The invisible enemy

Living with a chronic wound can be an incredibly isolating experience, but it’s a topic that gets little media or political attention. Wounds that fail to heal, such as diabetic foot ulcers, venous leg ulcers and pressure ulcers, create significant emotional and physical distress for patients. People often find their wounds, which are regularly associated with leaky exudate and an unpleasant smell, lead to disturbed sleep, anxiety, depression and reduced self-esteem. On the physical side of things, chronic wounds can lead to pain and mobility problems. In the worst-case scenario, a non-healing wound may even lead to amputation. Non-healing diabetic ulcers account for nearly 80% of all lower-limb amputations.

Even that’s only half of the story; it’s not just the patient who is impacted. Research has found that chronic wounds leave patients’ families experiencing severe emotional and physical trauma too. Then there’s the intense financial burden chronic wounds create for health systems. The annual cost to the NHS of managing 2.2 million wounds is estimated to be around £5bn. And this figure is only set to grow. Chronic wounds are increasing due to rising numbers of older people and those living with obesity or type-2 diabetes.

What’s more, dealing with wounds is not a simple task for healthcare professionals. Some chronic wounds don’t heal for several years. That’s not so surprising if you look at the biochemistry involved.

The healing process is a complex molecular choreography danced by immune cells and proteins. It can be broadly broken down into four distinct phases: haemostasis, inflammation, proliferation and maturation. Chronic wounds tend to get stuck at the second stage, when bacteria and fungi invade the wound bed and create infection, forcing the body to dial up its inflammatory response. Unfortunately, many bugs have developed a way of getting around the body’s defences. The microbes can band together in a sticky goo called a biofilm, which makes it much harder for the immune system to eradicate the infection. As a result, biofilms, which affect around 60% of chronic wounds, represent a significant challenge in wound healing, according to Karen Ousey, professor of skin integrity at the University of Huddersfield.

Biofilms are not unique to chronic wounds, though. We encounter one every day. “You have a biofilm every morning on your teeth,” she explains. We get rid of this sticky plaque by practising good oral hygiene and brushing it away in the bathroom, but it’s not so simple for open wounds that can be colonised by nasty bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus.

Biofilm trifecta

There are three stages to biofilm formation. First, free-floating bacteria or other microorganisms attach themselves to the wound. Then they colonise it. The bugs group up in a diverse community, learning from each other about how to evade antibiotics and antiseptics. Critical colonisation is the final stage, where the grouped bacteria exude a sticky covering called an extracellular polymeric substance (EPS). This provides a barrier against the patient’s immune system. Once the three-step process is complete, free-floating bacteria can detach from the structure and form new colonies, forcing the patient’s immune system to go into attack mode again, and producing even more inflammatory cells and proteins.

This leads to a chronic relapsing infection where the inflammation phase of wound-healing is never complete. “Ultimately, this creates a situation where the body is ineffectively fighting the organisms involved in the biofilm while also damaging healing tissue – causing a delay in the wound healing,” Ousey explains. “This is why it is imperative for clinicians to have the ability to diagnose them early.”

As well as affecting the body’s natural healing process, biofilms can blunt the standard tools healthcare professionals use for dealing with a chronic wound, such as hygiene, medication and dressings. “Biofilms cover the wound bed, and mean we can’t get the healing process to initiate in a timely fashion,” reveals Ousey. “When we try to clean the wound, we’re cleaning the biofilm rather than the wound itself. And if we apply antibiotics or use antimicrobial wound dressings, they won’t reach the wound bed because the biofilm stops it.”

A major issue with biofilms is that they can’t be seen with the human eye. That means many healthcare professionals are not able to identify their presence in time for patients to receive the most effective treatments. Even routine hospital tests can’t distinguish between floating bacteria that can be targeted with antibiotics and an attached biofilm that will not respond to them.

Although there are limited ways of detecting biofilms in a clinical setting, laboratory studies have revealed a few promising diagnostic tools, from those that track and identify biofilm-associated biomarkers to advanced microscopy. Genetic-sequencing technologies may also be employed to determine proteins associated with biofilm formation, while techniques involving electric currents and surface acoustic waves have shown promise in detecting biofilms in the laboratory. Ousey’s team at the University of Huddersfield has joined forces with testing laboratory Perfectus Biomed to investigate more practical ways for wound care clinicians to accurately identify and manage the presence of biofilms. The Huddersfield researchers will explore whether the highly-sensitive assays developed by the contract research organisation’s microbiologists will be suitable for detecting biofilms in real-life chronic wound patients.

For any hard-to-heal wound, the current standard of care involves cleaning and applying topical or systemic antimicrobials and dressings, explains Ousey. But if a biofilm is suspected, the main weapon healthcare professionals have against it is a process called debridement. This involves scraping away at poorhealing tissues in the wound with a sharp instrument such as a scalpel. While it’s a helpful tool, debridement can be a painful procedure that may affect patient adherence. And even after debriding a well-established biofilm, it can form again in as little as 24 hours.

Microbe destruction

Researchers are exploring more comfortable and less invasive ways for effectively tackling biofilms in chronic wounds. Using ultrasound is one potential option. Clinical studies have shown that debridement tools designed to blast off dead tissue and microbes with low-frequency ultrasonic waves can increase the effectiveness of antibiotics and promote wound healing in patients with diabetic foot ulcers. But trials directly comparing patients treated with ultrasound debridement to the standard scalpel procedure are needed.

Even once an effective debridement process has been established, Ousey points out that the choice of dressing is important too. “You want to maintain a nice warm healing environment,” she says. Healthcare professionals need to assess the wound carefully to determine the best course of action – checking, for instance, whether it’s too wet or too dry. “You don’t want to just slap a piece of gauze on there and put a plaster over the top of it.” Some dressings are better than others for dealing with biofilm. Alginate or polymeric foam dressings have been shown to prevent the reformation of biofilms. These are often impregnated with silver, iodine and methylene blue.

Researchers at the University of Bradford, working in conjunction with Unilever and 5D Health Protection Group, are focusing on developing new ways to break up the biofilm in chronic wounds. The team has received a £25,000 grant from the National Biofilms Innovation Centre to develop a low-cost wound dressing hydrogel prototype that will destroy biofilm as it forms. “Our work will focus on looking at ways to break up that biofilm, essentially to make them more exposed so they are then more susceptible to drugs used to kill them,” said Stephen Rimmer, head of chemistry and biosciences at the university in a statement. “Our job will be to create a delivery system for drugs using polymers or hydrogels.” The aim is to produce a prototype by December 2021.

Similarly, at the Indiana Centre for Regenerative Medicine and Engineering, researchers have developed a wound dressing with a difference. Their prototype uses an electrical field to zap the sticky layer of microorganisms. The dressing electrochemically selfgenerates 1V of electricity upon contact with body fluids such as wound fluid or blood, which is not enough to hurt or electrocute the patient but is sufficient to disrupt the biofilm and kill the microbes. The team discovered the dressing is not only successful in fighting the bacteria on its own but can be combined with other medications to boost its effectiveness. The dressing was even shown to help prevent new biofilm infections from forming, according to a paper published in the journal Annals of Surgery.

As well as advances in treatment and diagnostics, Ousey thinks there needs to be a focus on education. Healthcare professionals should be more aware of biofilms and the damage they cause, as well as the fact that they may not immediately be obvious in chronic wounds. “Many people think they can see a biofilm if the wound is a bit shiny, but you can’t see a biofilm with the naked eye,” she says. “Biofilms are invisible, just like the virus that causes Covid-19. If we could just see it in front of us, we’d be able to manage it so much better.”

Biofilm indicators

Signs that a wound is likely to be hard to heal because of the presence of biofilm include:

• history of or current recalcitrance to antibiotic or antimicrobial treatment
• treatment failure, even with appropriate antibiotic or antimicrobial treatment
• delayed healing
• cycles of recurrent infection/exacerbation
• excessive moisture and wound exudate
• low-level chronic inflammation
• low-level erythema.

Source: International Consensus Document, Journal of Wound Care

The ‘step-up, step-down’ biofilm care pathway

1. From around day one to day four, implement multimodal therapies, including: aggressive debridement (if indicated), biofilm-directed topical antimicrobials and systemic antibiotics. The use of systemic antibiotics should be backed up with microbiological data.

2. In the next stage, lasting up to approximately a week, assess the wound response while debriding as appropriate and continuing with personalised antimicrobial therapy.

3. As the wound improves, treatment should be de-escalated for up to approximately four weeks. In the de-escalation phase, assess inflammation and healing, implement maintenance debridement, reassess the antimicrobial strategy and manage host factors.

4. Depending on clinical response, the pathway may follow different paths at four weeks until full closure, if that is the stated aim of the care plan.

a. Where the wound shows potential for closure, then step down and continue with standard care.

b. Where the wound does not show promise of closure through a reduction in size, step up treatment with the introduction of advanced products and continue with the standard of care.

c. Otherwise, the full multidisciplinary team needs to be involved with any decision to shift to maintenance or palliative care.

Source: ‘Implementing TIMERS: the race against hard-to-heal wounds’, Journal of Wound Care