Article: Microfluidic tools to investigate pathologies in the blood microcirculation Journal: International Journal of Nanotechnology (IJNT) 2012 Vol.9 No.3/4/5/6/7 pp.529 - 547 Abstract: We show how microfluidics technology can be used to fabricate simple and innovative biomimetic tools to shed new light on physiopathological events occurring in the blood microcirculation. Examples of applications are given in the context of the acute respiratory distress syndrome (ARDS), an inflammatory disease of the lung triggered by a massive arrest of white blood cells in the lung microvasculature. The main challenge consists in building relevant micro-devices to reproduce key biological characteristics of blood capillaries. We present a series of tools that permit us to decouple the role of the multiple parameters involved in complex biological events. Straight narrow channels with non-adherent walls are used to characterise the passage of a cell in 4 m wide constrictions in the absence of adhesion, whereas channels covered by endothelial cells allow a quantitative measurement of cell adhesion in the absence of mechanical constraints. We show that incubation of white blood cells in sera of ARDS patients increases their stiffness, confirming the role of stiffness on the abnormal sequestration of white blood cells, whereas we could not bring to light a significant adhesion increase. The multiple branches and constrictions of the blood microvasculature network are mimicked here by series of interconnected crenelled constrictions with different symmetries. In symmetric crenels, cells adopt a stable deformed shape after a few constrictions and travel fast through successive constrictions with a constant orientation. In asymmetric channels, cell orientation and trajectory are perturbed between two constrictions. Unfavourable orientations upon entry can yield temporary or even definitive arrests with the stiffest cells. Finally, we present a new artificial micro-vessel with porous walls to mimic the porosity of real blood vessels. This new tool is useful to observe directly under a microscope the late stages of inflammation in the microvasculature such as immune cells transmigration, or the infection of a micro-vessel by pathogenic bacteria. Inderscience Publishers - linking academia, business and industry through research

Title: Microfluidic tools to investigate pathologies in the blood microcirculation

Authors: Pascal Preira; Thomas Leoni; Marie-Pierre Valignat; Annemarie Lellouch; Philippe Robert; Jean-Marie Forel; Laurent Papazian; Guillaume Dumenil; Pierre Bongrand; Olivier Théodoly

Addresses: Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France. ' Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France. ' Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France. ' Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France. ' Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France. ' Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE) UMR6236, CNRS/Université Aix-Marseille 2, Hôpital Nord, Chemin des Bourrely, 13015 Marseille Cedex 20, France. ' Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE) UMR6236, CNRS/Université Aix-Marseille 2, Hôpital Nord, Chemin des Bourrely, 13015 Marseille Cedex 20, France. ' Université Paris Descartes, Faculté de Médecine Paris Descartes, Paris F-75006, France; PARCC, Centre de Recherche Cardiovasculaire á l’HEGP, Inserm U970, 56 rue Leblanc, 75015 Paris, France. ' Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France. ' Université de la Méditerranée, Adhesion & Inflammation, INSERM U600-CNRS UMR6212, Case 937, 163 Avenue de Luminy, F-13009 Marseille, France

Abstract: We show how microfluidics technology can be used to fabricate simple and innovative biomimetic tools to shed new light on physiopathological events occurring in the blood microcirculation. Examples of applications are given in the context of the acute respiratory distress syndrome (ARDS), an inflammatory disease of the lung triggered by a massive arrest of white blood cells in the lung microvasculature. The main challenge consists in building relevant micro-devices to reproduce key biological characteristics of blood capillaries. We present a series of tools that permit us to decouple the role of the multiple parameters involved in complex biological events. Straight narrow channels with non-adherent walls are used to characterise the passage of a cell in 4 m wide constrictions in the absence of adhesion, whereas channels covered by endothelial cells allow a quantitative measurement of cell adhesion in the absence of mechanical constraints. We show that incubation of white blood cells in sera of ARDS patients increases their stiffness, confirming the role of stiffness on the abnormal sequestration of white blood cells, whereas we could not bring to light a significant adhesion increase. The multiple branches and constrictions of the blood microvasculature network are mimicked here by series of interconnected crenelled constrictions with different symmetries. In symmetric crenels, cells adopt a stable deformed shape after a few constrictions and travel fast through successive constrictions with a constant orientation. In asymmetric channels, cell orientation and trajectory are perturbed between two constrictions. Unfavourable orientations upon entry can yield temporary or even definitive arrests with the stiffest cells. Finally, we present a new artificial micro-vessel with porous walls to mimic the porosity of real blood vessels. This new tool is useful to observe directly under a microscope the late stages of inflammation in the microvasculature such as immune cells transmigration, or the infection of a micro-vessel by pathogenic bacteria.

Keywords: microfluidics; lung microvasculature; cell mechanics; cell adhesion; cell migration; cell transmigration; acute respiratory distress syndrome; ARDS; meningitis; blood microcirculation; blood circulation; biomimetics; inflammation; inflammatory diseases; lung disease; white blood cells; blood capillaries.

DOI: 10.1504/IJNT.2012.045340

International Journal of Nanotechnology, 2012 Vol.9 No.3/4/5/6/7, pp.529 - 547

Published online: 06 Feb 2012 *

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Title: Microfluidic tools to investigate pathologies in the blood microcirculation

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