Reconstructed Human Skin Models for Research and Screening Purposes
Functional 3D reconstructed human skin equivalents (HSEs) can be used for drug testing that avoids the excessive use of experimental animals. HSEs are three-dimensional systems that recapitulate most of the in vivo characteristics and in which cellular processes may be normalized compared to conventional monolayer cultures. These in vitro 3D HSEs are the result of more than 25 years of research and development by scientists from Leiden University Medical Center (LUMC) (The Netherlands). Within the Department of Dermatology, LUMC provide both healthy and diseased in vitro HSEs for animal-free compound screening and safety testing services and for co-development activities. HSEs are used in new product development and substantiation or product claims in cosmetic, pharmaceutical, food and environmental industries, but also in fundamental research within the field of experimental dermatology. These HSEs enable genomic, proteomic and drug development research not possible with traditional, unrepresentative or equally unavailable animal models, monolayer cell cultures or clinical test procedures. Uniquely, all in vitro HSEs are fully customizable to meet both the scientific and commercial demands of the customer.
Currently LUMC offer four different HSEs; the Leiden Epidermal model (LEM), the Full-Thickness model (FTM), the Fibroblasts-Derived Matrix model (FDM) and the Ex-vivo human skin (ExHs) (Figure 1).
1. LEM consists of keratinocytes seeded on a non-cellular matrix (e.g. inert filter membrane or de-epidermized dermis. These epidermal models are suitable for e.g. skin toxicity, irritation, or penetration tests. In 2008, the researchers pre-validated the Leiden epidermal model (LEM) for skin irritation and corrosion (El Ghalbzouri et al., 2008).
2 FTM consists of keratinocytes, melanocytes and a fibroblast-populated three-dimensional collagen matrix. This model closely resembles native human skin. This full-thickness skin model can be used for tests, predictive screening and research on for example wound healing that requires the complexity of human skin, i.e. where the interaction between epidermal and dermal cells is crucial.
3. FDM is similar to the FTM model, but the dermal compartment consists of human fibroblast-derived extracellular matrix. This model can be used as a tool to evaluate the effect of e.g. ingredients on dermal processes in skin aging.
4. By using intact fresh skin biopsies, the researchers can perform short-term studies on human skin. By placing these skin samples onto an inert filter they can culture these ex vivo skin models (ExHs) up to 1 week.
All models can be used for predictive screening or contract research that requires the complexity of human skin. Variations of these models can be generated by incorporation of other cell types (e.g. melanocytes, different types of fibroblasts, tumour cells etc.). The different models can also be grown at different oxygen concentrations.
Within the Department of Dermatology, LUMC have exploited the HSEs for more than ten years as a tool to conduct contract research for a number or large and medium size enterprises. These projects are focused on different aspects of healthy and diseased skin, such as; skin biology, dermal interactions, skin aging, wound healing, scars, treatment of bacterial infections by antibiotics and/or anti-microbial peptides. Some examples are given (Figure 2).
There is an unmet clinical need for dermatology to develop therapies for a large number of skin diseases, such as skin cancer (eg melanoma), wound healing, bacterial wound infections, and eczema. There are currently no suitable in vitro models to screen and validate novel targets, and test the effects of potential new therapies in vitro . Cosmetics, Food, Chemical, Pharmaceutical, Medical devices.
The models are available for contract research and for co-development activities.
Keywords: dermatology, skin, keratinocytes, fibroblasts, melanocytes, wound healing, infection, eczema, cancer, penetration, irritation
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