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Title: Tissue engineering of the kidney using a whole organ decellularisation approach
Author: He, Ming
ISNI:       0000 0004 6346 8196
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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End stage renal failure is associated with major morbidity and mortality, and renal transplantation is the optimal form of renal replacement therapy. However, since the number of organs available for transplantation is limited, an additional (e.g. bioengineered) source of organs for transplantation is both attractive and necessary. Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences towards the development of functional replacement tissues for clinical use. Within this field, the technique of whole organ decellularisation allows the preservation of the native vasculature and the complete 3-dimensional macro- and micro-architecture of the organ extracellular matrix (ECM) to create a whole organ ECM bioscaffold. This approach has been employed in the animal model to create viable and partially functional solid organ constructs, some of which have been implanted in vivo, including in the kidney. However, a number of major technical factors and challenges exist before clinical application can be considered, such as the pre-optimisation and standardisation of both decellularisation and recellularisation protocols. The current applications and methods in using xenogeneic whole organ ECM scaffolds to create potentially functional bio-artificial organ constructs for surgical implantation have been reviewed here; comparison of specific trends reveals the need for systematic rationalisation throughout the field. On this basis and using the rat model, the first aim of this project was to optimise the decellularisation process for whole kidney ECM bioscaffolds with regards to two fundamental parameters: concentration of decellularising agent and duration of perfusion, using the most common single decellularising agent drawn from the literature i.e. sodium dodecyl sulphate. Optimisation was determined with regards to structural and functional characteristics of the ECM bio-scaffold as assessed by histology, immunohistochemistry, quantitative assays of DNA and sulfated glycosaminoglycan content, and growth factor quantification. Secondly, recellularisation of the whole kidney bioscaffolds produced using this more optimised protocol was carried out to yield a viable and implantable organ graft/construct, with both primary renal cells and also adult-derived mesenchymal stem cells. Thirdly, both the decellularised and recellularised kidney constructs were implanted in vivo using the renal transplant model in order to investigate the long-term viability and function of the graft construct. This showed long-term viability and biocompatibility of the acellular (decellularised) kidney scaffold when implanted in vivo, but poor viability of all scaffolds (acellular or recellularised) when implanted in combination with vascular perfusion due to a postulated pro-thrombotic mechanism.
Supervisor: Stevens, Molly M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral