Wound healing in all types of EB

Creating a new EB expert through training in cutting-edge, EB-focussed scientific techniques establishes a platform for future EB research and strengthens direct links between clinical services and research infrastructure.

This funding is to support Dr Ajoy Bardhan in his training as a new expert in the field of EB research at the University of Birmingham, UK, where he will be supervised by Prof Adrian Heagerty and other senior EB experts. It is vital to train new EB specialists so that important research projects, involving patients and laboratory science, continue to develop. Dr Bardhan’s projects will investigate wound healing in all types of EB and explore potential targets for therapies to reduce scarring and cancer risk in DEB.

About our funding:

Research leader	Dr Ajoy Bardhan / Prof Adrian Heagerty
Institution	University of Birmingham, UK
Type of EB	All types of EB
Patient involvement	None
Funding amount	£125,263.24
Project length	4 years
Start date	September 2019
DEBRA internal ID	Heagerty_Bardhan1

Latest progress summary:

Dr Bardhan has teamed up with leading scientists in the fields of molecular biology, microbiome research, inflammation and proteomics to develop new ways to investigate EB across diverse areas including locomotion studies and anti-scarring therapeutics.
Dr Bardhan has been involved in our microbiome project where interesting early results suggest that different EB types lead to different microbes living on the skin which change differently when wounds begin healing. Studies have also provided evidence of immune responses that might cause damage rather than healing in some EB types.
This funding has also contributed to several spin-off projects following the formation of the new EB research group at Birmingham, all with the goal of trying to better understand EB and for developing new treatment options to help improve quality of life for those affected.

Dr Bardhan has published a review article about EB in 2020, a guide to diagnosing genetic skin disease for clinicians in 2021 and a report on a new genetic cause of EBS in 2022.
His work was presented in 2021 and 2022:

The good, the bad and the ugly: inflammation in epidermolysis bullosa wounds - 2021

Influencers in epidermolysis bullosa: the cutaneous microbiome - 2022

High relative abundance of bacillales is associated with epidermolysis bullosa (EB) at different stages of wound healing - 2022

Ground reaction forces (GRF) in patients with epidermolysis bullosa simplex (EBS) during walking - 2022

Cicatricial junctional epidermolysis bullosa: a forgotten subtype - 2022

Scratching the ocular surface: a retrospective review of ophthalmological manifestations in epidermolysis bullosa - 2022

Transitional care arrangements in epidermolysis bullosa: a prototype for wider dermatology - 2022

About our researchers:

Dr Ajoy Bardhan BSc, MBBS, MRCP (UK) (Dermatology)
Dr Bardhan is a Clinical Lecturer at the University of Birmingham and Honorary Consultant Dermatologist at University Hospitals Birmingham NHS Trust. Following undergraduate studies at Imperial College London and general professional training in Cambridge, he moved to Birmingham to pursue specialist training in Dermatology. His first post was at Solihull Hospital, where he returned to undertake a fellowship in EB under the auspices of the half-national highly specialised service led by Prof Heagerty, augmented by laboratory training at DGEM, under Prof McLean. Further experience within EB came as registrar at Birmingham Children’s Hospital. He combines clinical work with basic scientific research exploring multiple aspects of wound healing in EB, benefitting from excellent facilities, collaborators, and supervision from Profs Chapple and Heagerty.

Prof Adrian H M Heagerty BSc (Hons), MBBS, MRCP, MD, FRCP
Appointed as a Consultant Dermatologist at the Birmingham Skin Hospital in 1995, the opportunity arose in 1998 to start a new department of dermatology at Solihull Hospital, part of Birmingham Heartlands Hospital and now University Hospitals Birmingham NHS Foundation Trust. Prof Heagerty has links with the research community in Epidermolysis Bullosa and Pachyonychia Congenita. In his work as senior registrar, he was able to identify families with EB Simplex, (EBS) which resulted in the determination of the underlying abnormality in EBS. Combined with work in Junctional and Dystrophic forms of EB, and latterly as lead for the NHS England half national adult service for such patients, Prof Heagerty was able to work closely with Prof McLean, in the University of Dundee, exploring new technologies to inhibit gene expression, using the EB model as a paradigm. Prof Heagerty was appointed as Honorary Professor of Dermatology at The University of Birmingham, with sessions in the Institute of Inflammation and Ageing, working with Prof Chris Buckley, Kennedy Professor of Rheumatology, to explore the initiation of Psoriasis and Psoriatic Arthropathy, and with Prof Janet Lord and her colleagues examining the inflammatory responses and scarring in Dystrophic Epidermolysis Bullosa.

Why this research is important:

Whilst a huge amount of research continues into gene therapy, the EB community has clearly identified wound healing as an area of focus where advances in basic science research could be more readily and rapidly translated into improvements in quality of life for patients, via reduction of inflammation, scarring and fibrosis. We are fortunate in Birmingham to now have a number of facilities dedicated to exploration and amelioration of these very processes, and the establishment of links between world-class researchers, the EB clinic and wider EB community is starting to bear fruit and will hopefully bring real benefits for our patients in the near future.

Dr Ajoy Bardhan

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Researcher's abstract:

Grant Title: DEBRA Clinical Fellow

The development of a new Academic Dermatology post in the University of Birmingham will set the stage for developing novel research programmes with anticipated translational benefits and enhancement of clinical support for patients with EB at this centre, in particular taking advantage of cutting-edge facilities in inflammation research and the reduction and prevention of scarring, ensuring a clear and continuing focus on EB into the future.

Prof Adrian Heagerty, Adult EB Lead at Solihull Hospital, together with Prof Iain Chapple, Professor of Periodontology and Restorative Dentistry at University of Birmingham will be supervisors for Dr Ajoy Bardhan as he undertakes his MD thesis exploring multiple aspects of wound healing in EB. Combining clinical work and basic science research will provide him with hands-on experience to undertake future patient-focused and academic work in EB. Dr Bardhan will be involved in a range of projects with the Institute of Inflammation and Ageing and Institute of Clinical Sciences. The University of Birmingham has recently established a Centre for Scar Research, exploring new therapeutics to reduce scarring, with the Institute of Bioengineering developing new delivery models. The School for Sport, Exercise and Rehabilitation Sciences are also keen to explore interventions to improve quality of life in EB.
Projects across these centres will provide Dr Bardhan with a comprehensive background in current EB research.
He will also be supervised by Professors Logan, Metcalfe and Grover within the Institute of Bioengineering at the University of Birmingham with supervision from Dr Lisa Hill, who will support Dr Bardhan in analysing scarring, wound healing and cancer using a model in the laboratory, and Drs Melissa Grant, Sarah Kuehne and Josefine Hirschfield in exploring microbial-immune interplay in EB wounds.

DEBRA is already funding a project with Prof Chapple (Characterisation of the skin microbiome and investigation of neutrophil function in Epidermolysis Bullosa patients) and Dr Bardhan will actively complete molecular analysis of tissue samples as part of this project, to further characterise the inflammatory responses.
Dr Bardhan will also be employed through the Institute of Clinical Science as a Clinical Lecturer/Honorary Consultant Dermatologist in the Department of Dermatology at Solihull Hospital, undertaking in general dermatology and EB clinics funded by the NHS.

Researcher's progress update:

The major burden of EB is due to persistent and recurrent wounds that are slow to heal, at risk of infection, are associated with pain and itch, and require time intensive dressings. Timely wound healing and restoration of normal skin function is in part dependent upon the function of the immune system, which exists not only to clear damaging microbes (such as bacteria, viruses and fungi) on the skin, but also to remove and re-model dead tissue. However, not all microbes on the skin are damaging, and ‘good’ microbes can be important for skin health and to support and educate the immune system. The exact nature of microbes on the skin in different EB subtypes is not yet known, and nor has the immune response in EB wounds been characterised. Both a poorly responding and/or an exaggerated immune response could lead to abnormal wound healing, or the presence of too many ‘bad’ microbes and not enough ‘good’ microbes. It is also not known whether the microbes present upon the skin dictate the immune response, or whether conversely, the immune response dictates which microbes reside upon the skin.

We have taken skin swabs of individuals with different types of EB at the sites of new blister formation, and at 48 hours, to investigate how the microbes present change during the early stages of wound healing. We have also sampled blister fluid from fresh blisters, and taken blood from patients at the same time to analyse the way in which the immune cells have responded to wounding, as well as the protein content of the blister fluid (which reflects the function of cells at the site of injury). We have chosen to explore early events in wound healing, as this will likely influence later events in the wound healing process. By gaining insight into early damaging processes, we hope to be able to identify targets to modify and improve subsequent wound healing activity.

Interesting results suggest that EB skin harbours increased levels of potentially damaging microbes on the skin early in the wound healing process, and they also change differently during the early wound healing response. There are also reduced levels of potentially protective organisms. This has not previously been demonstrated in early EB wounds.
We have also seen evidence of exaggerated immune responses that might cause tissue damage rather than healing in particular EB subtypes. Further work is required to confirm and analyse why and how this might be the case, and also to be able to identify potential new targets for treatments that might be able to help correct these newly identified changes to try and improve healing for individuals with EB.

Importantly, this grant has also contributed to several spin-off projects following the formation of the new EB research group at Birmingham, all with the goal of trying to better understand EB and for developing new treatment options to help improve quality of life for those affected. (From 2023 progress report.)