Synthetic scaffold coating with adeno-associated virus encoding BMP2 to promote endogenous bone repair |
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Authors: | Kenneth M Dupont Joel D Boerckel Hazel Y Stevens Tamim Diab Yash M Kolambkar Masahiko Takahata Edward M Schwarz Robert E Guldberg |
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Institution: | (1) Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA;(2) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA;(3) Exponent Failure Analysis Associates, 3401 Market Street, Suite 300, Philadelphia, PA 19104, USA;(4) Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA;(5) Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA |
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Abstract: | Biomaterial scaffolds functionalized to stimulate endogenous repair mechanisms via the incorporation of osteogenic cues offer
a potential alternative to bone grafting for the treatment of large bone defects. We first quantified the ability of a self-complementary
adeno-associated viral vector encoding bone morphogenetic protein 2 (scAAV2.5-BMP2) to enhance human stem cell osteogenic
differentiation in vitro. In two-dimensional culture, scAAV2.5-BMP2-transduced human mesenchymal stem cells (hMSCs) displayed
significant increases in BMP2 production and alkaline phosphatase activity compared with controls. hMSCs and human amniotic-fluid-derived
stem cells (hAFS cells) seeded on scAAV2.5-BMP2-coated three-dimensional porous polymer Poly(ε-caprolactone) (PCL) scaffolds
also displayed significant increases in BMP2 production compared with controls during 12 weeks of culture, although only hMSC-seeded
scaffolds displayed significantly increased mineral formation. PCL scaffolds coated with scAAV2.5-BMP2 were implanted into
critically sized immunocompromised rat femoral defects, both with or without pre-seeding of hMSCs, representing ex vivo and
in vivo gene therapy treatments, respectively. After 12 weeks, defects treated with acellular scAAV2.5-BMP2-coated scaffolds
displayed increased bony bridging and had significantly higher bone ingrowth and mechanical properties compared with controls,
whereas defects treated with scAAV2.5-BMP2 scaffolds pre-seeded with hMSCs failed to display significant differences relative
to controls. When pooled, defect treatment with scAAV2.5-BMP2-coated scaffolds, both with or without inclusion of pre-seeded
hMSCs, led to significant increases in defect mineral formation at all time points and increased mechanical properties compared
with controls. This study thus presents a novel acellular bone-graft-free endogenous repair therapy for orthotopic tissue-engineered
bone regeneration. |
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