The body is fast, but it is not subtle. After a bad burn, it patches the damage quickly, often with scar tissue that can tighten, limit movement and leave skin without hair follicles, sweat glands or nerve endings.
Researchers are trying to change that by using 3D bioprinting to place a patient’s own skin cells into wounds, in the hope of helping the body rebuild healthier tissue instead of defaulting to emergency repair.
Each year, 11 million people require hospital care for burns. In larger burn wounds, scarring can cause long-term complications. Scar tissue grows more slowly than surrounding skin and can hinder movement. In children with extensive burns, it can also interfere with normal growth and development.
Scientists have long tried to find ways to push healing toward regeneration. In recent years, 3D bioprinting has emerged as one of the most promising options. The technique uses patients’ own precultured skin cells, suspended in an ink-like gel, to create personalized skin substitutes.
“The key is accessing the body’s ability to rebuild,” says wound healing researcher Johan Junker of Linköping University in Sweden. Our bodies, he says, “have been practicing this for millions of years, and we do it constantly, because our skin and every tissue in our body, more or less, always turns over. So why not just provide as good a set of building blocks as we can and then let nature do its thing?”
For nearly a century, the standard treatment for severe burn wounds has been split-thickness skin grafts. Surgeons take the epidermis and part of the dermis from an unburned area of the patient’s body and use it to cover the wound. But for extensive burns, there may not be enough healthy skin available. The method also does not eliminate scarring, because much of the skin’s function sits in the dermis, which is only partly replaced.
A product called denovoSkin has shown that scarless healing is possible in compassionate use cases for children with severe burns. It replaces the dermis as well as the epidermis. But it takes several weeks to produce and requires special laboratory facilities.
Bioprinting may get around some of those limits. Hafiza Parkar, a regenerative medicine researcher at the University of Pretoria in South Africa, says severe wounds are an overlooked health burden, especially in low- and middle-income countries.
In Sweden, Junker and materials scientist Daniel Aili have developed a bioink described as “skin in a syringe.” They used fibroblasts, the main cells of the dermis, collected from abdominal skin from tummy-tuck procedures. The cells were grown on porous gelatin beads in a bioreactor, where they formed dense microtissues in three days.
The team then added cell-laden microbeads to hyaluronic acid, which serves as the hydrogel base. The material forms a firm gel similar to skin’s natural scaffolding, but liquefies under pressure so it can pass through a syringe or printing nozzle.
When the bioprinted skin construct was implanted beneath the skin of mice, the cells survived printing and began forming healthy dermal tissue.
“We’re kind of tricking the cells in the wound,” Junker says. “Instead of ‘Oh no, I’m in a huge wound; this is horrible; I need to scar it up as fast as I can,’ tricking it into more of a ‘Oh OK, it’s time for me to do my regular thing and just turn over tissue and regenerate, as I always do.’”
The team is now testing the bioink in pigs before moving to clinical trials. Junker says the bioink will likely be applied by syringe if it reaches the clinic, though bedside robotic printing arms are also being developed.
One of those systems, a robotic printer called Ligō, has just gone through a clinical trial in Sydney. Developed by Inventia Life Science, it is designed to map a patient’s wound and print a matched construct directly into it, nanoliter by nanoliter.
“All we’re doing is structurally placing cells in the correct position to help the body reach that healing capacity and reinstate the integrity of skin,” says burn surgeon scientist and study lead Joanneke Maitz. “Instead of using an incubator in a laboratory, the body itself almost functions as the incubator.”
In that trial, Maitz and her colleagues printed onto donor sites rather than burns. They used epidermal cells taken from a biopsy during the same operation. Participants reported less pain at sites treated with LIGŌ than at sites treated with regular dressings, and the trial, reported at a meeting of the American Burn Association, found no adverse effects. The next phase will compare scarring outcomes.
Other teams are working outside the body with bench-top bioprinters. At the Wake Forest Institute for Regenerative Medicine in North Carolina, Anthony Atala and colleagues are building a full-thickness skin substitute using cells from all three skin layers.
That approach could help with the most severe wounds, including damage involving the hypodermis. But it also means cells must be cultured for three to four weeks before the substitute is printed and applied.
Atala says 3D bioprinting could make skin substitutes cheaper to produce at scale. “What the printer does is it gives you scalability,” he says. “You can reproduce the technology … at the same time, over and over again.”
His team tested a three-layer skin substitute in mice using all six main human cell types found in skin. They reported rapid healing, normal-looking skin and blood-vessel regrowth in Science Translational Medicine.
In pigs, a similar substitute using the four main pig skin cells healed with a basket-weave structure. Wounds treated with just hydrogel or a substitute made with nonpersonalized cells showed scarring and greater contraction instead. The substitute-treated wounds also produced more healing-promoting molecules and fewer scar-driving ones.
No skin construct has yet rebuilt new blood vessels, nerves and hair follicles in severe wounds the way researchers hope. But Atala’s pig results showed blood vessel regrowth and reduced scarring. The team is now fine-tuning the manufacturing process before clinical trials.
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