Developing tissue engineered models of oral mucosa and oral cancer to study novel therapeutic and diagnostic techniques.

Abstract

In the UK in 2008 over 1,800 people died from oral cancer. Despite advances in surgery and therapy the survival rates for those diagnosed with oral cancer have not significantly improved over the past 20 years. There is a need for both better detection and treatment. Early detection could reduce these mortality rates but unfortunately diagnosing oral cancer, which is often symptomless, in the early stages of the disease is incredibly challenging. More targeted treatments for oral cancer are also needed which can be administered to the site of disease with higher efficiency and accuracy to reduce side effects and allow higher concentrations of therapeutic agents to be delivered to tumour cells. This project used a tissue engineered oral mucosa model to develop models of oral cancer progression. These oral cancer models incorporated many pathological features of oral cancer progression including features seen in dysplastic epithelia, carcinoma in situ and early invasive squamous cell carcinomas. Multi-cellular tumour spheroids were created from an oral cancer cell line to model solid expanding tumour masses. The tissue engineered models of oral mucosa and the multi-cellular tumour spheroids were used to test the behaviour of polymersomes, a novel drug delivery system, in three dimensional tissues. Polymersome distribution and penetration in the tissue engineered models was examined over time, to investigate the potential of polymersomes to deliver therapeutic agents into and/or across the oral mucosa and into solid expanding tumours. Drug delivery agents that are able to reach the central hypoxic region of solid expanding tumours are particularly important as these cells are often resistant to both radio- and chemotherapy and correlate with poor patient prognosis. In addition, we explored the potential of polymersomes to cross the oral epithelial permeability barrier and act as delivery vehicles for topical delivery of therapies for oral mucosal diseases and as an alternative to parenteral administration for the systemic delivery of drugs. Results showed good penetration of polymersomes into the oral mucosa and the multi-cellular tumour spheroids demonstrating the potential to develop these drug delivery vehicles to deliver anti-cancer drugs and other therapeutic agents in the future. The tissue engineered models of cancer were next utilised to test four non-invasive diagnostic technologies. These included a cell metabolism marker, impedance spectroscopy, Fourier transform infra-red and optical coherence tomography. The results obtained from these different techniques showed varying degrees of promise with the images from OCT demonstrating that this technology has real diagnostic potential. The 3D models proved useful test-beds for some but not all of these diagnostic imaging techniques. They provide convenient models to tackle some of the key issues in the preclinical development of novel diagnostic technologies for oral cancer and oral dysplastic lesions