Inks created with a patient’s own cells might one day help the body regrow tissues

A hand touches a scalding hot plate, sharp pain erupts and immediately, the body gets to work. Damaged cells send out distress signals; immune cells rush in. As inflammation subsides, a coordinated repair process begins. Eventually, collagen fibers aligned in tight parallel rows will replace much of the damaged tissue. The wound heals, but it does not resemble normal skin.

For a small burn or cut, a scar is a small price to pay for rapid healing that mitigates the risk of infection. But in larger burn wounds, scarring can be devastating.

Each year, 11 million people require hospital care for burns. Long after the wounds have healed, scarring can cause complications. Unlike the random, basket-weave pattern that makes normal skin flexible and resilient, scar tissue tightens as it heals and, once mature, grows more slowly than surrounding skin. This can hinder movement and, in children with extensive burns, interfere with normal growth and development. Severe scars often lack hair follicles, sweat glands and nerve endings, reducing the ability to experience touch and to regulate body temperature.

Normal skin contains collagen fibers that grow in a random basket-weave pattern shown here, while in scar tissue collagen fibers typically grow parallel to each other.

Scientists have long tried to develop ways to nudge the body to build healthy tissue instead of defaulting to emergency repair. In recent years, 3D bioprinting technology has emerged as one of the most promising approaches. By depositing patients’ own, pre-cultured skin cells suspended in an ink-like gel, these printers can create personalized skin substitutes, kickstarting the regeneration process. While it is early days, the technology is coming closer to clinical reality.

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?”

Inks made of cells

For nearly a century, the gold standard for closing severe burn wounds has been split-thickness skin grafts. Surgeons remove the outermost layer of skin, the epidermis, and a sliver of the underlayer, the dermis, from an unburned part of the patient’s body, and use it to cover the wound.

But in cases of extensive burns, there may not always be enough healthy skin to graft. And while this approach improves healing and aesthetics, it doesn’t eliminate scarring, since much of the skin’s functionality resides in the dermis, which has been replaced only in part. (Harvesting skin from other parts of the body can introduce scarring there, too.)

Personalized skin substitutes created using traditional culture methods — multiplying cells in a lab dish, then layering them into a premade gel scaffold — have recently shown that scarless healing is possible: A product called denovoSkin, which replaces the dermis as well as the epidermis, has been used to treat children with severe burns in compassionate use cases. However, this approach requires special laboratory facilities and takes several weeks, which matters since the longer a wound remains open, the worse the risk of scarring. And the more severe the wound, the harder it is to build a viable three-dimensional skin substitute.

Bioprinting offers a way around some of these challenges, and a variety of research groups are working to find an optimal formula for the “ink” of such printable skin.

The severe wounds such technologies could treat are an overlooked health burden, says Hafiza Parkar, a regenerative medicine researcher at the University of Pretoria in South Africa, who is developing a 3D bioprinted skin substitute. Wound healing affects every single part of medicine, Parkar says, and the burden falls hardest on low- and middle-income countries.

In Sweden, Junker, with colleague materials scientist Daniel Aili and others, recently designed a bioink that could improve healing, which has been dubbed “skin in a syringe.” They began with fibroblasts — the main cells of skin’s middle layer, the dermis — collected from abdominal skin from tummy tuck procedures, and then grew the cells on porous gelatin beads in a bioreactor. Fibroblasts produce proteins that form the skin’s scaffolding, and release growth factors that dampen inflammation, helping to promote healing. In three days, the team found, the cells had formed dense microtissues.

The scientists then added microbeads laden with these cells to hyaluronic acid, which will serve as the bioink hydrogel base that holds everything together. Naturally occurring in the body, this water-binding molecule comprises molecular chains that, with a bit of chemistry, will cross-link, forming a firm gel akin to skin’s natural scaffolding. Usefully, it liquefies under pressure, behaving like ink as it passes through a syringe or printing nozzle.

Spheres of gelatin are seeded with skin cells and then mixed with a water-binding gel to yield “skin in a syringe,” shown here in a scanning electron microscope image.

Tests in which the bioprinted skin construct was implanted beneath the skin of mice showed that the cells survived printing and began forming healthy dermal tissue, a promising, albeit early, sign for scarless healing.

“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, whose skin and wound-healing processes closely resemble those of humans, before moving to clinical trials, which will reveal more about its ability to diminish scarring. Once it reaches the clinic, the bioink will likely be applied via syringe, says Junker. However, bedside robotic printing arms are on the horizon.