Date of Award
Doctor of Philosophy (PhD)
425 million people have diabetes worldwide, and by 2045 this number is estimated to increase to 629 million. The risk for cardiovascular diseases such as cardiomyopathy, hypertension, and atherosclerosis increase 5 and 2-fold for diabetic women and men respectively. Diabetic cardiomyopathy (DCMP) is a ventricular dysfunction that occurs in patients with diabetes independent of coronary artery disease, hypertension or valvular abnormalities. Hyperglycemia and dyslipidemia cause metabolic disturbances that adversely affect myocardial cells and extracellular matrix. These modifications alter overall myocardial structure and cardiac function, which can lead to heart failure.
As of now there is no specific marker for this disease and diagnosis is the same as other cardiomyopathies. Elucidating early stages of this disease is vital for early diagnosis, treatment, and possible therapy targets. Currently, rodent models and 2D cell cultures have been employed to analyze DCMP, however there are notable differences between rodents and humans that provide challenges when studying DCMP and cell cultures lack an extracellular matrix and dynamic environment crucial to the progression of this disease.
Our overall goal was to use tissue engineering to bridge this gap by developing platforms to study pathological mechanisms at the cellular and extracellular level. We examined cardiac tissue engineered constructs in: (1) a perfusion 3D Kube minibioreactor and (2) an electromechanical bioreactor customized in our lab. Each platform contained decellularized myocardium seeded with human cardiomyocytes for two weeks; “diabetic” conditions were simulated by increased glucose concentration. We were able to better mimic physiological conditions with our electromechanical bioreactor, compared to static and non-diabetic conditions, as well as to 2D cell culture. Methods for detecting cellular and matrix changes associated with DCMP were validated in a type 1 diabetic rodent model. Our tissue engineering platform shows promise for unveiling early cellular and matrix modifications in DCMP. This system could also be useful for studying human cells in other cardiac diseases, test treatments, and precondition myocardial-like tissue prior to implantation.
McCallum, Laura Elizabeth, "Tissue Engineering Platforms for Cardiac Pathology in Diabetes: In Vitro and In Vivo Studies" (2018). All Dissertations. 2565.