Blasting chronic wounds with ultrasound could reduce healing times by a third compared with current treatments, but how soon will it be before the technology reaches the clinic and what are the implications for pregnancy scans? Elly Earls finds out from the University of Sheffield’s Dr Mark Bass.

A blast of low-intensity ultrasound could cut the healing time of chronic wounds by nearly a third, a new study has found, reducing the need for limb amputation, something that is currently called for surprisingly frequently, particularly with elderly and diabetic patients. With the technology currently only in the animal testing phases, however, it’s still early days, and many hurdles still have to be overcome before ultrasound actually reaches chronic wound patients in the clinic. Moreover, questions have been asked about whether – given this new discovery – using ultrasound for pregnancy scans is as safe as is universally assumed.

Currently, more than 200,000 people in the UK alone suffer from chronic wounds, at a cost of more than £3.1 billion to the NHS. Common chronic wounds include pressure sores, which result from lying or sitting in the same position for too long, and skin ulcers, and these types of wounds are much more common in the elderly and those with diabetes as their bodies are less able to repair themselves.

When a young, healthy person is injured, connective tissue cells called fibroblasts migrate to the site of the wound and kick off the healing process. However, in the elderly and patients with diabetes, skin defects, such as insufficient blood flow, prevent this migration, making healing problematic and leading to amputation surprisingly often.

"The worst case with chronic wounds – and not an uncommon outcome – is amputation of the limb," says Dr Mark Bass, a lecturer in the Department of Biomedical Science’s Centre for Membrane Interactions and Dynamics (CMIAD) at the University of Sheffield, UK, and lead author of the study into using ultrasound for chronic wound healing, which was published in the Journal of Investigative Dermatology in July 2015.

"If you go to a chronic-wound clinic, you’ll probably see that most, if not all, patients are missing a toe, or something like that. That’s accepted as OK, although it is obviously not ideal, but once you get to removal of an entire leg, that can have a big impact on the life of the patient because they can no longer be independent and fully mobile. That’s the worst case scenario, but it actually comes to that quite often. Ideally, we would avoid the need for any level of amputation, and that is our target."

Lots of the things we were finding matched on to the bone healing process, but they matched even better on to skin healing signals that we were already aware of. So the obvious experiment was simply to see if we could actually accelerate skin healing.

Why ultrasound?
Currently, there are two approaches to treating chronic wounds. The first, and the most common approach by far, is battling the infection; the second is trying to reawaken the cells that would normally carry out the repairing process.
"The major approach is to combat the infection," Bass says. "So we’ll put the patient on antibiotics, apply dressings to the wound and then hope that if you get rid of the infection, the wound will heal itself normally.

"The second approach is to address the other side of the problem by trying to reactivate the cells that should be performing the healing process. However, the approaches to do that at the moment, which include trying to apply growth factors or stem cells to the wound to try to get the skin to heal normally, are prohibitively expensive."

The expense isn’t the only drawback: these approaches are also difficult to administer and often don’t work, as chronic wounds are extremely hostile environments. "If you put these things on the wound, they will be destroyed pretty quickly," Bass says.

So Bass and his team, made up of researchers from the School of Biochemistry at the University of Bristol, the Wound Biology Group at the Cardiff Institute of Tissue Engineering and Repair, and orthopaedic company Bioventus, as well as the University of Sheffield, decided to try to find a technique to reactivate the cells in and around a wound so it could heal itself without the need for additional agents; in other words, they wanted to wake up the body’s cells so they could perform their normal functions.

Enter ultrasound. This technology was of particular interest to the team because it has been used since the 1970s for healing bone fractures. "It was found that you could reduce fracture healing times and, more importantly, drive the closure of fractures that don’t repair by using ultrasound," Bass says. "So this idea has been around for quite a while."

The problem was that there was no real understanding of why it worked, making it difficult to sell to hospitals – "It was seen as some sort of voodoo," Bass remarks – so he and his colleagues decided to set about trying to understand the underlying processes and biology behind why ultrasound worked to heal bone fractures, and then apply this to chronic skin wounds.

Their findings pushed them forward to carry out the research that was eventually published in the Journal of Investigative Dermatology. "Lots of the things we were finding matched on to the bone healing process, but they matched even better on to skin healing signals that we were already aware of. So the obvious experiment was simply to see if we could actually accelerate skin healing, particularly in cases where there is defective healing," Bass recounts.

Rise and shine
So, how does ultrasound actually work to speed the healing of chronic wounds and how effective has the research shown it to be?
"The simplest explanation is that it just wakes the cells up," Bass summarises. "Our bodies naturally have the capacity to heal, but this can deteriorate. For example, in the cases of elderly and diabetic patients, the cells have stopped altogether – they’ve gone to sleep.

"What the low-intensity ultrasound does is it vibrates the membrane of the cell and starts kicking off some of the signals the cells would normally perform. That’s why it’s actually quite an attractive therapy; we’re not putting in a strange agent that’s going to cause the cell to do something unusual that could have side effects, we’re just encouraging the cells to do what they would do normally."
It’s surprisingly effective, according to Bass. "The biggest breakthrough moment was when we saw that the closure of the wound was actually being accelerated. Obviously, we thought it was going to happen, but we were surprised by how well it worked," he says.

"We thought it might be incremental but, actually, it was a big change – we’re talking about a 30% reduction in healing time, so it really was a big effect."

We thought it might be incremental but, actually, it was a big change – we’re talking about a 30% reduction in healing time, so it really was a big effect.

Ultrasound treatment also reduces infection, simply because the wound is made smaller faster. "Infection is largely dependent on the speed at which you close the wound," Bass explains. "If you’ve got an open wound, it’s far more likely to become infected, so if we accelerate the healing process, the time that it’s open is reduced."

Other advantages of ultrasound therapy over current treatment options include its ease of application and the fact that it sidesteps the necessity of removing wound dressings.

"Treatment for chronic wounds runs for weeks, months and sometimes over a year, so if you’ve got a very difficult procedure, that’s an obstacle," Bass explains. "However, a device that patients themselves could easily apply to the wound means it could be a lot easier for it to see clinical use. Moreover, because we’re treating the wound with a sound wave rather than a chemical, you could do it through a dressing, which is a big advantage."

Of mice and men
So far, the technique has been studied in old and diabetic mice with chronic wounds – with impressive results. The mice’s healing ability was restored to that of young, healthy animals, with healing times reduced from nine to six days. The next question, though, is whether it will work just as well in humans. Bass is cautiously optimistic.

"All the indications are that it’s going to work, but we need to test whether the findings are equally applicable to humans – that’s the thing that will get it into the clinic. There are differences between the skin composition and the healing processes between mice and humans, so it’s a big step."

Moreover, as the therapy has potential for so many types of wounds, trial design is likely to prove challenging. "[The broad potential] is a good thing but it’s also potentially a bad thing," Bass admits. "Chronic wounds have got lots of variations between patients and between wounds, so finding a way to design a trial where you’ll see a response that isn’t hidden by all the variation will be the tricky bit."

Bass and his team plan to overcome it by starting small. "Rather than tackling a really difficult chronic wound, we’re planning to work up to that," he says. "For example, if we look at burn victims, wounds are going to be far more uniform, so that could be a stepping stone to dealing with more complex chronic wounds, with the added benefit that we might be able to see treatment of burn victims along the way."

Of course clinical trials always take time but, despite that, Bass believes we could see ultrasound being used for wound healing within five years, if not sooner.

"Potentially, this technique could get into hospitals quite quickly because ultrasound as a concept has been used in hospitals for quite a long time, removing one of the biggest hurdles for introduction of new therapies – safety," he says. "Because ultrasound has been around for a while, we know that we’re not going to start inducing tumours or causing blood flow problems that you might encounter if you’re putting a chemical onto the skin."

There’s more good news, too. "We’re often asked whether, because we’re seeing an effect on cell behaviour from ultrasound, pregnancy scans create a problem. But the answer to that is a categorical no, for two main reasons," Bass stresses. "Firstly, we’re simply stimulating cells to do their normal thing, so even if the ultrasound was doing something, it wouldn’t be doing anything detrimental.

"Secondly, and more importantly, you need a period of stimulation before it does anything at all; you need continuous treatment on an area for about 12 minutes. With pregnancy scans, the probe is moved around and not held in one position for more than a few seconds, or a minute or two at most. So, there’s no real conflict between the existing uses in imaging and these potential uses in healing. We’ve not suddenly found a problem; it’s all good news."