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Title: Translational process engineering for tissue engineered hollow organ advanced therapy investigational medicinal products
Author: Proctor, Toby Joseph
ISNI:       0000 0004 7965 0523
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Tissue engineering has experienced increasing exposure and translational success in recent times, with tissue engineered products accounting for more than a quarter of approved advanced therapy medicinal products within Europe. Hollow organs represent a key target for developing novel therapies, typified by the recent success reported for tissue engineered hemilaryngeal replacements in a preclinical study. This thesis investigates the translational process engineering required to progress from a preclinical, good laboratory practice (GLP) process, to one that is compliant with good manufacturing practice (GMP) guidelines and suitable for clinical manufacture. A GLP decellularisation protocol was translated to conform to GMP-guidelines by modifying the existing standard operating procedure, and adapting an off-the-shelf bioreactor to form a closed-system for aseptic processing. The process was successfully validated for aseptic operation and decellularisation efficacy evaluated, relative to the preclinical process. The decellularised, human hemilarynx scaffolds produced were demonstrated to support bone marrow mesenchymal stromal cells (BM-MSCs) up to product release. A bespoke, modular bioreactor was designed and fabricated to enable manufacture of hemilarynges at scale. The bioreactor was successfully validated for aseptic use, whilst biocompatibility testing indicated no preclusion to use with BM-MSCs or epithelial cells. Proof-of-principle data supported the concept of epithelial sheet production inside the bioreactor, utilising a sheet-specific cassette. The bioreactor was retrospectively adapted to enable closed-system decellularisation processing of a third tissue-type, juvenile oesophagus. Acellular scaffold biomolecular composition and biomechanics were characterised, preceding implantation in a large-animal model. A second, bespoke bioreactor was designed, manufactured and employed to improve the manufacturing process. The combined human larynx data supported the award of a clinical trial authorisation, whilst the oesophageal work is now transitioning to a pivotal animal study. These findings support the application of bespoke bioreactor systems in process closure and translation towards robust, regulatory compliant, manufacturing processes for tissue engineered products.
Supervisor: Veraitch, F. ; Lowdell, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available