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Cited by 783D Printing in Biomedical ResearchTissue Engineering and Regenerative MedicineHerpesvirus Infections and Treatments

Modeling human HSV infection via a vascularized immune-competent skin-on-chip platform

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Sun, Sijie, Jin, Lei, Zheng, Ying, Zhu, Jia·2022·Nature Communications
DOI 10.1038/s41467-022-33114-1PMC PMC9485166
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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.

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  • The integrated vasculature contributes to spatially organized inflammatory readouts in the VSA platform.

    “Immune cells accumulated within the dermal compartment and localized near vascular structures, suggesting that the integrated vasculature contributes to spatially organized inflammatory readouts in the VSA platform 45 .”

    From Vascularized human skin assembloids model compartmental skin organization and immune responsiveness in vitro (2026) · cites this paper as [45]

  • There has been a complete absence of an endogenously differentiating vascularized, hair-bearing human skin equivalent that contains immune cell populations.

    “While many attempts to generate complex 3D skin equivalents have achieved vascularization, hair follicle generation, and immune cell co‐cultures, there has been a complete absence of endogenously differentiating a vascularized, hair‐bearing human skin equivalent that contains immune cell populations.[ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]”

    From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [21]

    The Introduction (page unavailable) describes separate advances in vascularized skin models and models incorporating immune cells or dermal papilla cells. It does not address whether a human skin equivalent combining endogenous differentiation, vasculature, hair, and immune cell populations was entirely absent. A search for hair-bearing, endogenously differentiating models found no passage establishing that claim. (LLM, conf=0.72)

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References 67 · Cited by 78

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Authors
Sun, S., Jin, L., Zheng, Y., & Zhu, J.
Affiliations
  • University of Washington (US)
  • Fred Hutch Cancer Center (US)
Corresponding author
Zhu, Jia
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-09-19
Volume
13
Issue
1
Pages
5481-5481
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-33114-1
PMC
PMC9485166
OpenAlex
W4296365813
Cited by
78
References
67
Citations by year
2026: 27 · 2025: 21 · 2024: 17 · 2023: 13
FWCI
3.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Foundation for the National Institutes of Health (AI143773, TR003208)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
Keywords
herpes simplex virus, vascularized tissue engineering, microfluidics, dermis, epidermis, genital herpes, interleukin-8, acyclovir, antiviral drug evaluation, disease modeling
MeSH terms
Acyclovir, Animals, Antiviral Agents, Herpes Simplex, Humans, Interleukin-8, Herpesvirus 1, Human

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