Mechanical Loading of Engineered Heart Muscle Tissues for Disease Modeling and Repair of the Human Heart
Heart failure, a condition where the heart muscle loses its ability to effectively contract and pump blood throughout the body, is often the result following significant cardiac damage. Though medication and lifestyle changes can delay heart failure progression, other factors, like the changes in mechanical loads on the tissue, are often not taken into account, and many of these patients will go on to need a heart transplant. In fact, nearly half of those patients diagnosed with heart failure will die within 5 years of their diagnosis, which is mainly attributed to a poor understanding of the factors that drive disease
progression (mechanical load, genetic factors, etc.) and the lack of available donor hearts suitable for transplantation. Tissue engineered heart muscle has recently emerged as a tool to test drug toxicity, to model disease, and to eventually repair and replace the human heart. However, current heart muscle tissue models are hampered by their limited ability to mimic physiologic mechanical loading, which precludes their use as models for drug screening or disease modeling. Further, many of these models also lack the geometric complexity to support advanced functions of the human heart, such as pumping fluid, which are necessary when we consider using these models to repair or replace the human heart. In this work, I first engineered a system that can be used to mimic physiologic hemodynamic loading conditions, including the preload (load that stretches heart muscle during chamber filling) and afterload (pressure that the heart must contract against to eject blood). Dynamic loading of healthy control engineered heart tissues (EHTs) in this model (dyn-EHT) led to adaptive heart muscle remodeling and increases in heart muscle function, including contractile stress generation, myofibrillar alignment, and electrical excitability. In contrast, dyn-EHTs generated from a patient with a desmoplakin mutation, a mutation that clinically results in arrhythmogenic cardiomyopathy, displayed maladaptive remodeling with excessive tissue lengthening and reduced contractile stress generation. These results are consistent with the clinical course of disease progression observed in human patients, including ventricular dilation and reduced cardiac output. As a first step towards producing engineered heart muscle with more advanced geometric complexity, I also manufactured a bioinspired, contractile human heart tube using Freeform Reversible Embedding of Suspended Hydrogels (FRESH) bioprinting. Heart tubes displayed dense layers of interconnected cardiomyocytes, unidirectional calcium wave propagation, and displacement of fluorescent beads with increased pressure generation during contraction. Finally, I used heart tube morphogenesis as a template to demonstrate that mechanical loading is critical in engineering more complex heart muscle structures. Here, I used 3D printing to insert structural asymmetries in prints, causing them to bend in a specified direction when a force was applied. Heart tube bending resulted in region-specific changes in myofibrillar alignment and calcium conduction. These findings suggest that mechanical loading is critical to engineered heart muscle formation, from manufacturing patient-specific disease models to personalized tissues and organs for heart repair and replacement.
- Biomedical Engineering
- Doctor of Philosophy (PhD)