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Development of a lung in vitro model to assess antimicrobial activity

In this project, Dr Hisham Al-Obaidi, Prof. Simon Andrews, Dr Glyn Barrett and Prof. Vitaliy Khutoryanskiy aim to develop an innovative non-biological lab model that resembles the human lungs to effectively predict how medicine will act when given to humans.

Lung infections, especially lower respiratory tract infections, are leading causes of transmissible deaths worldwide according to the World Health Organisation (2020). The majority of patients who suffer from lower respiratory tract infections have their lungs colonised by a particular strain of bacteria. These infections tend to have a greater impact on patients who already have existing lung problems such as cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD).

The bacteria Pseudomonas aeruginosa is the most common chronic lung infection in CF patients and lung failure is the main cause of death. P. aeruginosa has adapted and become resistant to many antibiotics that are normally used to treat infection. P. aeruginosa is also notoriously persistent in clinical settings which is attributed to its ability to form antibiotic-resistant biofilms. Biofilms are densely packed bacteria growing in communities on living or inert surfaces, surrounded by a matrix of polymers and other substances that help provide protection. The high level of antimicrobial resistance shown by P. aeruginosa biofilms is driving the need to develop new and more effective antibiotic treatments to combat it.

There are several current treatments for P. aeruginosa infections in the lungs. The most common, and the one recommended first, is the antibiotic ciprofloxacin (CFX). CFX is a broad-spectrum antibiotic which is known to have potent antibacterial effects against P. aeruginosa biofilms. It can be administered orally or intravenously, however neither of these methods have the ability to deliver high concentrations of CFX to the lungs. The systematic delivery of the drug through the body via these methods also causes side effects. Previous research by members of the team has identified that the development of a CFX inhalable version of the drug would be of great interest as a non-invasive route to directly target the infection site.

Assessing the effectiveness of inhaled drugs currently is tricky and methods for doing this currently cannot replicate the physiological conditions of the lungs, including the effects of mucus and other lung surfactants (fluids) or their effect on the activity of the drug. This is particularly important when creating a model to study conditions with abnormalities of the mucus, such as CF. The most common animal models used to research the deposition of inhaled particles are rodents, such as mice. These animals have different airway physiology to us and do not naturally breathe through their mouth, so forcing them to inhale these drugs in an unnatural way not only causes suffering but does not provide a physiologically accurate model of the human lungs.

The researchers will use the FRAME funding to create a model that should better simulate conditions in the lungs using synthetic materials to resemble mucus. The team will be able to control and vary the thickness of mucus to replicate different conditions inside the lungs, such as those seen in CF or COPD, adding P. aeruginosa to study the growth of biofilms and the effect of the mucus on the deposition and potential effectiveness of an inhaled antibiotic treatments.

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