Matrix metalloproteinase(MMP) sensitive hyaluronic acid hydrogel-nanoparticle complex와 rhBMP-2를 이용한 골재생

BONE REGENERATION WITH MMP SENSITIVE HYALURONIC ACID-BASED HYDROGEL, rhBMP-2 AND NANOPARTICLES IN RAT CALVARIAL CRITICAL SIZE DEFECT(CSD) MODEL

  • 남정훈 (서울대학교 치과대학 구강악안면외과학교실) ;
  • 박종철 (서울대학교 치과대학 구강악안면외과학교실) ;
  • 유상배 (서울대학교 치과대학 치학연구소) ;
  • 정용일 (광주 과학기술원 신소재공학과) ;
  • 태기융 (광주 과학기술원 신소재공학과) ;
  • 김정주 (고려대학교 의과대학 의공학교실, BK21 의공학사업단, 한국인공장기센터) ;
  • 박용두 (고려대학교 의과대학 의공학교실, BK21 의공학사업단, 한국인공장기센터) ;
  • 장정원 (서울대학교 치과대학 치학연구소) ;
  • 이종호 (서울대학교 치과대학 구강악안면외과학교실)
  • Nam, Jeong-Hun (Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University) ;
  • Park, Jong-Chul (Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University) ;
  • Yu, Sang-Bae (Dental Research Institute, School of Dentistry, Seoul National University) ;
  • Chung, Yong-Il (Department of Materials Science and Engineering, Gwangju Institute of Science and Technology) ;
  • Tae, Gi-Yoong (Department of Materials Science and Engineering, Gwangju Institute of Science and Technology) ;
  • Kim, Jung-Ju (Department of Biomedical Engineering, Biomedical Engineering, Brain Korea 21 2nd Project for Biomedical Science) ;
  • Park, Yong-Doo (Department of Biomedical Engineering, Biomedical Engineering, Brain Korea 21 2nd Project for Biomedical Science) ;
  • Jahng, Jeong-Won (Dental Research Institute, School of Dentistry, Seoul National University) ;
  • Lee, Jong-Ho (Department of Oral and Maxillofacial Surgery, School of Dentistry, Seoul National University)
  • 발행 : 2009.06.30

초록

As an efficient controlled release system for rhBMP-2, a functional nanoparticle-hydrogel complex, incorporated with matrix metalloproteinase(MMP) sensitive peptide cross-linker, was developed and used as a bone transplant. In vivo bone formation was evaluated by soft x-ray, histology, alkaline phosphatase(ALP) activity and mineral contents analysis, based on the rat calvarial critical size defect(8mm in diameter) model. Significantly, effective bone regeneration was achieved with the rhBMP-2 loaded MMP sensitive hyaluronic acid(HA) based hydrogel-Nanoparticles(NP) complex, as compared to only MMP HA, the MMP HA-NP without rhBMP-2, or even with the rhBMP-2. These improvements included the formation pattern of bone and functional marrow, the degree of calcium quantification, and the ALP activity. These results indicate that the MMP sensitive HA with nano-particle complex can be a promising candidate for a new bone defect replacement matrix, and an enhanced rhBMP-2 scaffold.

키워드

참고문헌

  1. Geiger M, Li RH, Friess W. Collgen sponges for bone regenerationwith rhBMP-2. Adv Drug Deliv Rev 2003;55:1613-29 https://doi.org/10.1016/j.addr.2003.08.010
  2. Sakiyama SE, Hubbel JA. Development of fibrin derivatives forcontrolled release of heparin-binding growth factors. J Control Release 2000;65:389-402 https://doi.org/10.1016/S0168-3659(99)00221-7
  3. Kim HD, Valentini RF. Retention and activity of BMP-2 in hyluronicacid-based scaffolds in vitro. J Biomed Mater Res 2002;59:573-84 https://doi.org/10.1002/jbm.10011
  4. Saito N, Okada T, Horiuchi H, Ota H, Takahashi J, Murakami M,et al. Local bone formation by injection of recombinanat humanbone morphogenetic protein-2 contained in polymer carriers.Bone 2003;32:381-386 https://doi.org/10.1016/S8756-3282(03)00028-0
  5. Laurent TC, Laurent UB, Fraser JR. Functions of hyaluronan.Ann Rheum Dis 1995;54:429-32 https://doi.org/10.1136/ard.54.5.429
  6. Entwistle J, Hall CL, Turley EA. HA receptors: regulations ofsignaling to the cytoskeleton. J Cell Biochem 1996;61:569-77 https://doi.org/10.1002/(SICI)1097-4644(19960616)61:4<569::AID-JCB10>3.0.CO;2-B
  7. Ladeda V, Ghiso JA, E Bal de Kier Joffe. Function and expression of CD44 during spreading, migration, and invasion of murine carcinoma cell. Exp Cell Res 1998;42:515-27 https://doi.org/10.1006/excr.1998.4094
  8. Zhang S, Chang MC, Zylka D, Turley S, Harrison R, Turley EA.The hyaluronan receptor RHAMM regulates extracellular-regulatedkinase. J Biol Chem 1998;273:11342-8 https://doi.org/10.1074/jbc.273.18.11342
  9. Kim JJ, Park YD, Tae GY, Lee KB, Hwang CM, Hwang SJ, etal. Characterization of low-molecular-weight hyaluronic acidbasedhydrogel and defferential stem cell responses in the hydrogelmicroenvironments. J Biomed Mater Res A 2009;88:967-75
  10. Kim JJ, Kim IS, Cho TH, Lee KB, Hwang SJ, Tae GY, et al.Bone regeneration using hyaluronic acid-based hydrogel withbone morphogenic protein-2 and human mesenchymal stem cells.Biomaterials 2007;28:1830-7 https://doi.org/10.1016/j.biomaterials.2006.11.050
  11. Lutolf MP, Lauer-Fields JL, Schmoekel HG, Metters AT, WeberFE, Fields GB, et al. Synthetic matrix metalloproteinase-sensitivehydrogels for the conduction of tissue regeneration: engineeringcell-invasion characteristics. Proc Natl Acad Sci USA 2003;100:5413-8 https://doi.org/10.1073/pnas.0737381100
  12. Kim JJ, Park YD, Tae GY, Lee KB, Hwang SJ, Kim IS, et al.Synthesis and characterization of matrix metalloprotease sensitive-low molecular weight hyaluronic acid based hydrogels. JMater Sci Mater Med 2008;19:3311-8 https://doi.org/10.1007/s10856-008-3469-3
  13. Hong SR, Chong MS, Lee SB, Lee YM, Song KW, Park MH, etal. Biocompatibility and biodegradation of cross-linkedgelatin/hyaluronic acid sponge in rat subcutaneous tissue. JBiomater Sci Polym Ed 2004;15:201-14 https://doi.org/10.1163/156856204322793584
  14. Chung YI, Tae GY, Yuk SH. A facile method to prepare heparin functionalizednanoparticles for controlled release of growth factors.Biomaterials 2006;27:2621-6 https://doi.org/10.1016/j.biomaterials.2005.11.043
  15. Chung YI, Lee SY, Tae GY. The effect of heparin on the gellationof Pluronic F-127 hydrogel. Colloid Surf A: PhysicochemEng Aspects 2006;284:480-4 https://doi.org/10.1016/j.colsurfa.2005.10.060
  16. Chung YI, Ahn KM, Jeon SH, Lee SY, Lee JH, Tae GY.Enhanced bone regeneration with BMP-2 loaded functionalnanoparticle-hydrogel complex. J Control Release 2007;121:91-9 https://doi.org/10.1016/j.jconrel.2007.05.029
  17. Piattellie A, Scarano A, Corigliano M, Piattelli M. Effects of alkalinephosphatase on bone healing around plasma-sprayed titaniumimplants a pilot study in rabbits. Biomaterials 1996;17:1443-9 https://doi.org/10.1016/0142-9612(96)87288-7
  18. Hosseinkhani H, Hosseinkhani M, Khademhosseini A,Kobayashi H. Bone regeneration through controlled release ofbone morphogenetic protein-2 from 3-D tissue engineered nanoscaffold.J Control Release 2007;117:380-6 https://doi.org/10.1016/j.jconrel.2006.11.018
  19. Ahn SH, Kim CS, Suk HJ, Lee YJ, Choi SH, Chai JK, et al.Effect of recombinant human bone morphogenetic protein-4 withcarriers in rat calvarial defects. J Periodontol 2003;74:787-97 https://doi.org/10.1902/jop.2003.74.6.787
  20. Schmoekel H, Schense JC, Weber FE, Gratz KW, Gnagi D,Muller R, et al. Bone healng in the rat and dog with nonglycosylatedBMP-2 demonstrating low solubility in fibrin matrices. J Orthop Res 2004;22:376-81 https://doi.org/10.1016/S0736-0266(03)00188-8