Overview of In Vitro Skin Models with Relevance to Preclinical Drug Development

Nonimmune-mediated idiosyncratic cutaneous reactions can arise from a variety of causes including cumulative toxicity, overdose, drug interactions, and metabolic alterations (Lee and Thompson, 2006). Viral infections can influence and increase the incidence of these cutaneous adverse drug reactions (Svensson et al., 2001 Lee and Thompson, 2006). Pharmacogenomics play an important role in individual susceptibility to adverse skin reactions as well (Lonjou et al., 2006 Tassaneeyakul et al., 2009 Aihara, 2011 KuUcantrakom et al., 2012 Pirmohamed, 2012 Borroni, 2015). 

3 OVERVIEW OF/A V/raO SKIN MODELS WITH RELEVANCE TO PRECLINICAL DRUG DEVELOPMENT 

Since the initial development of methods for in vitro cnlture of human keratinocytes (Rheinwald and Green, 1975), two-dimensional monolayer cultures of submerged keratinocytes have been widely utilized for skin-related research. Primary and immortalized fibroblast and melanocyte cultures are also now widely available for in vitro research and toxicology testing applications (Hsu and Herlyn, 1996 Costin and Hearing, 2007). Skin-resident immune cells (e.g., Langerhans cells) are difficult to isolate and maintain in primary culture. However, monocyte-derived dendritic cells and dendritic cells derived from cord blood precursors are well established, as are a variety of immortalized dendritic-like cell lines (Ayehunie et al., 2009 Reuter et al., 2011). 

Methods for in vitro reconstruction of three-dimensional (3D) differentiated human skin were developed during the 1980s (Bell et al., 1981). Cultured at the air-liquid interface (ALI), these in vitro reconstracted human epidermal (RhE) tissues display an in vivo-like stratified structure and functional epidermal layers including stratum comeum barrier. RhE may also be cocultured with dermal constructs containing viable fibroblasts (i.e., fuU-thickness models) as well as melanocytes (Fig. 12.1). The ALI culture format allows in vivo-like exposure and wounding scenarios including 

FIGURE 12.1 Examples of commercially available in vitro reconstructed human epidermal (RhE) tissues (a) EpiDerm partial thickness model produced from primary keratinocytes (h) EpiDermFT full-thickness coculture model including epidermal and dermal components and (c) MelanoDerm coculture model of primary keratinocytes and melanocytes. Reproduced with permission of MatTek Corporation, Ashland, MA. (See insert for color representation of the figure.) 

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