The skin as the largest human organ has several functions, such as natural protection for internal and external environmental influences. Three-dimensional (3D)-tissue engineering has emerged as a promising approach for the development of functional and physiologically relevant skin substitutes. Common methods of skin tissue engineering, as well as the 2-layer skin model, ignore the topographic features of the skin, and thus, often fail to accurately present the complex architecture and functionality of native skin. Today's challenge is to develop a skin-niche model (SKN) that exhibits the natural invaginations, contains stem cell-like keratinocytes and self-produced extracellular matrix (ECM) of fibroblasts. The invaginations on the one hand contain keratinocytes with an increased proliferative rate, which results in a longer lifespan of the SKN and, on the other hand, they increase the tear resistance. Today, there are no SKN that have applications in drug development or medicine.

Mimicking the topography of the dermis is still a challenge. To create a structure that approximates the physiological structure, a pattern is printed using 2-photon polymerization and then characterized by white light interferometer and scanning electron microscopy. The sample is then molded with sacrificial hydrogels. In the next step, the hydrogel patterns are molded with UV-crosslinkable protein-based bioinks and the topography is analyzed. Also, the viability and physiological function of the cells are determined using life cell imaging, immunocytochemistry and microscopy. The protein-based bioinks that contain dermal fibroblasts were incubated for several days, followed by seeding of the keratinocytes on the sample. In addition, the depth of the invaginations can influence adhesion, differentiation and proliferation. The optimum type of invagination is screened using nine different patterns on a single print. These different invagination sizes were examined in more detail. Molding the hydrogel pattern using protein-based bioink including fibroblasts showed that the dermal fibroblasts grow, proliferate and spread along the topographical structure. In addition, they produce ECM like fibronectin, which supports the adhesion of keratinocytes.

Developing a new skin model has become high priority in society in recent years. The number of animal experiments can be massive reduced in future through 3D-bioprinted models. New SKNs are important for research into new drugs and implants in wound healing and burns. The clusters of stem cell-like keratinocytes probably will increase the formation of new skin tissue, which should significantly increase wound healing compared to currently known models. In the future, the model will be further expanded by incubating at the air/liquid interface, allowing the top layer of keratinocytes to differentiate and grow a complete SKN.