Advanced therapies in pancreatic islet transplantation for type 1 diabetes mellitus
Wallace, Eimear J.
Wallace, Eimear J.
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Publication Date
2023-03-14
Type
Thesis
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Abstract
Type 1 diabetes mellitus is an autoimmune condition whereby β-cells are destroyed by the immune system causing the lack/absence of insulin production and resultant hyperglycaemia. Pancreatic islet transplantation is considered a potential cure for type 1 diabetes mellitus. However over 60% of macroencapsulated islets are lost immediately post transplantation due to hypoxia from inadequate early vascularisation. Pre vascularisation of implantation sites by delivering pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) is a potential solution to overcome islet loss. However, VEGF has a half-life of only 30-50 mins in vivo and if delivered in large quantities systemically can result in the formation of leaky blood vessels and oedema. In this thesis an alginic acid (AA)-carboxymethylcellulose (CMC) mechanoresponsive hydrogel was produced to electrostatically interact with VEGF165 and stabilise it in vivo. A pneumatically actuatable soft robotic drug delivery (SRDD) device was developed, and its actuation regime optimised to control the release of VEGF165 from the AA-CMC hydrogel to pre-vascularise an implant site for future islet transplantation. The VEGF-AA-CMC hydrogel/SRDD device was implanted for 7 days in non-diabetic rats and actuated once daily to release VEGF165 in a controlled manner locally at implant sites. Histological analysis of the implant site found controlled release of VEGF165 by the AA-CMC hydrogel/SRDD device significantly increased CD31+ and α-SMA+ blood vessel number and length density, significantly reduced radial diffusion distances and significantly increased the diameters of CD31+ blood vessels. Thus, indicating that controlled release of VEGF165 can stimulate angiogenesis at the implant site in non diabetic rats. In a diabetic rat model, the VEGF-AA-CMC hydrogel/SRDD device when implanted and actuated once daily for 7 days significantly increased CD31+ and α-SMA+ blood vessel number and length density, non-significantly reduced radial diffusion distances and significantly increased the diameters of α-SMA+ blood vessels. Therefore, demonstrating that controlled release of VEGF165 by the AA-CMC hydrogel/SRDD device can also stimulate angiogenesis at implant sites in diabetic conditions. The findings detailed in this thesis demonstrate that the AA-CMC hydrogel/SRDD device can control the release of bioactive VEGF165 and pre-vascularise implant sites. In the future this approach can be coupled with islet transplantation via macroencapsulation to increase the viability of transplanted islets to improve the treatment of type 1 diabetes mellitus.
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Publisher
NUI Galway