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

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  • Author(s): Tsai M;Tsai M; Kita A; Leach J; Rounsevell R; Huang JN; Moake J; Ware RE; Fletcher DA; Lam WA
  • Source:
    The Journal of clinical investigation [J Clin Invest] 2012 Jan; Vol. 122 (1), pp. 408-18. Date of Electronic Publication: 2011 Dec 12.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
      Microfluidic Analytical Techniques*; Hematologic Diseases/*etiology ; Microvessels/*pathology ; Microvessels/*physiopathology ; Thrombosis/*etiology; Anemia, Sickle Cell/blood ; Anemia, Sickle Cell/drug therapy ; Anemia, Sickle Cell/pathology ; Anemia, Sickle Cell/physiopathology ; Eptifibatide ; Hematologic Diseases/drug therapy ; 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 ; Microscopy, Fluorescence ; Microvessels/drug effects ; Models, Cardiovascular ; Peptides/pharmacology ; Platelet Aggregation Inhibitors/pharmacology ; Thrombosis/drug therapy ; Thrombosis/pathology ; Thrombosis/physiopathology
    • 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.
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    • Grant Information:
      K08-HL093360 United States HL NHLBI NIH HHS; PN2EY018244 United States EY NEI NIH HHS; R01 United States PHS HHS; K08 HL093360 United States HL NHLBI NIH HHS; PN2 EY018244 United States EY NEI NIH HHS; U54 HL112309 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Peptides)
      0 (Platelet Aggregation Inhibitors)
      NA8320J834 (Eptifibatide)
      X6Q56QN5QC (Hydroxyurea)
    • Publication Date:
      Date Created: 20111214 Date Completed: 20120306 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      PMC3248292
    • Accession Number:
      10.1172/JCI58753
    • Accession Number:
      22156199