When heat meets skin, the fiery encounter quickly mangles and kills the cells layer by layer. Burn surgeons are left with the challenge of rebuilding the largest organ in the human body.
They’re armed with an eclectic arsenal: grafts of skin from other parts of the body, skin cells brewed up to order, or engineered skin substitutes. These techniques have advanced slowly and incrementally over the past three decades. Despite more than 450,000 people with burns that require medical attention each year, innovations in tissue regeneration have been impeded by the scientific and logistical hurdles of clinical trials.
One recent success story, however, shows how incipient technologies can navigate decades of research and development to finally reach the clinic. In June 2021, the Food and Drug Administration approved StrataGraft — an off-the-shelf product that facilitates wound healing with a scaffold of skin cells — as a treatment for severe second-degree burns known as deep partial thickness burns. More than two decades and four clinical trials have helped Mallinckrodt Pharmaceuticals develop this relatively non-invasive new treatment that could appeal to patients and surgeons alike.
“It has been a very challenging space,” said Steve Romano, executive vice president and chief scientific officer at Mallinckrodt Pharmaceuticals. “The hopeful thing is now we have several opportunities to help burn patients heal that can be used in a complementary manner.”
Building better skin
When tackling a nasty burn, the goal for surgeons is to help the dead tissue grow back. Angela Gibson, a surgeon and wound healing researcher at the University of Wisconsin School of Medicine and Public Health who has been involved in clinical trials of StrataGraft, thinks of skin as similar to a lawn. “If you cut away the upper layers, it'll grow back if it has roots there.” In the skin, those roots are cells that remain intact in the lower layer called the dermis.
While many ancient strategies to spur regeneration — such as mixtures of wine and myrrh or cow dung and beeswax — may no longer be in fashion, the popular technique of grafting may have been practiced as early as three millennia ago (1). Compared to the patchwork that physicians attempted through the 19th century, today’s grafts use a more complex method developed in the mid-1900s to perforate a piece of skin into a mesh that can be stretched out to cover an area nine times as large as its original size.
These grafts, known as autografts when they come from the burn patients themselves, are less than a millimeter thick and cover the wound for weeks while the surrounding skin and blood vessels slowly subsume it. Gibson thinks of this as analogous to re-sodding your lawn. But unlike transplanting dirt, cutting skin from another part of the body can be painful for patients, creating a second wound that can be sizable depending on the extent of the burn that needs to be covered. “They describe it as one of the most distressing symptoms,” Romano said.
Innovations in the last 25 years provided more sophisticated ways to source skin. Epicel, for example, is a cultured epidermal autograft now made by Vericel. It is made of keratinocytes, an epidermal cell that makes keratin, from the patient that are grown in the lab into sheets of skin just a few cells thick for a surgeon to graft back onto the patient (2). AVITA Medical’s product, ReCell, speeds up the multi-week process. In just 30 minutes, surgeons can take a small sample of healthy cells from the patient and using materials from a compact kit, turn them into a solution to be sprayed back onto the burn — a little like re-seeding a lawn. An initial four-square-centimeter swatch of skin can become a solution that covers 80 times that area (3).
For patients, alternatives to large skin grafts are a welcome change “Their burns are painful enough. and they are very much on board to not have to have another painful wound,” Gibson said. “I don't know if I've had anyone say that they didn't want to try it.”
Skin cell fertilizer
Some lawns just need some fertilizer to kickstart their growth, and to Gibson, that’s what StrataGraft does for burned skin — while it also minimizes the need for additional healthy skin to cover the burn.
Out of the box, StrataGraft looks like a 100-square-centimeter gel sheet. On a microscopic level, it is made of a combination of keratinocytes and fibroblasts, all grown on a scaffold of collagen. The product is allogeneic: a single source of skin cells that have grown in the lab for years, packaged into a standard “off-the-shelf” product that can be used for any eligible patient.
“We can't call it skin,” Romano said. “But what we have produced is a product that as closely recapitulates skin as one can.”
Surgeons can suture the sheets onto a burn just like a skin graft. But contrary to its name, StrataGraft doesn’t actually graft into the patient’s burn. When the Mallinckrodt Pharmaceuticals scientists checked the cells in the wound three months after StrataGraft treatment, there was no DNA from the product. Instead, the cells make growth factors and other signaling molecules that spur the burned tissue to regenerate. “It's actually providing an opportunity for the patients to heal themselves,” Romano said.
The product’s path to FDA approval has been lengthy. Romano estimates that it has been almost 20 years since the product was developed in the lab, and its two most recent clinical studies, which provided the bulk of the data the FDA used in its decision, spanned the last decade. But after the second clinical trial, which showed StrataGraft-treated skin healing just as well as autografts in 15 patients, Romano had no doubts about replicating their success in Phase 3 (4).
The trials focused on deep partial thickness burns, but even within that category, they needed a very specific type of patient: people with two similar burns. Because burn healing can differ drastically between people, Mallinckrodt Pharmaceuticals scientists decided to have patients serve as their own controls in the trial. For each participant, one burn was treated with StrataGraft and the other with an autograft for comparison. The results of the 71-participant phase 3 trial led by Gibson looked just as good as the previous study. Wounds closed in 92% of patients who completed the study within 3 months (5). Only three patients needed an extra graft to seal the burn.
According to Romano, the clinical trials taught the company a lot about developing regenerative medicines. It was their first product in that category, so there were limited opportunities to learn lessons from developing similar drugs, Romano said.
Instead, Mallinckrodt Pharmaceuticals looked to surgeons to learn what features would make StrataGraft more convenient to use. For example, they decided to make the product in 100-square-centimeter pieces to minimize waste based on surgeons’ typical usage patterns. Training was also key; burns looked different as they healed with StrataGraft compared to other techniques, a discrepancy that caused surgeons a lot of concern at first.
“After a week, the tissue isn't quite there,” Gibson said. “You have this worry that the wound isn't closing the way you thought it would.” But when the wound looked much healthier a few weeks later, she realized that when it comes to wound healing, there’s more than meets the eye.
New frontiers of regeneration
Romano is hesitant to generalize, but his experience with StrataGraft highlighted the need for more research on tissue regeneration.
“It is a very challenging area because we just don't have enough foundation,” Romano said. “There's a lot of interaction with the body that is not as easily anticipated as it is for small molecules.” For Mallinckrodt Pharmaceuticals, receiving regenerative medicine advanced therapy (RMAT) designation helped them navigate the FDA approval process.
Gibson agrees that there’s a need to better understand the processes happening in the burn when it heals or interacts with products like StrataGraft. Clinical trials aren’t always the right setting for drawing these mechanistic conclusions because their endpoints tend to happen later in the healing process, such as during wound closure. For example, in the StrataGraft trial, Gibson would have liked to study the wound one week after treatment instead of three months later. “That's the disconnect between what I want to see clinically and scientifically versus what the FDA wants to see to make sure it's safe to put it on humans,” she said
She and her team at the University of Wisconsin School of Medicine and Public Health are now tackling these questions. They want to understand what makes certain wounds better or worse at healing under different conditions. This will fill one of the major gaps that Gibson has noticed in burn care: knowing which treatment to choose for a given burn.
“There is a lot of ‘art of medicine’ that goes into what we do,” Gibson said. “If a product fails, is it because the product’s not good or because you put it on the wrong wound?”
This is also on Mallinckrodt Pharmaceuticals scientists’ minds as they re-enter the clinical trial process to test StrataGraft for more severe full-thickness third-degree burns. A phase 2 trial is under way, but they don’t expect StrataGraft alone to have the same effectiveness that they’ve seen in partial thickness burns because there is less skin left in the wound to regenerate from. For full thickness wounds, Mallinckrodt Pharmaceuticals’ goal is to find ways to use StrataGraft in combination with conventional grafts — for example, as a “sandwich graft” — to at least reduce the amount of patient tissue required. They also plan to start recruiting for a pediatric trial in deep partial thickness burns by the end of the year.
Meanwhile, other therapeutic achievements in skin regeneration are emerging. In 2015, scientists and physicians in Europe teamed up to generate a custom skin transplant for a young patient with a genetic disease called junctional epidermolysis bullosa. This condition results from mutations in genes involved in skin integrity that lead to blistering and infections. The scientists used a strategy similar to Epicel — extracting keratinocytes from the patient and growing them in the lab — but they genetically modified the cells to fix their mutation (6). This new, more resilient skin was grafted back onto 80% of the patient’s body. This eliminated his skin symptoms even through a recent five-year follow-up report (7).
Gibson dreams of even better options for her patients. “The holy grail would be to have an off-the-shelf skin substitute that had all of the components of our natural skin,” she said. Based on her graduate research, she also thinks that genetic engineering can speed up regeneration in burn wounds by making cells better at fighting infection (8). She’s not optimistic that she’ll see all of these advances materialize during her career, but she knows what it’ll take to get close. “We need better science, and we need more collaboration.”
- Liu, H. F., Zhang, F., and Lineaweaver, W. C. History and Advancement of Burn Treatments. Ann Plast Surg 78, S2-S8 (2017).
- Hickerson, W. L., Remmers, A. E., and Recker, D. P. Twenty-Five Years' Experience and Beyond with Cultured Epidermal Autografts for Coverage of Large Burn Wounds in Adult and Pediatric Patients, 1989-2015. J Burn Care Res 40, 157-165 (2019).
- Holmes IV, J. H. et al. A Comparative Study of the ReCell® Device and Autologous Split-Thickness Meshed Skin Graft in the Treatment of Acute Burn Injuries. J Burn Care Res 39, 694-702 (2018).
- Schurr, M. J. et al. Phase I/II Clinical Evaluation of StrataGraft: A Consistent, Pathogen-Free Human Skin Substitute. J Trauma 66, 866-874 (2009).
- Gibson, A. L. F. et al. A phase 3, open-label, controlled, randomized, multicenter trial evaluating the efficacy and safety of StrataGraft® construct in patients with deep partial-thickness thermal burns. Burns 47, 1024-1037 (2021).
- Hirsch, T. et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature 551, 327-332 (2017).
- Kueckelhaus, M. et al. Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa - 5-Year Outcomes. N Engl J Med 385, 2264-2270 (2021).
- Gibson, A. et al. Nonviral human beta defensin-3 expression in a bioengineered human skin tissue: a therapeutic alternative for infected wounds. Wound Repair Regen 20, 414-424 (2012).