Plasma-activated antimicrobial hydrogel therapy (PAHT) for combatting infections in diabetic foot ulcers

In 2018 there were over 4.5 million people with diabetes in the UK, with this number expected to rise to 5 million by 2025. One of the most serious complications of diabetes is ulceration of the feet - a Diabetic Foot Ulcer (DFU). This is caused by a poor blood supply and nerve damage, meaning that patients cannot feel when they are starting to damage their feet by, for example, having poorly fitting shoes. Around 34% of patients with diabetes are likely to develop a DFU.
Once a DFU is established it can rapidly become infected (50% likelihood); once infected it is difficult to treat, taking months or even years to heal. Soft tissue infection can lead to bone infection, which is really only treatable by amputation. By the time a patient's DFUs get to the stage of requiring amputation the prognosis for the patient is grim: 70% of patients with DFU-associated amputations are dead within 5 years.
Infected DFUs are treated by antibiotics and surgical wound debridement: cutting away infected tissue. However antibiotics are becoming less effective, and with the rise of "superbugs" (known as antimicrobial resistance, AMR) infection will present a serious threat to anyone with an open wound. Consequently, there is an urgent need for non-antibiotic approaches for treating infected DFUs, to augment antibiotic treatment and to extend the "lifetime" of existing antibiotics (whilst new ones are developed).
The clinical need is to treat infected DFUs at an earlier stage before bone infection takes hold. And in a manner that doesn't just kill the surface bacteria (and fungi), but reaches microorganisms buried deep within the dense slimy colonies (biofilms) in which the organisms live. Our novel technology is based upon utilising electrically-excited gases (known as cold atmospheric plasma, CAP) to create and deliver potent antimicrobial agents deep into infected wounds via interaction of the CAP with a wound dressing and the wound itself. Antimicrobial agents are released from wound dressings applied over the DFU. In this research project, we will develop this technology and demonstrate its potential in robust laboratory-based models of real-world biofilms that are found in DFUs. To ensure that this project realises the potential to deliver patient benefit (as soon as possible) we will map out how to assess the health economic benefits and the parameters needed for a robust clinical trial. We will engage with healthcare providers and patients early, and will achieve this through a range of outreach activities.
This project is an important step in realising a novel technology treatment package that is cheap and easy to use, and which has the potential to greatly improve the care of patients with DFUs and decrease the need for amputation. This would improve patient quality of life, improve survival rates and save the NHS money.

This project will furnish a novel cold atmospheric plasma device (CAP) and antimicrobial-loaded hydrogel wound dressings that are plasma-activated. They will be used in combination for the treatment of biofilms in chronic wound infections. The technology is termed plasma-activated antimicrobial hydrogel therapy (PAHT). We will develop PAHT with an emphasis on diabetic foot ulcers (DFUs). Currently, there is a reliance on antibiotics in the treatment of infected DFUs, but these are becoming increasingly less effective and in the longer term the rise of antimicrobial resistance (AMR) poses a major threat to anyone with an open wound.
The principal beneficiaries of this research, in the medium to long term (< 7 yrs), are the plus 4.5 million people with diabetes in the UK, and the 34% of them who will develop a DFU at some point in their lives. Of these 50% will experience a significant infection. The consequence of a foot ulcer is serious - infection of DFUs can lead rapidly to bone infection, amputation and premature death.
In addition to the patients themselves, caring for patients with DFUs is very expensive to the NHS. As DFUs are generally slow to heal (if they heal at all) patients require frequent (weekly or so) visits to diabetic foot clinics for debridement and monitoring. The cost of limb amputation and concomitant need for social care is also very high. It is estimated that the NHS in England and Wales spends ca. £900M million p.a on DFU care and amputation (1% of NHS budget). This proportion of NHS budget will grow with increasing obesity rates and an ageing population. Beyond the NHS is a whole tier of (often unpaid) carers who have to look after patients with DFUs. This exacts a high social and economic cost on society.
In the shorter term, this project will furnish a better understanding of the microbe species present in real-world DFU biofilms and the means to fabricate robust models of these. Real-world biofilm models provide better in vitro models in which to test (any) new antimicrobial strategies. This will ensure a greater degree of success when these are progressed into in vivo studies.
In the medium term (< 5 years), we can deliver on the primary aim of this proposal, to research and develop a practical, cost effective, but multi-faceted technology that:
(a) prevents DFU infection progressing to the bone and hence to amputation;
(b) through resolving infection, speeds up healing of DFUs;
(c) decrease care costs for DFU patients.
PAHT will do this by CAP delivery of both antiseptic hydrogen peroxide (in a controlled dose to where and when it is needed) and antimicrobial release from a hydrogel dressing applied to the wound. This PAHT will improve a clinician's ability to decontaminate wounds (even deep-seated infection) and hence healing. Additionally, PAHT allows the delivery of higher levels of oxygen into the wound to enhance tissue perfusion and healing.
In the longer term (5-7 years) we will achieve real world impact. To achieve this impact, we will engage with clinicians and the public/patients from the outset. Both nationally and internationally, we will consolidate existing links with leading wound researchers and practitioners. One of the work packages focuses specifically on the next step to achieving impact, mapping out the parameters for a health economics study and a phase II first-in-man trial. To accelerate the utilisation of one variant (we are trialling 12) of PAHT, we will conduct one demonstrator project (DP) with our industry partner GAMA Healthcare. We will show how the combination of CAP and peracetic acid act in synergy in the decontamination of robust biofilm models. In year 3, within GAMA we will address the various challenges encountered in technology transfer and prototyping. This DP will advance PAHT to at least a TRL of 4 and introduce the technology to a potential industry partner.