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Microfluidic-based Strategies to Improve Islet and Encapsulated Islet Transplant for Type I Diabetes

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Title: Microfluidic-based Strategies to Improve Islet and Encapsulated Islet Transplant for Type I Diabetes
Author(s): Mendoza-Elias, Joshua E
Advisor(s): Oberholzer, Jose
Contributor(s): Magin, Richard L; Hetling, John R; Wang, Yong; Daniels, Kirstie K; Oberholzer, Jose
Department / Program: Bioengineering
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): β-cell, beta-cell, islet, islet of Langerhans, transplant, transplantation, islet physiology, islet pathophysiology, ischemia reperfusion injury, I/R injury, hypoxia, intermittent hypoxia preconditioning, cytoprotective, mitoprotective, alginate microencapsulation, islet encapsulation, retrieved encapsulated islet, intracellular calcium, mitochondrial potential changes, insulin, insulin kinetics, NADPH, barium, fura, fura attenuation, K-ATP channel, N+/K+-ATPase, VDCC channel, diazoxide, DMSO, multimodal microfluidic assessment, microfluidic-based assay, microfluidic, UIC-MS1, PDMS, carbon nanofiber, live-cell imaging, open-surface microfluidics, pumpless microfluidic chip, surface-tension driven microfluidics, Cynomolgus monkey islet transplantation, density purification of encapsulated islet, density model of encapsulated islet
Abstract: Project 1 concerns the impact of alginate capsule diameter on encapsulated islet function using an microfluidic-based islet function assay. The project begins with prototype and protocol development of the first microfluidic device to evaluated encapsulated islet function by evaluating: intracellular calcium ([Ca2+]i), mitochondrial potential changes (ΔΨm), and insulin kinetic ([Ins]) physiologic response profiles. Furthermore, the device is the first only device capable of testing naked islet as well as encapsulated islets in capsules with a diameter of 300-1700 µm. The device is deployed and allows the first comparative study of naked vs. 500 µm vs 1500 µm capsule. Study results were published (Nature Materials. 14(6): 643-651, 2015) in collaboration with the Anderson lab at the Massachusetts Institute of Technology (MIT). Project 2 deploys the microfluidic device developed in project 1 coupled with a hand-made and programmed solenoid oxygen valve system in order to study intermittent hypoxia preconditioning (IHP) of encapsulated human islets as a strategy to improve encapsulated islet function in a streptozotocin-induced diabetic nude mouse model. The project begins with the first description of the impact of IHP on the encapsulated human islet by in vitro microfluidic device evaluating: intracellular calcium ([Ca2+]i), mitochondrial potential changes (ΔΨm), NAD(P)H levels (ΔNADPH) and insulin kinetic ([Ins]) physiologic response profiles. Method to scale-up IHP using a 6-well oxygen insert and deployed in a streptozotocin-induced diabetic nude mouse model. Project 3 reports the first results of encapsulated islet function following retrieval from mouse and Cynomolgus monkey model from an ongoing collaboration between the Oberholzer lab (UIC) and the Anderson lab (MIT). Conflicting data indicating a decoupling of intracellular calcium with insulin kinetic data indicates that physiologically in retrieved capsules is altered and that barium may play a role. The impact of barium on insulin secretion is then pursued and interrogated by monitoring intracellular calcium [Ca2+]i using inhibitors of the insulin secretory pathway in low and high glucose conditions using islets from C57/B6 mice. Project 4 reports the development of the first technique capable of large-scale purification of loaded capsules from human encapsulated islet preparations. Human islets were encapsulated in a 500 µm diameter capsule at a seeding density of 10,000 IEq with an equal volume of empty capsules. Using a density gradient, the method demonstrates that postpurified encapsulated islet preparation volume can be reduced 30-50% (depending on Prepurification volume and starting purity) achieving loaded encapsulated purity of 70-90%, as compared to the prepurified preparation for 10,000 IEq and 20,000 IEq, respectively. Furthermore, increasing islet density and morphologic compactness, correlates with higher islet purity, viability scores, and in vitro function as indicated by: glucoses-stimulated insulin secretion (GSIS) assay, and microfluidic multimodal assessment of: intracellular calcium flux ([Ca2+]i), mitochondrial potentials changes ΔΨm). Invention disclosed to UIC OTM which is currently pursuing patent application. Project 5, pursued the development of the first open-surface microfluidic device with surface tension driven droplet flow for human islets. In collaboration with the Megaridis lab (UIC), a self-propelling fluid transport was achieved using a surface contrast (suprahydrophobic/superhydrophilic). A material system composed of carbon nanofiber deposited on acrylic substrate was demonstrated capable of detecting and resolving islet responses.
Issue Date: 2017-04-11
Type: Thesis
Date Available in INDIGO: 2017-10-27
Date Deposited: May 2017

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