Reduction of calcification of carbodiimide-processed heart valve tissue by prior blocking of amine groups with monoaldehydes.
OBJECTIVE
Failure of implanted bioprostheses due to calcification is a commonly occurring phenomenon. In order to prevent calcification, many alternative cross-linking methods to glutaraldehyde (GA) have been developed and evaluated.


METHODS
In a novel approach an improved carbodiimide (EDC) cross-linking method that comprises a two-step process was developed. First, the available amine groups in (tissue) collagen were blocked with a monoaldehyde, followed by an EDC-activated cross-linking reaction of the carboxyl groups in the tissue with a poly (propylene glycol) bis 2-(amino-propyl) ether (Jeffamine).


RESULTS
Samples processed via this method have shown a significantly reduced calcification in a subdermal juvenile rat model compared to samples with standard GA treatment. In the present study, heart valve tissue was blocked with various monoaldehydes, followed by reaction with Jeffamine using carbodiimide cross-linking chemistry. Leaflet calcification was almost eliminated using different aldehydes, whereas wall calcification was maximally 95% reduced when propionaldehyde was used as blocking agent, as compared to a carbodiimide cross-linked control without Jeffamine and blocked amine groups.


CONCLUSIONS
Amine blocking and cross-linking technology appears promising in the design of the next generation of tissue valves. Calcification was significantly reduced compared to GA cross-linking. The mechanistic insight of decreased wall calcification is still unknown, and research investigations are ongoing.
Everaerts
Frank
F
Medtronic Inc., Minneapolis, USA. Frank.Everaerts@medtronic.com
Gillissen
Mirian
M
Torrianni
Mark
M
Zilla
Peter
P
Human
Paul
P
Hendriks
Marc
M
Feijen
Jan
J
D000818:Animals; D001705:Bioprosthesis; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002234:Carbodiimides / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005976:Glutaral / Q000494:pharmacology*; D006350:Heart Valve Prosthesis; D006351:Heart Valves / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D019919:Prosthesis Implantation; D051381:Rats; D020318:Rats, Long-Evans; D013552:Swine
D002234:Carbodiimides; D003432:Cross-Linking Reagents; D005976:Glutaral