Skin models for the testing of transdermal drugs

Figures & data

Table 1 Skin models

Model	Advantages	Disadvantages
Human skin
In vivo	Gold standard	Often precluded for ethical and practical reasons
Ex vivo skin	Best surrogate for in vivo humans	Not readily available, variability
Animal skin
In vivo	Reasonably easy to obtain animals, can be scaled up to humans, hairless species available	Pigs: similar barrier to humans, but difficult to handle Rodents: different barrier properties from humans
In vivo chimeric model	Human skin xenografts on mice allows testing on living human skin	Technically difficult
Ex vivo skin	Easy to obtain	Different barrier properties, variability
Artificial membranes
Simple polymeric models	Useful for studying basic diffusion mechanisms, consistent and homogenous	Not representative of human skin
Lipid-based models	Useful for screening	Not representative of human skin
Reconstructed skin models
Reconstructed human epidermis	Built-in barrier properties	Usually more permeable than human skin
Living skin equivalents	Can be engineered to include a range of normal or disease features	Usually more permeable than human skin

Figure 1 Structure of the skin.

Table 2 In vivo animal disease models

Disease model	Characteristics	Drug delivered	Reference
Psoriasis mouse model	Epidermal VEGF-knockout mice used to identify specific role for VEGF in permeability-barrier maintenance		Elias et al^Citation96
Atopic dermatitis mouse model	Histamine H4(H4R)-knockout mice used to show H4R modulates inflammation in a chronic allergic dermatitis setting	H4R antagonists partially mimicked effects of H4R knockout	Rossbach et al^Citation97
Dermatophytosis guinea-pig model	Tinea corporis induced by application of Trichophyton mentagrophytes TIMM1189 inoculum on dorsal skin	Luliconazole	Koga et al^Citation121
Irritant dermatitis hairless guinea-pig model	Induced by daily exposure for 4 days to sodium lauryl sulfate	Basic, carbomer, isopropyl palmitate, glycerol, canola oil, and bisabolol creams	Andersen et al^Citation122
Squamous cell carcinoma mouse model	Dorsal UVB irradiation (minimal erythema dose) of SKH1 hairless mice	Diclofenac (anti-inflammatory COX2 inhibitor) as preventive drug	Burns et al^Citation98
	UV-induced T7 SCC line subcutaneously injected in the back of SKH1 hairless mice	Ingenol mebutate	Cozzi et al^Citation99
	UV radiation of SKH1 hairless mice	17AAG (heat-shock protein 90 inhibitor) alone or in conjunction with UVR treatments	Singh et al^Citation100
	Human skin SCC cell line SRB12-p9 subcutaneously injected into severe combined immunodeficiency (SCID) mice	Curcumin	Sonavane et al^Citation101
	Two-stage skin-carcinogenesis model in FVB/N mice: 1) topical treatment with carcinogen agent (DMBA), 2) tumor-promoter treatment (TPA), and 3) oral dose with a BRAF inhibitor (PLX4270)	5-Fluorouracil (5-FU)	Viros et al^Citation102
	Dorsal UVB irradiation (minimal erythema dose) of SKH1 hairless mice	5-Aminolevulinic acid (5-ALA) in conjunction with photodynamic therapy (PDT)	Wang et al^Citation103
Basal cell carcinoma mouse model	Neonatally irradiated Ptch1^+/− mice as a model of Hedgehog (Hh)-signaling pathway-dependent tumors	MK-4101, potent inhibitor of Hh-signaling pathway, had robust antitumor activity	Filocamo et al^Citation104
	BCC mouse model used to identify molecular mechanisms regulated by Sox9, leading to tumour initiation and invasion		Larsimont et al^Citation105
	Induced in PTCH-knockout mice by 1) treatment by tamoxifen administered intraperitoneally and 2) ionizing irradiation	CUR61414 (an inhibitor of the Hh signal-transduction molecule Smoothened)	Tang et al^Citation106
Melanoma mouse model	Tumor spheroid of B16/F0 melanoma cells subcutaneously inoculated in the auricle of NMRINu/Nu or C57/BL6 mice	Bortezomib (inhibitor of the 26S proteasome)	Schröder et al^Citation123
	B16BL6 melanoma cells subcutaneously injected into the notum of C57BL/l mice	Curcumin	Chen et al^Citation124
	B16 melanoma cells subcutaneously injected in the hip of BALB/c nude mice	Mitoxantrone (DNA-synthesis and-transcription inhibitor)	Yu et al^Citation125
Human–SCID mouse xenograft model: psoriasis	SCID mouse–human psoriasis skin model used for targeted topical immunotherapy	Kv1.3 channel blocker PAP-1	Kundu-Raychaudhuri et al^Citation108
Human–SCID mouse xenograft model: melanoma	Identified an intronic mutation as molecular basis for a RNA splicing-mediated RAF inhibitor-resistance mechanism and a pre-mRNA-splicing interference as a potential therapeutic strategy for drug resistance in BRAF melanoma	Vemurafenib, potent RAF-kinase inhibitor	Salton et al^Citation109
Human–SCID mouse xenograft model: melanoma	Effects of chemical inhibition of ALDH1 on the response of human melanoma xenografts to chemotherapy and the effects of ALDH1A1 RNA silencing on melanoma growth and metastasis; ALDH1 inhibition may be useful in melanoma treatment	ALDH1 inhibitors (eg, diethylaminobenzaldehyde) added to dacarbazine chemotherapy	Yue et al^Citation110

Abbreviations: UVB, ultraviolet B; SCC, squamous cell carcinoma; DMBA, 7,12-dimethylbenz-(a)anthracene; BCC, basal cell carcinoma; mRNA, messenger RNA; BRAF, v-Raf murine sarcoma viral oncogene homolog B; RAF, a serine/threonine protein kinase product of BRAF gene; ALDH, aldehyde dehydrogenase; SCID, severe combined immunodeficient; VEGF, vascular endothelial growth factor.

Table 3 Reconstructed skin-disease models

Disease model	Characteristics	Drug delivered	Reference
Psoriasis	Full-thickness skin model closely resembling in vivo epidermal architecture used to identify IL-17-responsive genes in psoriasis	Ixekizumab (IL-17 antagonist)	Chiricozzi et al^Citation111
	Human psoriatic skin equivalents used to study cytokine-induced gene expression	Retinoic acid, cyclosporine A	Tjabringa et al^Citation112
Atopic dermatitis	3-D reconstructed human epidermis model used to show filaggrin downregulation in the epidermis of atopic patients, either acquired or innate, may be directly responsible for some of the disease-related alterations	Inflammatory cocktail (polyinosinic–polycytidylic acid, TNFα, IL-4, and IL-13)	Pendaries et al^Citation113
Atopic dermatitis	Compromised reconstructed epidermis mimicking AD-related inflammation in vitro		Rouaud-Tinguely et al^Citation114
3-D model of dermatitis	Human foreskin fibroblasts HaCaT cells Memory-effector (CD45RO^+) T cells Scaffold material: tat tail collagen type I, fibronectin	Dexamethasone and tacrolimus	Engelhart et al^Citation115
3-D model of melanoma	3-D human skin reconstruct model incorporating melanocytic cells		Li et al^Citation116
3-D skin-reconstruction model of metastatic melanoma	Human malignant melanoma cells (A375) Normal human-derived epidermal keratinocytes (NHEKs) Normal human-derived dermal fibroblasts (NHDFs) Scaffold material: collagen type I	Roscovitine (cyclin-dependent kinase inhibitor)	Mohapatra et al^Citation117
3-D organotypic skin-melanoma spheroid model	Human melanoma cell lines SBCL2 (RGP), WM-115 (VGP), and 451-LU (MM) Human primary keratinocytes Human primary fibroblasts Scaffold material: rat tail collagen type I	TRAIL + ultraviolet B radiation TRAIL + cisplatin	Vörsmann et al^Citation118
3-D model of human cutaneous squamous cell carcinoma	Primary NHEKs Primary NHDFs, SCC12B2 and SCC13 cell lines Scaffold material: rat tail collagen type I Pretreatment with EGF	Erlotinib (tyrosine-kinase inhibitor)	Commandeuret al^Citation119
3-D model of scleroderma fibrosis	Model useful for testing in vivo the progression of scleroderma and to screen for antifibrotic drugs	Nilotinib, a tyrosine kinase inhibitor; human monoclonal anti-PDGFR antibodies	Luchetti et al^Citation120

Abbreviations: IL, interleukin; TNFα, tumor necrosis factor alpha; 3-D, three dimensional; NHEKS, Normal human-derived epidermal keratinocytes; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; SBCL-2 (RGP), an early radial growth phase cell line; WM-115 (VGP), a vertical growth phase cell line; MM, metastatic melanoma; NHDF, normal human-derived dermal fibroblasts.

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