These pioneering therapies are treating hard-to-heal wounds as never before

New technologies are helping rebuild the skin of people with diabetic ulcers, deep burns, and other severe injuries.

By Meryl Davids Landau
Published 23 May 2022, 11:24 BST
A patient with burns recovers in an intensive care unit.
A patient with burns recovers in an intensive care unit.
Photograph by Gaetan Bally, KEYSTONE via Redux

When Jacob Hyland, his wife Jamie, and their young baby went to their family property in rural Washington two years ago, they had no idea that the Cold Springs Fire was raging nearby. With no WiFi or cell service on the 40-acre ranch, they didn’t receive warnings to evacuate from the blaze, which ultimately consumed some 200,000 acres.

By the time Jacob, now 33, spotted the expansive orange hue across the sky at one in the morning, there was nowhere to run. The family huddled together against a rock face until the inferno, fuelled by 50 mile-an-hour winds, came over them. Extensively burned and suffering smoke inhalation, they somehow found the strength to trek to the Columbia River, which runs along their property, hoping for rescue. Tragically, their infant son, Uriel, did not survive, but two days later, as the couple lay on the bank drifting in and out of consciousness, a boat from the Fish and Wildlife Conservation Commission spotted them and transported them to an ambulance that whisked them to the burn unit at the University of Washington’s Harborview Medical Centre in Seattle.

Jacob, who agreed to be interviewed for this article, suffered third degree burns on more than 30 percent of his body, and his hands were charred almost beyond recognition. People with this level of damage require care by a broad team of healthcare workers not to succumb to their injuries, says his surgeon and critical care physician, Sam Arbabi.

Thanks to intensive medical care Jacob and Jamie survived. But the process of restoring their skin was arduous, involving months in the hospital and, for Jacob, more than a dozen operations.

Healing complex wounds, and especially large, deep burns like Jacob’s, is still a major challenge for medical professionals. But after decades of incremental gains, new technologies are making a difference. “Wound care is a very active area of research and innovation because it applies to so many types of people,” including patients having surgery, people who cut themselves at home, or workers who unexpectedly get chemical burns, says Andrew Vardanian, a plastic surgeon who treats severe wounds at UCLA Health. “Wounds are common because everybody has skin.” The expanding homeless population is also vulnerable to burns because the propane often used for winter heating easily ignites, Arbabi says.

Physicians and researchers expect to see a rise in the number of wounds in the coming years, and not just from wildfires, which have increased sharply in recent years partly due to climate change. Many populations are ageing, and older people have skin that is thinner, more prone to injury, and slower to rebound. There are also many millions suffering illnesses such as diabetes, and prediabetes – the disease characterised by wounds that fail to heal naturally.

Generating the most enthusiasm among scientists are stem cells, which, after years of slow progress are finally beginning to demonstrate their wound-healing potential.

“We have these exciting early results that suggest this is a great way to go therapeutically,” says George Murphy, a dermatopathologist and co-director of the Harvard Stem Cell Institute’s skin program, which is participating in some of the research.

As for Jacob’s injuries, a new synthetic biodegradable polymer called NovoSorb BTM was used to temporarily close some of the wounds and help generate healthy tissue. Later, skin was grafted onto his hands from his thighs, as well as from cadavers and animals. Other replacement skin came via a new cell harvesting device called Recell, which incubated a small amount of Jacob’s healthy skin cells in a solution, allowing it to be sprayed over a larger area so the wound would heal faster and with less scarring.

Although his hands don’t work the way they used too—a former mason, Jacob can now barely hold onto his keys or a cup of tea—he is thrilled that his doctors were able to save his charred limbs and transform them. “Without the grafts I believe I would have died,” says Jacob, who is especially struck by the softness of the skin on the back of his right hand where the sprayed-on product was used. “Science saved me.”

Assisting the body’s innate wound healing

For small injuries the remedies haven’t changed much from the instructions laid out on a clay tablet nearly 5,000 years ago, according to the history of wound healing chronicled in a medical journal: Clean and bandage the wound, then let Mother Nature do her job.

For the most part, this works well. Nick your finger with a kitchen knife or scorch your elbow on the stove, and while you shake off the pain and start making the salad, an unseen military brigade in the body begins the healing immediately. That’s because  skin is the first line of defence against the teeming microbes that can cause damage if they get inside. A wound degrades those defences.

Medical interventions, even for larger or complex wounds, are primarily intended to support the soldiers during their work. Wound healing occurs in four overlapping stages. The first is hemostasis, where blood vessels constrict and clot to quickly plug the wound and prevent bleeding. Next comes inflammation, where the wound is flooded with small proteins that summon immune cells and stimulate the growth of replacement tissues. [Learn more about inflammation and its treatments.]

Doctors long believed the initial inflammation could get in the way of healing, but now they understand it plays an important role in mobilising the cells needed to rebuild tissue, says Jennifer Elisseeff, a biomedical engineer and director of the Translational Tissue Engineering Center at Johns Hopkins University.

The third stage is proliferation, where the wound is rebuilt with collagen—the protein that provides structural support—along with enzymes, new blood vessels, and other substances. Finally, during maturation, a scar is formed while the tissue beneath continues to strengthen.

The promise of stem cell treatments

Of course, major injuries, such as burns, are so large and traumatic that this process is impeded. And wounds like the leg ulcers that afflict many diabetics are slow to heal because blood vessels narrowed by the disease limit the amount of oxygen and nutrients that can flow to the site.

Even in the best-case scenario, though, healed skin does not function exactly as before. That’s because sensory nerves, sweat glands, hair follicles, resident immune cells, and all the other complex structures typically found in the second layer of skin, called the dermis, are not rebuilt. “Skin is an amazing organ, structurally and functionally, and what you’ve got after it is replaced is a leathery patch,” Murphy says, noting that it does the job of protecting the body but lacks much of the function of normal skin.

That’s why scientists have long been excited about stem cells, especially what are known as mesenchymal stem cells—which naturally reside in the skin—because they have potential to speed up healing, Murphy says. The power of these stem cells is evident when babies are operated on in utero and emerge unscarred because the skin has completely regenerated. But for reasons that are not yet clear, stem cells lose these abilities after birth, Murphy says.

Trying to turn back the clock is an active area of study that is finally bearing fruit. Research published in January tested 31 people with open leg sores called venous ulcers that had resisted healing. The study used a type of mesenchymal stem cells known as ABCB5+ that naturally evade immune system rejection. The cells were harvested from the skin of human donors and concentrated in a liquid suspension before being placed into the wound and covered with a dressing. Within three months of the treatment, these once stubborn wounds shrank an average of 76 percent. Similar results were also found with foot ulcers, according to unpublished research by Rheacell, a German company that makes these specific mesenchymal stem cells.

Still, more, and larger clinical trials are needed, says Murphy, whose Harvard stem cell program codirector Markus Frank is a researcher in the Rheacell clinical trials. But these early results are an important step toward the promise stem cells can bring to wound care. “For me, the ultimate holy grail is not just getting the wound to heal using stem cells, but healing by regeneration,” which would restore all the complexities the skin had before the injury, he says.

Harnessing the immune response

Another strategy for wound healing employs the immune system, a connection that researchers had overlooked until recently. Johns Hopkins’ Elisseeff became intrigued with this field during a clinical trial in which she was testing a biomaterial for reconstructing facial tissue and discovered that the type of immune cells that congregated depended on which tissue it was adjacent to. She is now certain that immune cells are key factors in the regenerative process.

That initial discovery led her to test directed regenerative immunology. This includes a study in lab animals that shows how implanting certain biological materials increases the presence and duration of the immune system’s B cells, which can generate antibodies thought to be associated with wound healing.

Elisseeff also discovered that as we get older, the immune system’s T cells, which typically help the body fight foreign invaders, linger longer in the wound leading to unnecessary scarring. In research in mice that has not yet been reviewed by other scientists, it appears that altered communication with aged T cells is to blame, and that inhibiting certain immune signalling molecules can improve healing.

Innovations already in the game

In the meantime, physicians aren’t waiting for innovations to become clinically available. In recent years, several pioneering wound healing products have come on the market.

In the United States, in addition to the Recell spray-on skin grafts, the U.S. Food and Drug Administration also approved a product called Epicel, which uses a small amount of a burn patient’s skin to grow large grafts in the lab that can be placed over a scaffolding to heal sizeable wounds. Although this engineered skin substitute is currently expensive—hundreds of thousands of dollars to cover a badly burned torso, Arbabi says—it’s a major advance.

Another innovation is a suction device found to be valuable after surgical wounds have been closed. Negative pressure, where suction is applied to enhance blood flow and reduce swelling, has proven helpful for open wounds. In recent years, with its Prevena device, the 3M Company employs negative pressure to stitched-up wounds in the week following surgery. One multicentre study published last year that included 300 people undergoing knee replacement for the second time found those using the device for a week had 75 percent fewer complications that those wearing traditional wound dressings.

Advances have also been made in dressings themselves—one of those basic steps to wound healing outlined all those millennia ago. Dressings refer to anything put directly on the injury to aid healing, which once meant animal fats or honey or a concoction of herbs. Today, these dressings incorporate synthetic materials derived from algae, gel-like substances known as hydrocolloids, foams, or films that keep the moisture level in the wound balanced and may also deliver medicines and even growth factors to facilitate healing.

Despite all the improvements, “there is still not a perfect product currently available,” says Alexander Seifalian, a London-based expert on biomaterials who recently reviewed the state of wound dressings for the International Wound Journal.

Extensive research on dressings continue, including attempts to incorporate magnetic nanoparticles or stem cells in the dressings. Seifalian’s company is working on a dressing comprised of the strong but lightweight material known as graphene.

For some wounds, however, it’s not the innovation so much as experimentation with options currently available that makes the difference. That was the case for Susan Craighead, a 58-year-old retired Superior Court judge in Seattle who was born with the genetic condition epidermolysis bullosa, in which the skin easily blisters and tears. Over the years she tried numerous dressings on the inches-long weeping, non-healing wounds that took root on her back, buttocks, and torso.

Twenty years ago she found a silicone dressing that worked sufficiently, but the wounds lingered and more recently were becoming regularly infected. A year ago she changed to a new physician, Arbabi, who recommended Xeroform, a decades-old mesh containing a derivative of the metal bismuth, which has antimicrobial and other properties, that she was instructed to slather topical antibiotics on.

“Within a few weeks the sores I had had under my breasts for years were gone,” Craighead marvels. Those on her back have also greatly improved, although the buttocks sores remain. “My doctor thought it was just a simple suggestion, but for me, the switch was life changing.”

For Jacob Hyland, the extensive burns he and his wife experienced, along with the loss of their son, will never fully heal. But he is grateful for the cutting-edge treatments he received and for the progress that is slowly allowing him to stitch together a new life.

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