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BioMed Research International
Volume 2016, Article ID 2869572, 11 pages
http://dx.doi.org/10.1155/2016/2869572
Review Article

Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

1Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China
2Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China
3Beijing Key Laboratory for Genetic Research of Bone and Joint Disease, No. 1 Shuaifuyuan, Beijing 100730, China

Received 7 August 2016; Revised 16 October 2016; Accepted 24 October 2016

Academic Editor: Martín F. Desimone

Copyright © 2016 Bo Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Y. Liu, J. Lim, and S.-H. Teoh, “Review: development of clinically relevant scaffolds for vascularised bone tissue engineering,” Biotechnology Advances, vol. 31, no. 5, pp. 688–705, 2013. View at Publisher · View at Google Scholar · View at Scopus
  2. R. J. O'Keefe and J. Mao, “Bone tissue engineering and regeneration: from discovery to the clinic—an overview,” Tissue Engineering—Part B: Reviews, vol. 17, no. 6, pp. 389–392, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. C.-H. Lu, Y.-H. Chang, S.-Y. Lin, K.-C. Li, and Y.-C. Hu, “Recent progresses in gene delivery-based bone tissue engineering,” Biotechnology Advances, vol. 31, no. 8, pp. 1695–1306, 2013. View at Publisher · View at Google Scholar · View at Scopus
  4. A. J. Salgado, O. P. Coutinho, and R. L. Reis, “Bone tissue engineering: state of the art and future trends,” Macromolecular Bioscience, vol. 4, no. 8, pp. 743–765, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. U. Kneser, D. J. Schaefer, E. Polykandriotis, and R. E. Horch, “Tissue engineering of bone: the reconstructive surgeon's point of view,” Journal of Cellular and Molecular Medicine, vol. 10, no. 1, pp. 7–19, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. M. D. Kofron and C. T. Laurencin, “Bone tissue engineering by gene delivery,” Advanced Drug Delivery Reviews, vol. 58, no. 4, pp. 555–576, 2006. View at Publisher · View at Google Scholar · View at Scopus
  7. W. Zhang, X. Wang, S. Wang et al., “The use of injectable sonication-induced silk hydrogel for VEGF165 and BMP-2 delivery for elevation of the maxillary sinus floor,” Biomaterials, vol. 32, no. 35, pp. 9415–9424, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. J. R. Lieberman, A. Daluiski, and T. A. Einhorn, “The role of growth factors in the repair of bone. Biology and clinical applications,” Journal of Bone and Joint Surgery—Series A, vol. 84, no. 6, pp. 1032–1044, 2002. View at Google Scholar · View at Scopus
  9. J. R. Lieberman, A. Daluiski, S. Stevenson et al., “The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats,” Journal of Bone and Joint Surgery—Series A, vol. 81, no. 7, pp. 905–917, 1999. View at Google Scholar · View at Scopus
  10. M. R. Urist, “Bone: formation by autoinduction,” Science, vol. 150, no. 3698, pp. 893–899, 1965. View at Publisher · View at Google Scholar · View at Scopus
  11. M. R. Urist and B. S. Strates, “Bone morphogenetic protein,” Journal of Dental Research, vol. 50, no. 6, pp. 1392–1406, 1971. View at Publisher · View at Google Scholar · View at Scopus
  12. P. C. Bessa, M. Casal, and R. L. Reis, “Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts),” Journal of Tissue Engineering and Regenerative Medicine, vol. 2, no. 1, pp. 1–13, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. R. E. Geuze, L. F. H. Theyse, D. H. R. Kempen et al., “A differential effect of bone morphogenetic protein-2 and vascular endothelial growth factor release timing on osteogenesis at ectopic and orthotopic sites in a large-animal model,” Tissue Engineering - Part A, vol. 18, no. 19-20, pp. 2052–2062, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. P. C. Bessa, M. Casal, and R. L. Reis, “Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery),” Journal of Tissue Engineering and Regenerative Medicine, vol. 2, no. 2-3, pp. 81–96, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. Q. Cui, A. S. Dighe, and J. N. Irvine Jr., “Combined angiogenic and osteogenic factor delivery for bone regenerative engineering,” Current Pharmaceutical Design, vol. 19, no. 19, pp. 3374–3383, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. A. Mesfin, J. M. Buchowski, L. P. Zebala et al., “High-dose rhBMP-2 for adults: major and minor complications: a study of 502 spine cases,” Journal of Bone and Joint Surgery—Series A, vol. 95, no. 17, pp. 1546–1553, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. R. Fu, S. Selph, M. McDonagh et al., “Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis,” Annals of Internal Medicine, vol. 158, no. 12, pp. 890–902, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. D. Gothard, E. L. Smith, J. M. Kanczler et al., “Tissue engineered bone using select growth factors: a comprehensive review of animal studies and clinical translation studies in man,” European Cells and Materials, vol. 28, pp. 166–207, 2014. View at Google Scholar · View at Scopus
  19. H. Peng, V. Wright, A. Usas et al., “Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4,” Journal of Clinical Investigation, vol. 110, no. 6, pp. 751–759, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. H. Peng, A. Usas, A. Olshanski et al., “VEGF improves, whereas sFlt1 inhibits, BMP2-induced bone formation and bone healing through modulation of angiogenesis,” Journal of Bone and Mineral Research, vol. 20, no. 11, pp. 2017–2027, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Samee, S. Kasugai, H. Kondo, K. Ohya, H. Shimokawa, and S. Kuroda, “Bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) transfection to human periosteal cells enhances osteoblast differentiation and bone formation,” Journal of Pharmacological Sciences, vol. 108, no. 1, pp. 18–31, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. G. Li, K. Corsi-Payne, B. Zheng, A. Usas, H. Peng, and J. Huard, “The dose of growth factors influences the synergistic effect of vascular endothelial growth factor on bone morphogenetic protein 4-induced ectopic bone formation,” Tissue Engineering—Part A, vol. 15, no. 8, pp. 2123–2133, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. F. Cui, X. Wang, X. Liu, A. S. Dighe, G. Balian, and Q. Cui, “VEGF and BMP-6 enhance bone formation mediated by cloned mouse osteoprogenitor cells,” Growth Factors, vol. 28, no. 5, pp. 306–317, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Xiao, H. Zhou, G. Liu et al., “Bone marrow stromal cells with a combined expression of BMP-2 and VEGF-165 enhanced bone regeneration,” Biomedical Materials, vol. 6, no. 1, Article ID 015013, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Lovett, K. Lee, A. Edwards, and D. L. Kaplan, “Vascularization strategies for tissue engineering,” Tissue Engineering - Part B: Reviews, vol. 15, no. 3, pp. 353–370, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. R. K. Jain, P. Au, J. Tam, D. G. Duda, and D. Fukumura, “Engineering vascularized tissue,” Nature Biotechnology, vol. 23, no. 7, pp. 821–823, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. C. Fidkowski, M. R. Kaazempur-Mofrad, J. Borenstein, J. P. Vacanti, R. Langer, and Y. Wang, “Endothelialized microvasculature based on a biodegradable elastomer,” Tissue Engineering, vol. 11, no. 1-2, pp. 302–309, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. U. Saran, S. Gemini Piperni, and S. Chatterjee, “Role of angiogenesis in bone repair,” Archives of Biochemistry and Biophysics, vol. 561, pp. 109–117, 2014. View at Publisher · View at Google Scholar · View at Scopus
  29. H.-P. Gerber, T. H. Vu, A. M. Ryan, J. Kowalski, Z. Werb, and N. Ferrara, “VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation,” Nature Medicine, vol. 5, no. 6, pp. 623–628, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Mori, H. Yoshikawa, J. Hashimoto et al., “Antiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2,” Bone, vol. 22, no. 2, pp. 99–105, 1998. View at Publisher · View at Google Scholar · View at Scopus
  31. M. R. Hausman, M. B. Schaffler, and R. J. Majeska, “Prevention of fracture healing in rats by an inhibitor of angiogenesis,” Bone, vol. 29, no. 6, pp. 560–564, 2001. View at Publisher · View at Google Scholar · View at Scopus
  32. D. Kaigler, Z. Wang, K. Horger, D. J. Mooney, and P. H. Krebsbach, “VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects,” Journal of Bone and Mineral Research, vol. 21, no. 5, pp. 735–744, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. A. H. Zisch, M. P. Lutolf, and J. A. Hubbell, “Biopolymeric delivery matrices for angiogenic growth factors,” Cardiovascular Pathology, vol. 12, no. 6, pp. 295–310, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. A. H. Zisch, M. P. Lutolf, M. Ehrbar et al., “Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth,” FASEB Journal, vol. 17, no. 15, pp. 2260–2262, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. S. M. Bauer, R. J. Bauer, Z.-J. Liu, H. Chen, L. Goldstein, and O. C. Velazquez, “Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis, and collagen constriction in three-dimensional collagen gels,” Journal of Vascular Surgery, vol. 41, no. 4, pp. 699–707, 2005. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Andrae, R. Gallini, and C. Betsholtz, “Role of platelet-derived growth factors in physiology and medicine,” Genes and Development, vol. 22, no. 10, pp. 1276–1312, 2008. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Perets, Y. Baruch, F. Weisbuch, G. Shoshany, G. Neufeld, and S. Cohen, “Enhancing the vascularization of three-dimensional porous alginate scaffolds by incorporating controlled release basic fibroblast growth factor microspheres,” Journal of Biomedical Materials Research—Part A, vol. 65, no. 4, pp. 489–497, 2003. View at Google Scholar · View at Scopus
  38. Y.-H. Kim and Y. Tabata, “Dual-controlled release system of drugs for bone regeneration,” Advanced Drug Delivery Reviews, vol. 94, pp. 28–40, 2015. View at Publisher · View at Google Scholar · View at Scopus
  39. J. M. Kanczler and R. O. C. Oreffo, “Osteogenesis and angiogenesis: the potential for engineering bone,” European Cells and Materials, vol. 15, pp. 100–114, 2008. View at Google Scholar · View at Scopus
  40. R. Subbiah, M. P. Hwang, S. Y. Van et al., “Osteogenic/angiogenic dual growth factor delivery microcapsules for regeneration of vascularized bone tissue,” Advanced Healthcare Materials, vol. 4, no. 13, pp. 1982–1992, 2015. View at Publisher · View at Google Scholar · View at Scopus
  41. N. Kakudo, K. Kusumoto, Y. B. Wang, Y. Iguchi, and Y. Ogawa, “Immunolocalization of vascular endothelial growth factor on intramuscular ectopic osteoinduction by bone morphogenetic protein-2,” Life Sciences, vol. 79, no. 19, pp. 1847–1855, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. Z. S. Patel, S. Young, Y. Tabata, J. A. Jansen, M. E. K. Wong, and A. G. Mikos, “Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model,” Bone, vol. 43, no. 5, pp. 931–940, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. D. H. R. Kempen, L. Lu, A. Heijink et al., “Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration,” Biomaterials, vol. 30, no. 14, pp. 2816–2825, 2009. View at Publisher · View at Google Scholar · View at Scopus
  44. S. Young, Z. S. Patel, J. D. Kretlow et al., “Dose effect of dual delivery of vascular endothelial growth factor and bone morphogenetic protein-2 on bone regeneration in a rat critical-size defect model,” Tissue Engineering—Part A, vol. 15, no. 9, pp. 2347–2362, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. J. C. Roldán, R. Detsch, S. Schaefer et al., “Bone formation and degradation of a highly porous biphasic calcium phosphate ceramic in presence of BMP-7, VEGF and mesenchymal stem cells in an ectopic mouse model,” Journal of Cranio-Maxillofacial Surgery, vol. 38, no. 6, pp. 423–430, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Hernández, R. Reyes, E. Sánchez, M. Rodríguez-Évora, A. Delgado, and C. Évora, “In vivo osteogenic response to different ratios of BMP-2 and VEGF released from a biodegradable porous system,” Journal of Biomedical Materials Research Part A, vol. 100, no. 9, pp. 2382–2391, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. A. Das, B. A. Fishero, J. J. Christophel et al., “Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair,” Cell and Tissue Research, 2015. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Lv, P. Xiu, J. Tan, Z. Jia, H. Cai, and Z. Liu, “Enhanced angiogenesis and osteogenesis in critical bone defects by the controlled release of BMP-2 and VEGF: implantation of electron beam melting-fabricated porous Ti6Al4V scaffolds incorporating growth factor-doped fibrin glue,” Biomedical Materials (Bristol), vol. 10, no. 3, Article ID 035013, 2015. View at Publisher · View at Google Scholar · View at Scopus
  49. G. Neufeld, T. Cohen, S. Gengrinovitch, and Z. Poltorak, “Vascular endothelial growth factor (VEGF) and its receptors,” The FASEB Journal, vol. 13, no. 1, pp. 9–22, 1999. View at Google Scholar · View at Scopus
  50. Y. Zhang, V. Madhu, A. S. Dighe, J. N. Irvine Jr., and Q. Cui, “Osteogenic response of human adipose-derived stem cells to BMP-6, VEGF, and combined VEGF plus BMP-6 in vitro,” Growth Factors, vol. 30, no. 5, pp. 333–343, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. V. Madhu, C.-J. Li, A. S. Dighe, G. Balian, and Q. Cui, “BMP-non-responsive Sca1+CD73+CD44+ mouse bone marrow derived osteoprogenitor cells respond to combination of VEGF and BMP-6 to display enhanced osteoblastic differentiation and ectopic bone formation,” PLoS ONE, vol. 9, no. 7, Article ID e103060, 2014. View at Publisher · View at Google Scholar · View at Scopus
  52. Q. Kang, M. H. Sun, H. Cheng et al., “Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery,” Gene Therapy, vol. 11, no. 17, pp. 1312–1320, 2004. View at Publisher · View at Google Scholar · View at Scopus
  53. M. P. G. Bostrom, J. M. Lane, W. S. Berberian et al., “Immunolocalization and expression of bone morphogenetic proteins 2 and 4 in fracture healing,” Journal of Orthopaedic Research, vol. 13, no. 3, pp. 357–367, 1995. View at Publisher · View at Google Scholar · View at Scopus
  54. G. Wei, Q. Jin, W. V. Giannobile, and P. X. Ma, “The enhancement of osteogenesis by nano-fibrous scaffolds incorporating rhBMP-7 nanospheres,” Biomaterials, vol. 28, no. 12, pp. 2087–2096, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. M. T. Wolf, C. L. Dearth, S. B. Sonnenberg, E. G. Loboa, and S. F. Badylak, “Naturally derived and synthetic scaffolds for skeletal muscle reconstruction,” Advanced Drug Delivery Reviews, vol. 84, pp. 208–221, 2015. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Almubarak, H. Nethercott, M. Freeberg et al., “Tissue engineering strategies for promoting vascularized bone regeneration,” Bone, vol. 83, pp. 197–209, 2016. View at Publisher · View at Google Scholar
  57. A. C. Mitchell, P. S. Briquez, J. A. Hubbell, and J. R. Cochran, “Engineering growth factors for regenerative medicine applications,” Acta Biomaterialia, vol. 30, pp. 1–12, 2016. View at Publisher · View at Google Scholar · View at Scopus
  58. E. Pola, W. Gao, Y. Zhou et al., “Efficient bone formation by gene transfer of human LIM mineralization protein-3,” Gene Therapy, vol. 11, no. 8, pp. 683–693, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Yang, D. Wei, D. Wang, M. Phimphilai, P. H. Krebsbach, and R. T. Franceschi, “In vitro and in vivo synergistic interactions between the Runx2/Cbfa1 transcription factor and bone morphogenetic protein-2 in stimulating osteoblast differentiation,” Journal of Bone and Mineral Research, vol. 18, no. 4, pp. 705–715, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. B. Peterson, J. Zhang, R. Iglesias et al., “Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue,” Tissue Engineering, vol. 11, no. 1-2, pp. 120–129, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. H.-C. Shen, H. Peng, A. Usas, B. Gearhart, F. H. Fu, and J. Huard, “Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4,” Journal of Gene Medicine, vol. 6, no. 9, pp. 984–991, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. M. Yang, Q.-J. Ma, G. T. Dang, K. T. Ma, P. Chen, and C.-Y. Zhou, “In vitro and in vivo induction of bone formation based on ex vivo gene therapy using rat adipose-derived adult stem cells expressing BMP-7,” Cytotherapy, vol. 7, no. 3, pp. 273–281, 2005. View at Publisher · View at Google Scholar · View at Scopus
  63. H.-L. Lee, H. Y. Lee, Y. Yun et al., “Hypoxia-specific, VEGF-expressing neural stem cell therapy for safe and effective treatment of neuropathic pain,” Journal of Controlled Release, vol. 226, pp. 21–34, 2016. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Su, H. Xu, J. Sun, X. Gong, and H. Zhao, “Dual delivery of BMP-2 and bFGF from a new nano-composite scaffold, loaded with vascular stents for large-size mandibular defect regeneration,” International Journal of Molecular Sciences, vol. 14, no. 6, pp. 12714–12728, 2013. View at Publisher · View at Google Scholar · View at Scopus
  65. L. Lei, S. Wang, H. Wu et al., “Optimization of release pattern of FGF-2 and BMP-2 for osteogenic differentiation of low-population density hMSCs,” Journal of Biomedical Materials Research—Part A, vol. 103, no. 1, pp. 252–261, 2015. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Facca, C. Cortez, C. Mendoza-Palomares et al., “Active multilayered capsules for in vivo bone formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 8, pp. 3406–3411, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. B. De la Riva, E. Sánchez, A. Hernández et al., “Local controlled release of VEGF and PDGF from a combined brushite-chitosan system enhances bone regeneration,” Journal of Controlled Release, vol. 143, no. 1, pp. 45–52, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. B. S. Kim, J. S. Kim, S. S. Yang, H. W. Kim, H. J. Lim, and J. Lee, “Angiogenin-loaded fibrin/bone powder composite scaffold for vascularized bone regeneration,” Biomaterials Research, vol. 19, article 18, 2015. View at Google Scholar
  69. Y. Gao, S. Zhu, E. Luo, J. Li, G. Feng, and J. Hu, “Basic fibroblast growth factor suspended in Matrigel improves titanium implant fixation in ovariectomized rats,” Journal of Controlled Release, vol. 139, no. 1, pp. 15–21, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. Y. J. Jung, K. Kim, J. Heo et al., “Induction of angiogenesis by matrigel coating of VEGF-loaded PEG/PCL-based hydrogel scaffolds for hbmsc transplantation,” Molecules and Cells, vol. 38, no. 7, pp. 663–668, 2015. View at Publisher · View at Google Scholar
  71. C. H. Evans and J. Huard, “Gene therapy approaches to regenerating the musculoskeletal system,” Nature Reviews Rheumatology, vol. 11, no. 4, pp. 234–242, 2015. View at Publisher · View at Google Scholar · View at Scopus
  72. J. T. Sieker, M. Kunz, M. Weißenberger et al., “Direct bone morphogenetic protein 2 and Indian hedgehog gene transfer for articular cartilage repair using bone marrow coagulates,” Osteoarthritis and Cartilage, vol. 23, no. 3, pp. 433–442, 2015. View at Publisher · View at Google Scholar · View at Scopus
  73. V. J. Wright, H. Peng, A. Usas et al., “BMP4-expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice,” Molecular Therapy, vol. 6, no. 2, pp. 169–178, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. L. Zhu, D. Chuanchang, L. Wei, C. Yilin, and D. Jiasheng, “Enhanced healing of goat femur-defect using BMP7 gene-modified BMSCs and load-bearing tissue-engineered bone,” Journal of Orthopaedic Research, vol. 28, no. 3, pp. 412–418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Li, D. J. Stewart, H. P. Von Schroeder, E. S. Mackinnon, and E. H. Schemitsch, “Effect of cell-based VEGF gene therapy on healing of a segmental bone defect,” Journal of Orthopaedic Research, vol. 27, no. 1, pp. 8–14, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. C. Hélary and M. F. Desimone, “Recent advances in biomaterials for tissue engineering and controlled drug delivery,” Current Pharmaceutical Biotechnology, vol. 16, no. 7, pp. 635–645, 2015. View at Publisher · View at Google Scholar · View at Scopus
  77. T. Kaito, A. Myoui, K. Takaoka et al., “Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration by a PLA-PEG/hydroxyapatite composite,” Biomaterials, vol. 26, no. 1, pp. 73–79, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. Y. Yonamine, T. Matsuyama, T. Sonomura et al., “Effectable application of vascular endothelial growth factor to critical sized rat calvaria defects,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 109, no. 2, pp. 225–231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. Y.-C. Huang, D. Kaigler, K. G. Rice, P. H. Krebsbach, and D. J. Mooney, “Combined angiogenic and osteogenic factor delivery enhances bone marrow stromal cell-driven bone regeneration,” Journal of Bone and Mineral Research, vol. 20, no. 5, pp. 848–857, 2005. View at Publisher · View at Google Scholar · View at Scopus
  80. T. Luo, W. Zhang, B. Shi, X. Cheng, and Y. Zhang, “Enhanced bone regeneration around dental implant with bone morphogenetic protein 2 gene and vascular endothelial growth factor protein delivery,” Clinical Oral Implants Research, vol. 23, no. 4, pp. 467–473, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. M. Ramazanoglu, R. Lutz, C. Ergun, C. von Wilmowsky, E. Nkenke, and K. A. Schlegel, “The effect of combined delivery of recombinant human bone morphogenetic protein-2 and recombinant human vascular endothelial growth factor 165 from biomimetic calcium-phosphate-coated implants on osseointegration,” Clinical Oral Implants Research, vol. 22, no. 12, pp. 1433–1439, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. C. Schmitt, R. Lutz, H. Doering, M. Lell, J. Ratky, and K. A. Schlegel, “Bio-Oss® blocks combined with BMP-2 and VEGF for the regeneration of bony defects and vertical augmentation,” Clinical Oral Implants Research, vol. 24, no. 4, pp. 450–460, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. N. Lohse, N. Moser, S. Backhaus, T. Annen, M. Epple, and H. Schliephake, “Continuous delivery of rhBMP2 and rhVEGF165 at a certain ratio enhances bone formation in mandibular defects over the delivery of rhBMP2 alone—An experimental study in rats,” Journal of Controlled Release, vol. 220, pp. 201–209, 2015. View at Publisher · View at Google Scholar · View at Scopus
  84. H. Wang, G. Wu, J. Zhang et al., “Osteogenic effect of controlled released rhBMP-2 in 3D printed porous hydroxyapatite scaffold,” Colloids and Surfaces B: Biointerfaces, vol. 141, pp. 491–498, 2016. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Ueda, L. Hong, M. Yamamoto et al., “Use of collagen sponge incorporating transforming growth factor-β1 to promote bone repair in skull defects in rabbits,” Biomaterials, vol. 23, no. 4, pp. 1003–1010, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. Y. Tabata, K. Yamada, S. Miyamoto et al., “Bone regeneration by basic fibroblast growth factor complexed with biodegradable hydrogels,” Biomaterials, vol. 19, no. 7-9, pp. 807–815, 1998. View at Publisher · View at Google Scholar · View at Scopus
  87. F. M. Phillips, A. S. Turner, H. B. Seim III et al., “In vivo BMP-7 (OP-1) enhancement of osteoporotic vertebral bodies in an ovine model,” Spine Journal, vol. 6, no. 5, pp. 500–506, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. K. Sojo, Y. Sawaki, H. Hattori, H. Mizutani, and M. Ueda, “Immunohistochemical study of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2, -4 (BMP-2, -4) on lengthened rat femurs,” Journal of Cranio-Maxillofacial Surgery, vol. 33, no. 4, pp. 238–245, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Uchida, A. Sakai, H. Kudo et al., “Vascular endothelial growth factor is expressed along with its receptors during the healing process of bone and bone marrow after drill-hole injury in rats,” Bone, vol. 32, no. 5, pp. 491–501, 2003. View at Publisher · View at Google Scholar · View at Scopus
  90. T. Pufe, B. Wildemann, W. Petersen, R. Mentlein, M. Raschke, and G. Schmidmaier, “Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat,” Cell and Tissue Research, vol. 309, no. 3, pp. 387–392, 2002. View at Publisher · View at Google Scholar · View at Scopus
  91. T.-J. Cho, L. C. Gerstenfeld, and T. A. Einhorn, “Differential temporal expression of members of the transforming growth factor β superfamily during murine fracture healing,” Journal of Bone and Mineral Research, vol. 17, no. 3, pp. 513–520, 2002. View at Publisher · View at Google Scholar · View at Scopus
  92. T. Niikura, D. J. Hak, and A. Hari Reddi, “Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures,” Journal of Orthopaedic Research, vol. 24, no. 7, pp. 1463–1471, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. H. M. Blau and A. Banfi, “The well-tempered vessel,” Nature Medicine, vol. 7, no. 5, pp. 532–534, 2001. View at Publisher · View at Google Scholar · View at Scopus
  94. P. Carmeliet and R. K. Jain, “Angiogenesis in cancer and other diseases,” Nature, vol. 407, no. 6801, pp. 249–257, 2000. View at Publisher · View at Google Scholar · View at Scopus
  95. T. P. Richardson, M. C. Peters, A. B. Ennett, and D. J. Mooney, “Polymeric system for dual growth factor delivery,” Nature Biotechnology, vol. 19, no. 11, pp. 1029–1034, 2001. View at Publisher · View at Google Scholar · View at Scopus
  96. L. E. Benjamin, D. Golijanin, A. Itin, D. Pode, and E. Keshet, “Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal,” The Journal of Clinical Investigation, vol. 103, no. 2, pp. 159–165, 1999. View at Publisher · View at Google Scholar · View at Scopus
  97. J. E. Samorezov, E. B. Headley, C. R. Everett, and E. Alsberg, “Sustained presentation of BMP-2 enhances osteogenic differentiation of human adipose-derived stem cells in gelatin hydrogels,” Journal of Biomedical Materials Research—Part A, vol. 104, no. 6, pp. 1387–1397, 2016. View at Publisher · View at Google Scholar · View at Scopus
  98. K. Park, “Biodegradable thermosensitive polymer gel for sustained BMP-2 delivery,” Journal of Controlled Release, vol. 209, p. 337, 2015. View at Publisher · View at Google Scholar · View at Scopus
  99. B.-B. Seo, H. Choi, J.-T. Koh, and S.-C. Song, “Sustained BMP-2 delivery and injectable bone regeneration using thermosensitive polymeric nanoparticle hydrogel bearing dual interactions with BMP-2,” Journal of Controlled Release, vol. 209, pp. 67–76, 2015. View at Publisher · View at Google Scholar · View at Scopus
  100. M. Faßbender, S. Minkwitz, C. Strobel, G. Schmidmaier, and B. Wildemann, “Stimulation of bone healing by sustained bone morphogenetic protein 2 (BMP-2) delivery,” International Journal of Molecular Sciences, vol. 15, no. 5, pp. 8539–8552, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. M. T. Poldervaart, H. Wang, J. Van Der Stok et al., “Sustained release of BMP-2 in bioprinted alginate for osteogenicity in mice and rats,” PLoS ONE, vol. 8, no. 8, Article ID e72610, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. M. L. Springer, A. S. Chen, P. E. Kraft, M. Bednarski, and H. M. Blau, “VEGF gene delivery to muscle: potential role for vasculogenesis in adults,” Molecular Cell, vol. 2, no. 5, pp. 549–558, 1998. View at Publisher · View at Google Scholar · View at Scopus
  103. R. J. Lee, M. L. Springer, W. E. Blanco-Bose, R. Shaw, P. C. Ursell, and H. M. Blau, “VEGF gene delivery to myocardium: deleterious effects of unregulated expression,” Circulation, vol. 102, no. 8, pp. 898–901, 2000. View at Publisher · View at Google Scholar · View at Scopus
  104. M. T. Engsig, Q.-J. Chen, T. H. Vu et al., “Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones,” Journal of Cell Biology, vol. 151, no. 4, pp. 879–889, 2000. View at Publisher · View at Google Scholar · View at Scopus
  105. Q. Yang, K. P. McHugh, S. Patntirapong, X. Gu, L. Wunderlich, and P. V. Hauschka, “VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and β3-integrin,” Matrix Biology, vol. 27, no. 7, pp. 589–599, 2008. View at Publisher · View at Google Scholar · View at Scopus
  106. K. Henriksen, M. Karsdal, J.-M. Delaissé, and M. T. Engsig, “RANKL and vascular endothelial growth factor (VEGF) induce osteoclast chemotaxis through an ERK1/2-dependent mechanism,” The Journal of Biological Chemistry, vol. 278, no. 49, pp. 48745–48753, 2003. View at Publisher · View at Google Scholar · View at Scopus
  107. A. Weltermann, M. Wolzt, K. Petersmann et al., “Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 19, no. 7, pp. 1757–1760, 1999. View at Publisher · View at Google Scholar · View at Scopus
  108. G. Pintucci, S. Froum, J. Pinnell, P. Mignatti, S. Rafii, and D. Green, “Trophic effects of platelets on cultured endothelial cells are mediated by platelet-associated fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF),” Thrombosis and Haemostasis, vol. 88, no. 5, pp. 834–842, 2002. View at Google Scholar · View at Scopus
  109. E. Anitua, I. Andia, B. Ardanza, P. Nurden, and A. T. Nurden, “Autologous platelets as a source of proteins for healing and tissue regeneration,” Thrombosis and Haemostasis, vol. 91, no. 1, pp. 4–15, 2004. View at Google Scholar · View at Scopus