# Modeling atypical hemolytic uremic syndrome with hydrogel-based microvasculature-on-chip technologies

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $195,470

## Abstract

PROJECT SUMMARY ABSTRACT
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease that causes microvascular thrombosis,
especially in the kidneys, with a global mortality rate of 25%, and a frequent progression to end-stage renal
disease (ESRD)1,2. While aHUS is known to be associated with uncontrolled activation of the alternative pathway
(AP) of complement, the underlying pathophysiology of how AP activation causes endothelial injury and
thrombosis remains unclear, which largely limits the development of additional therapies for aHUS. Even with
the currently most effective drug, eculizumab, many still suffer from acute flare ups, progression to ESRD, and
extra-renal manifestations, which are thought to be associated with unregulated endothelial activation. The
proposed work aims to develop the first in vitro model of aHUS that incorporates all of the major
components thereof, including complement and other plasma proteins, platelets, red blood cells, intact
endothelium, extracellular matrix with physiologic biophysical properties, and shear stress, to not only
improve our understanding of the pathophysiology of this feared disease but also to explore new therapeutics
that may improve better clinical outcomes for aHUS patients. Here we hypothesize that a novel hydrogel-based
“endothelialized” microvasculature-on-a-chip that we recently invented recapitulates the in vivo microvascular
microenvironment and exhibits long-term (>2 months) microvasculature functionality. This can be used as an in
vitro model for aHUS, as our microvasculature-on-a-chip system enables the decoupling of the complex cellular
and molecular factors (including complement and regulators of complement activation) involved in the
pathophysiology of aHUS as well as quantitatively characterizes how these factors interact and lead to
endothelial injury or activation. These factors will be perfused into the engineered microvasculature, and
biomarkers of endothelial dysfunction, such as endothelial permeability, reduced nitric oxide and increased
reactive oxygen species, will be monitored in real time. In addition, the system will allow assessment of how
these factors synergistically lead to thrombi formation in the engineered microvasculature in the context of aHUS
through quantifying fibrin formation and platelet aggregate/microthrombi size. As eculizumab only blocks the
formation of the membrane attack complex in the terminal pathway of complement activation, this
microvasculature-on-a-chip model will enable the testing of other novel treatment strategies to promote
endothelial repair.
Successful completion of this study will result in the development of a novel and robust model for aHUS, gain a
better understanding of endothelial damage in aHUS and more broadly how the complement system interacts
with hemostasis and thrombosis, and provide insights into developing rational pharmacological approaches in
the management of aHUS and other thrombotic microangiopathies...

## Key facts

- **NIH application ID:** 9996696
- **Project number:** 5R21EB028519-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Satheesh Chonat
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,470
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996696

## Citation

> US National Institutes of Health, RePORTER application 9996696, Modeling atypical hemolytic uremic syndrome with hydrogel-based microvasculature-on-chip technologies (5R21EB028519-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9996696. Licensed CC0.

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