Treatment with bisphosphonates to mitigate calcification of elastin‐containing bioprosthetic materials

Abstract

This study evaluated the ability of bisphosphonates (BPAs) of different molecular structures to mitigate the calcification of porcine aortic wall (PAW) and bovine jugular vein wall (BJVW). Tissues cross-linked with glutaraldehyde (GA) or diepoxide (DE) were modified with pamidronic acid (PAM), alendronic acid (ALE), neridronic acid (NER) (type 1 BPAs); 2-(2 0 -carboxyethylamino)ethylidene-1,1-bisphosphonic acid (CEABA), 2-(5-carboxypentylamino)ethylidene-1,1-bisphosphonic acid (CPABA) (type 2); and zoledronic acid (ZOL) (type 3). After implanting the tissue samples subcutaneously in 100 rats, calcification was examined using atomic absorption spectrophotometry (60-day explants) and light microscopy after von Kossa staining (10-and 30-day explants). The calcium contents in GA-BJVW and GA-and DE-PAW increased up to 100-120 mg/g after 60 days, while being 3 times lower in DE-BJVW.In modified and nonmodified PAW samples, calcium phosphates appeared by day 10 and were associated with elastic fibers and devitalized cellular elements. In all groups of BJVW samples, mineralization began in elastic fibers near the subendothelial layer. In addition, calcified collagen was found in the GA-BJVW samples. Minimal calcification was found in GA-PAW treated with type 1 BPAs and CEABA. For DE-PAW and GA-BJVW, the calcium level significantly decreased with PAM and CEABA. Meanwhile, ALE and NER were effective for DE-BJVW.

Bovine jugular vein conduit: What affects its elastomechanical properties and thermostability?

“…12 We previously showed that cross-linking with diepoxide (ethylene glycol diglycidyl ether, DE) significantly reduced the calcification of the BJV wall (BJVW) in a subcutaneous rat model. 20,21 Epoxy treatment has been proven to reduce inflammatory responses, immunogenicity, and cytotoxicity of other bioprosthetic materials. [22][23][24] With this, as well as the excellent results obtained in previous experimental studies, [1][2][3][4] allow us to consider it expedient to develop cross-linking methods using epoxy compounds.…”

“…We previously showed that cross‐linking with diepoxide (ethylene glycol diglycidyl ether, DE) significantly reduced the calcification of the BJV wall (BJVW) in a subcutaneous rat model 20,21 . Epoxy treatment has been proven to reduce inflammatory responses, immunogenicity, and cytotoxicity of other bioprosthetic materials 22‐24 .…”

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

“…In particular, R2 may contain primary or secondary amines. This group can be used for BP immobilization by binding with an epoxy or aldehyde masking group that remains free after cross-linking of the biomaterial [ 15 , 16 , 19 ].…”

“…We hypothesized that it involves direct physicochemical effects in inhibiting calcium phosphate nucleation and crystallization. Using elastin-rich biomaterials implanted subcutaneously in rats, we previously demonstrated that the effectiveness of immobilized N-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 N-BPs, we found that PAM and 2-(2′-carboxyethylamino)ethylidene-1,1-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, cross-linked with GA or ethylene glycol diglycidyl ether (DE) [ 19 ].…”

“…Using elastin-rich biomaterials implanted subcutaneously in rats, we previously demonstrated that the effectiveness of immobilized N-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 N-BPs, we found that PAM and 2-(2′-carboxyethylamino)ethylidene-1,1-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, cross-linked with GA or ethylene glycol diglycidyl ether (DE) [ 19 ]. To unravel the mechanism of action of immobilized BPs, it is necessary to understand which changes they induce in the processes of accumulation and transformation of calcium phosphates in bioprosthetic materials.…”