Cultured skin makes large-scale transplantations possible

Large burns require skin grafting. Surgeons remove split-thickness skin grafts and apply them to the injured areas. Now skin that has been made in a laboratory is meant to help in covering burns as well as chronic wounds and thus promote the healing process. Researchers in Zurich have been working on this for more than 13 years.


Photo: Face of a woman, dried skin under the magnifying glass; Copyright: Atamanenko

The skin is our body's largest organ. If it gets damaged, it can become both a functional and an aesthetical burden; © Evgeny Atamanenko

At the Tissue Biology Research Unit of the Surgical Center of the University Children's Hospital Zurich, researchers are developing a skin replacement that matches full-thickness human skin. And they are successful. "We have recruited the first two patients for our Phase I clinical studies just a few days ago. Their cells are presently growing to become skin replacements," says Professor Ernst Reichmann, project director and - along with Professor Martin Meuli - one of the initiators of this research.

The foundation of this skin are so-called hydrogels that primarily consist of Type 1 collagen. Skin cells are taken from the patient during a biopsy and applied to the hydrogel, where they then grow and become the dermis, hypodermis and epidermis. "Those are skin grafts we are currently testing in a Phase I clinical trial. However, we are scientifically much farther ahead than this," says Reichmann.

Already possible, but not yet approved

The researchers are already able to pigment the epidermis by inserting melanocytes along with keratinocytes into the matrix. These melanocytes protect the skin from ultraviolet radiation and give it a natural color. "This way, the skin does not just perform its important protection task, but also fulfills a quite relevant aesthetic function," says the researcher from Zurich.

Besides pigmentation, the researchers are also able to produce blood vessels in the skin: "We can produce networks of blood and lymph vessels. That said, we are not allowed to test the pigmentation as well as the blood vessels in clinical trials yet," explains Reichmann. The regulatory authorities - those being Swissmedic in Switzerland, the European Medicines Agency (EMA) in Germany and the Food and Drug Administration (FDA) in the U.S. - do not authorize these options for clinical trials. On the one hand, the admission process takes a very long time and is extremely expensive. On the other hand, the researchers have to first convince the regulatory authorities that the melanocytes extracted for pigmentation will not turn into tumor cells (melanoma cells).

Vermehren und zusammenbauen

Until now, researchers tested the lab-assembled human skin on immuno-incompetent rats, so it will not get rejected by the animals. They take a small skin sample via biopsy from the patient, who needs new skin, break down the sample into the individual kinds of cells in the laboratory, proliferate these cells and then assemble them again with the help of hydrogels as an extracellular matrix. "Currently we routinely deal with the following kinds of cells, namely keratinocytes – that being epidermal cells, fibroblasts – hypodermal stromal cells, melanocytes and vessel cells of the hypodermis," says Reichmann. The scientists are able to grow all of these cells separately in culture and then assemble them again into a complex full-thickness skin graft just like with a modular system. The Swiss researchers and researchers worldwide are not able to produce hair follicles, perspiratory glands and nerve cords in the laboratory.

Photo: Colored tissue section of the human skin; copy;Tissue Biology Research Unit (Zürich)
Image to the right: Histological section and staining of human skin created in the lab of the Tissue Biology Research Unit (Zurich). The cell nuclei are visible as blue "spots". The cell nuclei of the lowest layer of the epidermis can be seen as a blue line. This cell layer contains keratinocyte stem cells. This is followed on top by the live part of the epidermis, seen in green. The orange layer consists of dead, bosselated epidermal cells. The blue dotted lower cell layer primarily consists of cells (fibroblasts) of the hypodermis; © Tissue Biology Research Unit (Zürich)

Lab-made skin has the essential characteristics of full-thickness skin that consists of a hypodermis and epidermis: it closes the wound and protects the body from mechanical and chemical injuries as well as from hypothermia.

Currently, portions of the patient's own full-thickness skin are being transplanted for small wounds. "Full-thickness skin is also the best option a surgeon has available for transplantation," says Reichmann. However, you can only take a small full-thickness skin sample from the patient to then attach it again at another spot. Otherwise, you risk large full-thickness skin wounds to seal other wounds. Therapeutically, this makes no sense. "This is why we aim to produce as much "created" full-thickness skin as possible from a small skin biopsy," the scientist explains.

Suited for deep skin injuries and pigmentation abnormalities

The lab-created skin is generally suited for all patients with skin lesions: burn patients with large-scale and deep skin injuries, for large birthmarks and debilitating scars, patients with chronic wounds, particularly if skin with blood vessels is going to be approved, or patients with so-called vitiligo - in this case particularly skin with pigmentation.

Now the researchers from Zurich are in the process of testing their developments on patients. After the Phase 1 studies where the skin replacement is checked for safety, Phase 2 studies follow, which are being conducted together with burn centers in the Netherlands and the Emergency Clinic in Berlin. "This is probably going to take place in 2015 and we hope that our development is then able to help many patients as quickly as possible."
Photo: Michalina Chrzanowska; Copyright: B. Frommann

©B. Frommann

The article was written by Michalina Chrzanowska and translated from German by Elena O'Meara.