Optimizing Glutaraldehyde-Fixed Tissue Heart Valves with Chondroitin Sulfate Hydrogel for Endothelialization and Shielding against Deterioration

Abstract

Porcine glutaraldehyde-fixed pericardium is widely used to replace human heart valves. Despite the stabilizing effects of glutaraldehyde fixation, the lack of endothelialization and the occurrence of immune reactions contribute to calcification and structural valve deterioration, which is particularly significant in young patients where valve longevity is crucial. This report shows an optimization system to enhance endothelialization of fixed pericardium to mimic the biological function of a native heart valve. The glutaraldehyde detoxification together with the application of a biodegradable methacrylated chondroitin sulfate hydrogel reduces aldehydes cytotoxicity, increases the migration and proliferation of endothelial cells, the recruitment of endothelial cell progenitors, and confers thrombo-resistance in fixed pericardium. The combination of glutaraldehyde detoxification and a coating with chondroitin sulfate hydrogel promotes in situ mechanisms of endothelialization in fixed pericardium. We offer a new solution to improve the long-life of bioprosthetic valves and explore means of making valves suitable to endothelialization.

Hybrid Pericardium with VEGF‐Loaded Hyaluronic Acid Hydrogel Coating to Improve the Biological Properties of Bioprosthetic Heart Valves

“…Clinically used BHVs usually fail within 12−15 years accompanied by severe calcification, which greatly restricts their further development. Endothelialization of BHVs may be one way to alleviate this because it can provide an inherent bioactive surface and modulate the interactions between smooth muscle cells, fibroblasts, and immune cells . The absence of endothelium can lead to the aggregation, proliferation, and migration of smooth muscle cells or immune cells, which may further result in the calcification of BHVs and cause loss of function.…”

“…The absence of endothelium can lead to the aggregation, proliferation, and migration of smooth muscle cells or immune cells, which may further result in the calcification of BHVs and cause loss of function. Unfortunately, BHVs crosslinked by glutaraldehyde have been reported to be cytotoxic and not suitable for endothelial growth and proliferation …”

“…When pericardia are used for BHVs in the clinic, they are likely to cause serious pathological calcification and result in clinical failure . One major reason for this is the lack of endothelialization . Endothelial cells have an important role in the regulation of hemostatic balance, coagulation, and the local behavior of platelets and leucocytes.…”

Regeneration of skeletal system with genipin crosslinked biomaterials

“… 12 The carbonyl groups in traditional chemical crosslinking reagents, such as glutaraldehyde and 1-ethyl-3-(3-dimethylamineproply) carbodiimide (EDC), can interact with hydroxyl and amino groups in natural biomaterials. 13 , 14 Based on Schiff base and acetalization reactions, dense three-dimensional hydrogel scaffolds can be formed after crosslinking. 15 However, these artificial chemical crosslinking reagents are more or less cytotoxic, causing cell death after seeding in the hydrogel and leading to low bioactivity or even tissue necrosis around the implantation area.…”

Bovine pericardial extracellular matrix niche modulates human aortic endothelial cell phenotype and function

“…Unfortunately, although this process reduces recipient acute graft-specific adaptive immune response, it fails to eliminate immunogenicity and chronic recipient immune responses persist 5 . Furthermore, GTA fixation chemically alters the biomaterial’s composition and liberates toxic aldehyde residues 6,7 , limiting repopulating cell viability, endothelialization 8,9 and recipient cell-mediated remodeling 10,11 . These limitations of GTA fixation result in biomaterial related complications including graft calcification and stenosis 2,12 .…”