• Primary Researcher: Prof Liam Grover
• Institution: University of Birmingham, UK
• Type of EB: RDEB
• Funding amount: €179,277.02 co-funded with DEBRA UK
• Project length: 2 years

The natural substance carrageenan was originally investigated as an ingredient to create the right consistency of spray to deliver the expensive biological molecules, decorin and resolvin to the inside of the mouth. However, the carrageenan was found to have anti-scarring potential of its own. It is cheaper, safer and more readily available, being derived from seaweed and used in many foods. Unlike the biological molecules which need special handling to dissolve in a spray and keep their healing properties, the carrageenan spray is very stable and easier to prepare.

The researchers believe the carrageenan blended spray can help reduce scarring in the mouths of people with EB by stopping the mouth cells becoming scarring cells, stopping scar tissue from being rapidly produced and by its lubricating effect to reduce friction when talking and eating. This work brings us a step closer to a mouth spray to treat EB symptoms.

The researchers published results of their work on spraying treatments to reduce Covid infection in 2021 and presented results at the 2022 DEBRA UK Members’ Weekend.

Primary Researcher

Liam Grover is a Professor in Biomaterials Science and the Director of the Healthcare Technologies Institute at the University of Birmingham UK. The Healthcare Technologies Institute brings together leading experts from a variety of disciplines across the University of Birmingham to advance new technologies and treatments that encourage better tissue healing and rehabilitation tools.

Co-researchers

Tony Metcalfe is a Professor of Wound Healing at the University of Birmingham. Tony has worked in academia, industry and the not-for-profit sectors and his research focus includes tissue repair, translational medicine and scar free healing.

Iain Chapple is Professor of Periodontology and Head of the School of Dentistry at the University of Birmingham UK and Consultant in Restorative Dentistry. He leads a strong team as part of Birmingham’s Periodontal Research Group, and is Director of Research for the Institute of Clinical Sciences at the University of Birmingham. Iain runs a national clinical oral and dental service for adult EB patients in close collaboration with Adrian Heagerty, a Consultant Dermatologist and EB expert, and is a leading a DEBRA UK funded project to understand more about the skin microbiome in EB.

Adrian Heagerty is a Consultant Dermatologist at University Hospitals Birmingham NHS Trust and and Honorary Professor of Dermatology at the Institute of Inflammation and Ageing at the University of Birmingham. Prof Heagerty is currently working on several research projects to improve the quality of life of people suffering from EB.

Collaborator

Prof Alan Smith, Director of Biopolymer Research Centre, University of Huddersfield.

Grant title

A novel spray delivery system for the treatment of mucosal scarring in epidermolysis bullosa.
This project worked towards the development of a new spray delivery system as both a treatment and preventive strategy for scarring that affects the mucosa or membranes in the body which characterises EB, and the associated morbidity. The overall aim was to formulate this delivery system so that it can be used to deliver three candidate anti-fibrotic molecules. Importantly, the final output of the project was three systems formulated and manufactured in a way that would allow them to be used in a comparative clinical trial, which will be funded either commercially or through an additional grant application.

The overall objectives of this project were to:

• Formulate, with clinicians and patient groups, an oral spray that can be used for delivery into the buccal (cheek) cavity.
• Absorb therapeutic antifibrotic molecules into this material and demonstrate their retained therapeutic potency during a period of storage and then spraying.
• Develop a GMP (Good Manufacturing Practice) process for manufacture and filling of the drug containing materials.
• Put in place the paperwork required for a phase I trial of the oral preparation.

All of the above objectives were believed to be achievable in a two-year project given that they have 1) undertaken the basic preparation of a spray-based gel technology, and 2) developed GMP processes to manufacture the material that we propose to use for spraying. Furthermore, the researchers had already undertaken biocompatibility testing of the materials in-line with ISO 10993 (an industry standard for biological testing, risk management and evaluation), and had performed human contact trials in intact skin. Both enabling the use of the preparations in the relatively short term.

The aim of this project was to develop a new spray that can help to prevent the scarring in the mouth that many members of the EB community experience following eating, drinking, or brushing the teeth. We want the spray to give good even coverage of the area, and then stick to the inside of the mouth, rather than running straight off. This will allow the anti-scarring molecules to do their job more effectively.

We have shown that a type of molecule called polysaccharides, which are naturally occurring and are often included in food products, show potent anti-fibrotic capability, with the most potent being carrageenan, which is obtained from seaweed. To do this, we established a model where we grow human fibroblast cells (a type of cell found in the skin and inside of the mouth) in a dish, and expose them to a molecule that promotes scarring. This induces a lot of changes in the fibroblasts, including the genes they express, and the proteins they produce. We then introduced different polysaccharides into the system, and showed many of them reduced the genes and proteins associated with scarring.

We also showed that our polysaccharides can interfere with collagen formation – too much collagen, laid down too fast and too densely, is what physically causes a scar to form. Many of our polysaccharides were able to slow down collagen fibril formation, or prevent it entirely.

Having shown that carrageenan, our most effective polysaccharide, was a potent anti-scarring molecule, we then looked at the material properties; we ideally want something will spray, but is also thick or even solid like, that will stick to the inside of the mouth for a long time. At high concentrations, carrageenan solutions are thick, but spray very badly. We therefore looked at ways to improve sprayability, while maintaining thickness. We looked at two strategies; blending with a second polysaccharide, and using salts to change the structure of the carrageenan at a small scale. We showed that the polymer blend increased both sprayability and adhesion to the inside of the mouth, and one of the salt formulations also increased spray area, as well as enhanced lubrication. This is important because it will reduce the frictional trauma in the mouth that kicks-off the blistering and ultimately leads to scarring.

We think that our new materials, which spray and stick to the inside of the mouth, can help lower scarring in the mouths of people with EB in three ways; stopping the mouth cells becoming scarring cells, stopping fast collagen laydown, and lubricating to reduce trauma. These materials also have a host of inherent advantages, such as relatively low cost, good stability for a long time, known safety (many of them have been used in food for decades). This also makes them easier to make and move down the pipeline to clinical trial and into people, hopefully to improve quality of life in the EB community.