Date of Award
4-29-2022
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Ischemia-induced diseases, such as myocardial infarction (MI), ischemic stroke and peripheral artery disease, affect more than 20 million people in the United States, with the highest mortality rate among all diseases. Ischemia causes cell death, damaged vasculature and inflammation, leading to tissue necrosis and organ failure. Current surgical interventions are associated with high risk of post-treatment complications; non-surgical treatments such as drug therapy and cell therapy have limited outcomes due to poor retention of the applied drugs/cells and the low efficacy of systemic delivery. To overcome these hurdles, biomaterials have been extensively studied to support cell survival and growth, sustainably release drugs, and promote ischemic tissue regeneration. In this dissertation, we used biomaterials including hydrogels, microparticles and nanoparticles and incorporated with cells, peptides and proteins to increase cell survival, promote angiogenesis and alleviate inflammation to promote ischemic tissue regeneration. In Chapter 1, we conducted literature study on the pathology of ischemia-induced diseases and discussed the benefits and limitations of current surgical and non-surgical treatments. We introduced biomaterials used in ischemic tissue engineering from three aspects: biomaterials to promote cell survival, biomaterials to stimulate vascularization and biomaterials to alleviate inflammation. In Chapter 2, we designed oxygen-releasing microspheres (ORMs) to continuously provide oxygen to the ischemic tissues to enhance cell survival. A series of functional ORMs were developed with various attractive features, including (1) photoluminescent ORMs whose release kinetics can be non-invasively and real-time monitored in vivo, (2) environment-sensitive ORMs which can adjust the release rate according to the environmental oxygen level, and (3) reactive oxygen species (ROS)-scavenging oxygen-releasing system that can capture ROS generated from ischemic tissues or from released oxygen. These functional oxygen-releasing systems effectively promoted the efficacy in various ischemic diseases, minimized the side effect of released oxygen and had higher potential for clinical translation. In Chapter 3 and 4, we designed oxygen-releasing nanoparticles that can be intravenously injected, target the disease region and continuously oxygenate the ischemic tissues. The effect of the released oxygen on cell survival, metabolism, vascularization and tissue regeneration was examined on mouse ischemic hindlimb model (Chapter 3) and MI model (Chapter 4), separately. In Chapter 5, we delivered the secretome of adipose-derived stem cells to the heart after MI to address the limitation of directly delivering stem cells. The paracrine factors can be optimized in vitro by tuning different culture conditions. The therapeutic efficacy of the secretome in cardiac repair was comprehensively characterized, with an emphasis on cell survival and angiogenesis. We also studied the synergistic effect of simultaneously delivering stem cell secretome and oxygen-releasing nanoparticles to the infarcted heart. In Chapter 6 and 7, we developed biomaterials to reduce inflammation and fibrosis, which are two critical therapeutic targets in ischemic tissue regeneration. We used two peptides, RYT and ECG, to inhibit IL-1 pathway, and TGFβ pathway, respectively. The sustained and targeted delivery of peptides were achieved by the nanoparticles described in previous chapters. We examined the efficacy of the peptides on suppressing IL-1-induced inflammatory response and TGFβ-induced fibrosis on a mouse MI model.
Language
English (en)
Chair
Jianjun Guan