A tissue chip with integrated digital immunosensors: In situ brain endothelial barrier cytokine secretion monitoring

Shiuan-Haur Su; Yujing Song; Andrew Stephens; Muyu Situ; Molly C McCloskey; James L McGrath; Anuska V Andjelkovic; Benjamin H Singer; Katsuo Kurabayashi

doi:10.1016/j.bios.2022.115030

A tissue chip with integrated digital immunosensors: In situ brain endothelial barrier cytokine secretion monitoring

Biosens Bioelectron. 2023 Mar 15:224:115030. doi: 10.1016/j.bios.2022.115030. Epub 2022 Dec 24.

Authors

Shiuan-Haur Su¹, Yujing Song¹, Andrew Stephens¹, Muyu Situ², Molly C McCloskey³, James L McGrath³, Anuska V Andjelkovic⁴, Benjamin H Singer⁵, Katsuo Kurabayashi⁶

Affiliations

¹ Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
² Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Department of Biomedical Engineering, University of Rochester, Rochester, NY, 14627, USA.
⁴ Department of Pathology and Neurosurgery, University of Michigan, Ann Arbor, MI, 48109, USA.
⁵ Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Weil Institute for Critical Care Research and Innovation, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: singerb@med.umich.edu.
⁶ Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, 48109, USA; Weil Institute for Critical Care Research and Innovation, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: katsuo@umich.edu.

Abstract

Organ-on-a-chip platforms have potential to offer more cost-effective, ethical, and human-resembling models than animal models for disease study and drug discovery. Particularly, the Blood-Brain-Barrier-on-a-chip (BBB-oC) has emerged as a promising tool to investigate several neurological disorders since it promises to provide a model of the multifunctional tissue working as an important node to control pathogen entry, drug delivery and neuroinflammation. A comprehensive understanding of the multiple physiological functions of the tissue model requires biosensors detecting several tissue-secreted substances in a BBB-oC system. However, current sensor-integrated BBB-oC platforms are only available for tissue membrane integrity characterization based on permeability measurement. Protein secretory pathways are closely associated with the tissue's various diseased conditions. At present, no biosensor-integrated BBB-oC platform exists that permits in situ tissue protein secretion analysis over time, which prohibits researchers from fully understanding the time-evolving pathology of a tissue barrier. Herein, the authors present a platform named "Digital Tissue-BArrier-CytoKine-counting-on-a-chip (DigiTACK)," which integrates digital immunosensors into a tissue chip system and demonstrates on-chip multiplexed, ultrasensitive, longitudinal cytokine secretion profiling of cultured brain endothelial barrier tissues. The integrated digital sensors utilize a novel beadless microwell format to perform an ultrafast "digital fingerprinting" of the analytes while achieving a low limit of detection (LoD) around 100-500 fg/mL for mouse MCP1 (CCL2), IL-6 and KC (CXCL1). The DigiTACK platform is extensively applicable to profile temporal cytokine secretion of other barrier-related organ-on-a-chip systems and can provide new insight into the secretory dynamics of the BBB by sequentially controlled experiments.

Keywords: Blood-brain-barrier; Cytokine secretion; Digital immunoassay; Multiplex biomarker detection; Organ-on-a-chip; Tissue chip.

MeSH terms

Animals
Biosensing Techniques*
Blood-Brain Barrier / metabolism
Brain / metabolism
Cytokines
Humans
Immunoassay
Lab-On-A-Chip Devices
Mice

Substances

Cytokines

Abstract

MeSH terms

Substances

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