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Collaboration in the CSIC White Paper “New Challenges in Biomedicine and Health”

The Spanish National Research Council (CSIC) is publishing the White Papers of the 14 strategic themes established on the basis of their scientific impact and social importance. The pen access to the White Paper of the fourth Challenge, New Challenges in Biomedicine and Health, is now avaailable. The book is the result of the “CSIC Scientific Challenges: Towards 2030”, in which the institution tackles the main issues and priorities for the future. This book is coordinated by Mario Delgado (Instituto de Parasitología y Biomedicina “López – Neyra”, Granada) and María Moros (Instituto de Nanociencia y Materiales de Aragón, Zaragoza).

Drs. Rosa Villa (Biomedical Applications Group, GAB and NANBIOSIS U8 Micro– Nano Technology Unit from CIBER-BBN and IMB-CNM-CSIC) collaborate in the eighth topic of the book: “New methods for diagnostic tools and prevention” and  is also a part of the seventh topic, “Advanced therapies“.

“New methods for diagnostic tools and prevention” is a highly interdisciplinary area, with a wide range in areas of research, methodologies and applications. It consists on contributions according to imaging modality for diagnostics, detection/screening methods, and prevention and personalised treatments.

The chapter mentions GAB efforts to develop biocompatible and biodegradable implants for neurological applica-tions, and wearable devices (implants and external) for the real time and continuous monitoring, and early diagnosis for in vivo applications. .

As for Organ-on-chips, it contains GAB‘s research in 3D microfluidics and sensors integration to simulate organ and tissuspecific micro-environments. These systems are applied for toxicological stud-ies and personalized medicine and represent a clear alternative to minimize animal experimentation.

In “Advanced therapies” the research in instrumentation for proton tomography and proton-range verification using prompt gamma rays is highly studied.

Biomedicine and Health

A lesson learnt from the pandemia caused by coronavirus is that solutions in health require coordinated actions. Beside this and other (re)emerging infectious diseases, Spain and Europe are suffering a plethora of disorders that are currently acquiring epidemic dimensions, including cancer, rare diseases, pain and food allergies, among others. New tools for prevention, diagnosis and treatment need to be urgently designed and implemented using new holistic and multidisciplinary approaches involving researchers, clinicians, industry and all stakeholders in the health system.

CSIC White Papers

What are the major scientific challenges of the first half of the 21st century? Can we establish the priorities for the future? How should the scientific community tackle them? This book presents the reflections of the Spanish National Research Council (CSIC) on 14 strategic themes established on the basis of their scientific impact and social importance.

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First Dresselhaus Prize of the SCN2 to María Jesús Ortiz

María Jesús Ortiz i Aguayo, graduate in Chemistry from the Autonomous University of Barcelona (UAB), has been the winner of the First Dresselhaus Prize, organized by the Catalan Society of Nanoscience and Nanotechnology (SCN2), of the 2020 edition.

The award recognizes the work “Development of a pH microsensor for the determination of hydrogen sulfide based on Inkjet Printing“, supervised by Maria del Mar Baeza Labat (UAB) and Gemma Gabriel Buguña, from the Biomedical Applications Group GAB and NANBIOSIS U8 Micro– Nano Technology Unit from CIBER-BBN and IMB-CNM-CSIC
The student also did her TFG with Dra. Gemma Gabriel at the IMB-CNM.

The second edition of the SCN² Dresselhaus Awards, convened in September 2020 and held during the third wave of COVID-19 in Catalonia, closed on April 19, 2021 with the publication of the three winners this year. Only up to three paid awards and up to three mentions are awarded for high quality work according to the Jury evaluation, this year there have been no special mentions. The awards recognize the excellence of nanoscience work.

Further information here

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New organ-on-chip models provide new information for targeted treatments in personalised medicine

Xavi Illa, Gemma Gabriel, Mar Alvarez and Rosa Villa, researchers of NANBIOSIS ICTS U8 Micro– Nano Technology Unit (from CIBER-BBN and the IMB-CNM-CSIC). are co-authors of two reviews that summarise the latest efforts in organ-on-chip technologies to emulate in vitro microfluidic systems. These devices are an opportunity to evolve the fields of biofabrication and sensing technology.

Organ-on-chip (OOC) technology has been an efficient tool in modern research to substitute laboratory mice and simulate tissue and organ-level physiology and function. In particular, these in vitro devices have been extensively applied to model the intestine, enhancing the research community’s knowledge about intestinal physiology and pathophysiology in order to develop targeted therapies for a more precise and personalised treatment of intestinal diseases.

Now, a review published in Biosensors & Bioelectronics signed by researchers of NANBIOSIS ICTS U8 Micro– Nano Technology Unit, collects information about the intestine models and highlights the necessity to integrate sensors into these in vitro models to shine light on the pathological mechanisms of intestinal disorders at their early stage. The detection of a disease at its early state would allow more efficient treatments and a better prognosis, reducing costs and enhancing the quality of life of the patients.

Last years’ research has had a significant impact in these complex microfluidic systems, though there is still a long way to go to increase biosensors capacity in their operations.

“The potential of the OOC technology is enormous. OOC technology may provide a true precision medicine, allowing the use of the patients’ own cells for performing drugs screening before treating the patient“, -explains Mar Álvarez– “To that end, we believe that the integration of sensors into this platforms is mandatory to understand and evaluate the functioning of the organ in real time, providing information that may be used for in-situ decision making”.

Hydrogel microfluidic platforms to improve the predictive capacities of the in vitro models

Another review article published by theese researchers in Applied Materials & Interfaces tackles the progress made in tissue barrier models, as they have a crucial role in regulating organ homeostasis. Current microfluidic systems do not properly mimic cells’ interaction, so recent developments have included biomaterials, such as hydrogels, to emulate these boundaries between tissues and external environment. A hydrogel acts as a microenvironment of the cell and it permits cell culture.

“The hydrogel mimics the real cell microenvironment, providing the mechanical cues needed to reproduce the proper organ physiology and function“, Mar Álvarez adds.

Recent developments in the fields of biofabrication show that hydrogels are able to mimic and change the tissue properties and dynamics, thus enabling an in vivo recreation for its reparation.

Articles of reference

Marrero D, Pujol-Vila F, Vera D, Gabriel G, Illa X,  Elizalde-Torrent A, Alvarez M, Villa R, Gut-on-a-chip: Mimicking and monitoring the human intestine. Biosensors and Bioelectronics. Volume 181, 1 June 2021, 113156. DOI https://doi.org/10.1021/acsami.0c21573

Vera D, García-Díaz M, Torras N, Alvarez M, Villa R, Martínez E. Engineering Tissue Barrier Models on Hydrogel Microfluidic Platforms, CS Appl. Mater. Interfaces 2021, 13, 12, 13920–13933 DOI https://doi.org/10.1016/j.bios.2021.113156

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Modulation of intercolumnar synchronization by endogenous electric fields in cerebral cortex with neuroprobes by NANBIOSIS unit 8

The collaboration of NANBIOSIS U8 Micro–Nano Technology Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN) at the IMB-CNM in the research carried out by scientist of Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS) and ICREA has bien acknowledged in the publication of the results by Science Advances. Rosa Villa and Xavi Illa have been in charge of the fabrication of the probes used, more specifically, neuroprobes were designed and manufactured with 16 Ti / Au microelectrodes (20 / 200nm) on flexible polyimide substrates with open areas to improve neuronal tissue viability according to specifications.

Abstract

Neurons synaptically interacting in a conductive medium generate extracellular endogenous electric fields (EFs) that reciprocally affect membrane potential. Exogenous EFs modulate neuronal activity, and their clinical applications are being profusely explored. However, whether endogenous EFs contribute to network synchronization remains unclear. We analyzed spontaneously generated slow-wave activity in the cerebral cortex network in vitro, which allowed us to distinguish synaptic from nonsynaptic mechanisms of activity propagation and synchronization. Slow oscillations generated EFs that propagated independently of synaptic transmission. We demonstrate that cortical oscillations modulate spontaneous rhythmic activity of neighboring synaptically disconnected cortical columns if layers are aligned. We provide experimental evidence that these EF-mediated effects are compatible with electric dipoles. With a model of interacting dipoles, we reproduce the experimental measurements and predict that endogenous EF–mediated synchronizing effects should be relevant in the brain. Thus, experiments and models suggest that electric-dipole interactions contribute to synchronization of neighboring cortical columns.

Article of refrence:

Modulation of intercolumnar synchronization by endogenous electric fields in cerebral cortex. Beatriz Rebollo, Bartosz Telenczuk,  Alvaro Navarro-Guzman,  Alain Destexhe and Maria V. Sanchez-Vives Science Advances  03 Mar 2021: Vol. 7, no. 10, eabc7772 DOI: 10.1126/sciadv.abc7772

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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 ICNM–CSIC 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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