Advanced therapies in pancreatic islet transplantation for type 1 diabetes mellitus
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Date
2023-03-14Embargo Date
2025-03-13
Author
Wallace, Eimear J.
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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.