Development of tissue-engineered respiratory mucosal replacement for patients requiring airway reconstruction

Epithelium is a dynamic interface between the body and its environment, internal and external. Replacement and regeneration of skin and cornea are major early targets for regenerative medicine, with several clinically applied products, including Holoclar, the first cellularised, engineered product licensed by EMA.1-6 However, the regeneration of internal mucosal surfaces has received little attention, despite important unmet clinical needs, such as mucosal loss after trauma, inflammation and cancer. If this product provides an epithelial cell layer within in the animal model, it provides a potential replacement to the present use of split-thickness skin grafts in mucosal reconstruction.

Patients/Healthcare: Presently, reconstruction of airway mucosal surfaces relies on primary healing, with associated scar, or use of split skin grafts. The latter may reduce stenosis, but necessitate painful and unsightly donor sites and permanently keratinised surfaces with chronic colonisation, poor mucus clearance, and halitosis. Provision of a replacement mucosal epithelial replacement for airway surgery would improve breathing post-operatively, reduce local infection (thus inflammation, granulation tissue), and reduce the incidence of stenosis and revision surgery. The use of a small biopsy also reduces pain at the graft source. This would greatly improve patient outcomes following airway reconstruction measured by symptom-relief, bed-stays, patient and healthcare costs, complications.

Regenerative science:

This study provides ample reverse translational opportunities with discovery science benefits. The creation of epithelial cells without the use of xenogenic products will provide information for other epithelial cell sheet based products. The removal of the 3t3J2 feeder layer will give rise to more epithelial based products to be investigated for translational research. The aids in the NC3Rs aims

Implanted mucosal surfaces are accessible for brushing/biopsy providing valuable information on cell morphology and mucosal integrity in vivo. This will enhance our understanding of how mucosal transplants integrate and regenerate within the native airway.

The small animal work will provide information on vasculariation


Commercialisation: Although protected IP by way of patents is difficult in this area, valuable knowhow will be generated. Being 'first-to-market' with an aerodigestive tract tissue engineered mucosal replacement will provide significant commercial gains for UK plc. Competition exists in dentistry (e.g. Mucograft- biomaterial sponge for small scale gingival repair), but no products offer cellularised, bespoke replacement for any size of airway mucosal defect. As with previous skin replacements, our product offers a novel means of screening drugs/small molecules/ATMP for use in airway patients, extending potential commercial gains for the UK and meeting NC3R aims.

Airway stenosis is a condition that leads to a narrowing of the windpipe. This leaves patients with severe breathing difficulties that limit their ability to perform day-to-day activities such as walking to the shops or getting dressed on their own. As the windpipe is narrowed, the natural secretions that are produced in the airways can also easily block it. This can lead to life threatening complications.

Whilst most patients can be treated with a series of minor surgical procedures to open up the airway, in some the narrowing is so severe that it requires major reconstructive surgery often with the use of a skin graft to replace areas of disordered mucous membrane. Whilst this procedure can be successful, in many it involves a long hospital stay, the need for repeated further surgical interventions and involves a wound on the thigh where skin is harvested. We are investigating the manufacture of an airway lining which is constructed from the patient's own oral mucosal cells. This new solution avoids the need for a skin graft, with its painful, unsightly donor site, and delivers more appropriate cells into the windpipe instead of skin cells, with functional and quality of life benefit, such as reducing halitosis and coughing. We propose our mucosal replacement will lead to a shorter hospital stay, fewer complications and reduce the need for revision surgery after major operations to repair the airways. If successful, the product could help patients with a wide range of disorders affecting the mucous membranes of the head, throat and mouth.

This project is designed to answer the critical "unknown unknowns" prior to the finalisation of an optimised tissue-engineered airway mucosal replacement for patients with severe airway stenosis and/or malacia. We present a step-wise approach from late-phase laboratory studies, through to small animal screening of key parameters, to the parallel development of a large animal (NIH minipig) model suitable for GLP preclinical studies. This two years' project will define our product and production process, and give a very broad indicator of safety and potential efficacy.

We will then seek funding for the next phase of development, which will comprise (a) a definitive, adequately powered, GLP study in our pig model above, designed following close liaison with the MHRA and (b) pre-GMP laboratory work to optimise the production process for a clinical grade product, including the development of SOPs, QC and RC. In combinations, these data, combined with our prior preliminary data and the outputs of the present project will form the basis of a Clinical Trials Authorisation application to the MHRA.

At this stage, we envisage that our early phase (I/IIa) clinical trial will be a small randomised trial comparing our product with the existing standard (split skin grafts). The trial design will be informed by our previous work on recruitment and governance around complex ATMP trials in surgery. It will further be developed in close collaboration with patients and carers, through our PPI programme (see Communications Plan), with particular attention to the most important patient-facing outcomes.

During the present project, we will consider the most appropriate possible routes to commercialisation and, thereby, ultimately implantation in the NHS and other healthcare systems. Again, we, and our partners in UCLBusiness, have considerable prior experience of taking ATMPs through such pipelines, and emphasise that there is no "one-size-fits-all", but rather that each product requires a carefully customised approach, taking into account potential market size, cost-benefit analyses and the arrival or otherwise of competitor products.