Recently, Kaushal et al. isolated endothelial progenitor cells (EPCs) from the peripheral blood of sheep and seeded them onto decellularized porcine iliac vessels. EPC-seeded grafts remained patent for 130 days as a carotid interposition graft in sheep (non-seeded grafts occluded within 15 days), and exhibited contractile activity and nitric-oxide-mediated vascular relaxation similar to native carotid arteries. Sales et al. have demonstrated that EPCs have the potential to provide both valvular interstitial and endothelial cellular functions, demonstrating the potential for EPCs to serve as a single autologous cell source for TEPV. In addition to the identification of clinically feasible cell sources, engineered soft tissues such as the TEPV require scaffolds with anisotropic mechanical properties that undergo large deformations (not possible with current PGA/PLLA non-wovens) coupled with controllable biodegradative and cell-adhesive characteristics. As a next step in fulfilling these design criteria, the Wagner lab has recently synthesized a family of poly (ester-urethane) ureas (PEUUs), including combination with type I collagen at various ratios to enhance cell attachment and increase biodegradation rates. Electrospun PEUU scaffolds have also been produced with biaxial mechanical properties that are remarkably similar to the native pulmonary valve, including the ability to undergo large physiologic strains and pronounced mechanical anisotropy. Moreover, a novel cell micro-integration technique has been developed that allows for successful integration of the cells directly into the scaffolds at the time of fabrication, eliminating cellular penetration problems. These encouraging results suggest that ES-PEUU scaffolds micro-integrated with EPCs can serve as successful TEPV scaffolds. We hypothesize that strategic combinations of individual mechanical factors relevant to heart valves-cyclic flexure, strain, and flow-can be determined that optimize ECM synthesis, organization, and mechanical properties of EPC seeded TEPV. Moreover, we hypothesize that the use of novel elastomeric scaffolds can add a critical degree-of-freedom for TEPV designs by allowing for large strains and highly controllable mechanical anisotropy. These hypotheses will be addressed by the following specific aims:
Specific Aim 1 - Optimize ES-PEUU scaffold mechanical anisotropy, layer and pore structures, and cellular integration for EPC-seeded TEPV leaflet applications.
Specific Aim 2 - Using optimized PEUU scaffolds of specific aim 1, conduct critical in-vitro """"""""scale-up"""""""" studies in intact TEPV under simulated physiological conditions.
Specific Aim 3 - Evaluate the EPC-seeded ES-PEUU scaffold's ability to perform in-vivo using a single leaflet model.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068816-08
Application #
8035309
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2002-03-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2011
Total Cost
$427,229
Indirect Cost
Name
University of Pittsburgh
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sakamoto, Yusuke; Buchanan, Rachel M; Sanchez-Adams, Johannah et al. (2017) On the Functional Role of Valve Interstitial Cell Stress Fibers: A Continuum Modeling Approach. J Biomech Eng 139:
Rego, Bruno V; Sacks, Michael S (2017) A functionally graded material model for the transmural stress distribution of the aortic valve leaflet. J Biomech 54:88-95
Soares, João S; Zhang, Will; Sacks, Michael S (2017) A mathematical model for the determination of forming tissue moduli in needled-nonwoven scaffolds. Acta Biomater 51:220-236
Soares, Joao S; Feaver, Kristen R; Zhang, Will et al. (2016) Biomechanical Behavior of Bioprosthetic Heart Valve Heterograft Tissues: Characterization, Simulation, and Performance. Cardiovasc Eng Technol 7:309-351
Soares, Joao S; Sacks, Michael S (2016) A triphasic constrained mixture model of engineered tissue formation under in vitro dynamic mechanical conditioning. Biomech Model Mechanobiol 15:293-316
Sakamoto, Yusuke; Buchanan, Rachel M; Sacks, Michael S (2016) On intrinsic stress fiber contractile forces in semilunar heart valve interstitial cells using a continuum mixture model. J Mech Behav Biomed Mater 54:244-58
D'Amore, Antonio; Soares, Joao S; Stella, John A et al. (2016) Large strain stimulation promotes extracellular matrix production and stiffness in an elastomeric scaffold model. J Mech Behav Biomed Mater 62:619-635
Hobson, Christopher M; Amoroso, Nicholas J; Amini, Rouzbeh et al. (2015) Fabrication of elastomeric scaffolds with curvilinear fibrous structures for heart valve leaflet engineering. J Biomed Mater Res A 103:3101-6
Carleton, James B; D'Amore, Antonio; Feaver, Kristen R et al. (2015) Geometric characterization and simulation of planar layered elastomeric fibrous biomaterials. Acta Biomater 12:93-101
D'Amore, Antonio; Amoroso, Nicholas; Gottardi, Riccardo et al. (2014) From single fiber to macro-level mechanics: A structural finite-element model for elastomeric fibrous biomaterials. J Mech Behav Biomed Mater 39:146-61

Showing the most recent 10 out of 53 publications