An Interleukin-4 and Interleukin-13 Induced Atopic Dermatitis Human Skin Equivalent Model by a Skin-On-A-Chip

Abstract

Currently, the mechanism of progression of atopic dermatitis (AD) is not well understood because there is no physiologically appropriate disease model in terms of disease complexity and multifactoriality. Type 2 inflammation, mediated by interleukin (IL)-4 and IL-13, plays an important role in AD. In this study, full-thickness human skin equivalents consisting of human-derived cells were fabricated from pumpless microfluidic chips and stimulated with IL-4 and IL-13. The morphological properties, gene expression, cytokine secretion and protein expression of the stimulated human skin equivalent (HSE) epidermis were investigated. The results showed epidermal and spongy formations similar to those observed in lesions in AD, and decreased expression of barrier-related filaggrin, loricrin and involucrin genes and proteins induced by IL-4Rα signaling. In addition, we induced the expression of carbonic anhydrase II (CAII), a gene specifically expressed in the epidermis of patients with AD. Thus, AD human skin equivalents can be used to mimic the key pathological features of atopic dermatitis, overcoming the limitations of existing studies that rely solely on mouse models and have been unable to translate their effects to humans. Our results will be useful for future research on the development of therapeutic agents for atopic dermatitis.

Advancements in Extracellular Matrix-Based Biomaterials and Biofabrication of 3D Organotypic Skin Models

“…117,127,169 Classical AD phenotypes including spongiosis, epithelial hyperplasia and compromised epidermal differentiation were observed in these models. 117,127,169 The impairment of epidermal barrier function was addressed by the knockdown of epidermal filaggrin in organotypic skin constructs, 170,171 but the role of ECM remodeling in AD pathogenesis remains unknown. Graff et al have generated a self-assembled AD model using AD fibroblasts-derived ECM (Figure 7a).…”

“…125,126 To improve dermal stability, collagen cross-linking in the SoC model can be achieved through the incorporation of the photo-cross-linking agent sulfosuccinimidyl 6-(4′-azido-2′-nitrophenylamino)hexanoate (Sulfo-SAN-PAH). 16,127 Sulfo-SANPAH contains a photoactivated nitrophenyl azide group that forms a double bond with the polydimethylsiloxane (PDMS) chip surface of the SoC model upon UV treatment, whereas the amine-reactive NHS ester of the Sulfo-SANPAH allows the binding of cells-embedded collagen matrix (Figure 6b). 16,127 Fibronectin can be added to enforce the collagen cross-linking effect of Sulfo-SANPAH.…”

“…16,127 Sulfo-SANPAH contains a photoactivated nitrophenyl azide group that forms a double bond with the polydimethylsiloxane (PDMS) chip surface of the SoC model upon UV treatment, whereas the amine-reactive NHS ester of the Sulfo-SANPAH allows the binding of cells-embedded collagen matrix (Figure 6b). 16,127 Fibronectin can be added to enforce the collagen cross-linking effect of Sulfo-SANPAH. According to Jeong et al, Sulfo-SANPAH treatment reduced the contraction rate of the skin-on-a-chip model by 40% when compared to the untreated counterpart, 16 which demonstrates the effectiveness of Sulfo-SANPAH as a collagen cross-linker in the SoC model.…”

“…The conventional static culture is also unable to define the precise positioning of cells within the dermal matrix and the epidermal layer . To overcome these limitations, advanced biofabrication technologies such as electrospinning, − 3D bioprinting, ,− and skin-on-a-chip (SoC) − ,,,,,− have been introduced in biofabricating the organotypic skin models.…”

Modeling an Optimal 3D Skin-on-Chip within Microfluidic Devices for Pharmacological Studies

“…AD is caused by epithelial barrier disruption and dysregulation of the immune Th2 response, with increased IL-4 and IL-13 that trigger the activation of JAK1/JAK2/TYK2-STAT6 and -STAT3 pathways, inhibiting the expression of filaggrin, loricrin, and involucrin. Thus, induced atopic dermatitis by IL-4 and IL-13 in a full thickness SoC showed greater disruption of epidermis, decreasing the expression of barrier proteins [ 58 ], particularly affecting the stratum corneum, with large intracellular spaces. However, the role of the cutaneous microbiota should not be overlooked since the overabundance of S. aureus and S. epidermis bacteria is related to AD [ 59 ].…”