Hair-raising artificial skin
Human skin is not only the largest organ in a human being, but is one of the most important, serving as barrier and point of contact with the outside world. Recreating and breeding skin in the laboratory as faithfully as possible is not only relevant for medicine, where it is used to treat burns victims, for example. It is also vital for the cosmetics industry, which can test new compounds on artificially cultivated skin before testing on live subjects. Researchers at the Technical University of Berlin, with the support of the German Ministry of Education and Research (BMBF), have developed a skin model that is not created using skin cells, but using cells taken from hair. And now they are trying to create artificial skin that has hair - just like in real life.
Skin that is created and bred in the laboratory has two major fields of application. In medicine it is often the last resort for patients who have suffered severe burns. In the cosmetics industry, artificial skin is used to test new substances - before new creams, lotions and lipsticks can be brought to market, they must of course be tested for skin tolerance. Because animal tests are in the meantime no longer allowed in Germany for this kind of testing, the skin model offers a cost-effective and reliable alternative.
Following injury, hair cells form new skin
To date, in order to replicate human skin - which consists of several layers - as faithfully as possible, scientists have had to follow the following steps: Two different cell types are isolated from human skin that is taken from the patient or accrued in operations: The dermal fibroblasts (dermis) and the cells, the keratinocytes, which create keratin and are found in the skin, hair, and nails. The fibroblasts are initially embedded in a protein solution. The keratinocytes are then seeded onto this base. After about three weeks these then form the epidermis. The great advantage of this model is also its great weakness, however. It is based on cultivated skin cells, which, when in a culture dish, do what they do best: They form skin. However, a biopsy sample as a germinal source will always be required for this procedure. With patients suffering from extensive burns, this is not always so straightforward. On top of this, it takes some time until the skin is fully grown. This is because differentiated cells divide on a fairly leisurely basis.
Scientists at the Technical University of Berlin now hope to solve both problems in one fell swoop using a new technique. They require just a few hairs to be able to eventually create virtually any amount of new skin. But what does the skin have to do with the hair? What at first sounds incredible is based on an observation that doctors made some time ago. If the skin is injured, adult stem cells migrate from hair in the vicinity of the injury to the wound, where they aid skin regeneration. Thus, stem cells from hair are in a position to form skin. Moreover, not just in the body, but also in the test tube. The hair-based method comes with a number of advantages. Besides the fact that a hair is more easily extracted than a piece of skin, adult stem cells divide more rapidly than differentiated skin cells. The result is that less time is required to cultivate the batch of artificial skin. Moreover, if the patient's stem cells are used, there is no rejection reaction. The biotech firm Euroderm is focused on applying the same mechanism to manufacture skin for transplantation into patients with chronic skin disease.
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No watering for cells in new bioreactor
To establish this procedure, the working group headed by Gerd Lindner at the Technical University of Berlin and the University Hospital of Schleswig-Holstein has joined forces with the Max Planck Institute for Biochemistry in Martinsried and ProBioGen AG. The project, which ran from 2005 to 2009, was supported with 1.3 million euros by the Federal Ministry of Education and Research. The Berlin company ProBioGen, specialists in the cultivation of cells, were involved with a specially designed bioreactor that continuously supplies the skin model with nutrient solution. "There were no batch processes available before," says Reyk Horland, who works alongside Gerd Lindner at the TU Berlin. "Watering was required every three days, which of course is not conducive to skin cells’ natural situation." The new bioreactor simulates the conditions in the body much more precisely.
The Berlin researchers’ responsibility was to isolate the stem cells from the hair, to multiply them, and to ultimately ensure that they do not lose their versatile properties in the process. The very first step - the isolation - is by no means straightforward. "There are two types of adult stem cells in hair follicles," explains Horland, mesenchymal and epithelial stem cells." The former are easy to find, as they can be seen through the microscope. The epithelial stem cells, however, are problematic. There is still no means of marking them properly, and to fish them out from the root sheath of the hair follicles. These must be obtained through something of a detour. The researchers set loose specific enzymes on the hair follicles in order to "digest" them. Several types of cells emerge in the resulting mash, including the required epithelial stem cells.
The last stage of evolution: artificial skin from hair
The two types of stem cells, which proliferate strongly following isolation, are adequate for recreating artificial skin in the Petri dish. Firstly, the mesenchymal cells are placed upon a support, a matrix. There, they differentiate into skin cells, and the first layer of skin emerges. After a while the epithelial stem cells are added. These become the keratin-forming keratinocytes, and form the next layer of skin. Finally, the skin-to-be is placed in a bioreactor to the extent that the upper-most cells of the skin model come into contact with the surrounding air. In nature, this is the signal for the cells to form the epidermis, the top layer of skin.
But even this improved method comes with a drawback. No hair will grow on the artificial skin. The opposite would be of interest most of all for manufacturers of skin creams and make-up. A model with skin and hair, the last step in the evolution of artificial skin, and the next challenge for the researchers at the Berlin University of Technology. They have come a great deal closer to this goal in recent months. "We can create an artificial hair follicles," says Horland. However, they remain somewhat smaller than their natural counterparts, and the hair that emerges from the follicles is thinner. In principle, however, it is extremely similar to natural hair.
Blood vessels to supply artificial hair
Just like the skin model, two stem cell types are used to create the hair follicles. So that they form hair and not skin, the researchers give them a push in the right direction by recreating the exact environment in the laboratory as found in nature. This so-called stem cell niche is clearly crucial in deciding which of the many roles that they have in their repertoire are adopted by the cells in this moment. "We believe that stem cells have a kind of memory, and remember where they are," says Horland. The technique appears to function as intended.
With the help of three-dimensional environment, the stem cells seem to realise that they are in a hair follicle, and react accordingly. The rest is (almost) routine for the scientists. Again, the process starts with the mesenchymal stem cells that serve as a basis, to which are added epithelial stem cells. A mechanism is now set in motion that occurs every day on our scalps and skin. The mesenchymal stem cells send growth signals to their epithelial colleagues; a new follicle emerges, and with this a new hair.
It will be a while until genuinely hairy skin can be recreated in the laboratory. In the next step, the researchers want to combine the follicles with blood vessels, which should keep them alive for days and weeks at a time. This is relevant because many cosmetic tests last for 60 days or more. The artificial follicle and the artificial skin must then be combined – no easy task. Wig-makers have nothing to fear yet, but the Berlin-based researchers will remain hard at work. "The patent is filed," says team leader Lindner. "Now we are looking for a business partner with whom we can further develop our hair."