Aragon Institute of Biomedical Research

Madrid, Spain

Aragon Institute of Biomedical Research

Madrid, Spain
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Virumbrales-Munoz M.,CIBER ISCIII | Virumbrales-Munoz M.,Aragon Institute of Engineering Research | Virumbrales-Munoz M.,Aragon Institute of Biomedical Research | Sridhar A.,University of Twente | And 18 more authors.
20th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2016 | Year: 2016

We report an oxygen sensitive cell culture matrix that is achieved by covalently coupling a Ruthenium complex to the primary amine groups in collagen (pre-gelation). The resulting matrix is thoroughly characterized with respect to native collagen using different techniques such as SEM and AFM. After testing the biocompatibility of the newly synthesized collagen matrix, we perform proofof-concept experiments demonstrating the capability of the matrix to act as an oxygen sensor. This matrix is particularly interesting for 3D monitoring of variations in the oxygen concentration in the vicinity of cells within a microfluidic device.

Ayuso J.M.,CIBER ISCIII | Ayuso J.M.,Aragon Institute of Engineering Research | Ayuso J.M.,Aragon Institute of Biomedical Research | Monge R.,CIBER ISCIII | And 25 more authors.
Neuro-Oncology | Year: 2017

Background: 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. Methods: 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. Results: 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. Conclusions: This paper shows the potential of microfluidic devices as advanced artificial systems capable of modeling in vivo nutrient and oxygen gradients during tumor evolution. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Ayuso J.M.,CIBER ISCIII | Ayuso J.M.,Aragon Institute of Engineering Research | Ayuso J.M.,Aragon Institute of Biomedical Research | Basheer H.A.,University of Bradford | And 18 more authors.
PLoS ONE | Year: 2015

We report the first application of a microfluidic device to observe chemotactic migration in multicellular spheroids. A microfluidic device was designed comprising a central microchamber and two lateral channels through which reagents can be introduced. Multicellular spheroids were embedded in collagen and introduced to the microchamber. A gradient of fetal bovine serum (FBS) was established across the central chamber by addition of growth media containing serum into one of the lateral channels. We observe that spheroids of oral squamous carcinoma cells OSC-19 invade collectively in the direction of the gradient of FBS. This invasion is more directional and aggressive than that observed for individual cells in the same experimental setup. In contrast to spheroids of OSC-19, U87-MG multicellular spheroids migrate as individual cells. A study of the exposure of spheroids to the chemoattractant shows that the rate of diffusion into the spheroid is slow and thus, the chemoattractant wave engulfs the spheroid before diffusing through it. Copyright: © 2015 Zanin et al.

Esteve V.,CIBER ISCIII | Esteve V.,University of Valencia | Berganzo J.,IKERLAN - IK4 | Monge R.,CIBER ISCIII | And 11 more authors.
Biomicrofluidics | Year: 2014

A new microfluidic cell culture device compatible with real-time nuclear magnetic resonance (NMR) is presented here. The intended application is the long-term monitoring of 3D cell cultures by several techniques. The system has been designed to fit inside commercially available NMR equipment to obtain maximum readout resolution when working with small samples. Moreover, the microfluidic device integrates a fibre-optic-based sensor to monitor parameters such as oxygen, pH, or temperature during NMR monitoring, and it also allows the use of optical microscopy techniques such as confocal fluorescence microscopy. This manuscript reports the initial trials culturing neurospheres inside the microchamber of this device and the preliminary images and spatially localised spectra obtained by NMR. The images show the presence of a necrotic area in the interior of the neurospheres, as is frequently observed in histological preparations; this phenomenon appears whenever the distance between the cells and fresh nutrients impairs the diffusion of oxygen. Moreover, the spectra acquired in a volume of 8?nl inside the neurosphere show an accumulation of lactate and lipids, which are indicative of anoxic conditions. Additionally, a basis for general temperature control and monitoring and a graphical control software have been developed and are also described. The complete platform will allow biomedical assays of therapeutic agents to be performed in the early phases of therapeutic development. Thus, small quantities of drugs or advanced nanodevices may be studied long-term under simulated living conditions that mimic the flow and distribution of nutrients. © 2014 AIP Publishing LLC.

Fernandez V.,University of Cantabria | Mena A.,AlphaSIP S.L. | Ben Aoun C.,University Pierre and Marie Curie | Pecheux F.,University Pierre and Marie Curie | And 3 more authors.
Microprocessors and Microsystems | Year: 2015

The design of "Lab on a Chip" microfluidic devices is, typically, preceded by a long and costly period of prototyping stages in which the system is gradually refined by an iterative process, involving the manufacturing of a physical prototype and the making of a lot of laboratory experiments. In this scenario, a virtual prototyping framework which allows the emulation of the behavior of the complete system is greatly welcome. This paper presents such a framework and details a virtual prototyping methodology able to soundly handle microfluidic behavior based on SystemC-AMS extensions. The use of these extensions will permit the communication of the developed microfluidic models with external digital or mixed signal devices. This allows the emulation of the whole Lab on a Chip system as it usually includes a digital control and a mixed-signal reading environment. Moreover, as SystemC-AMS is also being extended to cover other physical domains within the CATRENE CA701 project, interactions with these domains will be possible, for example, with electromechanical or optical parts, should they be part of the system. The presented extensions that can manage the modeling of a micro-fluidic system are detailed. Two approaches have been selected: to model the fluid analytically based on the Poiseuille flow theory and to model the fluid numerically following the SPH (Smoothed Particle Hydrodynamics) approach. Both modeling techniques are, by now, encapsulated under the TDF (Timed Data Flow) MoC (Model of Computation) of SystemC-AMS. © 2015 Elsevier B.V.

Stojkovic S.,University of Belgrade | Podolski-Renic A.,University of Belgrade | Dinic J.,University of Belgrade | Pavkovic Z.,University of Belgrade | And 12 more authors.
Molecules | Year: 2016

Chemoresistance and invasion properties are severe limitations to efficient glioma therapy. Therefore, development of glioma in vivo models that more accurately resemble the situation observed in patients emerges. Previously, we established RC6 rat glioma cell line resistant to DNA damaging agents including antiglioma approved therapies such as 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ). Herein, we evaluated the invasiveness of RC6 cells in vitro and in a new orthotopic animal model. For comparison, we used C6 cells from which RC6 cells originated. Differences in cell growth properties were assessed by real-time cell analyzer. Cells' invasive potential in vitro was studied in fluorescently labeled gelatin and by formation of multicellular spheroids in hydrogel. For animal studies, fluorescently labeled cells were inoculated into adult male Wistar rat brains. Consecutive coronal and sagittal brain sections were analyzed 10 and 25 days post-inoculation, while rats' behavior was recorded during three days in the open field test starting from 25th day post-inoculation. We demonstrated that development of chemoresistance induced invasive phenotype of RC6 cells with significant behavioral impediments implying usefulness of orthotopic RC6 glioma allograft in preclinical studies for the examination of new approaches to counteract both chemoresistance and invasion of glioma cells. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Etxebarria J.,CIC MicroGUNE | Etxebarria J.,IKERLAN - IK4 | Berganzo J.,CIC MicroGUNE | Berganzo J.,IKERLAN - IK4 | And 7 more authors.
Sensors and Actuators, B: Chemical | Year: 2014

This paper presents an in-plane pneumatically actuated membrane-type microvalve, entirely made of Cyclic Olefin Polymer (COP). The body of the valve is fabricated following a robust hot-embossing method with SU-8 master moulds, producing devices with repetitive dimensions at wafer-level. Sealing is performed by applying a suitable solvent on the COP membrane, rendering monolithic devices, free from assembly errors. Various design parameters have been studied to obtain different working regimes, with maximum flow rates of 8.5 ml/min being successfully regulated and fully stopped. Owing to its fabrication method and characteristics, these devices represent a reliable and low-cost solution for the integration of microfluidic control in mass-produced lab-on-a-chip devices. © 2013 Elsevier B.V.

News Article | December 15, 2016

'...the device allows early assessment of the effects of drugs, speeding up the adoption of those that are shown to be therapeutically effective...' "...the device allows early assessment of the effects of drugs, speeding up the adoption of those that are shown to be therapeutically effective..." "...while there have been major improvements in knowledge of cancer cell biology, clinical approval of new drugs has not kept pace until now..." RESEARCHERS at the University of Huddersfield have helped develop a lab device that could speed up the adoption of new anti-cancer treatments. It is a small, versatile and simple-to-use microfluidic system that consists of a series of chambers, enabling scientists to monitor the response of hypoxic cells - deficient in oxygen and therefore resistant to therapy - when drugs are introduced. Professor Roger Phillips and Dr Simon Allison at the University of Huddersfield formed a collaboration with researchers in Spain - based at institutions that include the Aragon Institute of Biomedical Research - after meeting them during a project that involved a UK scientific instrument-making company. This led to research and development of the new microfluidic device, now described in an article, with Professor Phillips and Dr Allison among the co-authors. Titled Development and characterisation of a microfluidic model of the tumour microenvironment, it appears in Scientific Reports, from the publishers of leading journal Nature. Professor Phillips is a specialist in the evaluation of new anti-cancer drugs, with a specific interest in the micro environments surrounding tumours as a target for drug development. He explained that the advantage of the new device - made of glass or plastic - is that it enables researchers to visualise the micro environment and monitor how cells respond in real time to the drug being tested. Also, the test cells - after being grown in the lab - can be spheroid, as opposed to the flat "2D" cells normally relied on by researchers. The "3D" nature of cells inside the microfluidic device means that it is possible to visualise what is happening to them internally. "We can see the drugs moving in, and see hypoxia developing in the centre," said Professor Phillips, who added that the new system could also be used for a wide range of other applications. One of the conclusions of the article in Scientific Reports is that while there have been major improvements in knowledge of cancer cell biology, clinical approval of new drugs has not kept pace. One strategy in response is to "develop new in vitro preclinical models that are better predictors of success in advanced preclinical and clinical testing". Now the microfluidic device will help address the urgent need for a new in vitro model able to mimic key aspects of the tumour microenvironment and therefore allow early assessment of the effects of drugs, speeding up the adoption of those that are shown to be therapeutically effective.

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