Vascularized skin-on-chip for modeling HSV infection

Abstract

“Herpes simplex virus (HSV) naturally infects skin and mucosal surfaces, causing lifelong recurrent disease worldwide, with no cure or vaccine. Biomimetic human tissue and organ platforms provide attractive alternatives over animal models to recapitulate human diseases. Combining prevascularization and microfluidic approaches, we present a vascularized, three-dimensional skin-on-chip that mimics human skin architecture and is competent to immune-cell and drug perfusion. The endothelialized microvasculature embedded in a fibroblast-containing dermis responds to biological stimulation, while the cornified epidermis functions as a protective barrier. HSV infection of the skin-on-chip displays tissue-level key morphological and pathophysiological features typical of genital herpes infection in humans, including the production of proinflammatory cytokine IL-8, which triggers rapid neutrophil trans-endothelial extravasation and directional migration. Importantly, perfusion with the antiviral drug acyclovir inhibits HSV infection in a dose-dependent and time-sensitive manner. Thus, our vascularized skin-on-chip represents a promising platform for human HSV disease modeling and preclinical therapeutic evaluation.

ab Schematics of the major components in native human skin and skin-on-chip. c Representative 3-D reconstructed confocal image showing an overview of the cytoskeleton of the micro-engineered epidermis and dermis with underlying endothelialized microvascular network (white arrow indicates microfluidic flow direction). F-actin for cell cytoskeleton (green), DAPI for cell nucleus (blue). d Representative 3-D reconstructed confocal image illustrating basale (bottom, K14+) and corneous (upper, anucleate) layers in the epidermis of skin-on-chip. F-actin (green), K14 (red), DAPI (blue). Scale bar: 20 µm. e A cross-sectional view of hematoxylin–eosin (H&E) stained epidermis in the skin-on-chip. Scale bar: 20 µm. f Maximum intensity projected confocal image of an endothelialized microvascular network in the dermis after two weeks of culturing. F-actin (green), DAPI (blue). Scale bar: 100 µm. g Projected confocal images showing endothelium marker (CD31) expression, lumen formation (yz), and fibroblast capping of endothelial vessel (bottom). CD31 (green), Vimentin (red), DAPI (blue). Scale bar: 100 µm. h Representative fluorescence image after perfusion with 40 kDa FITC-Dextran through the microvasculature for 20 min. Graph depicts fluorescence intensity across the microvasculature inside the dashed box at 7 min (red) and 10 min after perfusion (blue). Scale bar: 100 µm. i F-actin cytoskeleton arrangement in endothelial cells and related flow shear force. Right: enlarged view within the white boxes. Scale bar: 100 µm. j Representative confocal image showing new sprouting from the main vessel lumen after angiogenetic stimuli. Right image shows cross-sectional view (yz). CD31 (green), Vimentin (red), DAPI (blue). Scale bar: 100 µm. Data are provided in a Source data file.” Reproduced under Creative Commons Attribution 4.0 International License from Sun, S., Jin, L., Zheng, Y. et al. Modeling human HSV infection via a vascularized immune-competent skin-on-chip platform. Nat Commun 13, 5481 (2022).

Figures and the abstract are reproduced from Sun, S., Jin, L., Zheng, Y. et al. Modeling human HSV infection via a vascularized immune-competent skin-on-chip platform. Nat Commun 13, 5481 (2022). https://doi.org/10.1038/s41467-022-33114-1

Read the original article: Skin-on-chip contains a stratified epidermis and dermis with a functional microvascular network