Development of novel biomaterials and medical devices to improve diabetes treatment and ambient cell transportation
Domingo Lopez, Daniel A.
Domingo Lopez, Daniel A.
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Publication Date
2023-02-08
Type
Thesis
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Abstract
Diabetes mellitus is a global pandemic affecting to more than 500 million people worldwide, with Type 1 diabetics being the most at risk due to life-threatening hyper and hypoglycaemic complications. Islet transplantation aims to reverse Type 1 diabetes mellitus (T1DM) by the transplantation of healthy islets and re-establishing naturally insulin regulation. One of the major limitations stopping this therapy is its low graft survival, with an estimated 50-70% post-transplantation islet death reported. Hypoxia (lack of oxygen) and anoikis (lack of extracellular matrix (ECM) are two of the most important causes behind this low islet survival. These conditions can be aggravated when islets are encapsulated within macroencapsulation devices, which are needed to stop graft immune rejection. The overall objective of this PhD thesis is to develop novel biomaterials and medical devices to increase post-transplantation islet survival by targeting hypoxia and anoikis. This was achieved by the development of Oxygel, a biomaterial made of hyaluronic acid hydrogels (providing ECM-mimicking support) and perfluorocarbon emulsions (providing additional oxygen supply). This biomaterial was successfully formulated and optimized showing the rheological properties required for its delivery to a macroencapsulation device, and improved oxygen storage characteristics. Developed sterilization and scale-up oxygenation methodologies demonstrated that Oxygel could be produced at the scales required in a clinical setting. Oxygel demonstrated the ability to support the viability of several diabetes-relevant cell lines (including F/G-luciferaseexpressing mMSCs, INS-1E) and human islets in vitro, with the latter showing a substantial improvement in overall survival when compared to other encapsulation matrices. Alongside, a predictive mathematical model to analyze oxygen consumption within the graft was developed and validated, finding correlations between the predicted and experimentally determined oxygen durability times in cell-containing Oxygel. To further expand the applications of Oxygel and overcome some of the functionality concerns observed, this technology was adapted into a macroencapsulation dual chamber device. Dual chamber devices were developed and optimized using novel manufacturing techniques, achieving a prolonged and sustained oxygen transfer (for more than 80 h) to the cell-containing chamber. A porous version of this device was created (10 micron pores) along with a protective cover that will potentially allow for ambient transportation and implantation, within the same device. Finally, a novel methodology to transport therapeutic cells at room temperature was developed using these Oxygel-based dual chamber devices, aiming to provide a safer alternative to cryopreservation. Therapeutic cells (ECFCs) were successfully ambiently transported in these devices within a temperature-controlled packaging, showing comparable viability and superior tubologenesis in vitro, when compared to cryo-transported cells. Additionally, transported ECFCs showed functional activity upon implantation in an in vivo mice model for angiogenesis. Overall, the technologies presented in this manuscript have the potential to increase the success of cell transplantation therapies, with an special focus on the development of a bioartificial pancreas that can improve the quality of life of people with Diabetes Mellitus.
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NUI Galway