Near-Human tissue-engineered, dynamic model of the large airways

Recent advances in tissue-engineering and bio-printing have been dramatic. At a time when the costs and disease burden for healthcare systems is ever increasing, there is still an acute lack of valid, efficient systems for studying human biology. This paradigm applies to the respiratory tract at least as much as to any other system.
There can be no perfect animal models for human physiology of the respiratory tract, so it is inherently attractive to propose models that genetically replicate whole human tissues, organs or systems in a way that can be controlled and interrogated under different experimental conditions. Such models reduce animal use and distress also, in line with the '3R's' ethical principles. Recent advances in growing and bio-printing human tissues have shown great potential towards delivering exciting but tractable Near-Human alternatives to animal models for the study of human biology. These technologies are so promising that they also may ultimately deliver replacement organs for transplantation.
Professor Martin Birchall at UCL is a leading expert in the field of engineering human respiratory tract tissue, an area of particular focus for drug discovery at GlaxoSmithKline. Whilst studies into engineered airway tissue have already shown that new autologous tissue can be created in bioreactor environments and transplanted successfully back into patients, the potential to exploit these advances for discovery science has not yet been realised.
Research Plan:
The aim of this PhD studentship is to develop, optimise and miniaturise engineered respiratory tract models on decellularised, 'biologic', human and animal scaffolds, repopulated with human respiratory cells. Based on our GMP-ready processes, the student will test and refine scaffold, cell and bioreactor components to provide a prototype dynamic, reproducible Near Human physiological system; thereby ultimately creating the most powerful tool yet for providing new data on the human airway. Specifically this would require:
(i) Identification of ideal scaffold source(s)
The studentship will aim to compare the chemical, ultrastructural, and biomechanical properties of decellularised bronchi from human and animal (murine, porcine, ovine) sources. We have a regular source of human material through an agreement with NHS Blood and Transplant. We have advanced biomechanical testing systems (BOSE) and staff experienced in the chemical and physical analysis of the scaffold.
1.2 IMPACT SUMMARY (Up to 1500 characters)
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(ii) Translation of respiratory epithelial engineering to the selected scaffold(s)
We have developed reproducible techniques for growing a fully differentiated respiratory epithelium in air- liquid interface models, using a GMP-ready fibroblast feeder layer and human respiratory progenitor cells obtained by bronchoscopy. The Studentship will optimise the transfer of this epithelium to the decellularised scaffolds, either by growing in situ, or as a separate engineered layer.
(iii) Engineering a dynamic bioreactor
The epithelialised Near Human bronchus will be maintained in a dedicated bioreactor environment which will involve the circulation of culture media and air to reproduce normal airflow. We also have facilities for non-invasive testing, such as epithelial brushing and 'ex vivo' microscopy, including Raman microscopy, and photo-acoustic imaging. Earlier iterations of this bioreactor have allowed us to study cell migration and viability via labelling of cells with fluorogens.