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

Irina Y Zhuravleva,Svetlana S Shatskaya,Elena V Karpova,Anatoly T Titov,Yuliya F Polienko,Anna A Dokuchaeva,Tatyana P Timchenko

doi:10.3390/biomedicines10010065

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.

Highlights

Introduction iationsBioprosthetic heart valves (BHVs) have indisputable advantages over mechanical valves in terms of hemodynamics and the patient’s quality of life
Using elastin-rich biomaterials implanted subcutaneously in rats, we previously demonstrated that the effectiveness of immobilized N-bisphosphonic compounds (BPs) depends on the composition of the extracellular matrix (ECM), the cross-linker used, and the chemical structure of the immobilized compound, rather than on the amount of immobilized BP [19]
In a screening of six nitrogen-containing BPs (N-BPs), we found that PAM and 2-(20 -carboxyethylamino)ethylidene1,1-bisphosphonic acid (CEABA) (Figure 1) had the strongest inhibitory effect on the calcium-binding capacity of porcine aortic (Ao) and bovine jugular vein (Ve) walls, crosslinked with GA or ethylene glycol diglycidyl ether (DE) [19]

Summary

Introduction

Bioprosthetic heart valves (BHVs) have indisputable advantages over mechanical valves in terms of hemodynamics and the patient’s quality of life. While in 2008, the share of mechanical prostheses was 45.3% of total aortic valve replacements, in 2017, it was only 17% [1]. The number of implanted BHVs increased nearly two-fold in the same period [2]. The main disadvantage of BHVs is the high rate of calcific dysfunction, which limits their use, especially in young patients. Minimally invasive technologies, such as transcatheter heart valve replacement, have been actively developed. The number of transcatheter procedures is growing yearly and will continue to grow. Transcatheter heart valve leaflets are made from biological materials, mostly bovine or porcine pericardium; overcoming calcification is especially important for this progressive approach

Methods

Results

Discussion

Conclusion