing-impaired chronic wounds such as diabetic ulcers and periodontal lesions. However, limitations in predictability of tissue regeneration occur due, in part, to transient growth factor bioavailability in vivo. Here, we report that gene delivery of PDGF-B stimulates repair of oral implant extraction socket defects. Alveolar ridge defects were created in rats and were treated at the time of titanium implant installation with a collagen matrix containing an adenoviral (Ad) vector encoding PDGF-B (5.5 x 10(8) or 5.5 x 10(9) pfu ml(-1)), Ad encoding luciferase (Ad-Luc; 5.5 x 10(9) pfu ml(-1); control) or recombinant human PDGF-BB protein (rhPDGF-BB, 0.3 mg ml(-1)). Bone repair and osseointegration were measured through backscattered scanning electron microscopy, histomorphometry, micro-computed tomography and biomechanical assessments. Furthermore, a panel of local and systemic safety assessments was performed. Results indicated that bone repair was accelerated by Ad-PDGF-B and rhPDGF-BB delivery compared with Ad-Luc, with the high dose of Ad-PDGF-B more effective than the low dose. No significant dissemination of the vector construct or alteration of systemic parameters was noted. In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

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Histologic view of each group for 10 days and 14 days (a) and 2-D evaluations; bone-to-implant contact (BIC) (b), defect fill (c)(a) Histologic images were overlapped by fluorescent images made by calcein injection 3 days after surgery. The fluorescence indicates the original defect boundaries. The results of Ad-Luc defects shows sparse bone formation at day 10 and a lesser degree of bone maturation at 10 and 14 days. All the PDGF-related specimens showed increased new bone formation at 10 and 14 days compared to Ad-Luc group. Scale bar in top right panel represents 200 μm. (Original magnification: ×40). (b) In BIC analysis, 5.5×109 pfu/ml Ad-PDGF-B and rhPDGF-BB groups showed significantly higher ratio than the control group at 10 days and 5.5×109 pfu/ml Ad-PDGF-B showed significantly higher ratio than control group at 14 days. (c) In defect fill analysis, all three PDGF treatment groups showed higher fractions than Ad-Luc treated defects at 10 and 14 days. Black area in left side: dental implant, black asterisks; matured new bone, red asterisks; young new bone, and dashed line; borders of the osseous defect. Data are presented as mean and bars indicate standard error measurement (n=6-8).* p<0.05, ** p<0.01, Abbreviations: BIC: bone to implant contact.
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Figure 2: Histologic view of each group for 10 days and 14 days (a) and 2-D evaluations; bone-to-implant contact (BIC) (b), defect fill (c)(a) Histologic images were overlapped by fluorescent images made by calcein injection 3 days after surgery. The fluorescence indicates the original defect boundaries. The results of Ad-Luc defects shows sparse bone formation at day 10 and a lesser degree of bone maturation at 10 and 14 days. All the PDGF-related specimens showed increased new bone formation at 10 and 14 days compared to Ad-Luc group. Scale bar in top right panel represents 200 μm. (Original magnification: ×40). (b) In BIC analysis, 5.5×109 pfu/ml Ad-PDGF-B and rhPDGF-BB groups showed significantly higher ratio than the control group at 10 days and 5.5×109 pfu/ml Ad-PDGF-B showed significantly higher ratio than control group at 14 days. (c) In defect fill analysis, all three PDGF treatment groups showed higher fractions than Ad-Luc treated defects at 10 and 14 days. Black area in left side: dental implant, black asterisks; matured new bone, red asterisks; young new bone, and dashed line; borders of the osseous defect. Data are presented as mean and bars indicate standard error measurement (n=6-8).* p<0.05, ** p<0.01, Abbreviations: BIC: bone to implant contact.

Mentions: Based on the descriptive histology (Fig 2a), by day 10 a gradual defect resolution was observed over time in all groups. At days 10 and 14, woven bone and primary trabecular bone were noted at the coronal margin (red asterisks) in Ad-Luc-treated specimens, and thicker bone trabeculae and defect fill were evident in all PDGF-treated specimens (black asterisks in 5.5×108 and 5.5×109 pfu/ml Ad-PDGF-B, and rhPDGF-BB). Also at day 14, more mature bone apposition and near-complete defect fill was noted for all PDGF-treated specimens (Fig 2a, lower panel). The histomorphometric measurements of the 5.5×109 pfu/ml Ad-PDGF-B and rhPDGF-BB groups showed significantly higher bone-implant contact (BIC) than the Ad-Luc group at day 10 (p<0.05, Fig. 2b). Further, all PDGF groups revealed higher defect fill (DF) than Ad-Luc at days 10 (p<0.01, Fig. 2c) and 14 (p<0.05, Fig. 2c). An equivalent defect repair pattern was noted from the backscattered SEM (BS-SEM) images (Fig. 3a). At day 10, BS-SEM measurements also demonstrated a significant difference among all PDGF-treated groups compared with the Ad-Luc-treated group in both bone-area fraction (BAF, p<0.05, Fig 3b) and tissue mineral density (TMD, p<0.05, Fig 3c). A significant difference between rhPDGF-BB and Ad-Luc in TMD was also noted at day 14 (p<0.05, Fig. 3c). Completion of the defect fill was noted in all the animals by day 21, and no significant differences for any BS-SEM or histomorphometric parameters could be found among all the groups (data not shown).


PDGF-B gene therapy accelerates bone engineering and oral implant osseointegration.

Chang PC, Seol YJ, Cirelli JA, Pellegrini G, Jin Q, Franco LM, Goldstein SA, Chandler LA, Sosnowski B, Giannobile WV - Gene Ther. (2009)

Histologic view of each group for 10 days and 14 days (a) and 2-D evaluations; bone-to-implant contact (BIC) (b), defect fill (c)(a) Histologic images were overlapped by fluorescent images made by calcein injection 3 days after surgery. The fluorescence indicates the original defect boundaries. The results of Ad-Luc defects shows sparse bone formation at day 10 and a lesser degree of bone maturation at 10 and 14 days. All the PDGF-related specimens showed increased new bone formation at 10 and 14 days compared to Ad-Luc group. Scale bar in top right panel represents 200 μm. (Original magnification: ×40). (b) In BIC analysis, 5.5×109 pfu/ml Ad-PDGF-B and rhPDGF-BB groups showed significantly higher ratio than the control group at 10 days and 5.5×109 pfu/ml Ad-PDGF-B showed significantly higher ratio than control group at 14 days. (c) In defect fill analysis, all three PDGF treatment groups showed higher fractions than Ad-Luc treated defects at 10 and 14 days. Black area in left side: dental implant, black asterisks; matured new bone, red asterisks; young new bone, and dashed line; borders of the osseous defect. Data are presented as mean and bars indicate standard error measurement (n=6-8).* p<0.05, ** p<0.01, Abbreviations: BIC: bone to implant contact.
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Figure 2: Histologic view of each group for 10 days and 14 days (a) and 2-D evaluations; bone-to-implant contact (BIC) (b), defect fill (c)(a) Histologic images were overlapped by fluorescent images made by calcein injection 3 days after surgery. The fluorescence indicates the original defect boundaries. The results of Ad-Luc defects shows sparse bone formation at day 10 and a lesser degree of bone maturation at 10 and 14 days. All the PDGF-related specimens showed increased new bone formation at 10 and 14 days compared to Ad-Luc group. Scale bar in top right panel represents 200 μm. (Original magnification: ×40). (b) In BIC analysis, 5.5×109 pfu/ml Ad-PDGF-B and rhPDGF-BB groups showed significantly higher ratio than the control group at 10 days and 5.5×109 pfu/ml Ad-PDGF-B showed significantly higher ratio than control group at 14 days. (c) In defect fill analysis, all three PDGF treatment groups showed higher fractions than Ad-Luc treated defects at 10 and 14 days. Black area in left side: dental implant, black asterisks; matured new bone, red asterisks; young new bone, and dashed line; borders of the osseous defect. Data are presented as mean and bars indicate standard error measurement (n=6-8).* p<0.05, ** p<0.01, Abbreviations: BIC: bone to implant contact.
Mentions: Based on the descriptive histology (Fig 2a), by day 10 a gradual defect resolution was observed over time in all groups. At days 10 and 14, woven bone and primary trabecular bone were noted at the coronal margin (red asterisks) in Ad-Luc-treated specimens, and thicker bone trabeculae and defect fill were evident in all PDGF-treated specimens (black asterisks in 5.5×108 and 5.5×109 pfu/ml Ad-PDGF-B, and rhPDGF-BB). Also at day 14, more mature bone apposition and near-complete defect fill was noted for all PDGF-treated specimens (Fig 2a, lower panel). The histomorphometric measurements of the 5.5×109 pfu/ml Ad-PDGF-B and rhPDGF-BB groups showed significantly higher bone-implant contact (BIC) than the Ad-Luc group at day 10 (p<0.05, Fig. 2b). Further, all PDGF groups revealed higher defect fill (DF) than Ad-Luc at days 10 (p<0.01, Fig. 2c) and 14 (p<0.05, Fig. 2c). An equivalent defect repair pattern was noted from the backscattered SEM (BS-SEM) images (Fig. 3a). At day 10, BS-SEM measurements also demonstrated a significant difference among all PDGF-treated groups compared with the Ad-Luc-treated group in both bone-area fraction (BAF, p<0.05, Fig 3b) and tissue mineral density (TMD, p<0.05, Fig 3c). A significant difference between rhPDGF-BB and Ad-Luc in TMD was also noted at day 14 (p<0.05, Fig. 3c). Completion of the defect fill was noted in all the animals by day 21, and no significant differences for any BS-SEM or histomorphometric parameters could be found among all the groups (data not shown).

Bottom Line: Furthermore, a panel of local and systemic safety assessments was performed.No significant dissemination of the vector construct or alteration of systemic parameters was noted.In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.

ABSTRACT
Platelet-derived growth factor-BB (PDGF-BB) stimulates repair of healing-impaired chronic wounds such as diabetic ulcers and periodontal lesions. However, limitations in predictability of tissue regeneration occur due, in part, to transient growth factor bioavailability in vivo. Here, we report that gene delivery of PDGF-B stimulates repair of oral implant extraction socket defects. Alveolar ridge defects were created in rats and were treated at the time of titanium implant installation with a collagen matrix containing an adenoviral (Ad) vector encoding PDGF-B (5.5 x 10(8) or 5.5 x 10(9) pfu ml(-1)), Ad encoding luciferase (Ad-Luc; 5.5 x 10(9) pfu ml(-1); control) or recombinant human PDGF-BB protein (rhPDGF-BB, 0.3 mg ml(-1)). Bone repair and osseointegration were measured through backscattered scanning electron microscopy, histomorphometry, micro-computed tomography and biomechanical assessments. Furthermore, a panel of local and systemic safety assessments was performed. Results indicated that bone repair was accelerated by Ad-PDGF-B and rhPDGF-BB delivery compared with Ad-Luc, with the high dose of Ad-PDGF-B more effective than the low dose. No significant dissemination of the vector construct or alteration of systemic parameters was noted. In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

Show MeSH
Related in: MedlinePlus