Development of a Bioartificial Pancreas using Biodegradable Polyhydroxyalkanoate Polymers

Type 1 Diabetes progressively removes the sufferer’s ability to produce the blood glucose
regulating hormone insulin. Although insulin injections and islet replacement is effective,
poor patient compliance, immunosuppression need and progressive destruction of islets
mean that longer term solutions are required. One solution is Bioartificial pancreases (BAP),
where implanted islet cells are isolated from the immune system via semi-permeable
membranes. The present thesis by publication ascertains suitability of a bacterially-derived
class of polymers, polyhydroxyalkanoates (PHA) for use in BAPs. The proliferation, survival
and behavior of beta cell lines (BRIN-BD11) seeded onto PHA polymers as solvent cast films
was tested. Biocompatibility was confirmed on polymer films and BRIN-BD11 glucose
sensitivity was recorded using insulin ELISA, with PHA polymers showing no significant
differences to another polymer used in Bioartificial pancreas, polycaprolactone (PCL). For
work 2, Fused Deposition Modelling 3D printing produced multi-material bioartificial
pancreas (BAP). BAP was analyzed for cell survival using LIVE/DEAD assays, as well as insulin
ELISA assays over two weeks, finding that BAP displayed high cell survival, whilst exhibiting
glucose-sensitivity. Work 3 tested modified versions of BAP printed from oxygen-producing
PHA composites containing calcium peroxide (MOBAP). Biocompatibility was ascertained
with BRIN-BD11 grown on polymer films and when bioprinted. MOBAP was tested for insulin
secretion, cell survival and hypoxia response. Under hypoxia, MOBAP exhibited more
glucose sensitivity and less hypoxia-induced fluorescence than mcl-PHA controls. Work 4
produced PHA microspheres containing angiogenic 2-deoxy-D-ribose, compositing them into
a 3D-printable constructs. 2dDR was released over 72 hours, with the release inducing
heightened endothelial aortic cell protein expression, proliferation and metabolism, as well
as vascular growth induction ex ovo. Supplementary work explored production of PHAs
through bacterial fermentation and manufacture of reactive oxygen species-sequestering
constructs. Taken together, these studies display a testbed for a PHA bioartificial pancreas
suggestions for the design may be improved.