京尼平作为交联剂在天然生物材料改性中的应用_《中国修复重建外科杂志》

作者：

王旻 ¹ , 笪琳萃 ¹ , 谢艳 ² , 解慧琪 ¹

四川大学华西医院（成都，610041） 1再生医学研究中心·干细胞与组织工程研究室，2 消化内科;

关键词：

京尼平交联剂生物材料组织工程

DOI：

10.7507/1002-1892.20130128

视频：

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摘要 全文 图表 视频 参考文献 施引文献 补充材料

目的综述京尼平作为交联剂在天然生物材料改性中的应用及研究进展。方法查阅近年关于京尼平作为交联剂在天然生物材料改性中应用的相关文献，进行分析总结。结果天然交联剂京尼平交联效率高，细胞毒性显著低于传统人工合成的化学交联剂，交联后的生物制品稳定性强，抗酶解效果显著提高。结论京尼平有望替代人工合成的传统化学交联剂，为组织工程中天然生物材料的交联改性提供更好的选择。

引用本文： 王旻,笪琳萃,谢艳,解慧琪. 京尼平作为交联剂在天然生物材料改性中的应用. 中国修复重建外科杂志, 2013, 27(5): 580-585. doi: 10.7507/1002-1892.20130128 复制

1.	Hernández-Muñoz P, Villalobos R, Chiralt A. Effect of cross-linking using aldehydes on properties of glutenin-rich films. Food Hydrocolloids, 2004, 18(3): 403-411.
2.	Langmaier F, Mládek M, Mokrejš P. Hydrogels of collagen hydrolysate cross-linked with dialdehyde starch. J Therm Anal Calorim, 2009, 98(3): 807-812.
3.	Imamura E, Sawatani O, Koyanagi H, et al. Epoxy compounds as a new cross-linking agent for porcine aortic leaflets: subcutaneous implant studies in rats. J Card Surg, 1989, 4(1): 50-57.
4.	Nishi C, Nakajima N, Ikada Y. In vitro evaluation of cytotoxicity of diepoxy compounds used for biomaterial modification. J Biomed Mater Res, 1995, 29(7): 829-834.
5.	Cipriano PR, Billingam MB, Oyer PE, et al. Calcification of porcine prosthetic heart valves: a radiographic and light microscopy study. Circulation, 1982, 66(5): 1100-1104.
6.	Schoen FJ, Harasaki H, Kim KM, et al. Biomaterial associated calcification: Pathology, mechanisms, and strategies for prevention. J Biomed Mater Res, 1988, 22(A1 Suppl): 11-36.
7.	Speer DP, Chvapil M, Eskelson CD, et al. Biological effects of residual glutaraldehyde in glutaraldehyde-tanned collagen biomaterials. J Biomed Mater Res, 1980, 14(6): 753-764.
8.	Sung HW, Huang RN, Huang LL, et al. Feasibility study of a natural crosslinking reagent for biological tissue fixation. J Biomed Mater Res, 1998, 42(4): 560-567.
9.	Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg, 2008, 34(5): 796-801.
10.	Nickerson MT, Farnworth R, Wagar E, et al. Some physical and microstructural properties of genipin-crosslinked gelatin-maltodextrin hydrogels. Int J Biol Macromol, 2006, 38(1): 40-44.
11.	Somers P, De-Somer F, Cornelissen M, et al. Genipin blues: an alternative non-toxic crosslinker for heart valves? J Heart Valve Dis, 2008, 17(6): 682-688.
12.	Yao CH, Liu BS, Chang CJ, et al. Preparation of networks of gelatin and genipin as degradable biomaterials. Materials Chemistry and Physics, 2004, 83(2-3): 204-208.
13.	Nickerson MT, Patel J, Heyd DV, et al. Kinetic and mechanistic considerations in the gelation of genipin-crosslinked gelatin. Int J Biol Macromol, 2006, 39(4-5): 298-302.
14.	Sung HW, Chang Y, Chiu CT, et al. Crosslinking characteristics and mechanical properties of a bovine pericardium fixed with a naturally occurring crosslinking agent. J Biomed Mater Res, 1999, 47(2): 116-126.
15.	Sung HW, Chang Y, Liang IL, et al. Fixation of biological tissues with a naturally occurring crosslinking agent: fixation rate and effects of pH, temperature, and initial fixative concentration. J Biomed Mater Res, 2000, 52(1): 77-87.
16.	Mi FL, Tan YC, Liang HC, et al. In vitro evaluation of a chitosan membrane cross-linked with genipin. J Biomater Sci Polym Ed, 2001, 12(8): 835-850.
17.	Yoo JS, Kim YJ, Kim SH, et al. Study on genipin: a new alternative natural crosslinking agent for fixing heterograft tissue. Korean J Thorac Cardiovasc Surg, 2011, 44(3): 197-207.
18.	Yuan Y, Chesnutt BM, Utturkar G, et al. The effect of cross-linking of chitosan microspheres with genipin on protein release. Carbohydr Polym, 2007, 68(3): 561-567.
19.	Sung HW, Huang RN, Huang LL, et al. In vitro evaluation of cytotoxicity of a naturally occurring cross-linking reagent for biological tissue fixation. J Biomater Sci Polym Ed, 1999, 10(1): 63-78.
20.	Sung HW, Chen CN, Huang RN, et al. In vitro surface characterization of a biological patch fixed with a naturally occurring crosslinking agent. Biomaterials, 2000, 21(13): 1353-1362.
21.	Sung HW, Liang IL, Chen CN, et al. Stability of a biological tissue fixed with a naturally occurring crosslinking agent (Genipin). J Biomed Mater Res, 2001, 55(4): 538-546.
22.	Chen MC, Liu CT, Tsai HW, et al. Mechanical properties, drug eluting characteristics and in vivo performance of a genipin-crosslinked chitosan polymeric stent. Biomaterials, 2009, 30(29): 5560-5571.
23.	Yan LP, Wang YJ, Ren L, et al. Genipin-cross-linked collagen/chitosan biomimetic scaffolds for articular cartilage tissue engineering applications. J Biomed Mater Res A, 2010, 95(2): 465-475.
24.	Yang Y, Zhao W, He J, et al. Nerve conduits based on immobilization of nerve growth factor onto modified chitosan by using genipin as a crosslinking agent. Eur J Pharm Biopharm, 2011, 79(3): 519-525.
25.	Xi-xun Y, Fei L, Yuan-ting X, et al. In vitro study in the endothelial cell compatibility and endothelialization of genipin-crosslinked biological tissues for tissue-engineered vascular scaffolds. J Mater Sci Mater Med, 2010, 21(2): 777-785.
26.	Ng KW, Wanivenhaus F, Chen T, et al. Differential cross-linking and radio-protective effects of genipin on mature bovine and human patella tendons. Cell Tissue Bank, 2013, 14(1): 21-32.
27.	Sundararaghavan HG, Monteiro GA, Lapin NA, et al. Genipin-induced changes in collagen gels: Correlation of mechanical properties to fluorescence. J Biomed Mater Res A, 2008, 87(2): 308-320.
28.	Lima EG, Tan AR, Tai T, et al. Genipin enhances the mechanical properties of tissue-engineered cartilage and protects against inflammatory degradation when used as a medium supplement. J Biomed Mater Res A, 2009, 91(3): 692-700.
29.	Wang C, Lau TT, Loh WL, et al. Cytocompatibility study of a natural biomaterial crosslinker-genipin with therapeutic model cells. J Biomed Mater Res Part B Appl Biomater, 2011, 97(1): 58-65.
30.	Kim BC, Kim HG, Lee SA, et al. Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. Biochem Pharmacol, 2005, 70(9): 1398-1407.
31.	Liu Z, Zhou Q, Zhu J, et al. Using genipin-crosslinked acellular porcine corneal stroma for cosmetic corneal lens implants. Biomaterials, 2012, 33(30): 7336-7346.
32.	Madhavan K, Belchenko D, Tan W. Roles of genipin crosslinking and biomolecule conditioning in collagen-based biopolymer: Potential for vascular media regeneration. J Biomed Mater Res A, 2011, 97(1): 16-26.
33.	Yao CH, Liu BS, Hsu SH, et al. Biocompatibility and biodegradation of a bone composite containing tricalcium phosphate and genipin crosslinked gelatin. J Biomed Mater Res, 2004, 69(4): 709-717.
34.	Liang HC, Chang Y, Hsu CK, et al. Effects of crosslinking degree of an acellular biological tissue on its tissue regeneration pattern. Biomaterials, 2004, 25(17): 3541-3552.
35.	Huang LL, Sung HW, Tasi CC, et al. Biocompatibility study of a biological tissue fixed with a naturally occurring crosslinking reagent. J Biomed Mater Res, 1998, 42(4): 568-576.
36.	Chang Y, Tsai CC, Liang HC, et al. In vivo evaluation of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (genipin). Biomaterials, 2002, 23(12): 2447-2457.

1. Hernández-Muñoz P, Villalobos R, Chiralt A. Effect of cross-linking using aldehydes on properties of glutenin-rich films. Food Hydrocolloids, 2004, 18(3): 403-411.
2. Langmaier F, Mládek M, Mokrejš P. Hydrogels of collagen hydrolysate cross-linked with dialdehyde starch. J Therm Anal Calorim, 2009, 98(3): 807-812.
3. Imamura E, Sawatani O, Koyanagi H, et al. Epoxy compounds as a new cross-linking agent for porcine aortic leaflets: subcutaneous implant studies in rats. J Card Surg, 1989, 4(1): 50-57.
4. Nishi C, Nakajima N, Ikada Y. In vitro evaluation of cytotoxicity of diepoxy compounds used for biomaterial modification. J Biomed Mater Res, 1995, 29(7): 829-834.
5. Cipriano PR, Billingam MB, Oyer PE, et al. Calcification of porcine prosthetic heart valves: a radiographic and light microscopy study. Circulation, 1982, 66(5): 1100-1104.
6. Schoen FJ, Harasaki H, Kim KM, et al. Biomaterial associated calcification: Pathology, mechanisms, and strategies for prevention. J Biomed Mater Res, 1988, 22(A1 Suppl): 11-36.
7. Speer DP, Chvapil M, Eskelson CD, et al. Biological effects of residual glutaraldehyde in glutaraldehyde-tanned collagen biomaterials. J Biomed Mater Res, 1980, 14(6): 753-764.
8. Sung HW, Huang RN, Huang LL, et al. Feasibility study of a natural crosslinking reagent for biological tissue fixation. J Biomed Mater Res, 1998, 42(4): 560-567.
9. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg, 2008, 34(5): 796-801.
10. Nickerson MT, Farnworth R, Wagar E, et al. Some physical and microstructural properties of genipin-crosslinked gelatin-maltodextrin hydrogels. Int J Biol Macromol, 2006, 38(1): 40-44.
11. Somers P, De-Somer F, Cornelissen M, et al. Genipin blues: an alternative non-toxic crosslinker for heart valves? J Heart Valve Dis, 2008, 17(6): 682-688.
12. Yao CH, Liu BS, Chang CJ, et al. Preparation of networks of gelatin and genipin as degradable biomaterials. Materials Chemistry and Physics, 2004, 83(2-3): 204-208.
13. Nickerson MT, Patel J, Heyd DV, et al. Kinetic and mechanistic considerations in the gelation of genipin-crosslinked gelatin. Int J Biol Macromol, 2006, 39(4-5): 298-302.
14. Sung HW, Chang Y, Chiu CT, et al. Crosslinking characteristics and mechanical properties of a bovine pericardium fixed with a naturally occurring crosslinking agent. J Biomed Mater Res, 1999, 47(2): 116-126.
15. Sung HW, Chang Y, Liang IL, et al. Fixation of biological tissues with a naturally occurring crosslinking agent: fixation rate and effects of pH, temperature, and initial fixative concentration. J Biomed Mater Res, 2000, 52(1): 77-87.
16. Mi FL, Tan YC, Liang HC, et al. In vitro evaluation of a chitosan membrane cross-linked with genipin. J Biomater Sci Polym Ed, 2001, 12(8): 835-850.
17. Yoo JS, Kim YJ, Kim SH, et al. Study on genipin: a new alternative natural crosslinking agent for fixing heterograft tissue. Korean J Thorac Cardiovasc Surg, 2011, 44(3): 197-207.
18. Yuan Y, Chesnutt BM, Utturkar G, et al. The effect of cross-linking of chitosan microspheres with genipin on protein release. Carbohydr Polym, 2007, 68(3): 561-567.
19. Sung HW, Huang RN, Huang LL, et al. In vitro evaluation of cytotoxicity of a naturally occurring cross-linking reagent for biological tissue fixation. J Biomater Sci Polym Ed, 1999, 10(1): 63-78.
20. Sung HW, Chen CN, Huang RN, et al. In vitro surface characterization of a biological patch fixed with a naturally occurring crosslinking agent. Biomaterials, 2000, 21(13): 1353-1362.
21. Sung HW, Liang IL, Chen CN, et al. Stability of a biological tissue fixed with a naturally occurring crosslinking agent (Genipin). J Biomed Mater Res, 2001, 55(4): 538-546.
22. Chen MC, Liu CT, Tsai HW, et al. Mechanical properties, drug eluting characteristics and in vivo performance of a genipin-crosslinked chitosan polymeric stent. Biomaterials, 2009, 30(29): 5560-5571.
23. Yan LP, Wang YJ, Ren L, et al. Genipin-cross-linked collagen/chitosan biomimetic scaffolds for articular cartilage tissue engineering applications. J Biomed Mater Res A, 2010, 95(2): 465-475.
24. Yang Y, Zhao W, He J, et al. Nerve conduits based on immobilization of nerve growth factor onto modified chitosan by using genipin as a crosslinking agent. Eur J Pharm Biopharm, 2011, 79(3): 519-525.
25. Xi-xun Y, Fei L, Yuan-ting X, et al. In vitro study in the endothelial cell compatibility and endothelialization of genipin-crosslinked biological tissues for tissue-engineered vascular scaffolds. J Mater Sci Mater Med, 2010, 21(2): 777-785.
26. Ng KW, Wanivenhaus F, Chen T, et al. Differential cross-linking and radio-protective effects of genipin on mature bovine and human patella tendons. Cell Tissue Bank, 2013, 14(1): 21-32.
27. Sundararaghavan HG, Monteiro GA, Lapin NA, et al. Genipin-induced changes in collagen gels: Correlation of mechanical properties to fluorescence. J Biomed Mater Res A, 2008, 87(2): 308-320.
28. Lima EG, Tan AR, Tai T, et al. Genipin enhances the mechanical properties of tissue-engineered cartilage and protects against inflammatory degradation when used as a medium supplement. J Biomed Mater Res A, 2009, 91(3): 692-700.
29. Wang C, Lau TT, Loh WL, et al. Cytocompatibility study of a natural biomaterial crosslinker-genipin with therapeutic model cells. J Biomed Mater Res Part B Appl Biomater, 2011, 97(1): 58-65.
30. Kim BC, Kim HG, Lee SA, et al. Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. Biochem Pharmacol, 2005, 70(9): 1398-1407.
31. Liu Z, Zhou Q, Zhu J, et al. Using genipin-crosslinked acellular porcine corneal stroma for cosmetic corneal lens implants. Biomaterials, 2012, 33(30): 7336-7346.
32. Madhavan K, Belchenko D, Tan W. Roles of genipin crosslinking and biomolecule conditioning in collagen-based biopolymer: Potential for vascular media regeneration. J Biomed Mater Res A, 2011, 97(1): 16-26.
33. Yao CH, Liu BS, Hsu SH, et al. Biocompatibility and biodegradation of a bone composite containing tricalcium phosphate and genipin crosslinked gelatin. J Biomed Mater Res, 2004, 69(4): 709-717.
34. Liang HC, Chang Y, Hsu CK, et al. Effects of crosslinking degree of an acellular biological tissue on its tissue regeneration pattern. Biomaterials, 2004, 25(17): 3541-3552.
35. Huang LL, Sung HW, Tasi CC, et al. Biocompatibility study of a biological tissue fixed with a naturally occurring crosslinking reagent. J Biomed Mater Res, 1998, 42(4): 568-576.
36. Chang Y, Tsai CC, Liang HC, et al. In vivo evaluation of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (genipin). Biomaterials, 2002, 23(12): 2447-2457.

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京尼平作为交联剂在天然生物材料改性中的应用

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《中国修复重建外科杂志》

京尼平作为交联剂在天然生物材料改性中的应用

摘要 全文 图表 视频 参考文献 施引文献 补充材料

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