3-D Dermal Models

The Need for 3-D Dermal Models

Dermal toxicology testing is imperative to predict the adverse effects of novel drugs, chemicals, and cosmetics that are topically exposed. Historically, these compounds were tested using animal models, which oftentimes provide unreliable data due to the inherent physiological differences between humans and animals. Animal models are also expensive as well as low throughput. It is estimated that around 1,500 chemical compounds are synthesized in the United States each year, only a fraction of which can be tested using traditional animal testing methods.¹ To deter researchers from using conventional methodologies, the US Congress passed the FDA Modernization Act 2.0 that allows advanced cell cultures, like 3-D models, to be used in place of animal testing.² The idea of removing animals from the experimental workflow is not new. The concept of the 3R’s, that was originally introduced in 1959, outlined steps for Replacement, Reduction, and Refinement of animal testing.³ Latest advancements of in vitro cell culture have led to a paradigm shift where 3-D models are encouraged as they create a more ethical and economical pathway for drug discovery and toxicity testing.

Current Modus Operandi

3-D dermal models are constructed by creating a co-culture of primary cells found in the human skin and fabricated on a bed of collagen to mimic the structure of skin. Current dermal models in the field use varying degrees of co-culture and platforms. Usage of different epidermal and dermal cell types in 3-D models (e.g., keratinocytes, melanocytes, fibroblasts, and endothelial cells) make the models more physiologically relevant.⁴

Currently, the standard toxicology assays used to determine if a chemical is safe for human topical application or accidental exposure are skin absorption, corrosion, irritation, and sensitization assays. MTT, luciferase, and cell viability assays can be used in conjunction to determine the possible effect(s) of a drug. The Organization for Economic Co-operation and Development (OECD) guideline—considered the “bible” for toxicology testing—is a useful tool for researchers to determine which assay(s) and platform(s) should be used when performing a dermal toxicity test.⁵ These guidelines are currently used universally to determine best practices when creating 3-D models and executing toxicological assays.

The Future of Skin Toxicity Testing

As in vitro 3-D models become more popular in the toxicology space, there is always room for improvement and innovation. Some challenges researchers face with 3-D models—particularly dermal models—are scaling, including different cell types to be more physiologically relevant, and a long turnaround time. Improvements that could be made are the incorporation of all dermal and epidermal cell types in a single model, inclusion of an immune response, skin-on-a-chip with microfluidics, and possibility of long-term storage. Another innovative avenue for future improvements could be the incorporation of automation (e.g., 3-D bioprinting) during the manufacturing process, which could shorten the long turnaround time associated with 3-D models. As these technologies are more widely used, a GMP-compliant process using ISO 9001 documentation could produce a gold standard for 3-D dermal models.

ATCC’s inventory with various primary dermal cells isolated from human skin tissue and their immortalized counterparts can be used to build air-liquid interface (ALI) skin models. In these ALI models, the skin cells undergo differentiation to mimic human skin structure, creating physiologically relevant models for toxicology testing. ATCC is committed to meeting customer demands for 3-D dermal models as per our mission to provide credible biological products that meet the evolving needs of the scientific community.

Did you know?

ATCC provides renal, neural, airway, and skin cells for toxicology applications such as high-content screening, 3-D culture, spheroid culture, permeability assays, metabolic stability and survival studies, transport activity measurement, and more.

References

1. Naidu R, et al. Chemical pollution: A growing peril and potential catastrophic risk to humanity. Environ Int 156: 106616, 2021. Pubmed: 33989840
2. Han JJ. FDA Modernization Act 2.0 allows for alternatives to animal testing. Artif Organs 47(3): 449-450, 2023. Pubmed: 36762462
3. Animal Use Alternatives (3Rs) by USDA
4. Piasek AM et al. Building Up Skin Models for Numerous Applications - from Two-Dimensional (2D) Monoculture to Three-Dimensional (3D) Multiculture. J Vis Exp Oct 20:(200), 2023. PubMed: 37930006
5. OECD. Test No. 439: In Vitro Skin Irritation - Reconstructed Human Epidermis Test Method, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris.