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Wounded, Deeply
Autumn 2012

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regenerative medicine

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A few years ago, an article in the New York Times piqued the interest of Jeffrey Schneider. The story featured Doug Auld, a New Jersey–based artist, and showcased his paintings of burn victims. The portraits—poignant, detailed, provocative—captivated Schneider. These were people he knew. Not personally, mind you. None had been his patient at Spaulding Rehabilitation Hospital. Instead, Schneider recognized a spirit: an unswerving gaze that delivered a quiet challenge; a posture of pride that spoke of surviving trauma and confronting emotional pain. Schneider, an HMS assistant professor of physical medicine and rehabilitation and medical director of Spaulding’s trauma and burn program, invited Auld to the hospital.

Auld accepted and, as Schneider suspected, his presentation resonated with the hospital’s burn-care staff. But it was the strong positive reaction from patients, families, and other hospital staff to an exhibit of Auld’s work that was most gratifying to Schneider.

“To be the subject of a painting is empowering,” says Schneider, “and that strength was evident in the portraits. This is not the sort of art the public often sees.”

“It’s hard to say whether people thought the paintings were beautiful,” he adds. “But I think the purpose of art is more than just its aesthetic. Its beauty is in its purpose.” The same could be said of the work of the scientists and clinicians who advance the care and treatment of those who suffer severe burns.

Investigators in the field continually work to develop better methods for treating severe burns that consume the skin’s outer layer, the epidermis, and its physiologically complex inner layer, the dermis. Their work is not only delivering technical advances that improve the quality of life of burn patients; it is also helping in the development of synthetic skin that rivals the function and appearance of the real thing, bringing the prospect of a full-service, tissue-engineered artificial skin within reach.

painting of a young man showing scars from burns
In 2005, at age 21, Jelani stood for this Doug Auld portrait. Eight years earlier, Jelani and his two younger brothers had been caught in a fire that raged through their apartment.
 

Taxi Lab

Today, in the United States, 96 percent of the patients admitted to burn centers each year survive. Yet that high percentage is tempered by others: approximately 30 percent of patients with third-degree burns experience extensive scarring and lost mobility, while quality of life is diminished for nearly 70 percent because of pain and itch caused by pervasive nerve damage.

Some of the early landmark efforts to improve the outcomes of patients with severe burns grew out of work at HMS by investigators such as John Burke ’51. In 1979, Burke, who then headed the Shriners Burns Institute at Massachusetts General Hospital, partnered with biological engineer Ioannis Yannas at MIT to create a regenerative healing template, essentially what would become the first synthetic temporary skin substitute. Their initial aim, however, had been more modest: to reduce the extensive scarring that resulted from mesh grafts, skin patches that have slits incised into the undersurface to aid adhesion.

The team focused their efforts on the dermis because, unlike the epidermis, it does not spontaneously regenerate. In addition, the dermis of scarred skin differs physically and functionally from undamaged dermis.

“In scarred dermis, the collagen gets assembled in small fibers oriented compactly together, like the material in a lab coat,” explains Dennis Orgill ’85, an HMS professor of surgery at Brigham and Women’s Hospital. Orgill was a medical engineering student in Yannas’s laboratory during the years of collaboration with Burke. “In undamaged dermis, the collagen fibers are wavy and they interlace, like the fibers of a knitted sweater, so the tissue is flexible.”

To decipher how to encourage damaged tissue to regain flexibility as it heals, Burke and Yannas considered the cellular changes found in frozen-cadaver skin grafts. Freezing killed the cells, leaving a collagen matrix into which new cells could grow. To mimic this process, the team created a matrix of bovine collagen and shark cartilage. As the skin cells regenerated, the matrix degraded. In 2002, this semisynthetic template, now known as Integra, was approved for use by the U.S. Food and Drug Administration.

Around the same time that Burke and Yannas were engineering their template for skin cells, Howard Green, then at MIT and now the George Higginson Professor of Cell Biology at HMS, was experimenting with keratinocytes, the cells that form the skin’s epidermis, to determine how to grow generations of the cells in a laboratory dish.

When Green succeeded in cultivating keratinocyte stem cells and in growing enough of them to form a thin sheet of skin cells, he contacted Nicholas O’Connor, then head of the burn unit at the former Peter Bent Brigham Hospital, to talk about using the sheet as a skin graft.

Green and O’Connor debuted the use of the engineered graft, now called EpiCel, on the burned arm of an adult man. O’Connor took a postage stamp–sized skin biopsy from the man, and Green cultivated the cells to form sheets of tissue. As each sheet of cells filled the Petri dish in which it was growing, Green would shuttle it by taxi to O’Connor, who would graft the sheet onto the man’s wound. The grafts worked: Green’s technique marked the first successful growth of skin from stem cells.

With Open Arms

portrait of Jeffrey Schneider
Jeffrey Schneider
 

The work of Burke, Green, and other pioneers in the field set the stage for the technical advancements of recent decades. Take the problem of contractures, the almost crippling tightening of joints and skin that can accompany the formation of extensive scar tissue. Even in the most advanced burn-treatment centers, more than 30 percent of patients leave with contractures that make getting back to work, or to any sort of normality, a challenge.

Physical therapy can help. Patients stretch frozen joints with exercises and, in extreme cases, says Schneider, doctors will do serial casting; that is, flexing a joint into an open, extended position with a plaster cast for a few days, releasing it, then extending it and setting it again in a cast.

In the hope of eliminating this repetitive, often painful, procedure, Schneider devised a novel game-based approach for treating contractures. Patients play a typical joystick-controlled video game, only in this case, he says, “the arm becomes the joystick.”

Schneider designed the intervention for children who may have trouble motivating themselves to perform repetitive exercises. The child straps on a robotic exoskeleton and uses his or her arm to play the game. As mobility improves, the robotics can be adjusted so that the patient stretches farther.

“Children who experience discomfort when they try to bend their elbow ten times in a row, will, when immersed in the game, often not even think about what they are doing,” says Schneider.

Schneider is also investigating methods for eliminating the chronic pain and itch that burn victims report. Using a process called transcranial direct current electrical stimulation, which delivers a mild, 2-milliamp current into the dorsolateral prefrontal cortex, the region located just behind the forehead, Schneider and his research team have demonstrated changes in the abnormal brain processes that are involved in pain, changes that could potentially be used to effectively lower patients’ pain thresholds.

Fine Tuning

In contrast to Schneider’s function-related aids for burn sufferers, Orgill has been working to recreate the complicated physiology of skin.

portrait of Dennis Orgill
Dennis Orgill
 

“We’ve delivered real solutions that help patients today,” he says. “But we are still working on refinements, such as reproducing proper pigmentation and regenerating sweat glands or hair follicles. And we’re still trying to get the texture of the epidermis right.”

Although Orgill spends much of his time wearing scrubs and working in the surgical theater, he still thinks and acts like an engineer. “There are three knobs to turn when it comes to healing the wounds of burn victims,” he says.

One involves improving the template into which new skin regenerates. Orgill continues to tweak the thickness and the conformation of collagen in the regenerative template he developed decades ago, looking for combinations that speed healing and prevent infections. In areas where the dermis is comparatively thin, such as around the eyes, Orgill is trying to determine whether a thinner matrix would provide a better foundation for healing.

The second knob involves biologics, the actual cells and growth factors that go into the matrix. In his wound-research lab at Brigham and Women’s, this work is slowly progressing. “People think wounds are homogeneous,” says Orgill, “but there are many types of wounds. It is unlikely that just one growth factor is going to make a big difference for all wounds.” So Orgill is instead focusing more broadly: He’s working to figure out the science behind the healing influence of platelets, which release multiple growth factors that help form blood vessels and close wounds.

A Knob to Progress

The third knob involves mechanics. Orgill discovered that applying micromechanical forces to burn wounds speeds and improves their healing. The discovery was serendipitous. Orgill’s original intent had been to find a better method for removing fluid from wounds; eliminating fluid can improve graft adhesion and lessen the possibility of bacterial growth and infection. When his research team used a vacuum suction to remove fluid, they found the action produced “phenomenal responses when it came to the overall healing of the wound,” Orgill says.

Since then, Orgill has found the explanation behind the result: a slight tug on the healing cells promotes the activity of mast cells, which are key to cellular regeneration. It also seems to improve the formation of blood vessels, leading to the development of vessels that are thinner and less convoluted than those often found in regenerated skin tissue. Orgill has teamed up with another HMS researcher, Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering and the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, to develop advanced micromechanical wound-healing devices.

painting of a young woman's face showing scars and scar tissue from burns
Shayla sat for this portrait in 2005, nine years after fire had covered most of her then five-year-old body with severe burns. 
 

Ingber’s research team is also investigating ways to incorporate micromechanical environments with biochemical and cellular environments to achieve lifelike tissue. They have had success applying this principle to the creation of a series of biomimetic organs-on-a-chip that include a breathing lung and a peristaltic gut. Skin-on-a-chip, they hope, is not far off.

The hope for lifelike skin tissue has loomed as large for clinicians in burn units as it has for burn sufferers. “Patients want what you would want,” says Orgill. “They want skin that looks exactly like their own.”

From laboratory to burn unit to rehabilitation hospital, researchers at the School have been changing the fortunes of burn patients with advancements that allow them to survive and, more and more often, to resume their lives. Yet each advancement, and each patient, brings a renewed awareness of what there is left to do. In science as in art, the beauty is in fulfilling that mission.

Elizabeth Dougherty is an author and science writer based in Massachusetts.

Paintings: Doug Auld; images: R. Alan Leo

 

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Issue

Wounded, Deeply
Autumn 2012

Topics

regenerative medicine

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