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Analyzing The Risk Of Calcification In Materials Used For In Situ Heart Valve Tissue Engineering
Dewy C. Valk, van der1, Charlotte M. Hoes1, Yunia M.H. Rasenberg1, Wojtek Szymczyk1, Anat Akiva2, Anthal I.P.M. Smits1, Carlijn V.C. Bouten1.
1Eindhoven University of Technology, Eindhoven, Netherlands, 2Radbout University Medical Center, Nijmegen, Netherlands.

OBJECTIVE: Material-driven in situ tissue engineering (TE) of valvular grafts prospects a great alternative to current valve replacements. However promising, some risks need assessment to ensure safe clinical translation. Among these is calcific nodule formation, reported in 35% of current TE grafts in preclinical animal studies. This study established an in vitro model to assess calcification potential of materials for in situ TE.
METHODS: Three candidate materials for in situ TE were electrospun into fibrous scaffolds; Polycaprolactone (PCL), Bis-Urea extended PCL (PCL-BU), and BU-Polycarbonate (PC-BU). Scaffolds were seeded with porcine Valvular Interstitial Cells (pVICs) or used unseeded, and cultured for three weeks in phosphate-enhanced calcification medium (CM). PCL scaffolds were cultured in CM enhanced with Macrophage-conditioned inflammation medium (IM). Calcification and collagen formation were assessed with live hydroxyapatite and collagen staining.
RESULTS: After three weeks, PCL-BU and PC-BU scaffolds showed little calcification, although calcification in PCL scaffolds increased (Figure). Collagen formation was similar between PCL and PC-BU, but more compared to PCL-BU scaffolds. Expectedly, scaffolds cultured without pVICs stained negative for collagen and hydroxyapatite. Seeded PCL scaffolds cultured in IM showed increased calcification compared to CM.
CONCLUSIONS: This study showed a different calcification potential of materials used for in situ TE. Incorporation of a BU group into the scaffold decreases calcification, unrelated to the amount of collagen formation. Scaffold calcification is mediated by cellular activity and increases with inflammation. The established in vitro model can be used to assess if materials for in situ TE calcify, and why. Moving forward, this model can be extended with hemodynamic loads and patient specific culture conditions to assess risk of calcification under in vivo clinically relevant conditions. This data may support optimization of biomaterials for in situ valvular TE, aiding safe clinical translation.


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