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Experimental and mathematical modelling of the culture and cryopreservation of a bioartificial liver device utilizing a 3D cell scaffold construction

Kilbride, PJ; (2016) Experimental and mathematical modelling of the culture and cryopreservation of a bioartificial liver device utilizing a 3D cell scaffold construction. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Acute Liver Failure has poor prognosis; current treatment - liver transplant - cannot keep up with demand. Due to its regenerative capabilities, a damaged liver could heal if its functions were temporarily carried out by a separate device. A bioartificial liver device (BAL) could provide functional support while the organ heals, eliminating transplant and lifelong immunosuppression requirements. This device consists of a 2 litre biomass of alginate encapsulated HepG2 liver cells. The aim of this PhD is to cryopreserve this biomass in a single cassette and recover viable cell number within 72 h of thaw by researching the physical and biological implications of scaling-up cryopreservation from 2ml to 2 litres. Heat transfer, ice formation patterns, ice nucleation, and thawing profiles were examined and used to optimise cryopreservation protocols. Ice structure was substantially different after scale-up, with network solidification present in 2ml but progressive solidification in 2 litre volumes – this reduced post-thaw viable cell number 24 h post-thaw, but faster recovery eliminated differences by 48 h. There was a strong spatial element after scale-up - biologic freezing later demonstrated reduced post-thaw function. This was solved by inclusion of supernatant medium acting as a solute and heat sink. The warming rate of the 2.3 litre mass was reduced to <1°C/min – the critical step during thawing was the final melting step – this should be rapid. The effect of cold on hepatocyte proliferation was studied and a new method, termed here cryoanaptiksi, developed that uses chilling to induce rapid cell proliferation. Oxygenation and fluidisation of the bioreactor was modelled to determine more effective cell culture methods. Using optimised protocols, successful cryopreservation of the BAL has been demonstrated – a 4 times greater volume than any cryopreserved mammalian biomass recorded in the literature. This work gives strong foundation towards successful clinical delivery of a BAL.

Type: Thesis (Doctoral)
Title: Experimental and mathematical modelling of the culture and cryopreservation of a bioartificial liver device utilizing a 3D cell scaffold construction
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1497077
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