David T. Eddington

Sickle cell vasoocclusion and rescue in a microfluidic device

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 oxygen-dependent 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.

Review of an in vitro microfluidic model of sickle cell vaso-occlusion

Vaso-occlusive events are responsible for the majority of morbidity and mortality in sickle cell disease. Predisposing conditions are unclear, and proximal causes have not been established. Despite decades of intense study, until recently there has not been a well-controlled in vitro model of sickle cell vaso-occlusion. We have reported the development and initial use of such a model. Our experimental device relies on microfluidic technology and has allowed the initial analysis of the in vitro process of vaso-occlusion in terms of control parameters such as driving pressure, local oxygen concentration and flow vessel size. Our work demonstrates the potential of this type of device to lead to greater understanding of vaso-occlusive pathology including the role of adhesion molecules and inflammatory factors and possibly to improvements in monitoring and searches for new treatments.