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SELECTBIO Conferences Microphysiological Systems 2023: A Deep Dive into Technologies & Applications


Calcific Aortic Valve Disease on a Chip

Gretchen Mahler, Professor of Biomedical Engineering, Binghamton University

The development of calcific aortic valve disease (CAVD) is an active process and ranges from mild valve thickening (aortic sclerosis) to severe leaflet calcification (aortic stenosis). Early CAVD is characterized by the infiltration of immune cells into the extracellular matrix (ECM), reorganization of the ECM, and the deposition of oxidized low-density lipoproteins (oxLDLs), while late CAVD includes severe calcification, collagen disorganization, and the deposition of glycosaminoglycans (GAGs) in the fibrosa layer. In the United States, the prevalence of moderate to severe calcific aortic stenosis in patients =75 years old is 2.8% and is projected to more than double by 2050. Current treatments for CAVD include surgical valve replacement and/or minimal drug interventions tailored to other cardiovascular diseases. Advances in valve disease research have relied on animals and static cell cultures, but engineered, dynamic models may help to further the understanding of CAVD onset and progression. We have created a microfluidic model of the aortic valve fibrosa that includes a dynamic, 3D culture environment, physiologically relevant extracellular matrix, and aortic valve and immune cells that remain viable for up to 21 days. Our previous work demonstrated that the addition of GAGs, particularly chondroitin sulfate, to 3D collagen I hydrogels promoted endothelial to mesenchymal transformation and calcification in a static cell culture. Our results show that after 14 days in dynamic culture both low (1 dyne/cm2) and high (20 dyne/cm2) shear stress induce significant calcifications in the microfluidic model, that the addition of GAGs to the 3D matrix only slightly advances pathogenesis, and that the presence of endothelial cells results in more significant calcification. SEM/EDX was used to analyze chemical composition, composition distribution, and composition concentration of the static or dynamic cell culture samples that formed calcified nodules. Our microfluidic device-derived calcifications are primarily composed of octacalcium phosphates (Ca/P = 1.33), while human valve calcifications are primarily composed of hydroxyapatite. These results were generated without osteogenic medium. The addition of 50 µg/mL oxLdLs to the collagen I ECM in the microfluidic device resulted in hydroxyapatite nodules forming within two days at high (20 dyne/cm2) shear rates, and differentiation of monocytes toward M1 macrophages. No other dynamic in vitro models have reported the natural development of hydroxyapatites. Given that CAVD has no targeted medical therapies, the creation of a physiologically relevant model of the aortic valve fibrosa may lead to contributions in preclinical studies for new therapeutic interventions.

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