Inhibition of Bioprosthesis Calcification Due to Synergistic Effect of Fe/Mg Ions to Polyethylene Glycol Grafted Bovine Pericardium

Abstract

Calcification has limited the durability of bioprosthetic heart valves fabricated from glutaraldehyde pretreated porcine aortic valves or bovine pericardium (BP). The present study describes calcium antagonistic effect of polyethylene glycol grafted bovine pericardium (PEG-GABP) with Fe2+/Mg2+ delivery from a co-matrix system in rat subcutaneous model. Retrieved samples were biochemically evaluated for calcification and alkaline phosphate (AP) activity. Scanning electron micrographs of 21-day explants had shown excessive calcification with glutaraldehyde treated BP (control). However, the PEG grafting and Fe/Mg release had substantially inhibited the deposition of calcium on BP. The extractable alkaline phosphatase activity was also reduced with PEG grafting and metal ion release to BP. The extractable AP had shown peak activity at 72 h [for GATBP--250.5 +/- 1.2 nm pnp/mg protein/min enzyme activity (unit), PEG-GABP--165.2 +/- 16.6 units], but markedly reduced after 21 days (22.1 +/- 1.8 and 12.0 +/- 1.5 units, respectively). The initial high levels may be due to tissue injury via surgery, which mitigated with time. It is assumed that ferric ions may slow down or retard the calcification process by the inhibition of proper formation of hydroxy apatite while magnesium ions disrupt the growth of these crystals by replacing Ca2+. In addition it maybe hypothesized that these metal ions may inhibit the key element alkaline phosphatase, which acts as the substrate for mineralization. Hence, it is conceivable that a combination therapy via surface grafting of PEG and local delivery of low levels of ferric and magnesium ions may prevent the bioprosthesis associated calcification.

Metal Ion-Loaded Nanofibre Matrices for Calcification Inhibition in Polyurethane Implants

“…The small size of calcific deposits represented the inhibition of calcium-phosphate crystal formation in the initial stages of nucleation itself [ 67 ]. Thus, it appears evident that the released Mg 2+ and Fe 3+ ions prevented calcification by interrupting the formation of proper HAP crystals on the film surface, as proposed by Vasudev et al [ 27 ].…”

“…Ferric ions (Fe 3+ ) have also been reported to inhibit the progression of calcification via the generation of reactive oxygen species and oxidative stress mechanisms in vascular tissues [ 26 ]. Vasudev et al proposed that Fe 3+ ions slowed down the calcification process by the inhibition of HAP formation, while Mg 2+ ions disrupted the growth of HAP crystals by replacing Ca 2+ ions [ 27 ]. It was also hypothesised that both Fe 3+ and Mg 2+ ions can inhibit formation of alkaline phosphate which acts as a substrate for HAP crystal binding.…”

Calcification of Biomaterials and Diseased States

“…Metal ions, including iron, aluminum, and magnesium, are gaining popularity in current research because of their ability to bind to forming hydroxyapatite crystals in the serum and prevent further deposition [27]. Though the mechanism is not fully understood, it is hypothesized that ions such as magnesium bind where calcium typically would, preventing calcium deposits [28]. They also are thought to interrupt alkaline phosphatase activity [27].…”

A multifunctional bio-patch crosslinked with glutaraldehyde for enhanced mechanical performance, anti-coagulation properties, and anti-calcification properties

“…Post-modification of GA is intended to reduce biotoxicity after GA treatment using additives or removing free aldehyde groups, which might be the source of calcification. 10 Agents such as sodium borohydride, citric acid, l -lysine, l -glutamic acid and α-amino oleic acid have been shown to have high efficiency for aldehyde neutralization, 11–13 but their long-term effects need further study.…”