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A blister from a new pair of shoes might be a minor irritation for many people, but for those with diabetes, such wounds can become chronic, and — in severe cases — require amputation.

This isn’t uncommon, either. In 2017-18, just under 6,000 lower-limb amputations were performed on people with diabetes or peripheral vascular disease — a related circulatory disorder — in Australian hospitals.

So, what is it about diabetes that stymies wound repair, especially on feet?

In healthy wound healing, the cellular machinery performs a controlled routine of communication, division and destruction. Persistent high blood sugar levels, or hyperglycaemia, throws a spanner in these works.

‘Hyperglycaemia causes all cell types in a wound to be a little confused, so they don’t do their job properly,’ says Khalia Primer, a PhD candidate at the South Australian Health and Medical Research Institute who is studying wound healing in diabetes.

The problems start even before skin is broken. Hyperglycaemia damages nerves, especially in the hands and feet, which means cuts and scrapes go unnoticed.

Feet are particularly susceptible to chronic wounds — also called ulcers — for a couple of reasons, Primer says. We generally don’t look at or take care of feet as closely as we do hands, and ‘diabetes is often associated with comorbidities like obesity, so people can get pressure ulcers if they’re on their feet a lot,’ she adds.

Hyperglycaemia also disrupts the usual functioning of infection-fighting white blood cells. A faulty immune response extends the inflammatory phase of healing, and the ulcer can’t fully move onto the proliferative phase, in which functional tissue fills the wound site.

It’s because diabetic wounds stay open longer, with weaker defence against pathogens, that they’re more likely to develop an infection.

The proliferative phase is hampered in diabetes too. For instance, fibroblasts that usually produce and deposit collagen, which acts as scaffolding for new tissue, become dysfunctional in a high-sugar setting.

The typically low-oxygen (hypoxic) environment of a wound normally triggers endothelial cells to grow new blood vessels, bringing oxygen and nutrients to the site and removing waste. But for reasons mostly unclear, this does not happen in diabetic wounds, Primer explains.

And this is how what starts as a minor wound becomes an ulcer.

Chronic wound care

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Current diabetic foot ulcer treatment involves removing pressure from the wound, keeping it clean and dressed, and administering a course of antibiotics. Next is surgery to remove dysfunctional tissue from the wound — a procedure called debridement — and revascularisation, which restores blood flow to the area.

The last resort is amputation. Depending on wound location and severity, this could mean removing a toe, foot or part of a leg. To prevent this eventuality, researchers at the ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP) are developing new wound monitors and treatments.

Hyperglycaemia causes endothelial cells, which build new blood vessels, to ramp up mitochondrial respiration — an energy production method that uses oxygen.

This not only depletes precious oxygen in an already hypoxic wound, but also churns out loads of damaging molecules called reactive oxygen species, killing the cells. A probe developed by the CNBP’s Dr Roman Kostecki measures reactive oxygen species by-products to monitor endothelial cell stress.

Part of Primer’s project investigates how high-density lipoprotein (HDL) encourages new blood vessel growth. HDL’s traditional role is that of the ‘good’ blood cholesterol, but it also helps damaged endothelial cells appropriately adjust their metabolism amid low oxygen levels.

‘Using a mouse model, when we put HDL on wounds, they closed faster, grew more blood vessels and were less inflamed,’ Primer says.

New dressings, like those developed by RMIT University’s Dr Asma Khalid, may help people with diabetes heal faster too — especially if they incorporate monitoring devices and deliver medication.

Primer thinks diabetes management, including wound healing, will eventually be tailored to the individual patient.

‘I think we’ll combine patient metabolomics profiles with genetic information to get a really good picture of what’s happening in their body, then create therapies that affect multiple organ systems in different ways,’ she says.

‘Maybe that’s super optimistic of me, but I do think that’s what’s going to do it.’