Browsing by Subject "Cell transplantation"
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Item Development and Validation of a Multinuclear Magnetic Resonance Spectroscopy Toolkit for Bioartificial Pancreas Assessment(2016-06) Einstein, SamuelType 1 diabetes is a devastating disease with increasing incidence and prevalence. Insulin therapy, while life-saving, does not prevent severe complications that substantially increase both morbidity and mortality. Whole pancreas and pancreatic islet transplantation are treatments for diabetes, but favorable long-term outcomes are inconsistent and the procedures are restricted to a small group of patients due to a variety of limitations. These impediments include the current demand for donor pancreata far exceeding supply, allotransplantation requiring a lifetime of immunosuppression, and premature graft failure. Macroencapsulated tissue-engineered grafts (TEGs) may mitigate or eliminate these limitations by allowing the use of alternative cell sources (such as porcine or stem-cell-derived islets), providing immunoisolation, and encourage graft survival through therapeutic interventions. TEGs possess great potential, but require significant development to fulfill their promise of a safe, effective, and definitive cure for type 1 diabetes. To enable and expedite TEG development, novel techniques to assess oxygen status (pO₂) and viability were developed, validated, and applied. Hypoxia is currently the most significant obstruction preventing widespread utilization of TEGs, rendering measurements of TEG pO₂ critically necessary. Fluorine-19 magnetic resonance spectroscopy (¹⁹F-MRS) was adapted for in vivo pO₂ measurement in TEGs and validated with a well-established technique. It was found that ¹⁹F-MRS can be a robust, accurate, and noninvasive technique to monitor TEG pO₂ for long durations post-implantation. This technique was applied to the murine model and demonstrated that TEGs implanted subcutaneously experience hypoxia unconducive to supporting islet viability and function. Therefore, a method for the delivery of supplemental oxygen (DSO) to increase in vivo pO₂ was developed and its efficacy was evaluated with ¹⁹F-MRS. It was found that DSO can successfully increase the pO₂ of macroencapsulated TEGs and enhance islet survival. While providing crucial information, measuring pO₂ does not necessarily correlate to islet viability, necessitating the development of additional techniques. Islet viability was first assessed by measuring pO₂ with ¹⁹F-MRS and calculating the oxygen consumption rate (OCR) using a mathematical model. Finally, to facilitate in vivo viability assessment and increase measurement accuracy, oxygen-17 MRS was developed to directly measure and noninvasively quantify the OCR of TEGs.Item Tissue-engineered islet graft design and assessment(2012-10) Suszynski, Thomas MarkDiabetes mellitus is a metabolic disease characterized by an inability to maintain normoglycemia and is usually associated with an insufficient beta-cell mass. Islet transplantation (IT, a beta-cell replacement therapy) has exhibited promise in reversing the diabetic state, yet it remains an experimental therapy only among a small subset of patients and widespread availability remains elusive. A main reason for its limited use is the large islet dose required to produce insulin independence, often requiring tissue from multiple donor pancreata. Abundant evidence exists suggesting that acute and chronic islet loss and dysfunction occur in the post-IT period. The minimum islet dose could be reduced if the quality (potency, viability) of the islet product is improved. Since islets do not possess the cellular machinery to produce energy effectively in the absence of oxygen, strategies that improve oxygenation during the ischemic period (donor cardiac death to complete revascularization) are important to develop. Due to the many steps involved in the process (pancreas preservation, and islet isolation, purification, culture, assessment, transplant and engraftment), the quality of an islet preparation can change. Thus, it is critical to develop improved islet quality assessment tools that enable accurate and quantitative characterization of islet viability and potency, which can be performed prospectively, and which do not require much tissue for assessment or which rely on non-invasive methods. Furthermore, intrahepatic IT may not be the optimal approach, and tissue-engineered strategies for extrahepatic IT may be better. The work presented herein focuses on improving islet quality assessment, examining the oxygenation status of the intraportally transplanted islet, and developing a tissue-engineered strategy for the design and non-invasive assessment of islet graft viability - all with the hope that someday IT could be used to successfully treat many more diabetics.