Date of Award
Doctor of Philosophy (PhD)
Jason A. Burdick
Cardiovascular disease is a leading cause of death in the United States, and while mortality rates from acute myocardial infarctions (MI) are declining, many of these surviving patients will develop heart failure as a result of adverse left ventricular remodeling initiated by the ischemic attack. Cell therapies have been broadly explored in the clinic to promote cardiac repair after MI, but low engraftment of delivered cells has limited their translation and clinical efficacy. Additionally, the positive benefits of cell therapies may be due to paracrine signals that cells produce rather than the cells themselves, which has motivated the direct delivery of cell-derived therapies, such as growth factors, cytokines, and extracellular vesicles (EVs). However, with all of these therapies, new strategies to improve their engraftment and sustained presentation after MI are needed.
To address this concern, this dissertation engineers an injectable hydrogel through the mixing of hyaluronic acid functionalized with either adamantane or -cyclodextrin groups. This supramolecular assembly imparts shear-thinning and self-healing properties into the hydrogel that allows injection into the myocardium. After a thorough characterization of the hydrogel properties, select formulations are explored for the delivery of various cell-based therapeutics, including endothelial progenitor cells (EPCs), interleukin-10 (IL-1), and mesenchymal stromal cell (MSC)-derived EVs. These therapeutics are intended to improve outcomes after MI, through alterations in vascularization and the inflammatory response during remodeling.
Hydrogel delivery of EPCs significantly improves EPC retention when compared to the direct injection of EPCs in saline. This enhanced cell retention is correlated with improved cardiac function, reduced scar fraction, and increased vascular density in a rat MI model. IL-10 is delivered from the same hydrogel, using a degradable microgel carrier that allows decoupling of the hydrogel injectability from IL-10 release behavior. Delivery of this composite hydrogel with IL-10 to the heart in a rat MI model significantly reduced the presence of inflammatory cells and improved cardiac function and remodeling when compared to saline.
Finally, an injectable guest-host hydrogel is utilized to deliver EVs isolated from MSCs that are pre-conditioned to be pro-vasculogenic. EVs isolated from MSCs treated with different pre-conditioning regimens have varied protein content, and the delivery of pre-conditioned EVs using an injectable hydrogel improves EV retention in the heart and increases vascularization in the infarct region after MI. These findings indicate that a shear-thinning hydrogel can be used to deliver and enhance the retention of cells, cytokines, and EVs in the heart and enhanced therapeutic retention can result in improved outcomes for cardiac repair after MI. Overall, this thesis highlights the use of an injectable hydrogel as a therapeutic delivery vehicle toward translation of these therapeutics for clinical use.
Chen, Minna, "Injectable Hyaluronic Acid Hydrogels For The Delivery Of Cell-Based Therapeutics To The Heart" (2019). Publicly Accessible Penn Dissertations. 3582.