Epoxy Chitosan-Crosslinked Acellular Bovine Pericardium with Improved Anti-calcification and Biological Properties

Abstract

Glutaraldehyde (GA) was conventionally used to crosslink bovine pericardium to prepare bioprosthetic heart valves (BHVs), which usually fail within 10 years because of valve deterioration and calcification. To overcome the high cytotoxicity and severe calcification of GA-crosslinked BHVs, a quaternary ammonium salt of epoxy chitosan (epoxy group-modified 3-chlorine-2-hydroxypropyl trimethyl chitosan, abbreviated as “eHTCC”) was developed to modify the acellular bovine pericardium to substitute GA and improve its anti-calcification and biocompatible properties. Mechanical test, enzymatic stability test, blood compatibility assay, and cytocompatibility assay were used to investigate its mechanical property and biocompatibility. The anti-calcification effect of the eHTCC-modified bovine pericardium (eHTCC-BP) was assessed by in vitro assay and rat subcutaneous implantation assay. The results showed that eHTCC-BP could improve the mechanical properties and anti-enzymolysis ability of BP, as well as retain the original three-dimensional structure, compared with the uncrosslinked-BP group. Moreover, the in vivo calcification level of the eHTCC-BP group was much lower than that of the GA-BP group, which was 5.1% (2 weeks), 2.3% (4 weeks), and 0.8% (8 weeks) of the GA-BP group. In summary, this study demonstrated that eHTCC could be a potential crosslinking agent for the extracellular matrix for its favorable crosslinking effects, anti-enzymolysis, anti-calcification, and biocompatibility.

Development of Innovative Biomaterials and Devices for the Treatment of Cardiovascular Diseases

“…A kind of nonglutaraldehyde‐crosslinked bovine pericardium has been developed by the treatment of a quaternary ammonium salt of epoxy chitosan (epoxy‐group‐modified 3‐chlorine‐2‐hydroxypropyl trimethyl chitosan). [ 105 ] Compared to the Glut‐treated bovine pericardium, improved anticalcification property along with better biocompatibility and blood compatibility were demonstrated for the epoxy‐chitosan‐crosslinked bovine pericardium. However, relatively lower mechanical properties and enzymatic degradation resistance attributed to the relatively lower fixation of amine group on bovine pericardium might limit its further application in clinic.…”

Hybrid heart valves with VEGF-loaded zwitterionic hydrogel coating for improved anti-calcification and re-endothelialization

“…Glutaraldehyde is used as a crosslinker to stabilize collagen, but the toxicity of the aldehyde groups can lead to poor endothelization and residual aldehyde groups and impairing charges balances after glutaraldehyde treatment have been shown to be involved in the calcification of the bioprosthetic heart valve [ 11 , [16] , [17] , [18] ]. Some studies have reported that nonglutaraldehyde crosslinking agents such as epoxy chitosan [ 19 ], riboflavin [ 20 ], N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) [ 14 ] have been used for the anti-calcification treatment of heart valves. Although good results have been achieved, good blood biocompatibility cannot be guaranteed.…”

Poly(ethylene glycol)-Based Coatings for Bioprosthetic Valve Tissues: Toward Restoration of Physiological Behavior

“…As glutaraldehyde fixation has been shown to be a key contributor to structural tissue failure, this step is a priority candidate for process modification. Indeed, there have been many promising studies that have reduced calcification by using a different fixative, but these efforts have not translated to clinical success. − This is likely due to the high bar needed to obtain FDA approval for BPVs prepared with different fixatives: a change to the most substantial part of a class III medical device requires full reassessment of its abilities. In comparison, if changes are made to the post-glutaraldehyde fixation process, only the modification needs to be proven safe, as a glutaraldehyde-fixed BPV would be considered a predicate device for FDA approval purposes.…”