Research Progress of Genipin Cross-linking in Tissue Engineering in the Field of Cardiothoracic Surgery_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

SUN Fei , PAN Shu , SHI Hongcan.

Department of Thoracic Surgery，College of Clinical Medicine，Yangzhou University，Yangzhou 225001，Jiangsu，P. R. China;

Corresponding author：

Keywords：

Genipin; 　Tissue engineering; 　Biocompatibility; 　Mechanical property; 　Cross-linking

DOI：

10.7507/1007-4848.20130217

Video：

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Decellularized tissue engineering scaffolds appear to have the properties of similar structure and mechanical characteristics to native tissues，good biocompatibility，suitability for cell adhesion，growth and angiogenesis induction，and non-immunogenicity. Genipin has anti-inflammatory，antithrombotic and antioxidative features which can considerably suppress vascular and endothelial inflammatory activation，increase mechanical strength of biological scaffolds，inhibit inflammatory response and decrease degradation rate of biological scaffolds. By cross-linking with decellularized matrices，Genipin can further improve corresponding performance of tissue engineering matrices，which is very helpful to promote the application of tissue engineering into clinical practice of cardiothoracic surgery. This review focuses on recent research process and possible prospects of Genipin cross-linking in tissue engineering in the field of cardiothoracic surgery.

Citation： SUN Fei,PAN Shu,SHI Hongcan.. Research Progress of Genipin Cross-linking in Tissue Engineering in the Field of Cardiothoracic Surgery. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2013, 20(6): 714-718. doi: 10.7507/1007-4848.20130217 Copy

1.	Macchiarini P， Jungebluth P， Go T， et al. Clinical transplantation of a tissue-engineered airway. Lancet， 2008， 372 （9655）：2023-2030.
2.	Baiguera S， D'Innocenzo B， Macchiarini P. Current status of regenerative replacement of the airway. Expert Rev Respir Med， 2011， 5 （4）：487-494.
3.	Jungebluth P， Go T， Asnaghi A， et al. Structural and morphologic evaluation of a novel detergent-enzymatic tissue-engineered tracheal tubular matrix. J Thorac Cardiovasc Surg， 2009， 138 （3）：586-593.
4.	Zang M， Zhang Q， Chang EI， et al. Decellularized tracheal matrix scaffold for tissue engineering. Plast Reconstr Surg， 2012， 130 （3）：532-540.
5.	Jungebluth P， Bader A， Baiguera S， et al. The concept of in vivo airway tissue engineering. Biomaterials， 2012， 33 （17）：4319-4326.
6.	Laurance J. British boy receives trachea transplant built with his own stem cells. BMJ， 2010， 340：c1633.
7.	Elliott MJ， De Coppi P， Speggiorin S， et al. Stem-cell-based， tissue engineered tracheal replacement in a child：a 2-year follow-up study. Lancet， 2012， 380 （9846）：994-1000.
8.	Baiguera S， Del Gaudio C， Jaus MO， et al. Long-term changes to in vitro preserved bioengineered human trachea and their implications for decellularized tissues. Biomaterials， 2012， 33 （14）：3662-3672.
9.	Partington L， Mordan NJ， Mason C， et al. Biochemical changes caused by decellularization may compromise mechanical integrity of tracheal scaffolds. Acta Biomater， 2013， 9 （2）：5251-5261.
10.	Haag J， Baiguera S， Jungebluth P， et al. Biomechanical and angiogenic properties of tissue-engineered rat trachea using genipin cross-linked decellularized tissue. Biomaterials， 2012， 33 （3）：780-789.
11.	Sung HW， Chang WH， Ma CY， et al. Crosslinking of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res A， 2003， 64 （3）：427-438.
12.	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.
13.	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.
14.	Bhrany AD， Lien CJ， Beckstead BL， et al. Crosslinking of an oesop-hagus acellular matrix tissue scaffold. J Tissue Eng Regen Med， 2008， 2 （6）：365-372.
15.	Changa Y， Tsai CC， Liang HC， et al. In vivo evaluation of cellulaand acellular bovine pericardia fixed witha naturally occurring cross-linking agent （genipin）. Biomaterials， 2002， 23 （12）：2447-2457.
16.	Sung HW， Liang IL， Chen CN， et al. Stability of a biological tissuefixed with a naturally occurring crosslinking agent （genipin）. JBiomed Mater Res， 2001， 55 （4）：538-546.
17.	Grolik M， Szczubiałka K， Wowra B， et al. Hydrogel membranes based on genipin-cross-linked chitosan blends for corneal epithelium tissue engineering. J Mater Sci Mater Med， 2012， 23 （8）：1991-2000.
18.	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.
19.	Kim MS， Jun I， Shin YM， et al. The Development of genipin-crosslinked poly （caprolactone）（PCL）/gelatin nanoﬁbers for tissue engineering applications. Macromol Biosci， 2010， 10 （1）：91-100.
20.	Frohbergh ME， Katsman A， Botta GP， et al. Electrospun hydroxyapatite-containing chitosan nanoﬁbers crosslinked with genipin for bone tissue engineering. Biomaterials， 2012， 33 （36）：9167-9178.
21.	Lim HG， Kim SH， Choi SY， et al. Anticalciﬁcation effects of dece-llularization， solvent， and detoxiﬁcation treatment for genipin and glutaraldehyde ﬁxation of bovine pericardium. Eur J Cardiothorac Surg， 2012， 41 （2）：383-390.
22.	Yang M， Chen CZ， Shu YS， et al. Preseeding of human vascular cells in decellularized bovine pericardium scaffold for tissue-engineered heart valve：an in vitro and in vivo feasibility study. J Biomed Mater Res B Appl Biomater， 2012， 100 （6）：1654-1661.
23.	Saporito WF， Pires AC， Cardoso SH， et al. Bovine pericardium retail preserved in glutaraldehyde and used as a vascular patch. BMC Surg， 2011， 11 （37）：37.
24.	Schoen FJ， Levy RJ. Calcification of tissue heart valve substitutes：progress toward understanding and prevention. Ann Thorac Surg， 2005， 79 （3）：1072-1080.
25.	Manji RA， Zhu LF， Nijjar NK， et al. Glutaraldehyde-fixed bioprosthetic heart valve conduits calcify and fail from xenograft rejection. Circulation， 2006， 114 （4）：318-327.
26.	Till H， Muensterer OJ， Rolle U， et al. Staged esophageal lengtheningwith internal and subsequent external traction sutures leads to primary repair of an ultralong gap esophageal atresia with upper pouch trache-oesophagel fistula. J Pediatr Surg， 2008， 43 （6）：33-35.
27.	Arul GS， Parikh D. Oesophageal replacement in children. Ann R Coll Surg Engl， 2008， 90 （1）：7-12.
28.	Gilbert TW， Sellaro TL， Badylak SF. Decellularization of tissues and organs. Biomaterials， 2006， 27 （19）：3675-3683.
29.	Badylak SF. Xenogeneic extracellular matrix as a scaffold for tissue Reconstruction. Transpl Immunol， 2004， 12 （3-4）：367-377.
30.	Adair-Kirk TL， Senior RM. Fragments of extracellular matrix as mediators of inflammation. Int J Biochem Cell Biol， 2008， 40 （6-7）：1101-1110.
31.	Badylak SF， Gilbert TW. Immune response to biologic scaffoldmaterials. Semin Immunol， 2008， 20 （2）：109-116.
32.	Koch H， Graneist C， Emmrich F， et al. Xenogenic esophagus scaffolds fixed with several agents：comparative invivo study of rejection and inﬂammation. J Biomed Biotechnol， 2012， 2012：948320.
33.	Ott LM， Weatherly RA， Detamore MS. Overview of tracheal tissueengineering：clinical need drives the laboratory approach. Ann BiomedEng， 2011， 39 （8）：2091-2113.
34.	Hoshiba T， Lu H， Kawazoe N， et al. Decellularized matrices for tissueengineering. Expert Opin Biol Ther， 2010， 10 （12）：1717-1728.
35.	Crapo PM， Gilbert TW， Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials， 2011， 32 （12）：3233-3243.
36.	Englert C， Blunk T， Müller R， et al. Bonding of articular cartilage using a combination of biochemical degradation and surface cross-linking. Arthritis Res Ther， 2007， 9 （3）：47.
37.	Liang HC， Chang WH， Lin KJ， et al. Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration：in vitro and in vivo studies. J Biomed Mater Res A， 2003， 65 （2）：271-282.
38.	Wang GF， Wu SY， Rao JJ， et al. Genipin inhibits endothelial exocy-tosis via nitric oxide in cultured human umbilical vein endothelial cells. Acta Pharmacol Sin， 2009， 30 （5）：589-596.
39.	Koo HJ， Lim KH， Jung HJ， et al. Anti-inflammatory evaluation of gardenia extract， geniposide and genipin. J Ethnopharmacol， 2006， 103 （3）：496-500.
40.	Zhang CY， Parton LE， Ye CP， et al. Genipin inhibits UCP2-mediatedproton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab， 2006， 3 （6）：417-427.
41.	Yamazaki M， Chiba K. Genipin exhibits neurotrophic effects through a common signaling pathway in nitric oxide synthase-expressing cells. Eur J Pharmacol， 2008， 581 （3）：255-261.
42.	Sung HW， Huang RN， Huang LL， et al. Feasibility study of a naturalcrosslinking reagent for biological tissue fixation. J Biomed Mater Res， 1998， 42 （4）：560-567.
43.	Yu XX， Liu F， Xu YT， 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.
44.	Wang C， Lau TT， Loh WL， et al. Cytocompatibility study of a natural biomaterial crosslinker——Genipin with therapeutic model cells. J Biomed Mater Res B Appl Biomater， 2011， 97 （1）：58-65.
45.	Baiguera S， Macchiarini P， Ribatti D. Chorioallantoic membrane for in vivo investigation of tissue-engineered construct biocompatibility. J Biomed Mater Res B Appl Biomater， 2012， 100 （5）：1425-1434.

1. 　Macchiarini P， Jungebluth P， Go T， et al. Clinical transplantation of a tissue-engineered airway. Lancet， 2008， 372 （9655）：2023-2030.
2. 　Baiguera S， D'Innocenzo B， Macchiarini P. Current status of regenerative replacement of the airway. Expert Rev Respir Med， 2011， 5 （4）：487-494.
3. 　Jungebluth P， Go T， Asnaghi A， et al. Structural and morphologic evaluation of a novel detergent-enzymatic tissue-engineered tracheal tubular matrix. J Thorac Cardiovasc Surg， 2009， 138 （3）：586-593.
4. 　Zang M， Zhang Q， Chang EI， et al. Decellularized tracheal matrix scaffold for tissue engineering. Plast Reconstr Surg， 2012， 130 （3）：532-540.
5. 　Jungebluth P， Bader A， Baiguera S， et al. The concept of in vivo airway tissue engineering. Biomaterials， 2012， 33 （17）：4319-4326.
6. 　Laurance J. British boy receives trachea transplant built with his own stem cells. BMJ， 2010， 340：c1633.
7. 　Elliott MJ， De Coppi P， Speggiorin S， et al. Stem-cell-based， tissue engineered tracheal replacement in a child：a 2-year follow-up study. Lancet， 2012， 380 （9846）：994-1000.
8. 　Baiguera S， Del Gaudio C， Jaus MO， et al. Long-term changes to in vitro preserved bioengineered human trachea and their implications for decellularized tissues. Biomaterials， 2012， 33 （14）：3662-3672.
9. 　Partington L， Mordan NJ， Mason C， et al. Biochemical changes caused by decellularization may compromise mechanical integrity of tracheal scaffolds. Acta Biomater， 2013， 9 （2）：5251-5261.
10. 　Haag J， Baiguera S， Jungebluth P， et al. Biomechanical and angiogenic properties of tissue-engineered rat trachea using genipin cross-linked decellularized tissue. Biomaterials， 2012， 33 （3）：780-789.
11. 　Sung HW， Chang WH， Ma CY， et al. Crosslinking of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res A， 2003， 64 （3）：427-438.
12. 　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.
13. 　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.
14. 　Bhrany AD， Lien CJ， Beckstead BL， et al. Crosslinking of an oesop-hagus acellular matrix tissue scaffold. J Tissue Eng Regen Med， 2008， 2 （6）：365-372.
15. 　Changa Y， Tsai CC， Liang HC， et al. In vivo evaluation of cellulaand acellular bovine pericardia fixed witha naturally occurring cross-linking agent （genipin）. Biomaterials， 2002， 23 （12）：2447-2457.
16. 　Sung HW， Liang IL， Chen CN， et al. Stability of a biological tissuefixed with a naturally occurring crosslinking agent （genipin）. JBiomed Mater Res， 2001， 55 （4）：538-546.
17. 　Grolik M， Szczubiałka K， Wowra B， et al. Hydrogel membranes based on genipin-cross-linked chitosan blends for corneal epithelium tissue engineering. J Mater Sci Mater Med， 2012， 23 （8）：1991-2000.
18. 　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.
19. 　Kim MS， Jun I， Shin YM， et al. The Development of genipin-crosslinked poly （caprolactone）（PCL）/gelatin nanoﬁbers for tissue engineering applications. Macromol Biosci， 2010， 10 （1）：91-100.
20. 　Frohbergh ME， Katsman A， Botta GP， et al. Electrospun hydroxyapatite-containing chitosan nanoﬁbers crosslinked with genipin for bone tissue engineering. Biomaterials， 2012， 33 （36）：9167-9178.
21. 　Lim HG， Kim SH， Choi SY， et al. Anticalciﬁcation effects of dece-llularization， solvent， and detoxiﬁcation treatment for genipin and glutaraldehyde ﬁxation of bovine pericardium. Eur J Cardiothorac Surg， 2012， 41 （2）：383-390.
22. 　Yang M， Chen CZ， Shu YS， et al. Preseeding of human vascular cells in decellularized bovine pericardium scaffold for tissue-engineered heart valve：an in vitro and in vivo feasibility study. J Biomed Mater Res B Appl Biomater， 2012， 100 （6）：1654-1661.
23. 　Saporito WF， Pires AC， Cardoso SH， et al. Bovine pericardium retail preserved in glutaraldehyde and used as a vascular patch. BMC Surg， 2011， 11 （37）：37.
24. 　Schoen FJ， Levy RJ. Calcification of tissue heart valve substitutes：progress toward understanding and prevention. Ann Thorac Surg， 2005， 79 （3）：1072-1080.
25. 　Manji RA， Zhu LF， Nijjar NK， et al. Glutaraldehyde-fixed bioprosthetic heart valve conduits calcify and fail from xenograft rejection. Circulation， 2006， 114 （4）：318-327.
26. 　Till H， Muensterer OJ， Rolle U， et al. Staged esophageal lengtheningwith internal and subsequent external traction sutures leads to primary repair of an ultralong gap esophageal atresia with upper pouch trache-oesophagel fistula. J Pediatr Surg， 2008， 43 （6）：33-35.
27. 　Arul GS， Parikh D. Oesophageal replacement in children. Ann R Coll Surg Engl， 2008， 90 （1）：7-12.
28. 　Gilbert TW， Sellaro TL， Badylak SF. Decellularization of tissues and organs. Biomaterials， 2006， 27 （19）：3675-3683.
29. 　Badylak SF. Xenogeneic extracellular matrix as a scaffold for tissue Reconstruction. Transpl Immunol， 2004， 12 （3-4）：367-377.
30. 　Adair-Kirk TL， Senior RM. Fragments of extracellular matrix as mediators of inflammation. Int J Biochem Cell Biol， 2008， 40 （6-7）：1101-1110.
31. 　Badylak SF， Gilbert TW. Immune response to biologic scaffoldmaterials. Semin Immunol， 2008， 20 （2）：109-116.
32. 　Koch H， Graneist C， Emmrich F， et al. Xenogenic esophagus scaffolds fixed with several agents：comparative invivo study of rejection and inﬂammation. J Biomed Biotechnol， 2012， 2012：948320.
33. 　Ott LM， Weatherly RA， Detamore MS. Overview of tracheal tissueengineering：clinical need drives the laboratory approach. Ann BiomedEng， 2011， 39 （8）：2091-2113.
34. 　Hoshiba T， Lu H， Kawazoe N， et al. Decellularized matrices for tissueengineering. Expert Opin Biol Ther， 2010， 10 （12）：1717-1728.
35. 　Crapo PM， Gilbert TW， Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials， 2011， 32 （12）：3233-3243.
36. 　Englert C， Blunk T， Müller R， et al. Bonding of articular cartilage using a combination of biochemical degradation and surface cross-linking. Arthritis Res Ther， 2007， 9 （3）：47.
37. 　Liang HC， Chang WH， Lin KJ， et al. Genipin-crosslinked gelatin microspheres as a drug carrier for intramuscular administration：in vitro and in vivo studies. J Biomed Mater Res A， 2003， 65 （2）：271-282.
38. 　Wang GF， Wu SY， Rao JJ， et al. Genipin inhibits endothelial exocy-tosis via nitric oxide in cultured human umbilical vein endothelial cells. Acta Pharmacol Sin， 2009， 30 （5）：589-596.
39. 　Koo HJ， Lim KH， Jung HJ， et al. Anti-inflammatory evaluation of gardenia extract， geniposide and genipin. J Ethnopharmacol， 2006， 103 （3）：496-500.
40. 　Zhang CY， Parton LE， Ye CP， et al. Genipin inhibits UCP2-mediatedproton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab， 2006， 3 （6）：417-427.
41. 　Yamazaki M， Chiba K. Genipin exhibits neurotrophic effects through a common signaling pathway in nitric oxide synthase-expressing cells. Eur J Pharmacol， 2008， 581 （3）：255-261.
42. 　Sung HW， Huang RN， Huang LL， et al. Feasibility study of a naturalcrosslinking reagent for biological tissue fixation. J Biomed Mater Res， 1998， 42 （4）：560-567.
43. 　Yu XX， Liu F， Xu YT， 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.
44. 　Wang C， Lau TT， Loh WL， et al. Cytocompatibility study of a natural biomaterial crosslinker——Genipin with therapeutic model cells. J Biomed Mater Res B Appl Biomater， 2011， 97 （1）：58-65.
45. 　Baiguera S， Macchiarini P， Ribatti D. Chorioallantoic membrane for in vivo investigation of tissue-engineered construct biocompatibility. J Biomed Mater Res B Appl Biomater， 2012， 100 （5）：1425-1434.

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