Aortic valve stenosis results in approximately 50,000 valve replacement surgeries per year in the United States. These replacements are generally synthetic material, and some even require head-up orientation to function properly, which makes childhood cartwheels dangerous. This restriction of movement and the need for multiple surgeries in child patients with valve defects makes regenerated heart valve tissue implants an attractive alternative.
When the resident VICs are subjected to different biological stimuli, such as stiff culture substrates, they become activated from a quiescent fibroblast to a secretory myofibroblast phenotype. In this state, they maintain valve function by secreting extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs). However, if the regulation of this phenotype is lost, then they can actively mediate disease progression and valve hardening. Understanding the balance of the myofibroblast phenotype is critical to regenerating healthy aortic valves for transplantation.
To do so, I am studying the effect of culture substrate stiffness and cell-matrix interactions in both 2 and 3 dimensions using a PEG-based hydrogel platform. With a better understanding of how different physical and biochemical cues affect VIC activation and ECM expression, it may be possible to direct VICs to deposit healthy, new tissue for valve regeneration and transplantation.
S.T. Gould, N.J. Darling, K.S. Anseth, “Small Peptide Functionalized Thiol-Ene Hydrogels as Culture Substrates for Understanding Valvular Interstitial Cell Activation and de novo Tissue Deposition,” Accepted in Acta Biomaterialia. (2012).