Hamilton, Nicholas J.I.;
(2018)
Tissue-engineering airway mucosa for airway reconstruction and transplantation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Conventional therapies are unable to treat a subset of patients with upper airway stenosis. To overcome this, tissue-engineered tracheas have been trialled as a means of replacing the damaged section of airway. All examples have suffered from poor mucosalisation following implantation which results in infection, mucostasis and airway obstruction. The aim of this thesis was to investigate methods of regenerating a respiratory mucosal graft that could be used as part of a tracheal transplant. The relationship of the extracellular matrix to human respiratory epithelial cells (HBECs) was examined to establish the optimal protein composition of the mucosal scaffold. Collagen IV was demonstrated to be the leading adhesive protein acting via the integrin α2β1 and a Src and FAK mediated intracellular pathway. Laminin was shown to play a key role in promoting HBEC proliferation and was dependent on an integrin pathway containing the subunit β1. This study compared biological, biomimetic and synthetic scaffolds for their ability to support and differentiate a respiratory epithelial layer. Decellularised dermis was shown to be the optimal scaffold and a differentiated respiratory layer with mucocilary function was achieved in-vitro. The implantation of this engineered respiratory mucosa proved more challenging with loss of differentiation markers following grafting in rabbits and mice. An alternative strategy was developed whereby basal epithelial cells were encased in collagen and successfully grafted onto the surface of decellularised trachea. This represents the most effective method for re-epithelising an allogenic trachea before or after transplantation and could also be used to reline other parts of the upper airway.
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