(71f) Material Stiffness Directs Valvular Interstitial Cell Extracellular Matrix Production – A Study Using a Novel Material Platform

More than
100,000 Americans each year undergo aortic valve (AV) replacement due to valve
failure. An AV can become diseased, impairing the proper function of the valve.
Common treatments for a defective valve are either replacement with a decellularized biologic or a synthetic valve. These
treatments options are limited by short functional lifetime and thrombogenic surfaces. Tissue engineered heart valve will
have the ability to integrate with the surrounding tissue as well as to repair
and remodel. However, a greater understanding of valve cell biology is required
to induce analogous tissue formation. A diseased valve is associated with
stiffening of the tissue. Researchers have probed the impact of stiffness on
cell function but have had results complicated by the limitations of the in vitro models used. 

The
synthetic materials commonly used to fabricate cell culture platforms with
varied moduli are limited in applicability due to a restricted range of
achievable moduli and/or surface instabilities. The copolymer network n-octyl methacrylate (nOM) and diethylene glycol dimethacrylate (DEGDMA) offers attractive material
properties that overcome these limitations. We have fabricated co-polymer
networks with 3 to 33 wt% DEGDMA with bulk compressive modulus ranging from
25±2 to 4700±300 kPa. Nanoindentation determined
cellular level mechanics of the nOM / DEGDMA ranged
from 6.5 ± 0.00 to 1,562.5 ± 192 MPa.  The networks demonstrated consistent surface
properties of wettability/hydrophobicity,
chemical composition, and topography. The nOM/DEGDMA
substrates vary in modulus over three orders of magnitude while maintaining
comparable chemical and topographical surface features.

The
primary cells of the AV, valvular interstitial cells (VICs), were cultured on
the nOM/DEGDMA substrates. It was found that the rate of proliferation was not
impacted by the stiffness of the culture platform. Additionally, expression
levels of the markers of the active and osteoblastic-like cellular phenotypes
were not affected by the stiffness of the substrates. Production of collagen-I
and sulfated glycosaminoglycans did not change
between the different substrate moduli. However, elastin production was
significantly upregulated on the softest materials.
We have fabricated a cell culture platform that is capable of varying modulus over
a three orders of magnitude of a physiologically relevant range and used it to
study the changes of VIC functions.