Aortic valve stenosis (AVS) is a form of heart disease, characterized by the stiffening of the aortic valve leaflets. During inflammation caused by injury, cardiac fibroblasts change into an activated myofibroblast phenotype [1]. These myofibroblasts function to produce collagen fibers during inflammation which causes stiffening in the tissue [2]. After injury, myofibroblasts typically revert back to fibroblasts. However, persistent activation of the myofibroblasts causes fibrosis of the tissue and subsequently AVS.
The mechanism in which the valves stiffen presents differently between males and females. Males tend to have more calcium deposition into the tissue, while females tend to exhibit more collagen deposition surrounding the cell[3]. Although we can detect these differences, little is known about the mechanisms that cause this difference in disease presentation. The goal of our project is to develop a degradable hydrogel platform that will be able to mimic the microenvironment of the valve leaflets. Researchers can customize the components of the hydrogel and seed cells on them to study the cell's response to external stimuli.
Hydrogels are water swollen polymer networks that are used to recapitulate the mechanical and biochemical properties of the in vivo tissue microenvironment [3]. Our project employs the use of a 3D hydrogel, in which cells will be cultured in the hydrogel. Hydrogels are an invaluable cell culture platform that will help us understand change in cell phenotype during AVS disease progression.
Our hydrogel comprises of many different components in order to mimic ECM protein build-up during AVS progression. First, is a 8 arm PEG-norbornene as the polymer network backbone of the hydrogel. Next, is the RGD cell adhesive peptide, which promotes cell adhesion to the ECM. The MMP degradable crosslinker allows remodeling of the hydrogel by matrix metalloproteinases released by encapsulated cells. Lastly is our thiolated protein, a specially treated protein that has thiol groups that will click onto the hydrogel backbone attached to it.
A Visual Representation of the Hydrogel Composition
[1] Hinz, B. “The role of myofibroblasts in wound healing.” Current research in translational medicine vol. 64,4 (2016): 171-177. doi:10.1016/j.retram.2016.09.003
[2] Baum J, Duffy HS. Fibroblasts and myofibroblasts: what are we talking about? J Cardiovasc Pharmacol. 2011 Apr;57(4):376-9. doi: 10.1097/FJC.0b013e3182116e39. PMID: 21297493; PMCID: PMC3077448.
[3] Matilla, Lara et al. “Sex-Differences in Aortic Stenosis: Mechanistic Insights and Clinical Implications.” Frontiers in cardiovascular medicine vol. 9 818371. 24 Feb. 2022, doi:10.3389/fcvm.2022.818371
[4] Richbourg, Nate. Mesh Transport - Hydrogel Design. 31 May 2021, https://hydrogeldesign.org/the-model/mesh-transport/.
[5] Grim, Joseph C., et al. “A Reversible and Repeatable Thiol–Ene Bioconjugation for Dynamic Patterning of Signaling Proteins in Hydrogels.” ACS Central Science, vol. 4, no. 7, July 2018, pp. 909–16, https://doi.org/10.1021/acscentsci.8b00325.
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