A bioengineered, three-dimensional (3-D), human tissue model that recapitulates complex structures and functional units of living, human organs provides an attractive, animal model alternative platform to study human disease and accelerate drug development. Recent 3-D biofabrication progress has made it possible to replicate a 3-D human skin consisting of both the epidermis of differentiated stratums for external protection and the dermis containing collagen and fibroblasts for elasticity and mechanical strength. We have advanced this full-thickness skin equivalent by establishing a vascularized, immune competent skin-on-chip microfluidic platform to model viral-host interactions in human herpes simplex virus (HSV) infection, a disease affecting two-thirds of the human population with increasing worldwide prevalence and medical relevance. This human, skin-on-chip system closely mimics the natural skin architecture and is capable of drug perfusion and immune-cell infiltration, providing a practical in vitro system for modeling of HSV infection in humans and for antiviral drug screening and preclinical evaluation. We propose two specific aims in this application: 1) High-throughput screening to identify potential antiviral compounds for blocking HSV infection using fabricated 3-D skin model; 2) Validating candidate antivirals in vascularized 3-D skin models fabricated with patient-specific primary keratinocyte, fibroblast and endothelium cells from a cohort of diverse HSV outcomes. The proposed research will be conducted in a close partnership with the 3-D Bioprinting Laboratory at the National Center for Advancing Translational Sciences (NCATS). The collaboration will leverage the resources and capabilities of the NCATS program aiming to greatly advance the process of discovery and development of new medicines and improve prediction of the effectiveness and toxicity of novel therapeutics in treating humans. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Public Health Relevance

Biofabricated three-dimensional (3-D) human skin provides an effective and low-cost platform for drug discovery and preclinical evaluation. We propose to use 3-D biofabricated human skin, in collaboration with the National Center for Advancing Translational Sciences (NCATS), as an in vitro model system for screening and identification of antiviral drugs against herpes simplex virus infection in humans. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Research Demonstration--Cooperative Agreements (U18)
Project #
1U18TR003208-01
Application #
9985371
Study Section
Special Emphasis Panel (ZTR1)
Program Officer
Rudnicki, Dobrila Doda
Project Start
2020-03-16
Project End
2022-02-28
Budget Start
2020-03-16
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195