IRGs

Coronary artery and peripheral vascular disease are the largest causes of mortality in the United States [1]. To treat the consequences of this disease, clinicians rely on donor veins, arteries, or synthetic vascular grafts. Unfortunately, synthetic vascular grafts have had limited success as they occlude and fail within 5 years when used to replace small-diameter blood vessels [2]. This problem has motivated researchers and clinicians to explore tissue engineering approaches to replace blood vessels. However, one of the major challenges has been the development of biomaterials that would recreate mechanical and biochemical characteristics that would promote long-term graft survival [3]. Specifically, the scaffold used for cell growth should be biodegradable, strong, and elastic, as it has been shown that cyclic mechanical strain during tissue development can improve histological organization and enhance extracellular matrix synthesis [4]. Toward these goals, we have developed a new family of biodegradable and elastomeric copolymers based on citric acid and aliphatic diols. These copolymers, referred to as poly(diol citrates), have been shown to be biocompatible with cells, tissues, and blood. To achieve the range of burst pressures and compliance values that that are required for use in the body, we propose to engineer elastomeric poly(diol citrate) nanocomposites that include a poly(l-lactide) nanofiber network [5]. These elastomers will be initially used to optimize the biochemical and mechanical culture conditions for in vitro tissue engineering of a small diameter blood vessel. The specific aims of this research are to:

AIM #1: Synthesize elastomeric poly(diol citrate) nanocomposite biphasic scaffolds that have a high burst pressures (tensile strength of 0.80 MPa, similar to early bypass grafts) and degradation rates (total degradation time of 10-12 weeks). Specifically, we will synthesize poly(diol citrate) nanocomposites where the nanophase consists of poly(lactide-co-glycolide) (PLGA) nanoparticles or poly(L-lactic acid) (PLLA) nanofiber meshes. The chemical, mechanical, and degradation properties will be characterized.

AIM #2: Investigate the effect of long-term in vitro culture (12 weeks) on burst pressure, compliance, and suturability of the biphasic scaffold. Assess the effect of cyclic radial strain on the formation of a small-diameter vessel in vitro. Specifically, we will seed tubular bi-phasic scaffolds with vascular cells and culture the cell/scaffold construct under 2% (similar to low compliance vessels such as ePTFE) and 12% (similar to human arteries) pulsatile radial strain. The quality of the resulting tissue will be assessed via histology, biochemical assays, and mechanical tests and correlated with the amount of cyclic radial strain.

1. 2001 Heart and stroke statistical update. 2001, American Heart Association: Dallas, TX.
2. Haruguchi, H. and S. Teraoka, Intimal hyperplasia and hemodynamic factors in arterial bypass and arteriovenous grafts: a review. Journal of Artificial Organs, 2003. 6(4): p. 227-335.
3. Thompson, W., Reflection of the pathogenesis of abdominal aortic aneurysms. Cardiovascular Surgery, 2002. 10: p. 389-394.
4. Niklason, L.E., et al., Functional arteries grown in vitro. Science, 1999. 284(5413): p. 489-93.
5. Yang, J., A. Webb, and G. Ameer, Novel citric acid-based biodegradable elastomers for tissue engineering. Advanced Materials, 2004. 16(6): p. 511-516.