The predominant function of heart valves is to maintain unidirectional blood flow, which requires cyclic openness and closure of valves during cardiac systole and diastole. Heart valve diseases are commonly diagnosed clinically by stenosis (outflow obstruction due to incomplete openness) and regurgitation (backward flow resulting from inefficient closure). Specifically, aortic valve disease causes more than 100,000 hospitalizations every year in the United States, and the aortic valve replacement has become the second most common cardiac operation in the world. However, the underlying disease mechanisms are still poorly understood, and the current options for valve replacements have severe limitations. The Ross procedure, whereby the aortic valve is replaced by the patient’s pulmonary valve, eventually requires another valve for pulmonary position. Mechanical valves require lifelong anticoagulation drugs to reduce thromboembolic complications, and bioprosthetic valves have limited durability. Additionally, neither mechanical nor bioprosthetic valves are capable of accommodating somatic growth especially in children. Ultimately, these therapies result in valve failure and require subsequent valve replacement. The development of tissue engineered heart valves (TEHVs) would provide a means to reveal the mechanisms underlying valve diseases and construct valve substitutes in vitro.
Valvular interstitial cells (VICs), are known to be responsible for active extracellular matrix (ECM) remodeling in valve repair as well as disease progression. Thus, it is of critical importance to investigate VICs’ growth, differentiation and ECM production in an informative microenvironment mimicking physiological niches. In this project, biomimetic poly(ethylene glycol) diacrylate (PEGDA) hydrogels are under development to support VIC growth in a three-dimensional microenvironment and promote the production of ECM molecules found in native valve tissue. The precise control over the VIC microenvironment is realized by controlling the mechanical and biochemical properties of PEGDA hydrogels. Ultimately, this system could elucidate new information regarding valve diseases and lead to the next generation of TEHVs.
Collagen production by VICs encapsulated in biodegradable PEGDA hydrogels for 2 weeks
DAPI,Phalloidin, Collagen I, Collagen III
z projection of 130 μm stack, Scale bar=50 μm
I am working on designing an artificial heart valve made with the patient's own cells so it can grow with the body. Many researchers have been working in this field already, but the fact that there is not a better solution is a testament to the difficulty of the problem. Just think about the dynamic forces that heart valves would experience as they fully open and close with every single heart beat over your entire lifetime. Its really an intense mechanical problem, but heart valves are refined to do their job well. They have a layered structure with each layer giving the valve unique mechanical function. My novel solution will reproduce this layered structure into a polymer scaffold – with each polymer layer doing its job just like a normal valve. By focusing on biomechanics and by designing unique properties into each layer, I can design an artificial valve that will grow with the patient, avoid unwanted medication, and most importantly last a lifetime.
- Tseng H, Cuchiara ML, Durst CA, Cuchiara MP, Lin CJ, West JL, Grande-Allen KJ. "Fabrication and Mechanical Evaluation of Anatomically-Inspired Quasilaminate Hydrogel Structures with Layer-Specific Formulations." Ann Biomed Eng. 2012 Oct 5. PMID: 23053300.
- Durst CA, Cuchiara MP, Mansfield EG, West JL, Grande-Allen KJ. "Flexural Characterization of Cell Encapsulated PEGDA Hydrogels with Applications for Tissue Engineered Heart Valves." Acta Biomater. 2011 Feb 14. PMID:21329770.