Congenital heart disease is not only surprisingly prevalent (~1% of live births), but is deadly (most common congenital cause of death). While mechanical and bioprosthetic valves work relatively well in adult patients, mechanical valves require anticoagulation not compatible with a child's activities and bioprosthetic valves quickly calcify in children. Even if these complications could be resolved, neither of these valve replacements can grow with the child. Therefore, a child must undergo open-heart surgery every several years to replace the valve that has been """"""""outgrown."""""""" A tissue engineered heart valve (TEHV) would dramatically improve the lives of these patients. If cells from a given patient could be grown on a scaffold with the right signals, an implantable valve could be formed that could grow with the patient, making such repeated open-heart surgeries obsolete. While age-specific TEHVs are clearly needed, their complex structure, necessary for proper function, and how this structure changes with age has not been well characterized. In the first aim of this proposal layer, region, valve, and age-specific characterization of different matrix components will be performed on MV and AV from pigs ranging from the equivalent of young to elderly humans. Mechanical characterization will also be performed using uniaxial tensile testing and AFM compressive indentation. One of the largest challenges involved in making a TEHV is controlling cell phenotype, which can be done in a number of ways including by modifying the mechanical properties of a cell's substrate. Therefore in the second aim of this proposal, cells of each valve region and a range of ages will be seeded on hydrogel scaffolds of varying stiffnesses to determine the """"""""optimal"""""""" stiffness for each. Then the ability to use stiffness to modify cell phenotype will be examined by seeding """"""""young"""""""" valve cells of a given region on hydrogels with an """"""""elderly"""""""" stiffness, and by seeding cells of a given region on a stiffness correlating to a different region. Relevance to Public Health: This research proposal addresses the considerable burden of congenital valve disease, a prevalent disease with suboptimal treatment options. These studies will provide a comprehensive view of the elements needed for a successful age-specific TEHV. Consideration will be paid not only to biological factors, but mechanical properties and how these characteristics can be manipulated in the context of the complex, heterogeneous and changing valve. Such studies are crucial before a successful TEHV can be created. The goals of this proposal are clearly in line with those of the NHLBI to understand the causes and develop interventions for debilitating cardiac diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30HL094019-01
Application #
7545708
Study Section
Special Emphasis Panel (ZRG1-F10-H (21))
Program Officer
Meadows, Tawanna
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$26,321
Indirect Cost
Name
Rice University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Stephens, Elizabeth H; Fahrenholtz, Monica M; Connell, Patrick S et al. (2015) Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction. Cardiovasc Eng Technol 6:151-9
Stephens, Elizabeth H; Connell, Patrick S; Fahrenholtz, Monica M et al. (2015) Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain. Cardiovasc Eng Technol 6:141-50
Stephens, Elizabeth H; Kearney, Debra L; Grande-Allen, K Jane (2012) Insight into pathologic abnormalities in congenital semilunar valve disease based on advances in understanding normal valve microstructure and extracellular matrix. Cardiovasc Pathol 21:46-58
Stephens, Elizabeth H; Shangkuan, Jennifer; Kuo, Joyce J et al. (2011) Extracellular matrix remodeling and cell phenotypic changes in dysplastic and hemodynamically altered semilunar human cardiac valves. Cardiovasc Pathol 20:e157-67
Stephens, Elizabeth H; Durst, Christopher A; West, Jennifer L et al. (2011) Mitral valvular interstitial cell responses to substrate stiffness depend on age and anatomic region. Acta Biomater 7:75-82
Stephens, Elizabeth H; Saltarrelli, Jerome G; Baggett, L Scott et al. (2011) Differential proteoglycan and hyaluronan distribution in calcified aortic valves. Cardiovasc Pathol 20:334-42
Stephens, Elizabeth H; de Jonge, Nicky; McNeill, Meaghan P et al. (2010) Age-related changes in material behavior of porcine mitral and aortic valves and correlation to matrix composition. Tissue Eng Part A 16:867-78
Stephens, Elizabeth H; Carroll, Joshua L; Post, Allison D et al. (2010) Functional characterization of fibronectin-separated valve interstitial cell subpopulations in three-dimensional culture. J Heart Valve Dis 19:759-65
Stephens, Elizabeth H; Post, Allison D; Laucirica, Daniel R et al. (2010) Perinatal changes in mitral and aortic valve structure and composition. Pediatr Dev Pathol 13:447-58
Gupta, Vishal; Barzilla, Janet E; Mendez, Joe S et al. (2009) Abundance and location of proteoglycans and hyaluronan within normal and myxomatous mitral valves. Cardiovasc Pathol 18:191-7