Tissue Engineering Approaches to Treat COPD

The study is a pilot/laboratory study comparing lung tissue from control participants with tissue from COPD participants with a chronic bronchitis or emphysema phenotypes. Tissue will be characterised mechanically and biochemically.

Lung cells, including DASCp63/Krt5 with a possible role in disease pathology, will be isolated, expanded in vitro, characterised, and banked. Biomaterials will be selected and tested with regards to mechanical and physical properties and selected for use in the production of TELEs with properties matched to healthy and diseased lung tissue.

The resulting TELEs will be tested in an ex vivo tissue culture model to determine the extent of their integration with lung.

Chronic obstructive pulmonary disease (COPD) is currently ranked as the third leading cause of death with an annual associated global healthcare cost of £1.3 trillion (1). It is the second most common cause of emergency hospital admissions with high morbidity and mortality. COPD results in a progressive loss of lung function, leading to respiratory failure. This loss of lung function is associated with repetitive cycles of inflammation and parenchymal scarring leading to the development of emphysema. This is a consequence of the breakdown of the delicate parenchymal structures and lung remodelling, with accumulation of fibrous tissue and loss of the alveolar-capillary functional units that are essential for effective gas exchange. Macroscopically the lungs become stiffer and unable to support the patient through the physiological inhalation/exhalation breathing cycles (2).

The presence of emphysema also results in the loss of lung elastic recoil as pockets of air form in place of damaged bronchioles and alveoli reducing the available volume for the next inhalation. The collapse of the airways during exhalation leads to increased lung volumes causing hyperinflation and gas trapping. Patients become progressively symptomatic with increasing breathlessness, reduced exercise tolerance and poor quality of life.

The pharmacological treatment options for emphysema are limited; current therapy aims to improve airflow limitation, reduce airway inflammation and reduce exacerbations, but does not reverse lung damage (3). Lung transplantation and lung volume reduction surgery (LVRS) is available for a selected minority of patients with severe emphysema. The recent introduction of non-invasive endoscopic mechanical treatment with Valves reduces severely damaged lung volume and re-directs air to the healthier tissue while Coils improves elastic lung recoil (4, 5). These interventions however do not improve survival.

Previous work performed within our laboratories has determined that hydrogel/elastin-based constructs can achieve mechanical values consistent with those of the alveolar wall when seeded with lung fibroblasts (1). This raises the intriguing question of whether tissue-engineered constructs (TEC) could be used to restore mechanical integrity of the emphysematous lung, via air pocket displacement and local integration, and ultimately by regeneration of local lung architecture.

Coupled to the work described above a recent observation went some way to detailing the mechanism behind the previously misunderstood, but physiologically critical, capacity for lung tissue to regenerate following on from acute disease such as pneumonia or acute respiratory distress syndrome (6). The key appears to lie with a population of distal airway stem cells who co-express Trp63 (p63) and Keratin 5 (Krt5). These DASCp63/Krt5 cells appear to migrate to sites of injury in the lung where they have demonstrated differentiation capacity including lineages such as type I and II pneumocytes and bronchiolar secretory cells. It is crucial to our understanding of chronic lung disorders, and design of future cell-based therapies, whether these cells remain present and dormant in diseased lung tissue or lost through as yet unknown mechanisms.

Eligibility Criteria:
Inclusion Criteria:

* Men or women aged over 18 years- .
* Must be competent to give written informed consent.
* Scheduled to undergo clinical indicated surgery to remove lung tissue.

Exclusion Criteria:

* Patient unable to give informed consent
* Significant long term condition or lung pathology (infection, asthma, fibrotic lung diseases) other than that for which they have been referred for surgery.

Post Surgery

• Insufficient tissue removed to supply the laboratory study after consultation with the Consultant histopathologist.