Wound treatment: the chronic multi-billion-dollar problem

They might start as a blister from a new pair of shoes, or a scratch from an overly playful cat. But if these little injuries don’t heal properly, they create chronic wounds — and massive problems.

Besides inflicting weeks or even months of pain and misery on hundreds of thousands of Australians each year, chronic wounds also impose a hefty financial burden on the national healthcare system: one to the tune of around $3.5 billion annually.

Yet despite decades of research drilling into the molecular and cellular processes that underpin wound healing and how it goes wrong, the basic principles behind chronic wound care haven’t changed dramatically since the 1960s.

Generally, current clinical treatment involves cleaning the wound, then covering it with a dressing to keep it moist and free from infection. This is often accompanied by a course of antibiotics, and the body is encouraged to heal itself.

Should this prove ineffective, patients can go under the knife to try to restore blood flow to the wound site or remove unhealthy or non-viable tissue. In the most severe cases, this means amputating the entire afflicted limb.

So how did chronic wounds become the epic issue they are today, and what new treatments are on the horizon?

From little things big things grow

To understand how chronic wounds arise, we need to understand the tightly choreographed routine that is healthy healing.

Beneath a fresh scab, the body’s immune cells dispose of debris and fend off infections, new extracellular matrix provides scaffolding for functional tissue, blood vessels regrow into the wound, and scar tissue seals the skin again.

But for some, one or more of those steps fails. Crucially, if new blood vessels don’t grow, the wound site can’t receive the nourishment and oxygen it needs to rebuild. The wound stays open, becomes chronic, and is vulnerable to infection.

So it’s no surprise that most chronic wounds — also called ulcers — are caused by conditions of the circulatory system, says the University of Adelaide’s Prof Robert Fitridge, who is also a vascular surgeon at the Queen Elizabeth and Royal Adelaide Hospitals.

The lion’s share are venous ulcers. They’re mostly seen in older people with damaged leg vein valves. Blood pooling in their legs increases blood pressure. That sustained hypertension can cause ulcers to appear on and around ankles.

Venous ulcers are usually managed with compression bandages and stockings that prevent blood from collecting in the lower leg, but may also need minimally invasive surgical interventions.

Yet despite decades of research drilling into the molecular and cellular processes that underpin wound healing and how it goes wrong, the basic principles behind chronic wound care haven’t changed dramatically since the 1960s.

The next largest group of chronic wounds — and the ones Prof Fitridge tends to see in the operating room — are diabetic foot ulcers.

Diabetes whips up a perfect storm for chronic wounds. Persistent high sugar levels not only stymie blood vessel regrowth but also damage nerves and disrupt the immune response.

This means a cut or blister on the foot of a person with diabetes might go unnoticed. Without a properly functioning immune system, their non-healing wound is also more likely to become infected, Prof Fitridge says.

‘If you don’t have that protective sensation, then it can get quite nasty before you present to anyone: you may end up with an infection in the bone or an abscess in the soft tissues.’

The third major cause of chronic wounds in Australia is peripheral artery disease, where arteries become blocked, Prof Fitridge says. ‘About half of people with diabetic foot disease have artery disease too.’

And while most procedures Prof Fitridge performs these days are directly related to chronic wounds — diabetic foot ulcers in particular — this hasn’t always been the case. When he was fresh out of medical school in the early 1980s, most of his patients had arterial disease, and suffered aneurysms, caused by smoking. Diabetes was less common.

Over the decades, though, smoking rates dropped and obesity — along with associated conditions such as diabetes — rose. Now, diabetes is behind most lower-limb amputations in Australia, Prof Fitridge says.

‘There are around 4500 leg or foot amputations done per year, and more than 70 per cent of those will be diabetes-related.’

First Australians are overrepresented in this cohort: Indigenous people have 3 to 4 times the incidence of diabetes than the rest of the population, and a more than 10 times higher rate of ulcers and amputations.

Diabetic patients also need extra post-operative care and tend to stay in hospital between 10 days and 2 weeks, he adds.

‘That’s actually longer than a stroke patient, on average. And even in our practice, a quarter to a third of people who have foot surgery for diabetes will need to be readmitted or have more foot surgery down the track.’

Treatments today and on the horizon

Chronic wound management guidelines — such as those from Australia’s Baker Heart and Diabetes Institute and the International Working Group on the Diabetic Foot — are regularly reviewed and updated by experts, including Prof Fitridge.

Some recommendations have changed over the years. For instance, it wasn’t uncommon for a person with diabetic foot ulcer to take antibiotics for months on end. Now, it’s recommended a course of antibiotics is capped at 6 weeks.

But the most significant change in diabetic foot ulcer care Prof Fitridge has seen is the move to a multidisciplinary care model.

He co-founded the Multidisciplinary Diabetic Foot Service at the Royal Adelaide Hospital, Queen Elizabeth Hospital and Lyell McEwin Hospital, and says having specialists in fields such as endocrinology, podiatry, infectious diseases and nursing on hand helps direct appropriate care to patients faster.

To develop highly personalised treatment plans, Prof Fitridge is working with Dr Christina Bursill, co-director of the Vascular Research Centre at the South Australian Health and Medical Research Institute, to establish a wound biobank — the first of its kind in Australia.

The biobank will take biopsies and blood from thousands of patients with a chronic wound. Slews of ‘multi-omics’ data, including genomics, proteomics, metabolomics and glycomics, will be extracted, then analysed by machine learning algorithms to link patient genetic indicators and biomarkers with the most appropriate therapies.

‘So when we get people coming into the clinic, we could take a simple blood test then say, “OK, you have these characteristics, and this will be the best treatment for you to get the optimal outcome,”’ says Dr Bursill, who is also chief investigator of the ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP) Vascular Health group.

She and CNBP colleagues across Australia are also developing technologies and treatments to help patients across the board. One is a ‘tuneable’ degradable dressing made from silk that can potentially incorporate wound healing sensors and deliver drugs, all without initiating an immune response.

Dr Bursill’s research team is also working on a topical treatment containing high-density lipoprotein, or HDL, to reduce inflammation and coax new blood vessel growth.

Gene therapy, too, is a promising treatment avenue. Because fresh wounds have no or very little blood supply, they contain little oxygen. When faced with low oxygen levels, endothelial cells — which build new blood vessels in a process called angiogenesis — dial down their metabolic rate.

This semi-stasis preserves them until the inflammatory phase of healing subsides. Then they kick back into gear and create new blood vessels.

But in people with diabetes, endothelial cells ramp up their metabolism in low oxygen, produce harmful reactive oxygen species, and die. To counter this, Dr Bursill and her colleagues will use a lentivirus to deliver a gene to endothelial cells. The gene produces a protein called PDK4, which calms overactive endothelial cell metabolism.

Crucially, the lentivirus has been engineered so that the gene can be switched on and off with a common antibiotic, doxycycline, so endothelial cells can resume regular angiogenesis duties when the time is right.

Ultimately, Dr Bursill sees a future where chronic wounds are managed with a combination of new innovative monitoring tools and personalised medicine approaches. But developing these new technologies is imperative — now more than ever.

‘Before the novel coronavirus, diabetes was the largest-increasing epidemic in Australia — it’s our fastest growing chronic condition — so we need new treatment ideas.

‘We’re developing this precision approach with the biobank and at the other end is a therapy that homes in on one little protein in one cell type. Then in between, we have the silk dressing. I think they’re great ideas to help with care down the track.’