Skin from the factory – Automated Tissue Engineering on Demand
Fraunhofer Institute for Interfacial Engineering and Biotechnology
The skin is the first organ that has been grown successfully in the laboratory using tissue engineering methods. This is partly due to the fact that skin biopsies are readily available and skin cells are relatively easy to culture. Besides the goal of developing skin grafts, the use of artificial skin equivalents as in vitro test system has begun to move to the forefront. A decisive contribution to this was the 7th Cosmetic Directive, which requires the replacement of cutaneous absorption animal testing and chemical side affect tests with in vitro test systems by 2009. Additionally, chemicals have to be tested for toxic side effects as regulated by the EU directive REACH. Toxicity testing has traditionally required a large number of animal tests, which are both costly and time consuming. Laboratory prepared skin equivalents represent a real alternative. Additionally, skin models are also ideal, meaningful, and standardized test systems for the drug screening of chemical or pharmaceutical products.
Currently, the production of an in vitro skin test system requires six weeks and must be performed by trained personnel. This process hinders the market availability and cost-effectiveness of an ”off-the-shelf“ test system. The Fraunhofer Institutes IGB, IPA, IPT and IZI have joined together in a major project to overcome the costly and tedious challenge of the manual preparation of skin test systems by creating a fully automated production system for skin equivalents. Because the patented (Patent No. EP 1 290 145B1) three-dimensional (3D) skin model test system developed at Fraunhofer IGB is a well established system, it was perfectly suited as a standard model for an automated system.
Prerequisite: automated culture processes
The first step in the development of automated process in tissue engineering was the analysis and understanding of all steps, from the skin biopsy to a 3D skin model, and to be able to translate them into machine processes and environments. The next step was to unify the respective approaches and terminology of natural sciences and engineering to a common language, thereby simplifying the basic issues of automating a tissue engineering system. Within the project, the production of a synthetic collagen replacement of biocompatible and biodegradable polymers was also investigated. Other tasks were the development of a method for tripling the storage time of skin models from five to 15 days as well as a bioreactor for automated cell culture with a functionalized membrane for the expansion of the cells.
Fully automated production of skin models
- Fig. 2: Rear access to the system.
- Fig. 3: Mincing the tissue sample in module B.
- Fig. 4: Control before module D.
The fully automated manufacturing system to create a two-layer skin model was completed within the three-year project deadline. The automated process begins with the sterilization of skin biopsies. A gripper arm then transports the biopsies to a different module that separates the dermal cells and enzymes from the epidermal (Module B). These two different types of cells are then separated and seeded on cell culture surfaces and then cultured (Module C). The culture is monitored until the required numbers of cells have been grown. Once there are enough cells, the two cell types are combined to create a two-layer model. The cells forming the lower flexible dermis are then mixed with collagen (Module D). The model is then stored in a humid incubator set at body temperature for three weeks, after which the one centimeter diameter skin model is complete.
The automated production of the models could be successfully demonstrated. It is important to note that the entire mechanical process is divided into individual modules. This allows the modules to be exchanged in order to meet the requirements of producing different tissue types. This fully automated system can produce 5000 skins models per month at a cost below 50 euros per model.
For the first time, the creation of 3D skin equivalents is possible with a fully automated production system. The automation of the manufacturing process ensures reproducible and standardized processes in which the skin models can be produced economically.
The automated system will be in operation and skin models available to customers at the beginning of the third quarter of 2011. Many cooperation opportunities are available for customers in the fields of systems engineering and medical technologies, including the cosmetics, pharmaceutical and chemical industries. Future projects will include expanding the system to flexibly allow the creation of other tissue types.
We thank the Fraunhofer Future Foundation for funding the project “Mass Customized Organ Replicates – Tissue Engineering on Demand”.
- Fraunhofer Institute for Manufacturing Engineering and Automation IPA, Stuttgart, Germany
- Fraunhofer Institute for Production Technology IPT, Aachen, Germany
- Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany