Chronic wounds are a serious issue within healthcare environments. Referring to any wound that fails to proceed through the normal stages of healing (failing to improve after four weeks or heal after eight), they are estimated to affect 5.7 million patients in the US, costing the healthcare system around $20 billion every year.

The situation is no better in the UK. Often described as a ‘silent epidemic’, wounds impose an economic health burden comparable to managing obesity. According to one 2009 study, between 25 and 40% of hospital beds are occupied by patients with wounds, while over half of community nursing resources are devoted to wound management.

"We would like to study the prospects of using cold plasma to discover individual tissue-treatment modes that may lay the groundwork for personalised therapy."

As Dr Elena Petersen of the Moscow Institute of Physics and Technology (MIPT) explains, chronic wounds are notoriously difficult to treat, and this is becoming a greater problem than ever in an age of increasing antibiotic resistance.

“One of the factors complicating treatment is the infection that is often present in affected tissue,” she says. “During the exposure of the wound to the environment, it may be invaded by various bacteria. Thus, the treatment’s purpose becomes twofold: fight the infection on one hand and stimulate the tissue trophic processes on the other. Some microorganisms may be resistant to medication, which is one of the most serious problems in contemporary medicine.”

For Petersen, head of MIPT’s Cellular and Molecular Technologies laboratory, chronic wounds are a key point of focus. With collaborators from three institutions (MIPT, the Joint Institute for High Temperatures of the Russian Academy of Sciences, and Gamaleya Research Centre of Epidemiology and Microbiology), she recently published findings that could offer new hope to sufferers.

The paper, published in the Journal of Physics D: Applied Physics in September 2016, found that cold plasma therapy can lead to the rejuvenation of cells, killing bacteria in the process. Eventually, it could be developed into a treatment programme for patients with non-healing wounds.

“As one of the future directions of our research, we would like to study the prospects of using cold plasma to discover individual tissue-treatment modes that may lay the groundwork for personalised therapy,” says Petersen.

Incomplete healing

To understand why this research is so important, it may help to explore the pathophysiology of non-healing wounds and the reasons why conventional treatments tend to flounder. Most of the time, when tissue is wounded, the body undergoes a predictable series of events. Injury is followed by the inflammation phase, then the proliferative phase, and then the maturation phase, ultimately restoring the integrity of the tissue.

In the case of chronic wounds, the healing response is impaired, typically stalling at the inflammation stage.

“The reasons for this occurrence may be numerous,” says Petersen. “It may be due to an infection or contamination, causing the immune system to spend most of its energy on battling the bacteria and the toxins they produce, as well as removing dead cells from the wound area. Or it may be due to the conditions that the wound is exposed to – like excessive pressure, excessive humidity or repetitive trauma.”

Another important contributor is the overall state of the body. A person’s wound-healing capacity might be affected by blood-circulation problems, poor oxygenation, malnutrition or the slow cell division associated with ageing.

Increasingly, diabetes is a factor, as evidenced by the huge problem of diabetic foot ulcers. Because diabetes can lead to nerve damage, broken skin on the feet may not adequately repair itself and an ulcer may develop. Affecting around 5% of diabetics a year, foot lesions can require hospitalisation and, in extreme cases, amputation.

In some cases, a patient’s healing ability may also be affected by medical treatments they are receiving.

“For example, chemotherapy is aimed at decreasing cell-proliferation rates, so one of the side effects of this treatment is impeded ability to heal wounds,” says Petersen. “However, independent of the source of the impediment, microcirculation interruption and bacterial infection can be observed in the area of the wound. This may present a direct threat to the patient’s life.”

The upshot is that the problem becomes entrenched, with many wounds needing to be managed rather than treated. And, while prognosis varies significantly between individuals, the general rule is that healing cannot occur without addressing the underlying perturbations. Treatment is most often multidisciplinary, requiring input from a number of different specialists.

Cold plasma therapy might present a better option. It involves a plasma source generating jets of partially ionised gas at 30–40°C. While the technology has been around for some time, its applications within wound care are still nascent.

“Cold plasma is partly ionised non-thermal plasma generated at atmospheric pressure,” explains Petersen. “One of the methods to sterilise and treat infected wounds is subjecting them to cold plasma, either as a one-time or repeated procedure (lasting up to seven days). This approach is intended to use the sterilising properties of plasma, but some studies show that it can also accelerate wound healing by stimulating microcirculation and blood-vessel generation within the tissue.”

Untold potential

A previous study in this field returned inconclusive results. While it seemed clear that low-temperature plasma could treat infection and was well resisted by bodily tissues, its implications for wound healing were more ambiguous.

Petersen’s team wanted to determine whether the application pattern made any difference. Might the total number of plasma treatments and the interval between them have an impact?

Participants were divided into four groups – one group receiving a single application of treatment, the second group receiving two applications spaced two days apart, the third receiving three applications on three consecutive days and the control group receiving no treatment at all.

They then measured the growth in two types of cells important for wound healing: fibroblasts (connective tissue cells) and keratinocytes (epithelial cells). While the third group fared worse than the controls, registering a 29.1% drop in cell proliferation, the first and second group saw positive results, with the number of cells increasing by 42.6 and 32.0% respectively.

“In our research on cell cultures, we have shown that while daily subjection to plasma negatively impacts cell proliferation, a more positive effect may be achieved when subjecting the cells to plasma every other day,” says Petersen.

They also tested for an enzyme called ß-galactosidase – a marker for cell ageing. When subjected to cold plasma in this manner, cells demonstrated a significant drop in these metabolic products.

“This allows us to assume that cold plasma stimulates cell renewal, or sort of restarts them,” says Petersen.

The researchers hypothesised that this positive response could be linked to autophagy – a natural destructive process in which dysfunctional organelles are disassembled and cellular metabolism returned to normal. Further research will need to be undertaken, however, before they can pinpoint the precise molecular mechanism. The team is also interested in finding out whether the patient’s age makes any difference to the treatment’s efficacy.

“Before we can use cold plasma as a widely adopted medical treatment option, we need to accumulate a sufficient amount of knowledge and understanding of the damaged tissue response – its reaction to plasma when accompanying pathologies are present,” says Petersen. “Because the effects of subjecting live cells to cold plasma vary, it’s critical to understand the impact of additional factors that define the end result.”

If cold plasma therapy does become a viable treatment for chronic wounds, it will have significant advantages over those currently available. The approach is contact-free, painless and can combat infection, with a very low risk of bacterial resistance. In addition, wound care may not be its only potential application. Cold plasma therapy is generating a buzz in oncology, too, having been shown to obliterate tumour cells while leaving ordinary cells unscathed.

“Some preliminary studies show that cold plasma may be used to inhibit the tumour growth by triggering targeted cancer cell apoptosis, or programmed cell death. This is another venue we would like to explore,” says Petersen.

While it is too early to say whether cold plasma therapy will live up to its early billing, it seems clear that this is an important avenue for further investigation. For the millions of patients suffering with chronic wounds and the healthcare systems that sustain them, a treatment of this kind could be nothing less than revolutionary.

What is cold plasma therapy?

Plasma-based electrosurgical devices have numerous applications across medicine, not least tissue coagulation, cutting, desiccation and cauterising. However, despite their clinical benefits, these technologies involve tissue heating, and their effects are primarily heat-mediated.

Cold plasma, by contrast, refers to plasma with a low degree of ionisation. It interacts with surfaces non-thermally and does not damage healthy tissue. Instead, it exerts its effects by creating free radicals (reactive oxygen species and nitric oxide), which it conveys to the cells in appropriate quantities.

To date, cold plasma therapy has mostly been used to sterilise implants and surgical instruments, but direct therapeutic plasma applications (such as within wound care) are being investigated.