Immobilized Bisphosphonates as Potential Inhibitors of Bioprosthetic Calcification: Effects on Various Xenogeneic Cardiovascular Tissues

Abstract

Calcification is the major factor limiting the clinical use of bioprostheses. It may be prevented by the immobilization of bisphosphonic compounds (BPs) on the biomaterial. In this study, we assessed the accumulation and structure of calcium phosphate deposits in collagen-rich bovine pericardium (Pe) and elastin-rich porcine aortic wall (Ao) and bovine jugular vein wall (Ve) cross-linked with glutaraldehyde (GA) or diepoxy compound (DE). These tissues were then modified with pamidronic (PAM) acid or 2-(2′-carboxyethylamino)ethylidene-1,1-bisphosphonic (CEABA) acid. Tissue transformations were studied using Fourier-transform infrared spectroscopy. After subcutaneous implantation of the biomaterials in 220 rats, calcification dynamics were examined using atomic absorption spectrophotometry, light microscopy after von Kossa staining, and scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy The calcium content in all GA-cross-linked tissues and DE-cross-linked Ao increased to 100–160 mg/g on day 60 after implantation. BPs prevented the accumulation of phosphates on the surface of all materials and most effectively inhibited calcification in GA-cross-linked Ao and DE-cross-linked Pe. PAM containing -OH in the R1 group was more effective than CEABA containing -H in R1. The calcification-inhibitory effect of BPs may be realized through their ability to block nucleation and prevent the growth of hydroxyapatite crystals.

Calcification of Various Bioprosthetic Materials in Rats: Is It Really Different?

“…Thus, the initial increase in local phosphate concentration plays a crucial role in HAP nucleation. The anti-calcification effect of bisphosphonates [ 49 ] bound noncovalently can indirectly confirm this. Their phosphonate groups may compete with the inorganic phosphate of biological fluids for positively charged nitrogen.…”

Current development of bovine jugular vein conduit for right ventricular outflow tract reconstruction

“…Apart from amino acids and peptides, Zhuravleva et al assessed glutaraldehyde-treated BJV tissues modified with bisphosphonates. Both of the two bisphosphonates (pamidronic acid and 2-(2’ -carboxyethylamino)ethylidene-1,1-bisphosphonic acid) they studied were satisfactorily immobilized on the BJV tissue, and exhibited calcification-inhibitory effects through their ability to block nucleation and prevent the growth of hydroxyapatite crystals ( Zhuravleva et al, 2021 ). Ding et al took an even more sophisticated recipe, firstly introducing 2-amino-4-pentenoic acid as a co-crosslinker with carbon-carbon double bonds and then grafting on poly (ethylene glycol) diacrylate by radical polymerization, which not only resulted in better cytocompatibility but also improved hemodynamic property ( Ding et al, 2022 ).…”