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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.

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.

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.

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.

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.

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