In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology

• Published in: The Journal of clinical investigation Vol. 122; no. 1; pp. 408 - 418
• Main Authors: Tsai, Michelle, Kita, Ashley, Leach, Joseph, Rounsevell, Ross, Huang, James N, Moake, Joel, Ware, Russell E, Fletcher, Daniel A, Lam, Wilbur A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-01-2012
• Subjects: Anemia, Sickle Cell - blood; Anemia, Sickle Cell - drug therapy; Anemia, Sickle Cell - pathology; Anemia, Sickle Cell - physiopathology; Biomedical research; Blood; Blood circulation disorders; Blood diseases; Cell adhesion & migration; Complications and side effects; Hematologic Diseases - drug therapy; Hematologic Diseases - etiology; Hematologic Diseases - pathology; Hematologic Diseases - physiopathology; Hemolytic-Uremic Syndrome - blood; Hemolytic-Uremic Syndrome - drug therapy; Hemolytic-Uremic Syndrome - pathology; Hemolytic-Uremic Syndrome - physiopathology; Hemorheology; Human Umbilical Vein Endothelial Cells; Humans; Hydroxyurea - pharmacology; In Vitro Techniques; Investigations; Microfluidic Analytical Techniques; Microfluidics; Microscopy; Microscopy, Fluorescence; Microvessels - drug effects; Microvessels - pathology; Microvessels - physiopathology; Models, Cardiovascular; Pathophysiology; Peptides - pharmacology; Platelet Aggregation Inhibitors - pharmacology; Risk factors; Sickle cell disease; Technical Advance; Thrombosis; Thrombosis - drug therapy; Thrombosis - etiology; Thrombosis - pathology; Thrombosis - physiopathology; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI58753

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.