Reducing animal use in asthma research forms an important body of work at the NC3Rs, and almost £1.5m of funding is dedicated to finding ways to better understand asthma without using animals. Currently, more than 300 million people are thought to be affected by asthma worldwide. NC3Rs grant holder Dr Felicity Rose, University of Nottingham, writes about why asthma is so difficult to treat, and the potential for tissue engineering to address the urgent need to find an alternative approach.
Asthma remains a frustrating disease to understand. But what we do know is that there are many underlying genetic and environmental factors that can be quite unconnected but together cause the symptoms of wheeze and airway hyper-responsiveness that we term as ‘asthma’. Because of these multiple factors, there are subtle differences in individual cases of asthma, so there is no ‘one size fits all’ approach to treating the disease. This results in huge variation in how well current drugs work in different patients. Whilst new drugs have been in short supply over the years, there are some promising new ones currently in clinical trials, and there is a move towards personalising treatments in the hope that this approach will work better for individual patients.
Mouse models have been used widely in asthma research as, like us, they produce an immune response to an allergen or foreign body. These models have allowed us to achieve a broad understanding of the underlying mechanisms involved in allergic asthma. However, this strength has become a weakness. A number of potential new drugs developed from studies with animal models have proved unsuccessful when taken to human trials. This is thought to be because these animal models are unable to demonstrate the more subtle traits present in the human condition. This limitation has slowed the success of new drug development, leading to a dearth of new treatments being available. There is therefore a great need to find alternative methods to study the human disease and to test new drugs so that we can treat asthma more effectively.
Tissue engineering offers a new perspective
We’ve been able to culture the cells that make up the organs of our bodies in the laboratory for some time. However the methods involve culturing these cells in two dimensions, whereas in the body they are arranged in 3D. Tissue engineering offers new ways of culturing cells in the laboratory in 3D that can be applied to asthma research. The airway wall has distinct populations of different cell types that exist in their own unique environments. To recreate these environments we are learning new ways of using synthetic materials to produce 3D surfaces, called ‘scaffolds’. These can then be populated with cells isolated, with ethical approval, from human tissue from either healthy or diseased lungs for studying asthma. Within our research group using NC3Rs funding we have created various scaffolds that encourage these cells to grow in the same way as they do in the body, and we have started to culture them all together as a simple model of the airway wall. Once this has been optimised, we will be in a position to look at how these cells interact with each other.
The complete human lung is a hugely complex organ. Our model represents a section of the airway wall, the ‘bronchiole’, which is found between the trachea and the alveoli sacs (that are responsible for gas exchange). It provides a simple model that includes the cell types found in this structure arranged in 3D to mimic their natural environment. The hope is that this will help them function as they do in the body.
One current limitation of this model is that we are unable to mimic the rhythmical breathing and the mechanical strains these cells would experience in the body, although this is probably more relevant for alveoli tissue engineering.
Ensuring take-up by other research groups to make this a viable alternative
We are consciously using a non-degradable scaffold that is very stable over time and could be sent out to other groups if they wished to use them. We plan to publish the methods we’ve been using so that other groups could create similar scaffolds if they have the relevant equipment. We are also using a commercially available culture system, called a ‘bioreactor’, to culture our cells so once the system is optimised it should be relatively straight forward for other groups to utilise this approach. One would hope in the future that if groups of researchers can find evidence to show similar models can better replicate the tissue (as found in the body) in the laboratory than an animal model, then they will become a real alternative to animals for asthma research.
We also think this approach could be used to develop in vitro models of other human organs, and we have similar projects focused on the cornea and the gut. Very simply, most organs consist of tubes that have an epithelial layer that sits on a membrane and a more fibrous layer beneath this. If we can provide 3D models that recreate these general structures, hopefully these could be adapted for the basic tissue structures within similar but different organs.
NC3Rs work on asthma is supported by the NC3Rs Asthma Advisory Group, which was convened in May 2012 to identify opportunities for building on current work to replace and reduce the use of animals in asthma research. Dr Rose has received a strategic award from the NC3Rs for this research.
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