# The µSiM-hNVU - a human BBB platform for the study of brain injury mechanisms during systemic infection

> **NIH NIH R61** · UNIVERSITY OF ROCHESTER · 2020 · $635,123

## Abstract

Abstract
Long-term cognitive impairment affects more than 70% of sepsis survivors, but the underlying mechanisms
remain unknown. Though widely hypothesized, evidence of blood-brain barrier (BBB) dysfunction in septic
patients is limited by practical barriers to diagnostic studies in critically ill subjects. While BBB breakdown and
cognitive impairment are seen in animal models of sepsis, the complexity of sepsis in vivo and differences
between animal and human responses means that animal models cannot unambiguously identify the
circulating factors that cause brain injury in human sepsis. Therefore, we propose to develop the µSiM-hNVU
as an `on-chip' platform featuring a human iPSC-derived neurovascular unit (NVU; brain microvascular
endothelial cells, pericytes and astrocytes). The `blood side' will allow the flow-based introduction of blood-
borne cells and molecules with known or hypothesized roles in sepsis related brain injury, and the `brain side'
will feature iPSC-derived microglial cells serving as a reporter of the brain inflammatory status. The human
NVU will be built on a device platform – the µSiM – featuring ultrathin silicon nanomembranes that provide for
unhindered solute exchange between `blood' and `brain' compartments and glass-like optical quality for live cell
imaging and high-resolution microscopy. In the R61 phase, the device platform will be advanced for ease-of-
use including `plug-and-play' modules for flow and barrier measurements (TEER, diffusion), and compatibility
with a small-volume, digital-ELISA assay for secreted proteins. The µSiM-hNVU will be validated with
functional assays of blood-brain barrier (BBB) function, protein expression studies, and transcriptional analysis.
We will also build a iPSC NVU in which each cellular component of the NVU carries the ApoE4 allele. The
expression of the ApoE4 lipoprotein drives BBB dysfunction by a known pathway and increases the risk of
cognitive impairment in humans and animals experiencing brain inflammation. We will use the ApoE4-NVU as
a `diseased BBB on a chip” which we hypothesize will show enhanced vulnerabilities to candidate mechanisms
of brain injury identified by our team and others. Specifically, we will test the hypotheses that 1) pre-activated
monocytes invade the brain and drive microglial activation; 2) the damage associated molecular pattern
(DAMP) complex S100A8/A9 drive BBB breakdown to promote leukocyte infiltration and neuroinflammation;
and 3) circulating factors that degrade endothelial glycocaylx (e.g., heparinase) or contribute to systemic
inflammation (cell-free hemoglobin) promote CNS infiltration of leukocytes and subsequent neuroinflammation.

## Key facts

- **NIH application ID:** 10063709
- **Project number:** 1R61HL154249-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Britta Engelhardt
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $635,123
- **Award type:** 1
- **Project period:** 2020-09-03 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063709

## Citation

> US National Institutes of Health, RePORTER application 10063709, The µSiM-hNVU - a human BBB platform for the study of brain injury mechanisms during systemic infection (1R61HL154249-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10063709. Licensed CC0.

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