The pathophysiology of sickle cell disease is complicated by the
multiscale processes that link the molecular genotype to the
organismal phenotype: hemoglobin polymerization occurring in
milliseconds, microscopic cellular sickling in a few seconds or less
[Eaton WA, Hofrichter J (1990) Adv Protein Chem 40:63–279], and
macroscopic vessel occlusion over a time scale of minutes, the last
of which is necessary for a crisis [Bunn HF (1997) N Engl J Med
337:762–769]. Using a minimal but robust artificial microfluidic
environment, we show that it is possible to evoke, control, and
inhibit the collective vasoocclusive or jamming event in sickle cell
disease. We use a combination of geometric, physical, chemical,
and biological means to quantify the phase space for the onset of
a jamming event, as well as its dissolution, and find that oxygendependent sickle hemoglobin polymerization and melting alone
are sufficient to recreate jamming and rescue. We further show
that a key source of the heterogeneity in occlusion arises from the
slow collective jamming of a confined, flowing suspension of soft
cells that change their morphology and rheology relatively quickly.
Finally, we quantify and investigate the effects of small-molecule
inhibitors of polymerization and therapeutic red blood cell exchange on this dynamical process. Our experimental study integrates the dynamics of collective processes associated with occlusion at the molecular, polymer, cellular, and tissue level; lays the
foundation for a quantitative understanding of the rate-limiting
processes; and provides a potential tool for optimizing and individualizing treatment, and identifying new therapies.