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Genipin Blues: an alternative non-toxic crosslinker for heart valves?

Pamela Somers (UGent) , Filip De Somer (UGent) , Maria Cornelissen (UGent) , Stefaan Bouchez (UGent) , Frank Gasthuys (UGent) , RAJKISHAN NARINE (UGent) , Eric Cox (UGent) and Guido Van Nooten (UGent)
(2008) JOURNAL OF HEART VALVE DISEASE. 17(6). p.682-688
Author
Organization
Abstract
Background and aim of the study: One approach in tissue-engineering involves the implantation of decellularized, xenogenic scaffolds, with the expectation of repopulation in vivo. However, a major limitation of this method is the propensity to induce a strong immune host response. The study aim was to mitigate this immunogenicity by employing a crosslinking treatment with genipin. Methods: Porcine matrices were prepared using a detergent-enzymatic treatment and fixed in 0.01% or 0.001% aqueous genipin. The mechanical properties of the matrices were monitored by tensile strength testing. The survival of chicken fibroblasts was used to determine cell-friendliness of the matrices. Nonfixed, decellularized biological scaffolds (n = 3) were implanted in a sheep model and compared to an equal number of genipin-fixed scaffolds (n = 6). Matrices implanted in the pulmonary position were explanted after six weeks and examined using light and transmission electron microscopy. The antibody reaction against porcine tissue in sheep serum was also determined. Results: Statistically significant differences were found between non-fixed leaflets, 0.001% genipin-and 0.6% glutaraldehyde (GA)-fixed leaflets for work to maximum load (non-fixed 0.00646 J; genipin-fixed 0.00509 J; GA-fixed 0.00543 J) and stiffness (non-fixed 9281 N/m; genipin-fixed 16214 N/m; GA-fixed 14401 N/m). Genipin-treated matrices were not cytotoxic. For all concentrations of genipin a high proportion of viable cells was present (79-100%). Low-dose GA (10 mu g/ml) showed a distinct cytotoxicity (24.8% viability). At explant, an intense chronic inflammatory response was observed in non-fixed matrices, in contrast to genipin-fixed scaffolds. The sheep serum showed a marked decrease in IgG response in both 0.001% and 0.01% genipin-fixed matrices (IgG 30 and 20, respectively) when compared to non-fixed matrices (IgG 40). Conclusion: Genipin crosslinking of the matrices attenuated, but did not eliminate, the inflammatory host reaction. Whether genipin treatment might extend the durability of xenogenic scaffolds remains to be investigated.
Keywords
MATRIX, CONDUITS, TISSUE, PROLIFERATION, COLLAGEN, GLUTARALDEHYDE, IN-VIVO, VITRO

Citation

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MLA
Somers, Pamela, Filip De Somer, Maria Cornelissen, et al. “Genipin Blues: An Alternative Non-toxic Crosslinker for Heart Valves?” JOURNAL OF HEART VALVE DISEASE 17.6 (2008): 682–688. Print.
APA
Somers, P., De Somer, F., Cornelissen, M., Bouchez, S., Gasthuys, F., NARINE, R., Cox, E., et al. (2008). Genipin Blues: an alternative non-toxic crosslinker for heart valves? JOURNAL OF HEART VALVE DISEASE, 17(6), 682–688. Presented at the 3rd Biennial meeting of Heart Valve Biology and Tissue Engineering.
Chicago author-date
Somers, Pamela, Filip De Somer, Maria Cornelissen, Stefaan Bouchez, Frank Gasthuys, RAJKISHAN NARINE, Eric Cox, and Guido Van Nooten. 2008. “Genipin Blues: An Alternative Non-toxic Crosslinker for Heart Valves?” Journal of Heart Valve Disease 17 (6): 682–688.
Chicago author-date (all authors)
Somers, Pamela, Filip De Somer, Maria Cornelissen, Stefaan Bouchez, Frank Gasthuys, RAJKISHAN NARINE, Eric Cox, and Guido Van Nooten. 2008. “Genipin Blues: An Alternative Non-toxic Crosslinker for Heart Valves?” Journal of Heart Valve Disease 17 (6): 682–688.
Vancouver
1.
Somers P, De Somer F, Cornelissen M, Bouchez S, Gasthuys F, NARINE R, et al. Genipin Blues: an alternative non-toxic crosslinker for heart valves? JOURNAL OF HEART VALVE DISEASE. 2008;17(6):682–8.
IEEE
[1]
P. Somers et al., “Genipin Blues: an alternative non-toxic crosslinker for heart valves?,” JOURNAL OF HEART VALVE DISEASE, vol. 17, no. 6, pp. 682–688, 2008.
@article{515896,
  abstract     = {Background and aim of the study: One approach in tissue-engineering involves the implantation of decellularized, xenogenic scaffolds, with the expectation of repopulation in vivo. However, a major limitation of this method is the propensity to induce a strong immune host response. The study aim was to mitigate this immunogenicity by employing a crosslinking treatment with genipin. 
Methods: Porcine matrices were prepared using a detergent-enzymatic treatment and fixed in 0.01% or 0.001% aqueous genipin. The mechanical properties of the matrices were monitored by tensile strength testing. The survival of chicken fibroblasts was used to determine cell-friendliness of the matrices. Nonfixed, decellularized biological scaffolds (n = 3) were implanted in a sheep model and compared to an equal number of genipin-fixed scaffolds (n = 6). Matrices implanted in the pulmonary position were explanted after six weeks and examined using light and transmission electron microscopy. The antibody reaction against porcine tissue in sheep serum was also determined. 
Results: Statistically significant differences were found between non-fixed leaflets, 0.001% genipin-and 0.6% glutaraldehyde (GA)-fixed leaflets for work to maximum load (non-fixed 0.00646 J; genipin-fixed 0.00509 J; GA-fixed 0.00543 J) and stiffness (non-fixed 9281 N/m; genipin-fixed 16214 N/m; GA-fixed 14401 N/m). Genipin-treated matrices were not cytotoxic. For all concentrations of genipin a high proportion of viable cells was present (79-100%). Low-dose GA (10 mu g/ml) showed a distinct cytotoxicity (24.8% viability). At explant, an intense chronic inflammatory response was observed in non-fixed matrices, in contrast to genipin-fixed scaffolds. The sheep serum showed a marked decrease in IgG response in both 0.001% and 0.01% genipin-fixed matrices (IgG 30 and 20, respectively) when compared to non-fixed matrices (IgG 40). 
Conclusion: Genipin crosslinking of the matrices attenuated, but did not eliminate, the inflammatory host reaction. Whether genipin treatment might extend the durability of xenogenic scaffolds remains to be investigated.},
  author       = {Somers, Pamela and De Somer, Filip and Cornelissen, Maria and Bouchez, Stefaan and Gasthuys, Frank and NARINE, RAJKISHAN and Cox, Eric and Van Nooten, Guido},
  issn         = {0966-8519},
  journal      = {JOURNAL OF HEART VALVE DISEASE},
  keywords     = {MATRIX,CONDUITS,TISSUE,PROLIFERATION,COLLAGEN,GLUTARALDEHYDE,IN-VIVO,VITRO},
  language     = {eng},
  location     = {London, UK},
  number       = {6},
  pages        = {682--688},
  title        = {Genipin Blues: an alternative non-toxic crosslinker for heart valves?},
  volume       = {17},
  year         = {2008},
}

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