Ischemic heart disease (IHD) is the single leading cause of death in the world and restorative treatment for IHD poses a global healthcare challenge. Myocardial infarction, the predominate form of ischemic disease, occurs when the coronary arteries become restricted or obstructed, resulting in downstream ischemia. Native cardiomyocytes are starved of glucose and oxygen and die within minutes, leading to reduced cardiac function. Due to the formation of fibrotic tissue and the body’s inability to regenerate cardiac muscle, all loss of function is permanent. Tissue engineering offers a novel therapeutic solution in the form of engineered human cardiac tissue grown in vitro that could be implanted over the damaged heart, providing healthy replacement myocardium and thereby restoring function that was lost. Currently, improvements to the force production of tissue engineered myocardium are necessary before it will be an effective therapeutic replacement for native myocardium. We hypothesized that cell-matrix interactions and the anisotropic structure of native myocardial extracellular matrix (ECM), a defining characteristic of cardiac tissue that is absent in conventional engineered myocardium, may increase tissue force production. In this thesis, we design and evaluate a composite cardiac tissue scaffold platform composed of collagen microfibers embedded in a cell-seeded hydrogel bulk. First, hydrogel and cell parameters influencing cardiac tissue development and function were identified and optimized through a design of experiments (DOE) approach. Next, an automated process for producing organized collagen microfiber composites was developed and characterized. By modulating the organization of the embedded fibers, we tuned the mechanical anisotropy of the composite to emulate the anisotropy of native myocardium. Finally, the functional performance of these composite tissues was compared to the performance of tissues without fibers in vitro, and in vivo engraftment in the heart demonstrated a persistent fiber mesh that may mechanically support cardiac regeneration. Together, this work demonstrates the viability and utility of a collagen microfiber composite cardiac tissue platform with tunable mechanical properties that direct tissue development and function. For the wider field of tissue engineering, this represents a foundation for the development of more sophisticated collagen biomaterials that emulate the structural and mechanical complexity of native tissue.
Kaiser, Nicholas Jason,
"A Tunable Collagen Microfiber Platform for Engineered Cardiac Tissue"
(2019).
Engineering Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/0n1g-0189
