Yale researchers have developed a new technique for producing artificial skin that is likely to improve the reliability of overall skin graft performance, especially in recipients with impaired blood vessel development such as diabetics and the elderly.
The work is published in the December issue of the Federation of American Societies for Experimental Biology Journal (FASEB). The team has also recently won a Roche Organ Transplantation Research Foundation grant that supports cutting-edge organ transplantation research worldwide. Jeffrey Schechner, M.D., is principal investigator on the study and the grant.
Working with mice, Schechner, assistant professor of dermatology at Yale School of Medicine, and his team reported in FASEB that human skin can be developed with blood vessels derived from cultured endothelial cells. Skin engineered without blood vessels has been available for several years and is used to treat burns, trauma wounds, surgical excisions, non-healing ulcers and blistering diseases. These products improve wound healing, but long-term success of engineered skin grafts has failed and is likely due to inadequate delivery of oxygen and nutrients in the post-transplantation period.
"To address this problem we have developed a method of including endothelial cells, the cells that line blood vessels, to promote vascularization and perfusion of human skin equivalents in vivo," said Schechner. "The scaffold on which these skin equivalents were built is acellular dermis, which is currently used as a temporary coverage of wounds. This is skin in which all cellular constituents are eliminated leaving only a matrix that retains many critical mechanical and supportive properties."
The team seeded this matrix on one side with cells that form the outer epidermis and on the other side with endothelial cells, which were taken from the veins of umbilical cords, prior to implantation onto immunodeficient mice. The cells were modified to over-express the gene Bcl-2, a manipulation that has previously been shown to enhance the formation of blood vessels.
"Within two weeks grafts that contained the Bcl-2 expressing endothelial cells consistently developed blood vessels lined by human endothelial cells and were perfused by mouse blood," said Schechner. "This occurred prior to the ingrowth of mouse vessels."
The team also found that Bcl-2 cells enhanced the persistence of endothelial cells after engraftment and expedited the recruitment of supporting cells to the walls newly formed blood vessels, a hallmark of stability and functionality. The human endothelial lined vessels continued to survive and further mature over at least 8 weeks.
Other Yale researchers on the study included Saara K. Crane, Feiya Wang, Anya M. Szeglin, George Tellides, Marc I. Lorber, Alfred L.M. Bothwell and Jordan S. Pober
Citation: FASEB J.: Vol. 17: 2252 (December 2003)
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