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Evaluating biocompatibility is a core essential step to introducing a new material as a candidate for brain-machine interfaces. Foreign body reactions often result in glial scars that can impede the performance of the interface. Having a high conductivity and large electrochemical window, graphene is a candidate material for electrical stimulation with retinal prosthesis. In this study, non-functional devices consisting of chemical vapor deposition (CVD) graphene embedded onto polyimide/SU-8 substrates were fabricated for a biocompatibility study. The devices were implanted beneath the retina of blind P23H rats. Implants were monitored by optical coherence tomography (OCT) and eye fundus which indicated a high stability in vivo up to 3 months before histology studies were done. Microglial reconstruction through confocal imaging illustrates that the presence of graphene on polyimide reduced the number of microglial cells in the retina compared to polyimide alone, thereby indicating a high biocompatibility. This study highlights an interesting approach to assess material biocompatibility in a tissue model of central nervous system, the retina, which is easily accessed optically and surgically.

Abstract 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.

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 (

The cornea is a very particular tissue due to its transparency and its barrier function as it has to resist against the daily insults of the external environment. In addition, maintenance of this barrier function is of crucial importance to ensure a correct corneal homeostasis. Here, the corneal epithelial permeability has been assessed in vivo by means of non-invasive tetrapolar impedance measurements, taking advantage of the huge impact of the ion fluxes in the passive electrical properties of living tissues. This has been possible by using a flexible sensor based in SU-8 photoresist. In this work, a further analysis focused on the validation of the presented sensor is performed by monitoring the healing process of corneas that were previously wounded. The obtained impedance measurements have been compared with the damaged area observed in corneal fluorescein staining images. The successful results confirm the feasibility of this novel method, as it represents a more sensitive in vivo and non-invasive test to assess low alterations of the epithelial permeability. Then, it could be used as an excellent complement to the fluorescein staining image evaluation.

A novel sensing device for simultaneous dissolved oxygen (DO) and pH monitoring specially designed for biofilm profiling is presented in this work. This device enabled the recording of instantaneous DO and pH dynamic profiles within biofilms, improving the tools available for the study and the characterization of biological systems. The microsensor consisted of two parallel arrays of microelectrodes. Microelectrodes used for DO sensing were bare gold electrodes, while microelectrodes used for pH sensing were platinum-based electrodes modified using electrodeposited iridium oxide. The device was fabricated with a polyimide (Kapton®) film of 127 µm as a substrate for minimizing the damage caused on the biofilm structure during its insertion. The electrodes were covered with a Nafion® layer to increase sensor stability and repeatability and to avoid electrode surface fouling. DO microelectrodes showed a linear response in the range 0−8 mg L−1, a detection limit of 0.05 mg L−1, and a sensitivity of 2.06 nA L mg−1. pH electrodes showed a linear super-Nernstian response (74.2 ± 0.7 mV/pH unit) in a wide pH range (pH 4−9). The multi-analyte sensor array was validated in a flat plate bioreactor where simultaneous and instantaneous pH and DO profiles within a sulfide oxidizing biofilm were recorded. The electrodes spatial resolution, the monitoring sensitivity, and the minimally invasive features exhibited by the proposed microsensor improved biofilm monitoring performance, enabling the quantification of mass transfer resistances and the assessment of biological activity.

We have explored the feasibility of improving the quality of multiple recordings from spontaneously oscillating cortical slices. With that purpose we have taken advantage of the advances performed in the development of flexible neuproprobes, either fabricated on polyimide, SU-8, PDMS or parylene (Hassler et al. 2011). With these materials the contact between the electrodes and the tissue is enhanced with respect to the neuroprobes fabricated on rigid substrates, such as silicon or pyrex. However, we had to find a compromise between the necessity to achieve a good contact between the electrode and the slice and the need to allow the flow of oxygenated solution to the slice to maintain its healthy state when using flexible neuroprobes. To overcome this limitation, we have designed, fabricated and characterized a 16-electrode flexible neuroprobe that allocates an array of holes in its sensing area. This neuroprobe has been developed using SU-8 negative photoresist as a substrate material in the clean room facilities of the IMB-CNM. In particular, the neuroprobes have been fabricated following the process described in a previous article from the authors (Guimerà et al. 2013); using silicon wafers with an aluminum sacrificial layer as a support for the fabrication process. Then, the neuroprobes were released from the wafer by an anodic dissolution of the aluminum layer (Metz et al. 2005). In order to validate the usability of the fabricated device, the neuroprobes were used to record spontaneous slow oscillations to study the wave propagation along the cortical networks while manipulating them by means of pharmacological drugs or electric fields. We conclude that the perforated devices provide substantial improvement in the adherence of the electrodes to the tissue, on the mechanical stability of the recordings, and in the healthiness of the slices.

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 paper presents an entirely polymeric microfluidic system, made of cyclo olefin polymer (COP), with integrated gold microband electrodes for electrochemical applications in organic media. In the present work, we take advantage of the COP's high chemical stability to polar organic solvents in two different ways: (i) to fabricate gold microelectrodes using COP as a substrate by standard lithographic and lift-off techniques; and (ii) to perform electrochemical experiments in organic media. In particular, fourteen parallel gold microelectrodes with a width of 14 μm and separated from their closest neighbour by 16 μm were fabricated by lithographic and lift-off techniques on a 188 μm thick COP sheet. A closed channel configuration was obtained by pressure-assisted thermal bonding between the COP sheet containing the microelectrodes and a microstructured COP sheet, where a 3 cm long, 50 μm wide and 24 μm deep channel was fabricated viahot embossing. Cyclic voltammetric measurements were carried out in aqueous and organic media, using a solution consisting of 5 mM ferrocyanide/ferricyanide in 0.5 M KNO3and 5 mM ferrocene in 0.1 M TBAP/acetonitrile, respectively. Experimental currents obtained for different flow rates ranging from 1 to 10 μL min−1were compared to the theoretical steady state currents calculated by the Levich equation for a band electrode (R. G. Compton, A. C. Fisher, R. G. Wellington, P. J. Dobson and P. A. Leigh, J. Phys. Chem., 1993, 97, 10410–10415). In both cases, the difference between the experimental and the predicted data is less than 5%, thus validating the behaviour of the fabricated device. This result opens the possibility to use a microfluidic system made entirely from COP with integrated microband electrodes in organic electroanalysis and in electrosynthesis. [ABSTRACT FROM AUTHOR]

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 µm deep pillars of 15.3 µm 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 µm 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 µm 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. [ABSTRACT FROM AUTHOR]