In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology
Open Access
- 3 January 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (1), 408-418
- https://doi.org/10.1172/jci58753
Abstract
In hematologic diseases, such as sickle cell disease (SCD) and hemolytic uremic syndrome (HUS), pathological biophysical interactions among blood cells, endothelial cells, and soluble factors lead to microvascular occlusion and thrombosis. Here, we report an in vitro “endothelialized” microfluidic microvasculature model that recapitulates and integrates this ensemble of pathophysiological processes. Under controlled flow conditions, the model enabled quantitative investigation of how biophysical alterations in hematologic disease collectively lead to microvascular occlusion and thrombosis. Using blood samples from patients with SCD, we investigated how the drug hydroxyurea quantitatively affects microvascular obstruction in SCD, an unresolved issue pivotal to understanding its clinical efficacy in such patients. In addition, we demonstrated that our microsystem can function as an in vitro model of HUS and showed that shear stress influences microvascular thrombosis/obstruction and the efficacy of the drug eptifibatide, which decreases platelet aggregation, in the context of HUS. These experiments establish the versatility and clinical relevance of our microvasculature-on-a-chip model as a biophysical assay of hematologic pathophysiology as well as a drug discovery platform.Keywords
This publication has 59 references indexed in Scilit:
- Clinical microfluidics for neutrophil genomics and proteomicsNature Medicine, 2010
- How I use hydroxyurea to treat young patients with sickle cell anemiaBlood, 2010
- Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunctionPediatric Nephrology, 2010
- Fundamentals of microfluidic cell culture in controlled microenvironmentsChemical Society Reviews, 2010
- Functional endothelialized microvascular networks with circular cross-sections in a tissue culture substrateBiomedical Microdevices, 2009
- A physiologically realistic in vitro model of microvascular networksBiomedical Microdevices, 2009
- Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injuryNature Medicine, 2009
- Sickle Red Cell–Endothelium InteractionsMicrocirculation, 2009
- Sickle cell vasoocclusion and rescue in a microfluidic deviceProceedings of the National Academy of Sciences of the United States of America, 2007
- Macrorheology and adaptive microrheology of endothelial cells subjected to fluid shear stressAmerican Journal of Physiology-Cell Physiology, 2007