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News U8

Graphene sensors read low-frequency neural waves associated with distinct brain states

Xavier Illa, Anton Guimrea y Eduard Masvidal, researchers of the CIBER-BBN group GAB Lab at IMB-CNM led by Rosa Villa, are coauthors of a study recently published in “Nature Communication”, in which it is demonstrated that graphene-based active sensor arrays are a mature technology for large-scale application in wide frequency band neural sensing interfaces. NANBIOSIS U8 Micro– Nano Technology Unit has been used in the development of the research.

This research has been carruied out within the framework of the European Project “Graphene Flagship. The scientists have developed a sensor based on CVD graphene that detects brain signals in a wide frequency band, from extremely low frequencies to high frequency oscillations. The sensor is biocompatible and could be used to measure and predict brain states. Furthermore, the graphene sensors could be used in chronic implants due to their high stability in the brain.

Further information: News by the Graphene Flagship website.

Article of reference:

Garcia-Cortadella R, Schwesig G, Jeschke C, Illa X, Gray AL, Savage S, Stamatidou E, Schiessl I, Masvidal-Codina E, Kostarelos K, Guimerà-Brunet A, Sirota A, Garrido JA. Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity.  Nat Commun 12, 211 (2021). https://doi.org/10.1038/s41467-020-20546-w

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NANBIOSIS Scientific Women in the International Day of Women and Girls in Science

Today February 11 is the International Day of Women and Girls in Science, a day to raise awareness of the gender gap in science and technology.

According to the United Nations, while yet women and girls continue to be excluded from participating fully in science, science and gender equality are vital to achieve the internationally agreed development goals, including the 2030 Agenda for Sustainable Development. Thus, in recent years, the international community has made a great effort to inspire and promote the participation of women and girls in science.

NANBIOSIS wants to acknowledge  the efforts made by scientific women who struggle every day to contribute their bit to Science and highlight their essential role in nowadays research. Especially we want to recognize the work of scientists women involved in NANBIOSIS, whatever is the nature of their contribution: technical, scientific development, management, coordination, direction, etc; just to mention some examples:
Neus Ferrer and Mercedes Márquez in the Scientific Direction and Coordination of Unit 1 Protein Production Platform (PPP)
Pilar Marco and Nuria Pascual in the Management and Scientific Coordination of U2 Custom Antibody Service (CAbS) 
Miriam Royo in the Scientific Direction of U3 Synthesis of Peptides Unit
Nora Ventosa and Nathaly Segovia in the Scientific Direction and Technical Coordination of U6 Biomaterial Processing and Nanostructuring Unit
Isabel Oliveira and Teresa Galán in the Coordination of U7 Nanotecnology Unit
Rosa Villa and Gemma Gabriel in the Management and Scientific Coordination of U8 Micro – Nano Technology Unit
Gema Martínez in the Scientific Coordination of U9 Synthesis of Nanoparticles Unit
Fany Peña in the Scientific Coordination of U13 Tissue & Scaffold Characterization Unit
Mª Luisa González Martín and Margarita Hierro in the of Direction and Scientific Coordination of U16 Tissue & Scaffold Characterization Unit
Gemma Pascual and Isabel Trabado in the Coordination of the U17 Confocal Microscopy Service
Isolda Casanova in the Scientific Coordination of U18 Nanotoxicology Unit
Beatriz Moreno in the Scientific Direction of Unit 19 Clinical tests lab
Ibane Abásolo in the Scientific Coordination of Unit 20 In Vivo Experimental Platformt
Verónica Crisóstomo in the Scientific Direction of Unit 24 Medical Imaging 
Ana Paula Candiota in the Scientific Coordination of Unit 25 Biomedical Applications I 
Maria Luisa García in the Scientific Direction of U28 NanoImaging Unit from Bionand, recently incorporated to NANBIOSIS, Anna Aviñó in the Scientific Coordination of U29 Oligonucleotide Synthesis Platform (OSP) – and

Nerea Argarate in the coordination of NANBIOSIS

Thanks to all of you and your teams!

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Hybridization of men and machines, with Rosa Villa

Prof. Rosa Villa, Scientific Director of NANBIOSIS U8 Micro– Nano Technology Unit, and group leader of the research group of biomedical applications of ICNMCSIC and CIBER-BBN, has participated in the program of National Radio of Spain “The Open Future: Biobots” led by Tato Puerto.

Following the recent presentation by a team of American scientists of the design of “reprogrammable organisms”, halfway between a robot and a living being, that is, an extraordinary living machine made from frog cells, the program of National Radio of Spain called “Open Future” has dedicated a session to explain what are “Biobots” and to generate debate and reflexion with experts like Prof, Rosa Villa.

Asked about the current outlook and futute of the “Hybridization of men and machines“, Rosa Villa has explained that in the area of ​​micro and nanotechnology, (where her group works), the hybridization takes place to make neural interfaces, to interrelate with the human brain registering many more signals from the brain and being able to offer patients greater mobility for artificial prosthetics or even other human enhancement activities. The main problem for this at a technological level is that a series of biological and material processes have to be carried out while these processes need to be easilly integrated by the human body. The functioning of the brain is still very unknown, the brain is a very closed box, very well protected and inaccessible but the amount of signals that are registered is spectacular. The latest technologies and materials, such as graphene, make it possible to build sensors with smaller electrodes that allow many signal points to be recorded in the brain at the same time, with a signal quality that was not possible to reach until now which allows scientists to know a series of high and low frequency signals that give very useful information from the brain, not only to know how it works, but also to predict diseases such as epilepsy or Alzheimer’s.

The program can be listen here, in Spanish

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Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity

Researchers of Nanbiosis U8 Micro– Nano Technology Unit, from CIBER-BBN and IMB-CNM-CSCIC have published an article in Nature Communications on Graphene arrays for long-term and wireless mapping of epicortical brain activity. A collaborative work in the framework of the Brain Com and Graphene EU projects. The article mentions the participation of NANBIOSIS-ICTS.

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.

Article:

Garcia-Cortadella, R., Schwesig, G., Jeschke, C. et al. Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity. Nat Commun 12, 211 (2021). https://www.nature.com/articles/s41467-020-20546-w

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Inkjet Priting Technology, Manufacture and validation of electrochemical sensors in medical applications

Miguel Zea, a member of the NANBIOSIS U8 Micro– Nano Technology Unit presents a video explaining his research is based on the manufacture and validation of electrochemical sensors in medical applications: –“Using InkJet printing I have made sensors in different plastics and paper. Also using a novel approach in each sensor. I have made two pH sensors using novel Platinum and polymer inks and also a cortisol sensor on paper”.

With this video, Miguel Zea, participates in the second edition of ‘I investigate, I am CSIC’. It is a competition hold by The Spanish National Research Council (CSIC) for its doctoral students to disseminate their doctoral thesis. Through short videos of maximum duration of 3 minutes, predoctoral scientists explain their research and results for the public in general

Here you can see the video and vote with a like!

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Printed sensors, a low cost alternative for clinical detection

In today’s society there is a great interest in developing new technologies that allow low-cost mass manufacturing, also called “rapid prototyping” or “additive manufacturing”. Rapid prototyping includes technologies such as sterolithography, 3D printing, laser sintering or printed electronics, among others. All of these share digital design and manufacturing from the consecutive addition of layers, that is, techniques that allow creating almost any shape or geometric feature in a very fast time.
Printed electronics consists of printing inks on different types of substrates such as textiles, plastics, papers or films to make them “smart”. This technique is presented as an alternative to traditional silicon that is being implemented in sectors as varied as health and wellness, automotive and transport, professional sports, safety and protection, packaging, architecture and construction, and technical textiles. Printed electronics is one of the new technologies that will have a long history throughout the functional electronic device manufacturing space, with a wide range of applications, electronic designs, processes and materials, compared to conventional electronic and microelectronics based manufacturing technology in silicon. It is expected that in the next decade it will be part of everyday life, with products such as electronic skin, electronic tissues and organs or architectural elements that respond to external stimuli.
Among the many areas of interest of these technologies, one of them is the development of low-cost sensors for the medical or environmental area. For example, in these disciplines, it is essential to get devices that can be very economical or even single-use to promote sustainable environmental control and personalized medicine. Specifically with inkjet technology, researchers from NANBIOSIS Unit 8 Micro-Nano Technology Unit belonging to the Institute of Microelectronics of Barcelona (IMB-CNM, CSIC /and CIBER-BBN), have developed over the last few years multiple materials, inks, substrates and sensors for the development of electrochemical sensors in micrometric dimensions.

  • Inks: Most commercial inks are composed of a solvent that contains some material with insulating, conductive or semiconductor properties. As a general rule, an ink must be stable, with a particle size of several orders of magnitude smaller than the injector orifice, have a viscosity of less than 20 mPa s and a surface tension of less than 80 mN m-1. Although these values ​​may depend on the system in question. The final devices are obtained by selectively depositing in previously drawn areas, layer by layer, thin or thick structures on the substrates. They have worked with multiple commercial metallic inks such as gold, silver and platinum.
    Normally in an electrochemical system a noble material that is electrochemically stable is needed to be used in the working electrode and in the counter electrode, and for this gold or platinum are a good alternative. To make measurements with any electrochemical sensor, a reference electrode is essential since it is one that has a stable and constant potential over time and that allows us to reference our voltage value. We use the impression of an Ag / AgCl bilayer since it is one of the interfaces most used as a reference electrode. One of the main problems faced by miniaturization, however, is the rapid loss of the small volume of internal reference solution that these electrodes must have, which has a direct impact on their useful life and stability. For this, a polymeric membrane that can be printed was formulated, which allows the reference to have high performance compared to other commercial miniaturized reference electrodes (Ref1).
  • Substrates: a wide range of rigid, flexible, porous, plastic, fabric, etc. substrates can be used. However, the interaction of the ink with the substrate is crucial in determining the good quality of the printed pattern. For this reason, the properties of the inks are adapted for the different substrates with their own properties. For this reason, it is common practice to pretreat the substrate surface to improve hydrophobicity and adhesion issues mainly. It is common to use plastic substrates with a thickness of the order of microns that provide them with great flexibility and that are already specially treated to obtain excellent printing qualities. The deposition of uniform gold and silver conductive inks on porous substrates can be achieved by using a primer layer to seal the porosity of the membrane in specific and defined areas, with the aim of building a sensor device over the sealed area and leaving the rest of the intact substrate (Ref.2). With a paper substrate, alternatively we can print a silane ink, as a strategy that allows a monolayer of hydrophobic material to grow on the substrate and thus be able to obtain uniform lines of ink on its surface. (Ref.3)
  • Sensors developed: Dissolved oxygen (DO) (Ref.4) and pH (Ref.5) sensors have been developed using gold and platinum inks respectively, commercially available on plastic substrates. The inks have a specially designed formulation that allows their sintering at temperatures as low as 150 and 180 ° C for Au and Pt respectively. This is a key point in the development of low-cost sensors made on polymeric substrates or paper that cannot withstand high temperatures. These sensors integrate in a single platform all the basic elements for the registration of pH and DO, allowing measurements without any external electrode. DO is measured directly with a gold working electrode and pH sensors are achieved after electroplating an iridium oxide film on the platinum working electrode. In addition, this water-based platinum ink has another unique feature, it provides the electrode surface with high roughness, which promotes adhesion of the deposited sensor material, in this case iridium oxide. Long-term stability tests for more than 1 year demonstrate excellent stability of the mechanical sensor layer, and that it correlates perfectly with the different roughness of the printed platinum layer. Along the same lines and in relation to the development of inks, it has been possible to obtain a fully printed pH sensor based on a conductive polymer specially formulated to be printed by IJP . The measurements obtained with this ink have a good response in a wide pH range (pH 3 to 10) and the response in the physiological zone (pH 7-7.5) is well resolved, one of the main drawbacks of conductive polymers. We also present an IJP-printed electrochemical sensor for enzyme-free glucose analysis on flexible PEN substrate (Ref.6). In this case, CuO microparticles were used to modify the electrodes, and the detection of glucose was validated in concentrations that coincide with those of the tear fluid, which allows us to foresee applications in ocular diagnosis, where a painless control can be achieved and not invasive of diabetes by analyzing the glucose contained in tears.

(Ref.1): Moya A, Pol R, Martínez-Cuadrado A, Villa R, Gabriel G, Baeza M. Stable Full Inkjet-Printed Solid-State Ag/AgCl Reference Electrode. Analytical Chemistry 91 (2019) 15539-15546

(Ref.2): M. Ortega-Ribera; X. Guimerà; E. Sowade; M. Zea; X. Illa; E. Ramon; R. Villa; J. Gracia-Sancho; G. Gabriel. Online oxygen monitoring using integrated inkjet-printed sensors in a liver-on-a-chip system. Lab on a Chip. 18 – 14, pp. 2023 – 2035. 2018

(Ref.3): All Inkjet Printing Sensor Device on Paper: for Immunosensors Applications M Zea, A Moya, I Abrao-Nemeir, J Gallardo-Gonzalez, N Zine, A Errachid, … 2019 20th International Conference on Solid-State Sensors, Actuators and 

(Ref.4): Moya A, Sowade E, del Campo FJ, Mitra KY, Ramon E, Villa R, Baumann RR, Gabriel G. All-inkjet-printed dissolved oxygen sensors on flexible plastic Organic Electronics 39 (2016) 168-176

(Ref.5): Zea M, Moya A, Fritsch M, Ramon E, Villa R, Gabriel G Enhanced performance stability of iridium oxide based pH sensors fabricated on rough inkjet-printed platinum ACS Applied Materials & Interfaces 11 (2019) 15160-15169

(Ref.6): Romeo A, Moya A, Leung TS, Gabriel G, Villa R, Sánchez S. Inkjet printed flexible non-enzymatic glucose sensor for tear fluid analysis Applied Materials Today 10 (2018) 133-141

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Electrochemical sensors for cortisol detections: Almost there

Researchers of NANBIOSIS Unit 8 Micro– Nano Technology Unit at the Microelectronic Institute of Barcelona, (of IMB-CNM, CSIC / CIBER-BBN) has recently published a review in the TrAC Trends in Analytical Chemistry entitled “Electrochemical sensors for cortisol detections: Almost there” highlighting:

  • Overview of electrochemical techniques for cortisol detection published in the last five years.
  • Recent advances in cortisol detection by electrochemical immunoassays.
  • Potential of biosensing techniques for cortisol detection in biological matrices.
  • Importance of cortisol quantification for clinical applications.

Abstract

Mostly known as “the stress hormone”, cortisol has many essential functions in humans due to its involvement in regulation of blood pressure, immune system, metabolism of protein, carbohydrate, adipose, and anti-inflammatory action. Since a right cortisol balance is essential for human health, many efforts are currently being made to monitor the cortisol level in the human body. Cortisol levels are usually monitored in blood, plasma, serum, oral fluid, sweat, and hair samples through immunochemical and analytical methods, but in the last decade, electrochemical measurements are proving to be reliable techniques for cortisol quantification in biological matrices with the advantages of a fast response by portable and wearable devices. This review gathers the most recent developments and works on electrochemical sensors for cortisol detection, highlighting their high technology maturity and potential for clinical applications.

Article of reference:

Miguel Zea,Francesca G. Bellagambi,Hamdi Ben Halima,Nadia Zine,Nicole Jaffrezic-Renault,Rosa Villa,Gemma Gabriel,Abdelhamid Errachid; Electrochemical sensors for cortisol detections: Almost there, TrAC Trends in Analytical Chemistry, Volume 132, November 2020, 116058. https://doi.org/10.1016/j.trac.2020.116058

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Innovation Radar “Great EU-funded Innovations”

The Innovation Radar Platform is a European Commission initiative to identify high potential innovations and innovators in EU-funded research and innovation framework programmes based on their market readiness.

Researchers of NANBIOSIS U8 Micro– Nano Technology Unit, led by Rosa Villa, contribute to the @InnoRadarEU with two innovations related to their research on graphene-based neuroprobes:

Flexible neural probes for monitoring infraslow brain activity

This innovation was developed under the Horizon 2020 project GrapheneCore2 by CONSORCIO CENTRO DE INVESTIGACION BIOMEDICA EN RED (CIBER), FUNDACIO INSTITUT CATALA DE NANOCIENCIA I NANOTECNOLOGIA (ICN2) and AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS (CSIC)

Multiplexed Neurosensor Arrays based on GrapheneFETs and MOS2

This innovation was developed under the Horizon 2020 project BrainCom to generate a High-density cortical implants for cognitive neuroscience and rehabilitation of speech using brain-computer interfaces.

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Unlocking the brain with novel graphene technology

Researchers of NANBIOSIS U8 Micro– Nano Technology Unit of CIBER-BBN at the Barcelona Institute of Microelectronics have participated in the recent developments of a new graphene-based detection platform that could be the gateway to unlock superior understanding of the brain by providing a measure of high brain activity resolution and in real time. This research has been developed within the framework of the EU BrainCom project.

The European Union’s Horizon 2020 research project, BrainCom, is coordinated by the ICN2 Advanced Electronic Materials and Devices Group led by Professor José A. Garrido and the CIBER BBN GBIO Group and the Nanbiosis U8 platform participate. (Anton Guimera, Xavier Illa, Ana Moya, Elisabet Prats and Rosa Villa)

Arguably, a better understanding of the working principles of the human brain remains one of the major scientific challenges of our time. Despite significant advances made in the field of neurotechnology in recent years, neural sensing interfaces still fall short of equally meeting requirements on biocompatibility, sensitivity, and high spatio-temporal resolution. The European Union Horizon 2020 research project BrainCom, coordinated by the ICN2 Advanced Electronic Materials and Devices Group led by ICREA Prof. José A. Garrido, is tackling these problems. BrainCom brings together experts from the fields of neurotechnology, neuroscience, and ethics to develop novel technologies capable of overcoming these limitations and shed light onto the mechanisms of information encoding and processing in the brain.

In four research articles published between March and April 2020 — featured in Elsevier’s Carbon, IOP’s 2D Materials, Wiley’s Small, and American Chemical Society’s Nano Letters — researchers from the BrainCom consortium present the technological advances achieved in the project, discuss in-depth methodology, and demonstrate novel capabilities for high resolution sensing of the brain’s electrical activity. The recent developments exploit the unique properties of graphene, an atom-thick layer of carbon, which conforms with the soft and convoluted surface of the brain providing an excellent neural sensing interface. Graphene sensors have an additional advantage that represents a turning point in neural engineering: the sensing mechanism of these graphene active sensors (so-called transistors) is compatible with  electronic multiplexing, a technology that enables transmitting the signals detected by multiple sensors through a single micrometric wire. This implies that the number of sensors on the neural implants can be increased while minimizing the footprint of the connectors required to link the implants to external electronic equipment.

This technology, developed in close collaboration with Dr Anton Guimerà at the CSIC Institute of Microelectronics of Barcelona (IMB-CNM, CSIC), has been evaluated in pre-clinical studies at the laboratory of neuroscientist Prof. Anton Sirota at Ludwig-Maximilians Universität (LMU, Munich). A collaborative and multidisciplinary approach is crucial for the success of the project, which aims at addressing a very hard scientific and technological challenge. The human brain has an astonishing complexity, consisting out of as many as 100 billion neurons. To fully understand the underlying principles of such a convoluted system requires the simultaneous detection of the electrical activity of large neural populations with a high spatial and temporal resolution. Unfortunately, current neural sensing technologies present a trade-off between spatial resolution and large-area coverage of the brain surface. The work carried out by the BrainCom project’s researchers shows how graphene-based sensors represent an outstanding building block for such large scale and highly sensitive neural interfaces. As explained in the recently published papers, graphene sensors can be reduced in size to the dimension of about one single neuron, while maintaining a high signal quality. In addition, their sensitivity expands over a wide range of frequencies; from infra-slow oscillations to very fast signals elicited by individual cells.

These findings clear the path for a scale-up of graphene sensor technology towards arrays with an ultra-high-count of sensors. Such biocompatible and high bandwidth neural interfaces can have a great impact on the development of neuroprosthesis, which enable a direct communication between the brain and a computer. These results represent the fruition of long-term EU research initiatives, which pursue the ambitious goal of restoring speech to impaired patients by reading the signals in their brains, which are related to their intentional speech. The research consortium will now focus on upscaling the production of these neural interfaces and testing their performance in safe human clinical trials. This and other applications of graphene sensors are also supported by the EU Graphene Flagship within the Biomedical Technologies work package.

Reference Articles:

Garcia-Cortadella R, Schaefer N, Cisneros-Fernández J, Re L, Illa X, Moya-Lara A ,Santiago S, Guirado G, Villa R, Sirota A, Serra-Graells F, Garrido JA, Guimerà-Brunet A Switchless Multiplexing of Graphene Active Sensor Arrays for Brain Mapping Nano Letters (2020) DOI: 10.1021/acs.nanolett.0c00467

Garcia-Cortadella R, Masvidal-Codina E, de la Cruz J, Schaefer N, Schwesig G, Jeschke C, Martínez-Aguilar J, Sánchez-Vives MV, Villa R, Illa X, Sirota A, Guimerà-Brunet A, Garrido JA Distortion‐Free Sensing of Neural Activity Using Graphene Transistors Small (2020) 1906640, March 2020. DOI: 10.1002/smll.201906640

Schaefer N, Garcia-Cortadella R, Martínez-Aguilar J, Schwesig G, Illa X, Moya Lara A, Santiago S, Hébert C, Guirado G, Villa R, Sirota A, Guimerà-Brunet A, Garrido JA Multiplexed Neural Sensor Array of Graphene Solution-Gated Field-Effect Transistors 2D Materials 7(2), 2020. DOI: 10.1088/2053-1583/ab7976

Schaefer N, Garcia-Cortadella R, Bonaccini Calia A, Mavredakis N, Illa X, Masvidal-Codina E, de la Cruz J, del Corro E, Rodríguez L, Prats-Alfonso E, Bousquet J, Martínez-Aguilar J, Pérez-Marín AP, Hébert C, Villa R, Jiménez D, Guimerà-Brunet A, Garrido JA Improved metal-graphene contacts for low-noise, high-density microtransistor arrays for neural sensing Carbon 161, 647-655, 2020. DOI: 10.1016/j.carbon.2020.01.066

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Rosa Villa, Scientific Director of NANBIOSIS U8, New CIBER-BBN group leader

Rosa Villa Sanz, the Scientific Director of NANBIOSIS U8 Micro– Nano Technology Unit was appointed group leader the CIBER during the last meeting of the Permanent Commission of CIBER-BBN, replacing Prof. Jordi Aguiló.

Rosa Villa Sanz, graduated in Medicine from the University of Barcelona and has a doctorate from the Autonomous University of Barcelona in 1993 and a specialist in Nuclear Medicine (MIR-Hospital de Bellvitge-Barcelona), is a scientific researcher at the CSIC and leader of the Biomedical Applications Group of the Barcelona Institute of Microelectronics (CSIC), whose main research interests are the design and manufacture of Micro and Nano Systems for Biomedical Applications.

Prof. Villa has participated in more than 30 national and European projects, being a principal researcher in 10 of them, she has obtained the approvals by the Spanish Agency of Medicines and Medical Devices (AEMPS) for the conduct of 4 clinical trials in collaboration with pharmaceutical companies and clinical groups and is the founder of a spin-off (Barcelona Liver Bioservice SL). Rosa Villa also directs a consolidated research group recognized by the Agència de Gestió d’Ajuts Universitaris i de Recerca since 2014 (Bio-Micro-Nano-Systems group [2019 SGR 988]) and since 2016 co-directs the BioMEM TECNIO group of the Generalitat de Catalunya. Rosa Villa is Scientific of NANBIOSIS Unit 8 since the creation of NANBIOSIS.

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