Annals of Biomedical Engineering

, Volume 38, Issue 3, pp 632–639 | Cite as

BMP-2/PLGA Delayed-Release Microspheres Composite Graft, Selection of Bone Particulate Diameters, and Prevention of Aseptic Inflammation for Bone Tissue Engineering

  • Ye Ji
  • Gong ping Xu
  • Zhi peng Zhang
  • Jing jun Xia
  • Jing long Yan
  • Shang ha Pan
Article

Abstract

Autogenous bone grafts are widely used in the repair of bone defects. Growth factors such as bone morphogenetic protein 2 (BMP-2) can induce bone regeneration and enhance bone growth. The combination of an autogenous bone graft and BMP-2 may provide a better osteogenic effect than either treatment alone, but BMP-2 is easily inactivated in body fluid. The objective of this study was to develop a technique that can better preserve the in vivo activity of BMP-2 incorporated in bone grafts. In this study, we first prepared BMP-2/poly(lactic-co-glycolic acid) (PLGA) delayed-release microspheres, and then combined collagen, the delayed-release microspheres, and rat autologous bone particulates to form four groups of composite grafts with different combinations: collagen in group A; collagen combined with bone particulates in group B; collagen combined with BMP-2/PLGA delayed-release microspheres in group C; and collagen combined with both bone particulates and BMP-2/PLGA delayed-release microspheres in group D. The four groups of composite grafts were implanted into the gluteus maximus pockets in rats. The ectopic osteogenesis and ALP level in group D (experimental group) were compared with those in groups A, B, and C (control groups) to study whether it had higher osteogenic capability. Results showed that the composite graft design increased the utility of BMP-2 and reduced the required dose of BMP-2 and volume of autologous bone. The selection of bone particulate diameter had an impact on the osteogenetic potential of bone grafts. Collagen prevented the occurrence of aseptic inflammation and improved the osteoinductivity of BMP-2. These results showed that this composite graft design is effective and feasible for use in bone repair.

Keywords

Growth factor Delayed-release microsphere Bone particulate Bone particulate diameter Aseptic inflammation Bone tissue engineering 

References

  1. 1.
    Agrawal, C. M., and K. A. Athanasiou. Technique to control pH in vicinity of biodegrading PLA-PGA implants. J. Biomed. Mater. Res. 38:105–114, 1997.CrossRefPubMedGoogle Scholar
  2. 2.
    Baas, J., B. Elmengaard, T. B. Jensen, T. Jakobsen, N. T. Andersen, and K. Soballe. The effect of pretreating morselized allograft bone with rhBMP-2 and/or pamidronate on the fixation of porous Ti and HA-coated implants. Biomaterials 29:2915–2922, 2008.CrossRefPubMedGoogle Scholar
  3. 3.
    Bullens, P. H., H. W. Bart Schreuder, M. C. de Waal Malefijt, N. Verdonschot, and P. Buma. Is an impacted morselized graft in a cage an alternative for reconstructing segmental diaphyseal defects? Clin. Orthop. Relat. Res. 467:783–791, 2009.CrossRefPubMedGoogle Scholar
  4. 4.
    Cao, X., and M. S. Schoichet. Delivering neuroactive molecules from biodegradable microspheres for application in central nervous system disorders. Biomaterials 20:329–339, 1999.CrossRefPubMedGoogle Scholar
  5. 5.
    Cook, R. O., R. K. Pannu, and I. W. Kellaway. Novel sustained release microspheres for pulmonary drug delivery. J. Control Release 104:79–90, 2005.CrossRefPubMedGoogle Scholar
  6. 6.
    Isobe, M., Y. Yamazaki, M. Mori, K. Ishihara, N. Nakabayashi, and T. Amagasa. The role of recombinant human bone morphogenetic protein-2 in PLGA capsules at an extraskeletal site of the rat. J. Biomed. Mater. Res. 45:36–41, 1999.CrossRefPubMedGoogle Scholar
  7. 7.
    Iwasaki, Y., S. Sawada, K. Ishihara, G. Khang, and H. B. Lee. Reduction of surface-induced inflammatory reaction on PLGA/MPC polymer blend. Biomaterials 23:3897–3903, 2002.CrossRefPubMedGoogle Scholar
  8. 8.
    Judas, F., M. H. Figueiredo, A. M. Cabrita, and A. Proenca. Incorporation of impacted morselized bone allografts in rabbits. Transplant. Proc. 37:2802–2804, 2005.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim, M. S., H. H. Ahn, Y. N. Shin, M. H. Cho, G. Khang, and H. B. Lee. An in vivo study of the host tissue response to subcutaneous implantation of PLGA- and/or porcine small intestinal submucosa-based scaffolds. Biomaterials 28:5137–5143, 2007.CrossRefPubMedGoogle Scholar
  10. 10.
    Kim, S. E., J. H. Park, Y. W. Cho, H. Chung, S. Y. Jeong, E. B. Lee, and I. C. Kwon. Porous chitosan scaffold containing microspheres loaded with transforming growth factor-beta1: implications for cartilage tissue engineering. J. Control Release 91:365–374, 2003.CrossRefPubMedGoogle Scholar
  11. 11.
    King, T. W., and C. W. Patrick, Jr. Development and in vitro characterization of vascular endothelial growth factor (VEGF)-loaded poly(DL-lactic-co-glycolic acid)/poly(ethylene glycol) microspheres using a solid encapsulation/single emulsion/solvent extraction technique. J. Biomed. Mater. Res. 51:383–390, 2000.CrossRefPubMedGoogle Scholar
  12. 12.
    Kligman, M., D. E. Padgett, R. Vered, and M. Roffman. Cortical and cancellous morselized allograft in acetabular revision total hip replacement: minimum 5-year follow-up. J. Arthroplasty 18:907–913, 2003.CrossRefPubMedGoogle Scholar
  13. 13.
    Kligman, M., A. Rotem, and M. Roffman. Cancellous and cortical morselized allograft in revision total hip replacement: a biomechanical study of implant stability. J. Biomech. 36:797–802, 2003.CrossRefPubMedGoogle Scholar
  14. 14.
    Lam, X. M., E. T. Duenas, A. L. Daugherty, N. Levin, and J. L. Cleland. Sustained release of recombinant human insulin-like growth factor-I for treatment of diabetes. J. Control Release 67:281–292, 2000.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu, H., E. B. Slamovich, and T. J. Webster. Less harmful acidic degradation of poly(lacticco-glycolic acid) bone tissue engineering scaffolds through titania nanoparticle addition. Int. J. Nanomed. 1:541–545, 2006.CrossRefGoogle Scholar
  16. 16.
    Ma, T., J. Gutnick, B. Salazar, M. D. Larsen, E. Suenaga, S. Zilber, Z. Huang, J. Huddleston, R. L. Smith, and S. Goodman. Modulation of allograft incorporation by continuous infusion of growth factors over a prolonged duration in vivo. Bone 41:386–392, 2007.CrossRefPubMedGoogle Scholar
  17. 17.
    Pekkarinen, T., O. Hietalal, T. Jamsa, and P. Jalovaara. Gamma irradiation and ethylene oxide in the sterilization of native reindeer bone morphogenetic protein extract. Scand. J. Surg. 94:67–70, 2005.PubMedGoogle Scholar
  18. 18.
    Peppas, N. A., and R. Langer. New challenges in biomaterials. Science 263:1715–1720, 1994.CrossRefPubMedGoogle Scholar
  19. 19.
    Pereira, G. C., E. N. Kubiak, B. Levine, F. S. Chen, and P. E. Di Cesare. Cavitary acetabular defects treated with morselized cancellous bone graft and cementless cups. Int. Orthop. 31:445–450, 2007.CrossRefPubMedGoogle Scholar
  20. 20.
    Perri, B., M. Cooper, C. Lauryssen, and N. Anand. Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: a case study. Spine J. 7:235–239, 2007.CrossRefPubMedGoogle Scholar
  21. 21.
    Rucker, M., M. W. Laschke, D. Junker, C. Carvalho, A. Schramm, R. Mulhaupt, N. C. Gellrich, and M. D. Menger. Angiogenic and inflammatory response to biodegradable scaffolds in dorsal skinfold chambers of mice. Biomaterials 27:5027–5038, 2006.CrossRefPubMedGoogle Scholar
  22. 22.
    Steens, W., J. F. Loehr, J. Wodtke, and A. Katzer. Morselized bone grafting in revision arthroplasty of the knee: a retrospective analysis of 34 reconstructions after 2–9 years. Acta Orthop. 79:683–688, 2008.CrossRefPubMedGoogle Scholar
  23. 23.
    Suganuma, J., and H. Alexander. Biological response of intramedullary bone to poly-L-lactic acid. J. Appl. Biomater. 4:13–27, 1993.CrossRefGoogle Scholar
  24. 24.
    Sung, H. J., C. Meredith, C. Johnson, and Z. S. Galis. The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis. Biomaterials 25:5735–5742, 2004.CrossRefPubMedGoogle Scholar
  25. 25.
    Tabata, Y. Nanomaterials of drug delivery systems for tissue regeneration. Methods Mol. Biol. 300:81–100, 2005.PubMedGoogle Scholar
  26. 26.
    Tagil, M. The morselized and impacted bone graft. Animal experiments on proteins, impaction and load. Acta Orthop. Scand. Suppl. 290:1–40, 2000.PubMedGoogle Scholar
  27. 27.
    Tanaka, E., Y. Ishino, A. Sasaki, T. Hasegawa, M. Watanabe, D. A. Dalla-Bona, E. Yamano, T. M. van Eijden, and K. Tanne. Fibroblast growth factor-2 augments recombinant human bone morphogenetic protein-2-induced osteoinductive activity. Ann. Biomed. Eng. 34:717–725, 2006.CrossRefPubMedGoogle Scholar
  28. 28.
    Tang, P. F., Q. Yao, H. Y. Sun, P. Huang, G. Cui, and J. F. Wang. Preparation and evaluation of recombinant human bone morphogenetic protein-2 loaded microsphere. J. Clin. Rehabil. Tissue Eng. Res. 12:1001–1004, 2008.Google Scholar
  29. 29.
    Van Beusekom, H., O. Sorop, M. Weymaere, D. Duncker, and W. van der Giessen. The neointimal response to stents eluting tacrolimus from a degradable coating depends on the balance between polymer degradation and drug release. Euro Intervention 4:139–147, 2008.PubMedGoogle Scholar
  30. 30.
    Voor, M. J., R. Madsen, A. Malkani, D. Togawa, and T. W. Bauer. Impaction grafting for femoral component revision in a goat model using washed morselized cancellous allograft. Orthopedics 31:443, 2008.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang, Y., J. L. Yan, B. Zhang, H. W. Wang, and J. J. Xia. Composite of autologous morselized cancellous bone grafts with bone morphogenetic protein in repairing bone defect. Chin. J. Clin. Rehabil. 9:42–44, 2005.Google Scholar
  32. 32.
    Yoon, S. J., S. H. Kim, H. J. Ha, Y. K. Ko, J. W. So, M. S. Kim, Y. I. Yang, G. Khang, J. M. Rhee, and H. B. Lee. Reduction of inflammatory reaction of poly(d,l-lactic-co-glycolic acid) using demineralized bone particles. Tissue Eng. A 14:539–547, 2008.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2010

Authors and Affiliations

  • Ye Ji
    • 1
  • Gong ping Xu
    • 1
  • Zhi peng Zhang
    • 1
  • Jing jun Xia
    • 1
  • Jing long Yan
    • 1
  • Shang ha Pan
    • 2
  1. 1.Department of Orthopaedic SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Central LaboratoryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina

Personalised recommendations