We propose to emulate and model key mechanical and biochemical conditions of developing heart valves towards the ultimate goal of creating a robust tissue engineered heart valve (TEHV). We hypothesize that growth factors critical to embryonic valve development regulate valve interstitial cell (VIC) extracellular matrix (ECM) synthesis and remodeling in a tension- dependent manner. We propose that a quantitative understanding of growth factor-tension interactions will reveal conditions which stimulate VICs to produce tissues with high glycosaminoglycan (GAG) content that resist shortening. To test our hypothesis, VICs will be cultured in small-scale tissue models made from natural proteins which allow for control over tension generated by the cells and rapid analysis of tissue mechanical and biochemical properties in a high-throughput manner. We will quantitatively assess the effect of tissue tension and combinations of exogenous addition of transforming growth factor-beta1, epidermal growth factor, and bone morphogenetic protein-2 on tissue mechanics and composition and model the balance between ECM secretion and degradation computationally. The results from this systematic study will have a direct impact on tissue engineered heart valve (TEHV) development by determining optimal culture conditions for robust tissue formation with minimal shortening. The findings will also increase our understanding of how growth factors and mechanical stimuli coordinate valve development and repair and lead to pathological remodeling. The approach of creating immature tissue under low tension based on embryonic valve development is an innovative departure from standard TEHV fabrication paradigms.
Tissue engineered heart valves (TEHVs), which have the potential to self-repair or grow with the patient, are a promising alternative to mechanical and bioprosthetic valve replacements, especially for pediatric patients. Yet valve leakage due to leaflet shortening due to tissue retraction limits the success of current TEHV approaches. The proposed project draws from knowledge of embryonic valve development and computational modeling to develop solutions to prevent leaflet shortening.
|Cirka, Heather; Monterosso, Melissa; Diamantides, Nicole et al. (2016) Active Traction Force Response to Long-Term Cyclic Stretch Is Dependent on Cell Pre-stress. Biophys J 110:1845-1857|
|Kural, Mehmet H; Billiar, Kristen L (2016) Myofibroblast persistence with real-time changes in boundary stiffness. Acta Biomater 32:223-230|
|Kural, Mehmet H; Billiar, Kristen L (2014) Mechanoregulation of valvular interstitial cell phenotype in the third dimension. Biomaterials 35:1128-37|
|Rudnicki, Mathilda S; Cirka, Heather A; Aghvami, Maziar et al. (2013) Nonlinear strain stiffening is not sufficient to explain how far cells can feel on fibrous protein gels. Biophys J 105:11-20|
|Kural, Mehmet Hamdi; Billiar, Kristen Lawrence (2013) Regulating tension in three-dimensional culture environments. Exp Cell Res 319:2447-59|
|Quinlan, Angela M Throm; Billiar, Kristen L (2012) Investigating the role of substrate stiffness in the persistence of valvular interstitial cell activation. J Biomed Mater Res A 100:2474-82|
|Cirka, Heather A; Koehler, Stephan A; Farr, William W et al. (2012) Eccentric rheometry for viscoelastic characterization of small, soft, anisotropic, and irregularly shaped biopolymer gels and tissue biopsies. Ann Biomed Eng 40:1654-65|
|John, Jeffrey; Quinlan, Angela Throm; Silvestri, Chiara et al. (2010) Boundary stiffness regulates fibroblast behavior in collagen gels. Ann Biomed Eng 38:658-73|