title: Glioblastoma on a microfluidic chip: Generating pseudopalisades and enhancing aggressiveness through blood vessel obstruction events.
abstract: Glioblastoma (GBM) is one of the most lethal tumor types. Hypercellular regions, named pseudopalisades, are characteristic in these tumors and have been hypothesized to be waves of migrating glioblastoma cells. These "waves" of cells are thought to be induced by oxygen and nutrient depletion caused by tumor-induced blood vessel occlusion. Although the universal presence of these structures in GBM tumors suggests that they may play an instrumental role in GBM's spread and invasion, the recreation of these structures in vitro has remained challenging.
  
  
  
  Here we present a new microfluidic model of GBM that mimics the dynamics of pseudopalisade formation. To do this, we embedded U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we can mimic and control blood-vessel obstruction events associated with this disease.
  
  
  
  Through the use of this new system, we show that nutrient and oxygen starvation triggers a strong migratory process leading to pseudopalisade generation in vitro. These results validate the hypothesis of pseudopalisade formation and show an excellent agreement with a systems-biology model based on a hypoxia-driven phenomenon.
  
  
  
  This paper shows the potential of microfluidic devices as advanced artificial systems capable of modeling in vivo nutrient and oxygen gradients during tumor evolution.
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ayuso
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Monge
authors.affiliation: Institute of Applied Mathematics in Science and Engineering, Castilla-La Mancha University, Ciudad-Real, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Martínez-González
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Virumbrales-Muñoz
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Llamazares
authors.affiliation: MEMS/MST Department, Ikerlan S. Coop., Mondragón, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Berganzo
authors.affiliation: Department of Pathology (Neuropathology), Hospital Universitario 12 de Octubre Research Institute, Madrid, Spain.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Hernández-Laín
authors.affiliation: Department of Design and Manufacturing Engineering, University of Zaragoza, Zaragoza, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Santolaria
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Doblaré
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hubert
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Neuro-oncology Unit, Health Institute Carlos III-UFIEC, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Gómez
authors.affiliation: Institute of Applied Mathematics in Science and Engineering, Castilla-La Mancha University, Ciudad-Real, Spain.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: Pérez-García
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Ochoa
authors.affiliation: Group of Applied Mechanics and Bioengineering. Centro Investigación Biomédica en Red. Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Aragón Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain.|Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Zaragoza, Spain.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Fernández
mesh_terms: D001932:Brain Neoplasms / Q000098:blood supply* / Q000503:physiopathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000098:blood supply* / Q000503:physiopathology*; D006801:Humans; D056656:Lab-On-A-Chip Devices; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation* / Q000379:methods*; D044085:Microfluidics; D008959:Models, Neurological
keywords: SU-8; glioblastoma; microfluidics; migration; pseudopalisades