Fischell Department of Bioengineering Theses and Dissertations
Permanent URI for this collectionhttp://hdl.handle.net/1903/6628
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Item A TISSUE-ENGINEERED PLACENTAL BARRIER MODEL FOR TOXICOLOGY AND PHARMACOLOGY APPLICATIONS(2019) Arumugasaamy, Navein; Fisher, John P; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Throughout history, there have been two major instances where a substance caused thousands of birth defects, yet it took a few years for the causation to be noted: thalidomide, in the late 1950s and early 1960s, and Zika Virus, just recently in 2014 to 2016. In both instances, the developing fetus was indirectly exposed to the substance through the placental barrier. Pregnant women took thalidomide as a medication or were stung by mosquitos and exposed to Zika Virus. These examples clearly show why models of the placental barrier and downstream fetal tissues are critically needed. Herein, I present our work on the development and utilization of a biomimetic placenta-fetus model. The three objectives in this work were to: (1) develop and validate the tissue-engineered BPB model through study of biologically relevant substances; (2) assess the effects of SSRIs on the BPB’s cells and evaluate the drugs’ transport profile across the barrier; and, (3) assess how SSRIs influence cardiomyocyte signaling and injury biomarker release following passage through the BPB. We suggest that this work provides a critically needed and biologically relevant placenta-fetus model, useful as a method to assess pharmacology and toxicology properties of medications and other substances. Moreover, the knowledge gained through the studies performed may hopefully improve clinical care of pregnant women through enhanced understanding of how a medication impacts both the pregnant mother-to-be and her developing fetus.Item BIOMIMETIC NANOSTRUCTURES FOR THERANOSTIC APPLICATIONS(2015) Kuo, Yuan-Chia; D'Souza, Warren D; Raghavan, Srinivasa R; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Theranostic nanostructures are those that have both therapeutic as well as diagnostic function, e.g., due to having a combination of drugs as well as imaging agents in them. Such structures, especially those that can selectively home in on cancer tumors, have received considerable attention recently. Although many different structures have been synthesized, their complexity, high cost, and poor biocompatibility have limited their clinical application. In this study, we focus on creating new classes of theranostic nanostructures using simple routes (via self-assembly) and utilizing inexpensive and biocompatible materials. In our first study, we describe a class of liposomal probes that can allow certain tumors to be imaged by magnetic resonance imaging (MRI). Tumors, such as those of head and neck cancer, are known to over-express the epidermal growth factor receptor (EGFR). Our liposomal probes bear anti-EGFR antibodies as well as chelated gadolinium (Gd), a positive (image-brightening) contrast agent for MRI. To synthesize these probes, we use a strategy that is carefully designed to be simple and scalable: it employs two steps that each involve self-assembly. The resulting probes bind in vitro to EGFR-overexpressing tumor cells compared to controls. Moreover, cancer cells with bound probes can be tracked by MRI. In the future, these probes could find clinical use for tracking the efficacy of cancer treatment in real-time. Next, we report a class of microscale (3 to 5 µm) containers derived from erythrocytes (red blood cells). Micro-erythrosomes (MERs) are produced by emptying the inner contents of these cells (specifically hemoglobin) and resuspending the empty structures in buffer. We have developed procedures to functionalize the surfaces of the MERs with targeting moieties (such as anti-EGFR antibodies) and also to load solutes (such as fluorescent dyes and MRI contrast agents) into the cores of the MERs. Thus, we show that MERs are a versatile class of microparticles for biomedical applications. In our final study, we show that the MERs from the previous study can be sonicated to yield nanoscale structures, termed nano-erythrosomes (NERs), with average sizes around 120 nm. NERs are membrane-covered nanoscale containers, much like liposomes. They show excellent colloidal stability in both buffer as well as in serum at room temperature, and they are able to withstand freeze-thaw cycling. Moreover, NER membranes can be decorated with fluorescent markers and antibodies, solutes can be encapsulated in the cores of the NERs, and NERs can be targeted towards mammalian cells. Thus, NERs are a promising and versatile class of nanostructures for use in nanomedicine.