Collective Hydrodynamics and Kinetics of Sickle Cell Vaso-Occlusion and Rescue in a Microfluidic Device

The pathophysiology of sickle cell disease, the first to be implicated with a genetic origin, is complicated by the multi-scale nature of the processes that link the molecular genotype to the organismal phenotype. Here, we show that it is possible to evoke, control and inhibit the vaso-occlusive crisis event in sickle cell disease using an artificial microfluidic environment. We use a combination of geometric, physical, chemical and biological means to quantify the phase space for the onset of a jamming crisis, as well as its dissolution.

The microfluidic chip is designed to independently vary the various parameters that control the onset of vaso-occlusion in a sickle cell crisis. This device allows us to dissect and probe the hierarchical dynamics of this multi-scale process by manipulating the geometrical, physical, chemical and biological determinants of the process. The chip consists of a series of bifurcating channels of varying diameters that grossly mimics the geometry of vasculature. By controlling the physical pressure gradient across the chip, we can vary the kinetic time scale for transit of red blood cells. The channels are separated from a gas reservoir by a thin gas-permeable polydimethylsiloxane (PDMS) membrane. As the geometries are microscopic, gas diffusion is rapid and the oxygen concentration in the microchannels is governed by the concentration in the gas reservoir. By changing the mixture of this reservoir, we control oxygen concentrations in the channels and hence the onset of microscopic hemoglobin polymerization. By using blood with varying concentrations of HbS and different hematocrits, we can mimic the variability among individuals. This device was used to study the phase space of jamming governed by pressure, channel dimensions and oxygen concentration. Our experimental study integrates the dynamics of collective processes at the molecular, polymer, cellular and multi-cellular level; lays the foundation for a quantitative understanding of the rate limiting processes; provides a potential tool for optimizing and individualizing treatment; and serves as a bench test for dynamical drugs.