Heart valve diseases require hospitalization of more than 90,000 Americans each year, but there are very few options for treating heart valve dysfunction, and even less is known about the mechanisms the underlie valve disease. The essential function of heart valves is made possible by the unique microstructural arrangement of fibrous extracellular matrix proteins within the valve leaflet tissue, but these valvular structure- function relationships have not been translated into the next generation of valve tissue engineering investigations and for in vitro analyses of valvular cell biology and disease. The primary microstructural attributes of aortic valves are their anisotropic nature and their interconnected, layered structure, which provide valvular interstitial cells (VICs) with heterogeneous pericellular environments. These characteristics are not provided by the polymer mesh scaffolds being investigated for tissue engineered heart valves (TEHVs), and there is little consensus about optimal strategies to produce a cellular leaflet scaffolds. Many groups including ours have investigated natural and synthetic gel-based scaffolds for studies of VIC biology and pathology, but these have generally seeded VICs within or atop homogeneous structures. Electrospinning can produce layered structures and anisotropy, but this approach is highly sensitive to operating parameters. We propose to integrate these heterogeneous structure and material characteristics of heart valves into hydrogel biomaterials. Hydrogel biomaterials (particularly poly ethylene glycol diacrylate, PEGDA) are appealing for use as TEHV scaffolds because they have tunable structure and mechanics, can be readily bio- functionalized, and can easily encapsulate cells. Research concerning these materials;however, has generally been focused on their biological activities, as opposed to the development of advanced material behavior. The goal of the proposed work is to apply novel patterning and layering methodologies to generate advanced 3D hydrogels that mimic the complex microstructure and material behavior of aortic valve tissues. We are ideally positioned to generate these materials, having expertise in the characterization of heart valve microstructure, material behavior, and mechanobiology as well as the use of patterning to govern biological ligand presentation and more recently to generate novel structures and regions of differential material behavior within PEGDA hydrogels. These advanced structures will have tremendous impact on the next generation of TEHV scaffolds and could also be used as more faithful biomimetic platforms for 3D investigations of valvular cell biology and disease mechanisms. The following aims will be performed to accomplish this goal: 1. Compare electrospinning, laser printing photolithography, and 2-photon absorption confocal patterning approaches to generate anisotropic hydrogels demonstrating a valve-like biological-shape stress-strain curve. 2. Optimize semi-interpenetrating approaches to develop composite laminate hydrogel scaffolds. 3. Pattern interconnecting structures into the layers of the composite laminate hydrogels.

Public Health Relevance

More than 90,000 Americans each year are hospitalized for heart valve disease, but there are very few options for treating valve disease. In order to grow replacement heart valves, we propose to develop new materials that mimic the complicated interior structure and mechanical behavior of heart valves, and also have the potential to guide normal heart valve cell behavior. These new material structures may also help us understand why ordinarily durable heart valves become diseased.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107765-04
Application #
8644870
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$446,216
Indirect Cost
$147,895
Name
Rice University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Zhang, Xing; Xu, Bin; Puperi, Daniel S et al. (2015) Integrating valve-inspired design features into poly(ethylene glycol) hydrogel scaffolds for heart valve tissue engineering. Acta Biomater 14:21-Nov
Tseng, Hubert; Puperi, Daniel S; Kim, Eric J et al. (2014) Anisotropic poly(ethylene glycol)/polycaprolactone hydrogel-fiber composites for heart valve tissue engineering. Tissue Eng Part A 20:2634-45
Tseng, Hubert; Cuchiara, Maude L; Durst, Christopher A et al. (2013) Fabrication and mechanical evaluation of anatomically-inspired quasilaminate hydrogel structures with layer-specific formulations. Ann Biomed Eng 41:398-407