Implantation models for cardiac tissue engineering.

Abstract

Congestive heart failure (CHF) is a major medical challenge in developed countries. There are currently 4.8 million patients in the US living with CHF and the current economic cost is estimated to be $23.2 Billion annually. Current therapeutic strategies to treat CHF are limited to surgical transplantation, pharmacological intervention and mechanical cardiac support. Although these treatment options have significantly improved the quality of patient care, there are certain limitations to each of these approaches. Cardiac tissue engineered in vitro may provide an alternative treatment modality for CHF by providing transplantable tissue which can have direct applicability in cases of local myocardial infarct. The first part of the research describes a method for engineering 3-dimensional contractile cardiac tissue, termed <italic> cardioids</italic>. The <italic>cardioids</italic> exhibit several characteristics of normal cardiac physiology. <italic>Cardioids</italic> generate a peak active force of up to 75 muN and can be paced at physiological relevant frequencies of 1--5 Hz without notable fatigue. In addition, cardioids exhibit positive inotropy in response to ionic calcium and positive chronotropy in response to epinephrine. In the second part of this research, an alternative method for engineering 3-dimensional contractile cardiac tissue is described. The most attractive feature of the second method is that capillaries are engineered within the cardiac tissue construct. A significant improvement in contractility is observed with a peak active force of 800 muN. In the third part of this research we describe two implantation models to promote angiogenesis in previously engineered <italic>cardioids</italic>. In the first model, <italic>cardioids </italic> are housed in a support silicone chamber, the femoral artery and femoral vein are routed through the chamber and the entire chamber implanted in synergic recipients. In the second model, <italic>cardioids</italic> are anchored onto custom made acrylic support frames and then secured within a subcutaneous pocket in synergic recipients. Both models promoted angiogenesis within the engineered cardiac tissue resulting in a significant improvement in the contractility of <italic>cardioids</italic>.