2021 Innovation Grant winner Dr Hisham Al-Obaidi from the University of Reading, was awarded £6,500 to develop a synthetic lung model which could be used to replace animal tests for inhaled antibiotic drug development.

The problem

Lung infections, especially lower respiratory tract infections, are leading causes of death by transmissible diseases worldwide, with the majority of patients having their lungs colonised by different bacteria. These infections tend to have a greater impact on patients who already have existing lung problems such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis.

Unlike oral or intravenous treatments, delivering a drug via the lungs avoids first pass metabolism that happens in the liver. The lungs have low enzymatic activity resulting in less of the drug being metabolised before delivering its therapeutic effect. This means there’s a faster onset of action as the drug is delivered directly to the affected site. In addition, an inhalation method allows the drug to be dispensed in powder form, which reduces any storage stability issues and improves the shelf life.

Current methods to test inhaled antibiotics are based on animal models. The most common animals used are rodents, but they breathe through their nose, so testing oral inhalation on rodents requires drugs to be passed through an unnatural route for their breathing, which does not mimic drug deposition in humans.

The project

Innovation Grant winner Dr Hisham Al-Obaidi and his team at the University of Reading are using the grant to develop a lung in vitro model to assess antimicrobial activity. The aim is to replace testing in animals with an in vitro model that resembles the human lungs.

The approach Hisham and his team took was to use a non-biological model that can be very effective at predicting how the medicine will act when given to humans. The model is based on their previous research in which the environment in the lungs was simulated using synthetic materials that resemble lung mucus. The team incorporated a type of bacteria that infect the lungs so when they tested antibiotics in the in vitro system, the drugs were able to interact with the bacteria as they would in real lungs.

The images above show an Andersen Cascade Impactor. This is an instrument used to estimate aerosol particle deposition and acts as a model of the human lung. It has 8 levels, each representing different respiratory regions, that enable testing using bacteria grown on plates in the presence and absence of aspirated powdered antibiotics that enter the system from the ‘inhaler’ at the top.

The first two stages of the project involved formulating the inhaled powders and the development of a synthetic hydrogel to mimic lung mucus. They then went on to assess how bacteria interact with this artificial mucus.

Synthetic mucin was layered on top of agar plates and inserted at different levels within the lung model. The toxicity of the hydrogel to bacteria was first assessed, before they moved on to test the penetration of the antibiotics throughout the different simulated regions of the ‘lung’.

By inserting mucin-coated bacterial plates at different levels, and incubating the plates after they’ve been exposed to ‘inhaled’ particles of antibiotic powder, the team can assess how far the drugs are penetrating throughout the ‘lung’ and how effective this route of drug delivery may be.

The results showed that the drug penetrated down through the lung, passed through the hydrogel ‘mucus’ and eliminated the bacteria.

The potential

The team at Reading are currently completing the validation of the model, including assessing the activity of inhaled antibiotic particles on fully developed colonies grown on agar plates, to see if any viable cells can be recovered. Determining the survival rates of bacterial colonies that have had a chance to grow and develop before they are exposed to antibiotics will be even more relevant when considering how a patient with an established lower respiratory tract infection may respond to inhaled antibiotic treatment.

Hisham is intending to publish the outcome of this valuable research soon. He is also planning to apply for a larger research grant to develop this model even further.