# Developing a multiscale understanding of biophysical processes in sickle cell disease

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $592,802

## Abstract

PROJECT SUMMARY
In this renewal, we seek to understand the origin of heterogeneity in sickle cell disease (SCD), which is present
at every scale from molecules to the clinic, and is the major impediment to clinical management and the
development of new therapies. Moreover, therapy often increases heterogeneity, with some patients responding
strongly to therapy and others unresponsive. Our central hypothesis is that heterogeneity originates with
intracellular kinetics of sickle hemoglobin (HbS) self-assembly that translates into heterogeneous populations of
RBCs, which drive strong non-Newtonian fluid behavior in whole blood and alterations in the systemic circulation
that precipitate pathologies such as endothelial injury, vaso-occlusion, aneurysm, and stroke. Thus, the ability to
guide therapeutic intervention and to develop new therapies is ultimately hindered by our limited understanding
of heterogeneity in the context of multiscale biophysical processes in SCD pathophysiology. In this work, we will
develop a biophysical framework for SCD pathophysiology that spans from molecules to the systemic circulation,
that is experimentally validated at every scale, and that allows us to predict the effects of multiscale
heterogeneity. Specifically, we will: (1) Develop a quantitative framework for HbS polymerization that
accurately predicts the kinetics of self-assembly; (2) Define the connection between the distribution of
HbS polymer and mechanical properties among a population of RBCs; (3) Understand how cellular
heterogeneity drives non-Newtonian blood rheology and altered flow in the systemic circulation. The
work in this renewal builds on key conceptual advances made during our last 3 years of funding: HbS self-
assembly kinetics have previously been underestimated by at least an order of magnitude; HbS polymer is
heterogeneously distributed in RBCs at finite oxygen tension; velocity profiles in sickle blood demonstrate strong
non-Newtonian effects; blood flow in SCD patients is altered throughout the circulation with aberrantly large wall
shear stress relative to healthy blood. This work also leverages a unique and enabling set of tools that we have
developed during the last 3 years of funding: the highest spatiotemporal resolution measurements of single HbS
fiber assembly to-date; the first platform capable of quantifying HbS polymer in large populations of single RBCs
under well-defined oxygen tension; a platform capable of quantifying viscoelastic properties of large populations
of RBCs under well-defined oxygen tension; the ability to quantify submicron velocity fields in flowing blood at
physiologic hematocrit; a platform to quantify sickle blood flow within physiologic oxygen gradients. Building on
these tools and insights, this renewal work will develop and validate a multiscale model describing how
heterogeneity propagates from the molecular to cellular to system levels, and we will develop experimental tools
that can be used for clinica...

## Key facts

- **NIH application ID:** 10209656
- **Project number:** 2R01HL132906-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** David Kevin Wood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $592,802
- **Award type:** 2
- **Project period:** 2017-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209656

## Citation

> US National Institutes of Health, RePORTER application 10209656, Developing a multiscale understanding of biophysical processes in sickle cell disease (2R01HL132906-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10209656. Licensed CC0.

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