Biomimetic heterogeneous scaffolds for a layered tissue engineered heart valv

This dissertation describes strategies that I have developed to introduce mechanical and biochemical heterogeneity into synthetic tissue engineering scaffolds for heart valves. For a tissue engineered heart valve to work well, it must meet the mechanical demands of the natural heart valve and support healthy valve cell behavior. Natural heart valve leaflets have a heterogeneous structure with distinct layers that provide the valve with unique mechanical functions. My research focused on mimicking the mechanics and biochemical signaling of each layer so that the entire scaffold will function similar to the natural valve. Three specific strategies to add heterogeneity into tissue engineered heart valve scaffolds are described in this thesis. First, I designed an innovative method to direct the proper spatial arrangement of cell adhesive peptides in order to promote the correct organization of the two different cell types in the valve (valve endothelial cells and valve interstitial cells). Second, hyaluronan hydrogels were utilized as a mechanical and biochemical mimic of the middle, spongiosa layer of heart valves. Third, I learned how valve interstitial cells respond to synthetic fibrous structure in 3D culture by designing a composite scaffold made from poly(ethylene glycol) hydrogels and electrospun polyurethane fibers. The electrospun fibers were incorporated to give the valve scaffold the anisotropic, viscoelastic, and non-linear mechanical behavior similar to native valves, while the hydrogel material functioned as a cell-friendly substrate. These specific research projects provide methods and results that advance the heart valve tissue engineering field while having broad applicability to other tissue engineering applications, especially for tissues which have a layered structure and a stratified distribution of multiple cell types. The results of this research also lay the groundwork for constructing heart valve scaffolds for the purpose of in vitro disease modeling. A synthetic heart valve model based on this research would be more consistent than explant animal valves and could be used to study the initiation and progression of heart valve disease.