Title: Oral progenitor-derived vesicles as a novel treatment for chronic skin wounds in the aged population
Funder: Dunhill Medical Trust

Abstract: Whilst acute skin wounds heal through a series of complex, yet overlapping phases, chronic skin (leg) wounds are characteristically non-healing, remaining static in the chronic inflammatory phase. These wounds rapidly become colonised with the normal skin microflora and often become infected with opportunistic pathogens which detrimentally affect the skin cells [1,2] making such wounds notoriously difficult to treat and heal (often leading to limb amputation). Whilst research has continued in this area over many decades, there remains no universally accepted optimal treatment. Such chronic wounds are highly debilitating for affected individuals, affecting their quality of life through resultant distress, low self-esteem, depression and pain [3]. In the UK, approximately 200,000 people suffer from chronic, non-healing wounds with the cost to the NHS for treating such wounds around £4.5-5.1bn [4]. These figures are expected to increase dramatically in the coming decades as a result of our ageing population. Our aim is to develop a novel anti-bacterial treatment option for chronic wounds based on particles known as small extracellular vesicles (SEVs; also known as exosomes) produced by an oral progenitor (stem) cell population (oral mucosal lamina propria-progenitor cells; OMLP-PCs) which we have patent protected to permit downstream translation. We have already demonstrated that in addition to the OMLP-PCs themselves [5], the SEVs produced by the oral progenitor cells display direct anti-bacterial properties against chronic wound bacteria from patients (Annex 1) and now we want to further expand our research to, ultimately, drive development of clinical therapies for aged individuals. Specifically, we will: • Establish whether the SEVs have effective anti-biofilm properties • Utilise SEVs as part of a combination therapy to reduce/repurpose antibiotic use • Determine the mechanism(s) of action in the above to enable us to optimize SEV therapy development for patient benefit, by analysing the functional protein and micro-RNA components of the SEVs

Lay abstract: Chronic skin wounds, such as leg ulcers, are non-healing wounds, which many older patients suffer from, sometimes over many years. Once these wounds become infected with bacteria, they are increasingly difficult to treat, because they form communities within the wound known as bacterial biofilms. Routinely used antibiotics often do not work against these bacterial communities, due to increased drug resistance by these biofilm-growing bacteria, which prevents healing. The over-use of antibiotics in these patients is only adding to the growing world-wide problem of antibiotic resistance. Chronic skin wounds are extremely expensive to treat, costing the NHS an estimated £4.5-5.1 billion in 2015. In addition to these treatment costs, chronic wounds are extremely hard for patients to live with, causing high levels of pain and suffering. We have already published research showing that stem cells from the mouth (from the inside of the cheek) have pro-healing effects, but also that they are antibacterial. Our most recent studies have now shown that this antibacterial effect by the cells is also seen for small medicinal particles released by the cells. What we want to do as part of this application to the Dunhill Medical Trust is, to determine whether these small medicinal particles can: (a) reduce bacteria within the biofilms and; (b) be used in combination with antibiotics (as has been demonstrated for other agents) to reduce the antibiotic concentrations needed for treatment. This would allow us to use ‘older’ antibiotics than cannot currently be used routinely in patients, because they are now highly poisonous at the concentrations needed. Reinforcing both of these strands of research, we will try and determine the mechanism(s) of action for the antibacterial effects we are seeing. In this way, we could in the future, be able to design special treatment options for individual patients (e.g. a specific ‘super charged’ small medicinal particles), to hopefully give back to aged patients a quality of life that they are sadly currently lacking.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION