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Electroretinography (ERG) is a clinical test employed to understand and diagnose many retinopathies. ERG is usually performed by placing a macroscopic ring gold wire electrode on the cornea while flashing light onto the eye to measure changes in the transretinal potential. However, macroscopic gold electrodes are severely limiting since they do not provide a flexible interface to contact the sensitive corneal tissue, making this technique highly uncomfortable for the patient. Another major drawback is the opacity of gold electrodes, which only allows them to record the ERG signal on the corneal periphery, preventing central ERG recordings. To overcome the limitations of metal-based macroscopic ERG electrodes, flexible electrodes are fabricated using graphene as a transparent, flexible, and sensitive material. The transparency of the graphene is exploited to fabricate microelectrode arrays (MEAs) that are able to perform multisite recording on the cornea. The graphene-based ERG electrodes are benchmarked against the widely used gold electrodes in a P23H rat model with photoreceptor degeneration. This study shows that the graphene-based ERG electrodes can faithfully record ERGs under a wide range of conditions (light intensity, stage of photoreceptor degeneration, etc.) while offering additional benefits for ERG recordings such as transparency and flexibility., J.d.l.C. and D.N. contributed equally to this work. This project received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement nos. 881603 (GrapheneCore3). This work was within the project FIS2017-85787-R funded by the “Ministerio de Ciencia, Innovación y Universidades” of Spain, the “Agencia Estatal de Investigación (AEI),” and the “Fondo Europeo de Desarrollo Regional (FEDER/UE).” Support was also provided by the French state funds managed by the Agence Nationale de la Recherche within the Programme Investissements d'Avenir, LABEX LIFESENSES (ANR-10-LABX-65) and IHU FOReSIGHT (ANR-18-IAHU-0001). The ICN2 is supported by the Severo Ochoa Centres of Excellence program, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706), and by the CERCAProgram/Generalitat de Catalunya. E.d.C. acknowledges the Spanish MINECO Juan de la Cierva Fellowship JC-2015-25201. This work made use of the Spanish ICTS Network MICRONANOFABS partially supported by MICINN and the ICTS “NANBIOSIS,” more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the IMB-CNM. J.d.l.C. would like to thank Laura García for the work on the images and figures throughout the whole paper writing process. E.d.C acknowledges the grant RYC2019-027879-I financed by MCIN/AEI /10.13039/501100011033. The project leading to these results have received funding from “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR19/52160003. These activities are co-funded with 50% by the European Regional Development Fund under the framework of the ERFD Operative Programme for Catalunya 2014–2020 with the support of the Department de Recerca i Universitat (GraphCAT 001-P-001702).

Correction for ‘Organ-on-a-chip with integrated semitransparent organic electrodes for barrier function monitoring’ by Denise Marrero et al., Lab Chip, 2023, https://doi.org/10.1039/d2lc01097f.

This paper presents a 1024-channel neural read-out integrated circuit (ROIC) for solution-gated GFET sensing probes in massive muECoG brain mapping. The proposed time-domain multiplexing of GFET-only arrays enables low-cost and scalable hybrid headstages. Low-power CMOS circuits are presented for the GFET analog frontend, including a CDS mechanism to improve preamplifier noise figures and 10-bit 10-kS/s A/D conversion. The 1024-channel ROIC has been fabricated in a standard 1.8-V 0.18-mum CMOS technology with 0.012 mm 2 and 36 mu W per channel. An automated methodology for the in-situ calibration of each GFET sensor is also proposed. Experimental ROIC tests are reported using a custom FPGA-based muECoG headstage with 16times 32 and 32times 32 GFET probes in saline solution and agar substrate. Compared to state-of-art neural ROICs, this work achieves the largest scalability in hybrid platforms and it allows the recording of infra-slow neural signals.

Over the last few years, the intestine has been extensively studied using in vitro microfluidic systems, commonly known as gut-on-a-chip (GOC) devices. This interest has been due not only to the importance of the intestine's proper functions but also to the relationship that this organ and the microbiota that inhabits it has with the rest of the body's organs. The increased complexity of these in vitro systems, together with the need to improve our understanding of intestinal physiology interdependencies, has led to greater focus on the integration of biosensors within these devices. However, the current number of GOC devices with integrated sensors for monitoring relevant physiological parameters are very limited and demand the use of external analytical techniques that delay the analysis and prevent real-time decision-making. This paper reviews the various materials, technologies, and structures that have been used both for mimicking the physiology of the intestine and monitoring relevant physiological parameters, such as permeability of the gut barrier, dissolved oxygen concentration, cytokines profile and the production of microbial short-chain fatty acids. We also propose alternative biosensing techniques demonstrated in other in vitro and lab-on-a-chip devices that could be translated to GOC models. A critical analysis of the requirements, limitations, and current challenges on the microenvironment replication and monitorization of GOC models is included, with a particular focus on the physiological parameters and biomarkers that should be detected simultaneously in real-time to get a proper framework of the gut function that until now, have not received the necessary attention.

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., This work has been funded by the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 732032 (BrainCom) and Graphene Flagship Grant Agreements No. 785219 (GrapheneCore2) and 881603 (GrapheneCore3). The ICN2 is supported by the Severo Ochoa Centres of Excellence program, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706), and by the CERCA Program/Generalitat de Catalunya. R.G.C. is supported by the International Ph.D Program La Caixa-Severo Ochoa (Programa Internacional de Becas “la Caixa”-Severo Ochoa). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MICINN and the ICTS “NANBIOSIS”, more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) at the IMB-CNM. This work is within the project FIS2017-85787-R funded by the “Ministerio de Ciencia, Innovación y Universidades” of Spain, the “Agencia Estatal de Investigación (AEI)”, and the “Fondo Europeo de Desarrollo Regional (FEDER/UE)”. A.S. and G.S. were also supported by Bundesministerium für Bildung und Forschung [grant number 01GQ0440]. R.G.C. acknowledges that this work has been done in the framework of the Ph.D in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona.

Graphene solution-gated field-effect transistors (g-SGFETs) are promising sensing devices to transduce electrochemical potential signals in an electrolyte bath. However, distortion mechanisms in g-SGFET, which can affect signals of large amplitude or high frequency, have not been evaluated. Here, a detailed characterization and modeling of the harmonic distortion and non-ideal frequency response in g-SGFETs is presented. This accurate description of the input-output relation of the g-SGFETs allows to define the voltage- and frequency-dependent transfer functions, which can be used to correct distortions in the transduced signals. The effect of signal distortion and its subsequent calibration are shown for different types of electrophysiological signals, spanning from large amplitude and low frequency cortical spreading depression events to low amplitude and high frequency action potentials. The thorough description of the distortion mechanisms presented in this article demonstrates that g-SGFETs can be used as distortion-free signal transducers not only for neural sensing, but also for a broader range of applications in which g-SGFET sensors are used.

Mapping the entire frequency bandwidth of brain electrophysiological signals is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously DC-shifts, infraslow oscillations (, This work has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 881603 (GrapheneCore3). ICN2 is supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant no. SEV-2017–0706), and by the CERCA Programme/Generalitat de Catalunya. A.B.C. is supported by the International PhD Programme La Caixa-Severo Ochoa (Programa Internacional de Becas ‘la Caixa’-Severo Ochoa). This work has made use of the Spanish ICTS Network MICRONANOFABS, partially supported by MICINN and the ICTS ‘NANBIOSIS’, more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the IMB-CNM. We also acknowledge funding from the Generalitat de Catalunya (2017 SGR 1426), and the 2DTecBio project (FIS2017-85787-R) funded by the Ministerio de Ciencia, Innovación y Universidades of Spain, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER/UE). Part of this work was co-funded by the European Regional Development Funds (ERDF) allocated to the Programa operatiu FEDER de Catalunya 2014–2020, with the support of the Secretaria d’Universitats i Recerca of the Departament d’Empresa i Coneixement of the Generalitat de Catalunya for emerging technology clusters devoted to the valorization and transfer of research results (GraphCAT 001-P-001702). A.B.C. acknowledges that this work has been carried out within the framework of a PhD in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona. R.C.W. is funded by a Senior Research Fellowship awarded by the Worshipful Company of Pewterers. D.R. is a Biotechnology and Biological Sciences Research Council (BBSRC) LIDo sponsored PhD student. We thank M. Walker and L. Lemieux (UCL Queen Square Institute of Neurology) for their comments on the manuscript.

Poor metal contact interfaces are one of the main limitations preventing unhampered access to the full potential of two-dimensional materials in electronics. Here we present graphene solution-gated field-effect-transistors (gSGFETs) with strongly improved linearity, homogeneity and sensitivity for small sensor sizes, resulting from ultraviolet ozone (UVO) contact treatment. The contribution of channel and contact region to the total device conductivity and flicker noise is explored experimentally and explained with a theoretical model. Finally, in-vitro recordings of flexible microelectrocorticography (μ-ECoG) probes were performed to validate the superior sensitivity of the UVO-treated gSGFET to brain-like activity. These results connote an important step towards the fabrication of high-density gSGFET μ-ECoG arrays with state-of-the-art sensitivity and homogeneity, thus demonstrating the potential of this technology as a versatile platform for the new generation of neural interfaces.

Low-frequency noise (LFN) variability in graphene transistors (GFETs) is for the first time researched in this work under both experimental and theoretical aspects. LFN from an adequate statistical sample of long-channel solution-gated single-layer GFETs is measured in a wide range of operating conditions while a physics-based analytical model is derived that accounts for the bias dependence of LFN variance with remarkable performance. LFN deviations in GFETs stem from the variations of the parameters of the physical mechanisms that generate LFN, which are the number of traps (Ntr) for the carrier number fluctuation effect (ΔN) due to trapping/detrapping process and the Hooge parameter (αH) for the mobility fluctuations effect (Δμ). ΔN accounts for an M-shape of normalized LFN variance versus gate bias with a minimum at the charge neutrality point (CNP) as it was the case for normalized LFN mean value while Δμ contributes only near the CNP for both variance and mean value. Trap statistical nature of the devices under test is experimentally shown to differ from classical Poisson distribution noticed at silicon-oxide devices, and this might be caused both by the electrolyte interface in GFETs under study and by the premature stage of the GFET technology development which could permit external factors to influence the performance. This not fully advanced GFET process growth might also cause pivotal inconsistencies affecting the scaling laws in GFETs of the same process., This work was funded by the European Union's Horizon 2020 research and innovation program under Grant Agreement No. GrapheneCore2 785219 and No. GrapheneCore3 881603, Marie Skłodowska-Curie Grant Agreement No. 665919 and Grant Agreement No. 732032 (BrainCom). We also acknowledge financial support by Spanish government under the projects TEC2015-67462-C2-1-R, RTI2018-097876-B-C21 (MCIU/AEI/FEDER, UE) and project 001-P-001702-GraphCat: Communitat Emergent de grafè a Catalunya, co-funded by FEDER within the framework of Programa Operatiu FEDER de Catalunya 2014–2020. The ICN2 is also supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706).

Sensor arrays used to detect electrophysiological signals from the brain are paramount in neuroscience. However, the number of sensors that can be interfaced with macroscopic data acquisition systems currently limits their bandwidth. This bottleneck originates in the fact that, typically, sensors are addressed individually, requiring a connection for each of them. Herein, we present the concept of frequency-division multiplexing (FDM) of neural signals by graphene sensors. We demonstrate the high performance of graphene transistors as mixers to perform amplitude modulation (AM) of neural signals in situ, which is used to transmit multiple signals through a shared metal line. This technology eliminates the need for switches, remarkably simplifying the technical complexity of state-of-the-art multiplexed neural probes. Besides, the scalability of FDM graphene neural probes has been thoroughly evaluated and their sensitivity demonstrated in vivo. Using this technology, we envision a new generation of high-count conformal neural probes for high bandwidth brain machine interfaces., This work has been funded by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement 732032 (BrainCom), Grant Agreement 85219 and 881603 (Graphene Flagship). The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, Grant SEV-2017-0706), and by the CERCA Programme/Generalitat de Catalunya. R.G.C. and N.S. acknowledge that this work has been done in the framework of the Ph.D. in Electrical and Telecommunication Engineering at the Universitat Autonoma de Barcelona. R.G.C is supported by the International Ph.D. Programme La Caixa - Severo Ochoa (Programa Internacional de Becas “la Caixa”-Severo Ochoa). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MICINN and the ICTS “NANBIOSIS”, more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) at the IMB-CNM. This work is within the project 2DTecBio (FIS2017-85787-R) funded by the “Ministerio de Ciencia, Innovacion y Universidades” of Spain, the “Agencia Estatal de Investigacion (AEI)”, and the “Fondo Europeo de Desarrollo Regional (FEDER/UE)” and has received funding from Generalitat de Cataluña 2017 SGR 1426.

The use of graphene transistors for transducing neural activity has demonstrated the potential to extend the spatiotemporal resolution of electrophysiological methods to lower frequencies, providing a new tool to understand the role of the infra-slow activity.

Epithelia and endothelia delineate tissue compartments and control their environments by regulating the passage of ions and solutes. This barrier function is essential for the development and maintenance of multicellular organisms, and its dysfunction is associated with numerous human diseases. Recent advances in biomaterials and microfabrication technologies have evolved in vitro approaches for modelling biological barriers. Current microphysiological systems have become more efficient and reliable in mimicking the cell microenvironment. Additionally, methods for the quantification of barrier permeability have long provided significant insight into their underlying mechanisms. In this review, we outline the current techniques to quantify the barrier function of engineered tissues, and we also give an overview of recent microphysiological systems of biological barriers that emulate the microenvironment and microarchitecture of native tissues., This work has been supported by grants from the Ministerio de Economía y Competitividad (MINECO) (SAF2014–62114-EXP, DPI2015–65401-C3–3-R, and RYC-2013-14479) and from CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN).

The interconnection of different tissue-tissue interfaces may extend organ-on-chips to a new generation of sophisticated models capable of recapitulating more complex organ-level functions. Single interfaces are largely recreated in organ-on-chips by culturing the cells on opposite sides of a porous membrane that splits a chamber in two or by connecting the cells of two adjacent compartments through microchannels. However, it is difficult to interconnect more than one interface using these approaches. To address this challenge, we present a novel microfluidic device where cells are arranged in parallel compartments and are highly interconnected through a grid of microgrooves, which facilitates paracrine signaling and heterotypic cell-cell contact between multiple tissues. In addition, the device includes electrodes on the substrate for the measurement of transepithelial electrical resistance (TEER). Unlike conventional methods for measuring the TEER where electrodes are on each side of the cell barrier, a method with only electrodes on the substrate has been validated. As a proof-of-concept, we have used the device to mimic the structure of the blood-retinal barrier by co-culturing primary human retinal endothelial cells (HREC), a human neuroblastoma cell line (SH-SY5Y), and a human retinal pigment epithelial cell line (ARPE-19). Cell barrier formations were assessed by a permeability assay, TEER measurements, and ZO-1 expression. These results validate the proposed microfluidic device with microgrooves as a promising in vitro tool for the compartmentalization and monitoring of barrier tissues., This work is part of the requirements to achieve the PhD degree in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona, and it was supported by grants from Ministerio de Economía y Competitividad (MINECO) (SAF2014-62114-EXP and SAF2016-77784-R) and Fundació La Marató de TV3 (Exp. 201629-10). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MINECO and the ICTS 'NANBIOSIS', more specifically by the Micro-Nano Technology Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) at the IMB-CNM.

6 Figuras, Developing new standardized tools to characterize brain recording devices is critical to evaluate neural probes and for translation to clinical use. The signal-to-noise ratio (SNR) measurement is the gold standard for quantifying the performance of brain recording devices. Given the drawbacks with the SNR measure, our first objective was to devise a new method to calculate the SNR of neural signals to distinguish signal from noise. Our second objective was to apply this new SNR method to evaluate electrodes of three different materials (platinum black, Pt; carbon nanotubes, CNTs; and gold, Au) co-localized in tritrodes to record from the same cortical area using specifically designed multielectrode arrays. Hence, we devised an approach to calculate SNR at different frequencies based on the features of cortical slow oscillations (SO). Since SO consist in the alternation of silent periods (Down states) and active periods (Up states) of neuronal activity, we used these as noise and signal, respectively. The spectral SNR was computed as the power spectral density (PSD) of Up states (signal) divided by the PSD of Down states (noise). We found that Pt and CNTs electrodes have better recording performance than Au electrodes for the explored frequency range (5-1500 Hz). Together with two proposed SNR estimators for the lower and upper frequency limits, these results substantiate our SNR calculation at different frequency bands. Our results provide a new validated SNR measure that provides rich information of the performance of recording devices at different brain activity frequency bands (, This work was supported by Ministerio de Ciencia, Innovación y Universidades (Spain), BFU2017-85048-R and PCIN-2015-162-C02-01 (FLAG ERA) to MVSV, and by CERCA Programme/Generalitat de Catalunya.

Brain-computer interfaces and neural prostheses based on the detection of electrocorticography (ECoG) signals are rapidly growing fields of research. Several technologies are currently competing to be the first to reach the market; however, none of them fulfill yet all the requirements of the ideal interface with neurons. Thanks to its biocompatibility, low dimensionality, mechanical flexibility, and electronic properties, graphene is one of the most promising material candidates for neural interfacing. After discussing the operation of graphene solution-gated field-effect transistors (SGFET) and characterizing their performance in saline solution, it is reported here that this technology is suitable for μ-ECoG recordings through studies of spontaneous slow-wave activity, sensory-evoked responses on the visual and auditory cortices, and synchronous activity in a rat model of epilepsy. An in-depth comparison of the signal-to-noise ratio of graphene SGFETs with that of platinum black electrodes confirms that graphene SGFET technology is approaching the performance of state-of-the art neural technologies.

Biomonitoring is a research topic that has largely relied on cell culture systems. Recently, the development of “Organ-on-a-Chip” (OC) platforms and the need for a continuous monitoring of these systems has increased its interest. However, the biomonitorization in these systems is still at its infancy due to the difficulty to adapt the sensors to microfluidic OC systems. In this work we have fabricated a modular, versatile, scalable, multi-analyte sensing platform, which integrates dissolved oxygen (DO), Na, K and pH sensors for monitoring their concentrations in small volume of biological fluids. The platform is fabricated by means of rapid prototyping techniques using polymeric substrates, and incorporates all the necessary elements to measure the four analytes. It was designed with four gold sensing electrodes, and integrates a gold counter electrode and an Ag/AgCl pseudo-reference electrode for the electrochemical measurements in small volumes (0.83 μL) of samples. The sensors featured good sensitivities of 3.60 ± 0.2 nA (mg L) for DO and 69 ± 1 mV decade for pH. Na and K μISE exhibited sensitivities of 57 ± 1 mV decade and 52 ± 2 mV decade, and low limits of detection 5 × 10 M and 0.5 × 10 M respectively. This platform allows the dynamic measurement of the biological fluids parameters simultaneously, in real time and with a rapid response. The versatility of the platform allows its adaptation in any microfluidic cells culture systems. The novel multi-sensor platform has been validated in controlled buffers and with artificial urine (AU). A proof-of-concept using real mice urine (RU) has been carried out, demonstrating the good behaviour of the multi-sensing platform.

Recording infraslow brain signals (, This work was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 696656 (Graphene Flagship) and no. 732032 (BrainCom). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MINECO and the ICTS ‘NANBIOSIS’, more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) at the IMB-CNM. E.M.C. acknowledges that this work has been done in the framework of the PhD in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona. E..C. thanks the Spanish Ministerio de Economía y Competitividad for the Juan de la Cierva postdoctoral grant IJCI-2015–25201. T. Durduran acknowledges support from Fundació CELLEX Barcelona, Ministerio de Economía y Competitividad /FEDER (PHOTODEMENTIA, DPI2015–64358-C2–1-R), the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2015–0522) and the Obra Social “la Caixa” Foundation (LlumMedBcn). M.V.S.V. acknowledges support from MINECO BFU2017-85048-R. ICN2 is supported by the Severo Ochoa programme fromSpanish MINECO (grant no. SEV-2017-0706).

Transepithelial electrical measurements in the renal tubule have provided a better understanding of how kidney regulates electrolyte and water homeostasis through the reabsorption of molecules and ions (e.g., H2O and NaCl). While experiments and measurement techniques using native tissue are difficult to prepare and to reproduce, cell cultures conducted largely with the Ussing chamber lack the effect of fluid shear stress which is a key physiological stimulus in the renal tubule. To overcome these limitations, we present a modular perfusion chamber for long-term culture of renal epithelial cells under flow that allows the continuous and simultaneous monitoring of both transepithelial electrical parameters and transepithelial NaCl transport. The latter is obtained from electrical conductivity measurements since Na+ and Cl- are the ions that contribute most to the electrical conductivity of a standard physiological solution. The system was validated with epithelial monolayers of raTAL and NRK-52E cells that were characterized electrophysiologically for 5 days under different flow conditions (i.e., apical perfusion, basal, or both). In addition, apical to basal chemical gradients of NaCl (140/70 and 70/140 mM) were imposed in order to demonstrate the feasibility of this methodology for quantifying and monitoring in real time the transepithelial reabsorption of NaCl, which is a primary function of the renal tubule., This work is part of the requirements to achieve the PhD degree in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona, and it was supported by grants from Ministerio de Economía y Competitividad (MINECO) (SAF2014-62114-EXP, DPI2015-65401-C3-3-R, and DPI2011-28262-C04-02). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MINECO and the ICTS 'NANBIOSIS', more specifically by the Micro-Nano Technology Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) at the IMB-CNM.

Cortical slow oscillations (SO) of neural activity spontaneously emerge and propagate during deep sleep and anesthesia and are also expressed in isolated brain slices and cortical slabs. We lack full understanding of how SO integrate the different structural levels underlying local excitability of cell assemblies and their mutual interaction. Here, we focus on ongoing slow waves (SWs) in cortical slices reconstructed from a 16-electrode array designed to probe the neuronal activity at multiple spatial scales. In spite of the variable propagation patterns observed, we reproducibly found a smooth strip of loci leading the SW fronts, overlapping cortical layers 4 and 5, along which Up states were the longest and displayed the highest firing rate. Propagation modes were uncorrelated in time, signaling a memoryless generation of SWs. All these features could be modeled by a multimodular large-scale network of spiking neurons with a specific balance between local and intermodular connectivity. Modules work as relaxation oscillators with a weakly stable Down state and a peak of local excitability to model layers 4 and 5. These conditions allow for both optimal sensitivity to the network structure and richness of propagation modes, both of which are potential substrates for dynamic flexibility in more general contexts.

Type I diabetes mellitus is characterised by the destruction of the insulin producing beta cells within the pancreas by the immune system. After the success of Edmonton protocol, islet transplantation has shown to be a promising therapy, but with the Achilles´ heel of the need of using immunosuppressive drugs. Currently, cell encapsulation technology represents a real alternative to protect transplanted islets from the host´s immune attack. Although preliminary in vitro studies with encapsulated cells have been traditionally performed under static conditions in terms of viability and efficiency, these static cultures do not represent a close approach to in vivo environments. We have developed and characterised different alginate-poly-l-lysine-alginate (APA) microcapsules loaded with the insulin producing 1.1B4 cell line. Static in vitro studies confirmed a constant insulin secretion and a boost of the secretion when the medium was enriched with glucose. Nevertheless, these results were not completely reproduced in a dynamic system by APA liquefied microcapsules containing 1.1B4 cells. The dynamic culture setting created by a microfluidic device, allowed the determination of the glucose response in APA liquefied microcapsules, showing that dynamic conditions can mimic better physiological in vivo environments.

Transepithelial electrical resistance (TEER) measurements are regularly used in in vitro models to quantitatively evaluate the cell barrier function. Although it would be expected that TEER values obtained with the same cell type and experimental setup were comparable, values reported in the literature show a large dispersion for unclear reasons. This work highlights a possible error in a widely used formula to calculate the TEER, in which it may be erroneously assumed that the entire cell culture area contributes equally to the measurement. In this study, we have numerically calculated this error in some cell cultures previously reported. In particular, we evidence that some TEER measurements resulted in errors when measuring low TEERs, especially when using Transwell inserts 12 mm in diameter or microfluidic systems that have small chamber heights. To correct this error, we propose the use of a geometric correction factor (GCF) for calculating the TEER. In addition, we describe a simple method to determine the GCF of a particular measurement system, so that it can be applied retrospectively. We have also experimentally validated an interdigitated electrodes (IDE) configuration where the entire cell culture area contributes equally to the measurement, and it also implements minimal electrode coverage so that the cells can be visualized alongside TEER analysis., This work is part of the requirements to achieve the PhD degree in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona and it was supported by grants from CIBER-BBN, CSIC (PIE-201450E116) and Ministerio de Economía y Competitividad (SAF2014-62114-EXP and DPI2015-65401-C3-3-R). CIBER-BBN is funded by Instituto de Salud Carlos III. We are grateful to Drs. Pierre-Olivier Couraud (INSERM, France), Babette Weksler (Weill Cornell Medical College, New York, NY) and Ignacio Romero (Open University, Milton Keynes, UK) for kindly providing the hCMEC/D3 cell line. We would also acknowledge to Dr Mercedes Unzeta (Universitat Autònoma de Barcelona, Spain) for her advice and providing materials to perform the experiments with the cells.

An experimental study of a micromachined non-porous pillar array column performance under non-retentive conditions is presented. The same pillar structure has been fabricated in cyclo-olefin polymer (COP) chips with three different depths via hot embossing and pressure-assisted thermal bonding. The influence of the depth on the band broadening along with the already known contribution arising from the top and bottom cover plates has been studied. The experimental results exhibit reduced plate heights as low as 0.2, which are in agreement with the previous experimental work. Moreover, the constant values of the reduced Van Deemter expression are also in accordance with the previous studies. A more exhaustive study of the C-term band broadening is also presented, showing that comparing the space between the pillars with different open tubular rectangular channels offers a good estimation of the C-term band broadening that is obtained experimentally. These experimental results, hence, confirm that micromachined pillar array columns fabricated in COP can achieve the same performance as the ones fabricated in silicon for the presently studied pillar channel design.

Low power micromachined gas sensors based on suspended micro-hotplates are presented in this work. The sensors were fabricated using Porous Silicon Technology. Two different metal-modified nanostructured sensitive materials were deposited on top of the active area of the micro-hotplates, using the micro-dropping technique: SnO"2:Pd and WO"3:Cr. For the characterization of both gas sensors, measurements in NH"3 ambient took place, in isothermal mode of operation. Improved sensors characteristics were obtained for SnO"2:Pd sensors, compared to WO"3:Cr, for these operating conditions.

A 16-electrode flexible microprobe presenting an array of holes in its sensing area has been developed using SU-8 negative photoresist as a substrate material. The design of the microprobe consisted on six groups of 2-3 electrodes (50 μm in diameter and separated by 200 μm) placed in-between the array of holes. Distances between each group were appropriated for recording from a ferret slice, allowing us to evaluate the close versus the distant network activity. The holes were designed to allow the flow of oxygenated solution through the probe when measuring the neural activity of cortical slides maintained in vitro, while the gold electrodes have been modified with platinum black to decrease its impedance value and, therefore, improve the measurements. In particular, with this SU-8 microprobe it has been possible to register spontaneous slow oscillations and also induced activity in all 16 channels. The holes were useful to position puffers that allowed us to locally delivered drugs (glutamate) and to register its response. In addition, they were also used for sticking electrodes to simultaneously record single units that allowed us the synchronous recording of population activity (local field potential) with the electrodes of the probe and single unit activity (with glass or tungsten electrodes), demonstrating the feasibility of using SU-8 for the fabrication of neural microprobes as it can be customized to the required design.

In this work, we present the use of interdigitated electrodes (IDEs) for performing electrical impedance spectroscopy (EIS) measurements to monitor a microfluidic blood brain barrier model. In particular, an electrode configuration which would not impair the optical visualization of the cell culture is proposed. Numerical studies have been performed to evaluate the electrical impedance sensitivity of the proposed tetrapolar configuration along the cell barrier in a given microfluidic chamber geometry. The system has been validated using a home-made cyclo olefin polymer (COP) bioreactor and perforated poly (methyl methacrylate) (PMMA) sheets with different pore densities in order to simulate different cell barrier impedances.

WO 3 –Cr, SnO 2 –Pd and TiO 2 –Cr nanoparticles have been prepared following a sol–gel route. The additive-modified nanostructured metal oxides have been deposited on hotplate platforms by microdropping. Functional gas test of the sensitive layers to ammonia has been performed in stationary and pulsed mode of operation. The pulsed mode fastened the regeneration of the surface yielding an enlargement of the sensor response and a decrease of the transient time. The improved sensing response to ammonia was particularly marked for the WO 3 –Cr based gas sensor.

Interdigitated microband electrodes are important electroanalytical tools, and have been used in the construction of advanced sensing and biosensing devices for a long time. Nanoband-based systems, on the other hand, are more difficult to come by, as their fabrication involves the use of costly and scarce e-beam lithography resources. In this work we present the fabrication of interdigitated nanobands down to 400 nm using optical techniques exclusively. The process combines a step-and-repeat process to define Cr-Au nano- and microbands, and a standard lithography to pattern the active areas and contacts through an SU-8 passivation layer. This work presents the physical and electrochemical characterization of these devices, and our results also show that generator-collector experiments at these nanometric devices can be used in conventional electroanalytical applications, but also to measure electrode kinetics. While electrode kinetics does not affect collection efficiency to a great extent, the fast mass transport rates achieved at these devices makes the voltammetric current critically dependent on electron transfer rates., The authors wish to thank CSIC for funding this work through project 2010TW0022. This work is supported in part by the Ministry of Education, Taiwan, under the ATU plan. Financial support from the National Science Council, Taiwan, under contract no. NSC 100-2923-E-005-001-MY3, is also gratefully acknowledged. Ll Abad gratefully acknowledges a JAE-Doc fellowship from CSIC partially funded by European Social Fund.

Experimental measurements to study the retention capacity and band broadening under retentive conditions using micromachined non-porous pillar array columns fabricated in cyclo olefin polymer are presented. In particular, three columns with different depths but with the same pillar structure have been fabricated via hot embossing and pressure-assisted thermal bonding. Separations of a mixture of four coumarins using varying mobile phase compositions have been monitored to study the relation between the retention factor and the ratio of organic solvent in the aqueous mobile phase. Moreover, the linear relation between the retention and the surface/volume ratio predicted in theory has been observed, achieving retention factors up to k=2.5. Under the same retentive conditions, minimal reduced plate height values of h(min)=0.4 have been obtained at retention factors of k=1.2. These experimental results are compared with the case of non-porous and porous silicon pillars. Similar results for the plate heights are achieved while retention factors are higher than the non-porous silicon column and considerably smaller than the porous pillar column, given the non-porous nature of the used cyclo olefin polymer. The feasibility of using this polymer column as an alternative to the pillar array silicon columns is corroborated.

Mesoporous silica with KIT-6 structure was investigated as a preconcentrating material in chromatographic systems for ammonia and trimethylamine. Its adsorption capacity was compared to that of existing commercial materials, showing its increased adsorption power. In addition, KIT-6 mesoporous silica efficiently adsorbs both gases, while none of the employed commercial adsorbents did. This means that KIT-6 Mesoporous silica may be a good choice for integrated chromatography/gas sensing micro-devices.

The current paper describes the development and characterization of a pillar array chip that is constructed out of a sandwich of cyclo olefin polymer (COP) sheets. The silicon master of a 5 cm long pillar array was embossed into the COP, yielding 4.3 microm deep pillars of 15.3 microm diameter with an external porosity of 43 % and a well designed sidewall region to avoid side wall induced band broadening. A closed channel configuration was obtained by pressure assisted thermal bonding to a non-processed COP lid. Injection of coumarin dye plugs and detection with a fluorescence microscope showed very close agreement of this channel configuration to theoretical expectations in terms of band broadening. This agreement is due to the low taper, the optimized sidewall region and the excellent bonding quality between the two polymer sheets, even at the pillar area. Under non-retained conditions (pure methanol as mobile phase), plate heights as low as 4 microm were obtained. Under retained conditions, using the native hydrophobic properties of the COP channel (in 70/30 v/v water/methanol mixture as mobile phase), a minimum plate height of 6 microm was obtained. A 4 component separation was successfully achieved, demonstrating that COP is a cheap and efficient alternative for silicon and silica based liquid chromatography formats.

The development of an integrated gas chromatographic system using micro and nanotechnologies is presented in this paper. For this purpose, the different components of the chromatographic system, namely the preconcentrator, the chromatographic column and the gas sensors are being investigated and developed, and the actual state of this investigation is presented. The proposed target application comes from the agrofood industry, in particular the determination of the fish freshness. The structure of the preconcentrator has been fabricated using deep reactive ion etching (DRIE). The same fabrication technique has been employed for the patterning of the silicon microcolumns, which have been sealed with Pyrex glass. Inlet and outlets have been connected and initial experiments of functionalization have been performed. Gas sensors have been obtained by microdeposition of doped WO 3 or SnO 2 nanomaterials on microhotplates and their responses to the gases of interest have been measured, proving that the target gas concentrations can be detected.

We describe a unique, versatile bioreactor consisting of two plates and a modified commercial porous membrane suitable for in vitro analysis of the liver sinusoid. The modular bioreactor allows i) excellent control of the cell seeding process; ii) cell culture under controlled shear stress stimulus, and; iii) individual analysis of each cell type upon completion of the experiment. The advantages of the bioreactor detailed here are derived from the modification of a commercial porous membrane with an elastomeric wall specifically moulded in order to define the cell culture area, to act as a gasket that will fit into the bioreactor, and to provide improved mechanical robustness. The device presented herein has been designed to simulate the in vivo organization of a liver sinusoid and tested by co-culturing endothelial cells (EC) and hepatic stellate cells (HSC). The results show both an optimal morphology of the endothelial cells as well as an improvement in the phenotype of stellate cells, most probably due to paracrine factors released from endothelial cells. This device is proposed as a versatile, easy-to-use co-culture system that can be applied to biomedical research of vascular systems, including the liver., This work was supported by: CSIC (PIE 201450E116) (RV); Instituto de Salud Carlos III (FIS PI11/00235) (JGS); Ministerio de Economía y Competitividad (SAF2012-31238) (CP); European Union (Fondos FEDER, ‘‘una manera de hacer Europa’’) (JGS and CP); European Community’s Seventh Framework Programme(ECFP7/2007-2013, grant agreement 229673) (JGS); CIBER-EHD (funded by Instituto de Salud Carlos III) (JGS and CP); and CIBER-BBN (funded by Instituto de Salud Carlos III) (RV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The cornea is a transparent structure composed of three layers: the epithelium, the stroma and the endothelium. To maintain its ransparency the stroma remains in a constant state of dehydration. Consequently, any ion flow disorder through the covering layers can compromise the barrier function and, therefore the corneal homeostasis. Since ionic permeability has a fundamental impact on the passive electrical properties of living tissues, in this work it is proposed and demonstrated a diagnosis method based on tetrapolar impedance measurements performed by electrodes placed on the corneal surface. The contribution of each cornea layer to the total measured impedance has been analysed over a frequency range. Following the obtained guidelines, a flexible probe with integrated electrodes has been developed and manufactured using SU-8 photoresin. The feasibility of the proposed method has been evaluated in vivo by monitoring corneal epithelium wound healing. Obtained impedance measurements have been compared with measurements of permeability to sodium fluorescein from different excised corneas. Successful results demonstrate the feasibility of this novel flexible sensor and its capability to quantify corneal permeability in vivo in a non-invasive way.

Maintenance of the complex phenotype of primary hepatocytes in vitro represents a limitation for developing liver support systems and reliable tools for biomedical research and drug screening. We herein aimed at developing a biosystem able to preserve human and rodent hepatocytes phenotype in vitro based on the main characteristics of the liver sinusoid: unique cellular architecture, endothelial biodynamic stimulation, and parenchymal zonation. Primary hepatocytes and liver sinusoidal endothelial cells (LSEC) were isolated from control and cirrhotic human or control rat livers and cultured in conventional in vitro platforms or within our liver‐resembling device. Hepatocytes phenotype, function, and response to hepatotoxic drugs were analyzed. Results evidenced that mimicking the in vivo sinusoidal environment within our biosystem, primary human and rat hepatocytes cocultured with functional LSEC maintained morphology and showed high albumin and urea production, enhanced cytochrome P450 family 3 subfamily A member 4 (CYP3A4) activity, and maintained expression of hepatocyte nuclear factor 4 alpha (hnf4α) and transporters, showing delayed hepatocyte dedifferentiation. In addition, differentiated hepatocytes cultured within this liver‐resembling device responded to acute treatment with known hepatotoxic drugs significantly different from those seen in conventional culture platforms. In conclusion, this study describes a new bioengineered device that mimics the human sinusoid in vitro, representing a novel method to study liver diseases and toxicology.