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Engineering glioblastoma microenvironment in a chip to study cell response

J. M. Ayuso, 1,2,3, R. Monge, 1,2,3; G.A. Llamazares, 1,2,3, M. Virumbrales, 1,2,3; A. Vigueras, 1,2,3; P. Sánchez,1, 2, 3; M. Olave, 1, 2, 3; M. Doblaré, 1, 2, 3; L. J. Fernández, 1, 2, 3; I. Ochoa, 1, 2, 3.

1 Group of Structural Mechanics and Materials Modelling (GEMM). Centro Investigacion Biomedica en Red. Bioingenieria, biomateriales y nanomedicina (CIBER-BBN), Spain
2 Aragón Institute of Engineering Research (I3A), University of Zaragoza, Spain
3 Aragon Institute of Biomedical Research, Instituto de Salud Carlos III, Spain

Nowadays, cancer is seen as a multifactorial process, in which tumor cells coexist with the stromal cells and interact with the surrounding tissue. As a result, a very complex microenvironment, involving complex mechanisms such as hypoxia, acidosis or nutrient gradients, is frequently observed in many different tumors. The recreation of such microenvironment in-vitro would be extremely desirable, as it is involved in tumor progression, treatment outcome and patient prognosis. Recently, microfabrication and microfluidics have arisen as promising technologies for the development of high-performance cell culture systems. In this work, we will describe a polystyrene-based microfluidic system capable to recreate some of the most relevant characteristics of a complex tumor microenvironment, focusing on glioblastoma.

Glioblastoma (GBM) is the most common and lethal malignant primary brain tumor and is characterized by necrotic foci typically surrounded by areas of high cellularity known as pseudopalisades. GBM cells can cause thrombotic events, leading to a nutrient and oxygen starvation in the vicinities. Therefore, under these circumstances GBM cells migrate towards oxygen and nutrient enriched regions.

The developed microdevice is provided of different juxtaposed chambers. Different cell populations, normal astrocytes and GBM cells, can be confined in each chamber within 3D hydrogels. Controlling cell density we can induce the oxygen starvation in the GBM-containing chamber whereas the astrocyte-containing chamber remains under normoxic conditions. The presented system allows real-time motorization of the oxygen profile in the different chambers, studying how hypoxia is generated and spreads along the system. Effects of this hypoxia and nutrient starvation in cell viability can be observed as well, showing how necrotic regions or a migratory response appear in the system. Finally, effects of different drugs can be studied under this user-defined microenvironment, enabling the drug response under normoxia or hypoxia in the GBM cells as well as the astrocytes.

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