From left, Jeni Lee, Maelene Wong, and Gina MacBarb working on tissue engineering in Griffiths Laboratory
Video depicting blood movement through canine mitral valve.
Lagendorff Heart Profusion System depicting rat heart in close up
Cardiovascular disease is the single most important cause of morbidity and mortality in the United States (US), with a combined annual cost of $444 billion which equates to one sixth of all healthcare expenditure in the US. Coronary heart disease alone, leading to myocardial infarction (MI), is estimated to cause 1 of every 6 deaths in the US (American Heart Association, 2011).
Similarly, heart failure is mentioned in one in every nine death certificates in the US. Cardiovascular disease frequently results in decreased quality of life, limitation in exercise capacity, and the need for life long medical therapy. According to Centers for Disease Control and Prevention, one third of American adults are currently living with the effects of cardiovascular disease.
Cardiovascular disease results in decreased performance of the cardiovascular system. During the early stages of disease, the body is able to employ compensatory mechanisms to overcome this reduction in cardiovascular performance. However, these mechanisms are not curative, but rather utilize the body’s normal ability to increase cardiac performance with exercise to maintain normal resting cardiovascular performance. In the chronic situation, these same compensatory mechanisms mediate negative changes in the cardiovascular system which stimulates further progression of disease. Ultimately, as disease continues to progress, heart failure ensues. Erosion of normal exercise capacity results in patients demonstrating lethargy and poor exercise capacity. Failure of the heart to ensure blood flow results in pooling of blood in venous vascular beds and fluid leakage into the tissues of the body (congestion).
Tissue engineering approaches aim to overcome the debilitating and ultimately fatal consequences of cardiovascular disease, by producing replacement tissues (e.g., heart valves) and organs (e.g., whole hearts). All tissues and organs are composed of the same basic structures, consisting of cells, extracellular matrix (supporting substance between cells – ECM) and signaling molecules. A tissue engineering approach aims to combine these essential components to generate a functional replacement tissue or organ. Several tissue engineering approaches are currently under intense investigation. However, the key to achieving the seemingly simple goal of replicating normal tissue and organ development and growth remains elusive.
Our laboratory focuses on animal-derived ECM as a scaffold into which patient cells and signaling molecules can be placed to form the desired tissue or organ. Utilization of animal tissue has the advantage that it is available in essentially unlimited supply and also provides an ECM which is identical to that of the desired tissue type. However, the critical impediment to utilization of animal-derived ECM is that such material contains molecules which stimulate an aggressive host immune response upon implantation (antigens).
The main objectives of our research are to (1) identify and understand the antigenic components of animal-derived tissues and organs which stimulate an immune rejection response upon implantation, (2) utilize the principles of protein biochemistry to achieve removal of these antigenic components, while leaving the ECM unchanged, and (3) investigate the interaction between cells and ECM scaffolds towards achieving the goal of generating tissue engineered tissues and organs. Our laboratory has pioneered a new paradigm in the production of immunologically-acceptable animal-derived ECM scaffolds, which preserve ECM structure-function relationships and recellularization capacity. Through application of our antigen-removal paradigm, we aim to overcome the impediments previously encountered with the use of xenogeneic scaffolds in tissue engineering applications.