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J Heart Valve Dis. 1996 Sep;5(5):518-25.

Amide cross-linking: an alternative to glutaraldehyde fixation.

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Biomedical Design, Inc., Atlanta, GA 30318, USA.



A new fixation method for bioprosthetic tissues is being developed, which does not utilize the standard glutaraldehyde treatment. This method, referred to as Ultifix, uses a coupler and a coupling enhancer with or without one or more coupling agents. It fixes the tissue by linking the amine and the carboxyl moieties through amide bonds either directly, or indirectly when coupling agents form bridges. The amide bonds thus formed are more stable than the Schiff-base bonds formed by glutaraldehyde. All compounds used during the fixation process and their by-products are water-soluble, and are easily removed by washing. In addition, the by-products are not toxic, as opposed to glutaraldehyde, which induces toxic reactions after implantation. The tests described in the manuscript were specifically aimed at evaluating the cross-linking efficacy of the process on heart valve tissues, as well as their resistance to calcification in the rat model.


Porcine aortic roots and porcine pericardium were fixed using the coupling agents 1,6-hexane diamine (DIA) and suberic acid (SUA) in the presence of the coupler 1-ethyl-3(-3 dimethyl aminopropyl) carbodiimide hydrochloride (EDC) and the coupling enhancer N-hydroxysulfosuccinimide (sulfo-NHS). The tissues were then evaluated for their resistance to thermal denaturation, to enzymatic digestion, and to calcification when implanted subdermally in rats for two, four, eight and 16 weeks.


The results demonstrate that the cusps and the wall of porcine aortic roots, and porcine pericardium, are as well stabilized and as cross-linked by Ultifix as they are by the standard glutaraldehyde method. In addition, the cusps of the porcine aortic root and the porcine pericardium, but not the wall of the porcine aortic root, calcify minimally and significantly less when implanted subdermally for up to 16 weeks in three week old rats than the control material fixed with glutaraldehyde.


The Ultifix process of cross-linking bioprosthetic heart valves may thus be a good alternative to the standard glutaraldehyde process of fixation, with increased durability and without toxic effects.

[Indexed for MEDLINE]

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