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Published On July 30, 2021

CLINICAL RESEARCH

The Other Plasma

The fourth state of matter—and not the compound in blood that goes by the same name—may be on track to transform wound and cancer care.

Between 2016 and 2019, German physicians at two clinics invited their patients with diabetic foot ulcers—wounds that heal slowly, often on the bottom of the feet—to join a small randomized clinical trial. The patients in the trial’s experimental arm would receive a treatment that was, quite literally, from space. Using technology fine-tuned by German and Russian scientists on the International Space Station, the researchers exposed the wounds, eight times over two weeks, to a glowing, charged substance called cold atmospheric plasma (CAP) to measure whether it expedited healing. 

It did: In July 2020, they reported that the foot wounds of the 28 people in the experimental group shrank more and closed faster, on average, than the wounds of people in the control group. “Having a non-healing wound over many months is both frustrating and dangerous,” says study leader Bernd Stratmann from Herz- und Diabeteszentrum NRW, a circulatory clinic in Bad Oeynhausen that is perhaps best known as the largest heart transplant center in Europe. “We are hopeful that plasma can help in these cases.”

This isn’t biological plasma—the liquid part of blood, which removes cellular waste and carries red blood cells. Rather, it’s plasma as physicists think of it, the fourth state of matter. Plasma forms when energy is added to a gas and its atoms dissociate into free, negatively charged electrons and positively charged ions. Plasma forms during lightning strikes as well as inside the sun and other stars. Virtually all—99.9%—of known cosmic matter is in a plasma state, residing not only in the stars but also in the disks around black holes and the magnetosphere of the Earth.

But all of that is hot plasma. Over the past few decades, scientists have developed efficient ways to make plasma at room temperature, producing a substance known as cold atmospheric plasma. Beginning in 2001, German and Russian astronauts living on the ISS launched a series of experiments designed to fine-tune and study plasma-producing technologies. Without the confounding effects of heat and gravity, they found new ways to generate cold plasma that could be reproduced on Earth. 

Physicists and biologists have long known that cold plasma is a remarkable sterilizer, capable of killing almost any pathogenic bacteria, fungi or virus on a surface. Lab studies going back nearly 20 years suggest cold plasma is also safe in such applications, doing scant harm to healthy eukaryotic cells in human tissue. But a 2015 study did find that plasma could damage healthy epithelial prostate cells, and more work is needed to determine whether it has the potential to cause harm in particular applications.  

A steady flow of experimental investigations, case studies and small clinical trials over the past two decades have hinted that plasma may also have a range of positive effects on healthy human tissue. It can temporarily boost blood flow and activate the growth of skin cells, although how it does that remains elusive. 

The German trial was the first randomized study of plasma to treat diabetic ulcers, but plasma treatments for skin ulcers and skin cancer have been approved in Germany since 2013. Researchers at the Max Planck Center for Extraterrestrial Physics, near Munich, helped design the ISS experiments, and German expertise has fostered research leading to the approval of several plasma-delivering devices. The center has since launched a company to investigate new applications, including in medicine. 

Killing bad cells while promoting good ones—if indeed that’s what plasma therapy does—would hold promise for treating a variety of wounds and conditions. In a 2020 lab study, researchers found that plasma may act against pathogenic bacterial species found in dog saliva, suggesting that it could help treat dog bites. In a 2013 study, researchers reported that plasma expedited the healing of wounds from skin grafts. Other teams have looked at chronic wounds—such as ulcers in bedridden patients—as well as burns. 

But one of the most promising frontiers may be cancer treatment. The plasma process generates “reactive species” of oxygen and nitrogen, atoms that readily interact with the molecules of the living cells they encounter. Because lab studies suggest that tumor cells are more vulnerable than healthy tissue to reactive species, plasma might be harnessed as a kind of targeted cancer therapy. A few small studies, mostly on animals, have reported that plasma—both alone and in combination with chemotherapy—may help control tumor growth.   

Plasma treatments face formidable challenges before they become more widely used, however, says physician Diethelm Tschoepe, who worked with Stratmann on the trial in Germany. Researchers outside of Germany still need to be convinced of the value of plasma treatments, however. The international medical community is awaiting evidence that would come from the larger, randomized, multicenter clinical trials that Tschoepe hopes to see. “We would like to have bigger studies, so that people could accept CAP as a therapeutic instrument,” he says. 

Several research milestones await, the largest of which may be nailing down how exactly the treatment works. Those reactive nitrogen and oxygen species, for instance, may disrupt the microbial DNA or structures on the surface of non-human cells. But they might also cause harm to living tissue. Although stem cells, for example, require low levels of those reactive species to continue to renew themselves, excessive amounts might lead to their exhaustion and death. Plasma also generates electric fields, magnetic fields and light on the visible and ultraviolet spectrums—any or all of which may contribute in some way to its effects. 

There will also need to be research to match the best plasma delivery system to a particular injury. “There are so many types of wounds—deep wounds, ulcers, post-surgical intensive care wounds,” Tschoepe says. “We have a variety of ideas about how to apply the plasma, but every application must prove its efficacy.”

Dermatologist Stefan Emmert, who uses plasma in his dermatology clinic in Rostock, Germany, says that guidelines to standardize the use of plasma also need to be in place. He’s part of a group of researchers developing those, and he hopes to have them finished by the end of 2021. 

He’s optimistic that other countries will start to approve and use plasma-based treatments in the near future. “You can compare this with laser technologies, which took 40 to 50 years to implement as medical treatments,” he says. “In plasma, we’re still in the first 15 years. I think this is a normal time frame to implement a new therapy.”