In Third-Degree Burn Treatment, Hydrogel Helps Grow New, Scar-Free Skin

Johns Hopkins researchers have developed a jelly-like material and wound treatment method that, in early experiments on skin damaged by severe burns, appeared to regenerate healthy, scar-free tissue.

In the Dec. 12-16 online Early Edition of Proceedings of the National Academy of Sciences, the researchers reported their promising results from mouse tissue tests. The new treatment has not yet been tested on human patients. But the researchers say the procedure, which promotes the formation of new blood vessels and skin, including hair follicles, could lead to greatly improved healing for injured soldiers, home fire victims and other people with third-degree burns.

The treatment involved a simple wound dressing that included a specially designed hydrogel -- a water-based, three-dimensional framework of polymers. This material was developed by researchers at Johns Hopkins' Whiting School of Engineering, working with clinicians at the Johns Hopkins Bayview Medical Center Burn Center and the Department of Pathology at the university's School of Medicine.

Third-degree burns typically destroy the top layers of skin down to the muscle. They require complex medical care and leave behind ugly scarring. But in the journal article, the Johns Hopkins team reported that their hydrogel method yielded better results. "This treatment promoted the development of new blood vessels and the regeneration of complex layers of skin, including hair follicles and the glands that produce skin oil," said Sharon Gerecht, an assistant professor of chemical and biomolecular engineering who was principal investigator on the study.

Gerecht said the hydrogel could form the basis of an inexpensive burn wound treatment that works better than currently available clinical therapies, adding that it would be easy to manufacture on a large scale. Gerecht suggested that because the hydrogel contains no drugs or biological components to make it work, the Food and Drug Administration would most likely to classify it as a device. Further animal testing is planned before trials on human patients begin. But Gerecht said, "It could be approved for clinical use after just a few years of testing."

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John Harmon, a professor of surgery at the Johns Hopkins School of Medicine and director of surgical research at Bayview, described the mouse study results as "absolutely remarkable. We got complete skin regeneration, which never happens in typical burn wound treatment."

If the treatment succeeds in human patients, it could address a serious form of injury. Harmon, a coauthor of the PNAS journal article, pointed out that 100,000 third-degree burns are treated in U. S. burn centers like Bayview every year. A burn wound dressing using the new hydrogel could have enormous potential for use in applications beyond common burns, including treatment of diabetic patients with foot ulcers, Harmon said.

Guoming Sun, Gerecht's Maryland Stem Cell Research Postdoctoral Fellow and lead author on the paper, has been working with these hydrogels for the last three years, developing ways to improve the growth of blood vessels, a process called angiogenesis. "Our goal was to induce the growth of functional new blood vessels within the hydrogel to treat wounds and ischemic disease, which reduces blood flow to organs like the heart," Sun said. "These tests on burn injuries just proved its potential."

Gerecht says the hydrogel is constructed in such a way that it allows tissue regeneration and blood vessel formation to occur very quickly. "Inflammatory cells are able to easily penetrate and degrade the hydrogel, enabling blood vessels to fill in and support wound healing and the growth of new tissue," she said. For burns, the faster this process occurs, Gerecht added, the less there is a chance for scarring.

Originally, her team intended to load the gel with stem cells and infuse it with growth factors to trigger and direct the tissue development. Instead, they tested the gel alone. "We were surprised to see such complete regeneration in the absence of any added biological signals," Gerecht said. Sun added, "Complete skin regeneration is desired for various wound injuries. With further fine-tuning of these kinds of biomaterial frameworks, we may restore normal skin structures for other injuries such as skin ulcers." Gerecht and Harmon say they don't fully understand how the hydrogel dressing is working. After it is applied, the tissue progresses through the various stages of wound repair, Gerecht said. After 21 days, the gel has been harmlessly absorbed, and the tissue continues to return to the appearance of normal skin.

The hydrogel is mainly made of water with dissolved dextran -- a polysaccharide (sugar molecule chains). "It also could be that the physical structure of the hydrogel guides the repair," Gerecht said. Harmon speculates that the hydrogel may recruit circulating bone marrow stem cells in the bloodstream. Stem cells are special cells that can grow into practically any sort of tissue if provided with the right chemical cue. "It's possible the gel is somehow signaling the stem cells to become new skin and blood vessels," Harmon said.

Additional co-authors of the study included Charles Steenbergen, a professor in the Department of Pathology; Karen Fox-Talbot, a senior research specialist from the Johns Hopkins School of Medicine; and physician researchers Xianjie Zhang, Raul Sebastian and Maura Reinblatt from the Department of Surgery and Hendrix Burn and Wound Lab. From the Whiting School's Department of Chemical and Biomolecular Engineering, other co-authors were doctoral students Yu-I (Tom) Shen and Laura Dickinson, who is a Johns Hopkins Institute for NanoBioTechnology (INBT) National Science Foundation IGERT fellow. Gerecht is an affiliated faculty member of INBT.

The work was funded in part by the Maryland Stem Cell Research Fund Exploratory Grant and Postdoctoral Fellowship and the National Institutes of Health.

The Johns Hopkins Technology Transfer staff has filed a provisional patent application to protect the intellectual property involved in this project.

Environment Clean Generations

Bioengineered Skin

Scientists at Universidad Carlos III de Madrid (UC3M -- Carlos III University) are participating in research to study how to make use of the potential for auto regeneration of stem skills from skin, in order to create, in the laboratory, a patient's entire cutaneous surface by means of a combination of biological engineering and tissue engineering techniques.

The ability to generate mice that can have part of their skin replaced with human skin allows in vivo studies to be carried out; these studies could not be carried out any other way, given that human volunteers cannot be used due to ethical considerations. (Credit: UC3M)

Skin is a tissue that naturally renews itself throughout our lives thanks to the existence of epidermic stem cells. "We have found that this regenerative potential can be preserved in vitro (in the laboratory) if the cells are joined and become part of generated skin using tissue bioengineering techniques," explains Marcela del Río, of UC3M's Bioengineering. The research group in which she participates, made up of scientists from the UC3M, from CIEMAT (the Center for Energy, Environmental and Technological Research) and CIBERER (the Center for Biomedical Research in the Rare Disease Network) of the Carlos III Health Institute, has been working with this type of adult stem cells for years, with the objective of using them to regenerate patients' skin.

The researchers have already been able to join together these epidermic stem cells into skin created by means of bioengineering, and they have observed that the cells preserve the regenerative potential that they normally have in our skin. That is, using a small biopsy from a specific patient, they can generate almost the entire cutaneous surface of that individual in the lab. "The regenerative capacity of epidermic stem cells in these conditions is overwhelming, and it leads to the possibility of using these cells as a target for even more complex protocols, such as gene therapy," indicates Marcela del Río, who is a professor in the new Biomedical Engineering degree program at this Madrid university.

Patches of healthy skin

In fact, these researchers have already demonstrated, at the pre-clinical level, that it is possible to isolate epidermic stem cells from patients with different genetic skin diseases, cultivate them and, using molecular engineering as a first step, incorporate the therapeutic genes into each patient's genome to take the place of the one that the patient does not have or that functions abnormally. Afterwards, in the second step, the stem cells would be assembled into patches ready to be transplanted onto the patients.

In recent studies, researchers have isolated stem cells from patients suffering from Netherton syndrome, a genetic illness characterized by an excessive peeling of the skin that leads to a loss of the barrier function of the skin, which inhibits the loss of fluids so that we do not become dehydrated, or which stops pathogens that can cause infections from entering our bodies. These patients have a neonatal mortality rate of between 10 and 15 percent; the molecular basis of this pathology lies in a mutation of one gene, known as SPINK-5.

This gene inhibits the production of a protein that controls the process of skin shedding, ensuring that it occurs correctly. "What we did in this case -- explains Marcela del Río -- was to transfer a normal SPINK-5 gene to a patient's stem cells and later use these cells to generate skin that could be transplanted to experimental models, such as mice."

The results, which were recently published in the Journal of Investigative Dermatology, were that human skin that was regenerated in these immunodeficient mice showed a completely normal peeling process, so that epidermic structure and function were reestablished. "These pre-clinical studies could be transferred to clinical practice in the medium term, and could become a therapeutic strategy for patients who might otherwise have no treatment available to them," concludes the researcher.

by "environment clean generations"