Development of novel biomaterials and medical devices to improve diabetes treatment and ambient cell transportation
Date
2023-02-08Embargo Date
2025-02-06
Author
Domingo Lopez, Daniel A.
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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.