Butler, Colin R; (2018) Strategies to improve epithelialisation of tissue engineered airway constructs. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Patients with significant airway stenosis and end-stage airway disease are faced with a dismal prognosis and often clinical solutions are not possible. Tracheal replacement has been historically challenging and is often associated with high failure rates. Methods to replace the airway are complex, and a plethora of strategies have been developed. Currently, many grafts have failed and do not meet ideal requirements for tracheal replacement. Tissue engineering, where a like-for-like engineered replacement is created, has long been considered as a possible solution. Tissue engineering encompasses a number of technologies, including combining biomaterials and cells to generate therapeutics. In the airway, replacement and regeneration of epithelium is key to restoration of normal barrier functions of the airway, and differentiation is also necessary to restore tissue homeostasis. Studies based upon decellularised scaffolds engrafted with autologous cells have shown poor epithelialisation. The reasons for this have been unclear and has required attention. This work describes investigations aiming to improve epithelial engraftment in scaffolds intended for use in tissue engineered tracheas. Characterisation of potential scaffold materials identified a significant hurdle; the need for high seeding densities for epithelial cell engraftment. This makes cell delivery a challenge as small biopsies are the only feasible source of cells that can be delivered in an autologous fashion. This work attempted to characterise and isolate putative stem/progenitor cells populations. It found that co-culture of airway epithelial cells with 3T3-J2 feeder cells, similar to traditional epidermal keratinocyte expansion, in combination with a Rho-associated kinase (ROCK) inhibitor conferred significant population doubling advantage and maintained airway epithelial differentiation capacity in in vivo and ex vivo models. Attempts to determine the mechanism behind the cell expansion methods have suggested maintenance of telomeres together with inhibition of senescence pathways as means to maintain putative stem cell populations.

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