Gemma Gabriel

Study of functional viability of SU-8-based microneedles for neural applications

This paper presents the design, fabrication, packaging and first test results of SU-8-based microneedles for neural applications. By the use of photolithography, sputtering and bonding techniques, polymer needles with integrated microchannels and electrodes have been successfully fabricated. The use of photolithography for the patterning of the fluidic channel integrated in the needle allows the design of multiple outlet ports at the needle tip, minimizing the possibility of being blocked by the tissue. Furthermore, the flexibility of the polymer reduces the risk of fracture and tissue damage once the needle is inserted, while it is still rigid enough to allow a perfect insertion into the neural tissue. Fluidic and electric characterization of the microneedles has shown their viability for drug delivery and monitoring in neural applications. First drug delivery tests in ex vivo tissue demonstrated the functional viability of the needle to deliver drugs to precise points. Furthermore, in vivo experiments have demonstrated lower associated damages during insertion than those by stereotaxic standard needles.

Magnetic entrapment for fast, simple and reversible electrode modification with carbon nanotubes: Application to dopamine detection

Carbon nanotubes (CNT) have been exploited for an important number of electroanalytical and sensing purposes. Specifically, CNT incorporation to an electrode surface coating increases its roughness and area, provides electrocatalytic activity towards a variety of molecules, and improves electron transfer. This modification is generally based on the irreversible deposition of CNT on surface. Nevertheless, CNT are highly porous materials that might promote molecule non-specific adsorption and/or electrodeposition, which could induce sample-to-sample cross-contamination and affect measurement specificity and reproducibility. This drawback has been often circumvented by combining CNT with charged polymers able to repel molecules of opposed charge. We demonstrate that single-walled CNT (SWCNT) have a strong tendency to non-specifically adsorb onto the surface of protein-coated magnetic particles (MP). Magnetic capture of those MP generates CNT coentrapment and allows extremely fast, simple and reversible production of SWCNT electrodes. We have exploited this phenomenon for the production of modified screen-printed electrodes (MP/CNT-SPE), which have been characterized by Scanning Electron Microscopy. The surface has been additionally optimized by evaluating the electrochemical performance of SPE modified with different amounts and proportions of MP and CNT. The modified devices have then been used for dopamine detection. MP/CNT-SPE generated improved assay sensitivity, lower limit of detection, and up to 500% higher current signals than bare electrodes. Magnetic entrapment is proposed as a promising strategy for the fast, simple and reversible generation of nanostructured electrodes of enhanced performance within a few minutes and electrode re-utilisation by simple magnet removal and surface washing.

Manufacturing and full characterization of silicon carbide-based multi-sensor micro-probes for biomedical applications

Semi-insulating silicon carbide (SiC) is a fully processable semiconductors substrate that is commonly used as an alternative to conventional silicon (Si) in high-power applications. Here we examine the feasibility of using SiC as a substrate for the development of minimally invasive multi-sensor micro-probes in the context of organ monitoring during transplantation. In particular, we make a thorough comparison of Si and SiC material mechanical and electrical properties, and we extend this analysis to life-like situations using completed devices. Our results show that SiC outperforms Si in all respects, with a four times higher modulus of rupture for SiC devices and a 10-fold increase in the frequency range for electrical measurements in SiC-based probes. These results suggest that SiC should be preferably used over Si in all biomedical applications in which device breakage must be avoided or very precise electrical measurements are required.

SU-8 microprobe with microelectrodes for monitoring electrical impedance in living tissues

This paper presents a minimally invasive needle-shaped probe capable of monitoring the electrical impedance of living tissues. This microprobe consists of a 160 microm thick SU-8 substrate containing four planar platinum (Pt) microelectrodes. We design the probe to minimize damage to the surrounding tissue and to be stiff enough to be inserted in living tissues. The proposed batch fabrication process is low cost and low time consuming. The microelectrodes obtained with this process are strongly adhered to the SU-8 substrate and their impedance does not depend on frequency variation. In vitro experiments are compared with previously developed Si and SiC based microprobes and results suggest that it is preferable to use the SU-8 based microprobes due to their flexibility and low cost. The microprobe is assembled on a flexible printed circuit FPC with a conductive glue, packaged with epoxy and wired to the external instrumentation. This flexible probe is inserted into a rat kidney without fracturing and succeeds in demonstrating the ischemia monitoring.

Easily made single-walled carbon nanotube surface microelectrodes for neuronal applications.

The present work examines the feasibility of a simple method for using single-walled carbon nanotubes (SWNT) to fabricate multielectrode arrays (MEA) for electrophysiological recordings. A suspension of purified SWNTs produced by arc discharged was directly deposited onto standard platinum electrodes. The in vitro impedance and electrochemical characterizations demonstrated the enhanced electrical properties of the SWNT microelectrode array. To test its functionality we performed extracellular ganglion cell recordings in isolated superfused rabbit retinas. Our results showed that SWNT based electrode arrays have potential advantages over metal electrodes and can be successfully used to record the single and multi-unit activity of ganglion cell populations.

SU-8 based microprobes with integrated planar electrodes for enhanced neural depth recording

Here, we describe new fabrication methods aimed to integrate planar tetrode-like electrodes into a polymer SU-8 based microprobe for neuronal recording applications. New concepts on the fabrication sequences are introduced in order to eliminate the typical electrode-tissue gap associated to the passivation layer. Optimization of the photolithography technique and high step coverage of the sputtering process have been critical steps in this new fabrication process. Impedance characterization confirmed the viability of the electrodes for reliable neuronal recordings with values comparable to commercial probes. Furthermore, a homogeneous sensing behavior was obtained in all the electrodes of each probe. Finally, in vivo action potential and local field potential recordings were successfully obtained from the rat dorsal hippocampus. Peak-to-peak amplitude of action potentials ranged from noise level to up to 400-500 μV. Moreover, action potentials of different amplitudes and shapes were recorded from all the four recording sites, suggesting improved capability of the tetrode to distinguish from different neuronal sources.

SU-8-based microneedles for in vitro neural applications

This paper presents novel design, fabrication, packaging and the first in vitro neural activity recordings of SU-8-based microneedles. The polymer SU-8 was chosen because it provides excellent features for the fabrication of flexible and thin probes. A microprobe was designed in order to allow a clean insertion and to minimize the damage caused to neural tissue during in vitro applications. In addition, a tetrode is patterned at the tip of the needle to obtain fine-scale measurements of small neuronal populations within a radius of 100 µm. Impedance characterization of the electrodes has been carried out to demonstrate their viability for neural recording. Finally, probes are inserted into 400 µm thick hippocampal slices, and simultaneous action potentials with peak-to-peak amplitudes of 200–250 µV are detected.

Dynamic characterization of external and internal mass transport in heterotrophic biofilms from microsensors measurements

Knowledge of mass transport mechanisms in biofilm-based technologies such as biofilters is essential to improve bioreactors performance by preventing mass transport limitation. External and internal mass transport in biofilms was characterized in heterotrophic biofilms grown on a flat plate bioreactor. Mass transport resistance through the liquid-biofilm interphase and diffusion within biofilms were quantified by in situ measurements using microsensors with a high spatial resolution (<50xa0μm). Experimental conditions were selected using a mathematical procedure based on the Fisher Information Matrix to increase the reliability of experimental data and minimize confidence intervals of estimated mass transport coefficients. The sensitivity of external and internal mass transport resistances to flow conditions within the range of typical fluid velocities over biofilms (Reynolds numbers between 0.5 and 7) was assessed. Estimated external mass transfer coefficients at different liquid phase flow velocities showed discrepancies with studies considering laminar conditions in the diffusive boundary layer near the liquid-biofilm interphase. The correlation of effective diffusivity with flow velocities showed that the heterogeneous structure of biofilms defines the transport mechanisms inside biofilms. Internal mass transport was driven by diffusion through cell clusters and aggregates at Re below 2.8. Conversely, mass transport was driven by advection within pores, voids and water channels at Re above 5.6. Between both flow velocities, mass transport occurred by a combination of advection and diffusion. Effective diffusivities estimated at different biofilm densities showed a linear increase of mass transport resistance due to a porosity decrease up to biofilm densities of 50xa0gxa0VSS·L(-1). Mass transport was strongly limited at higher biofilm densities. Internal mass transport results were used to propose an empirical correlation to assess the effective diffusivity within biofilms considering the influence of hydrodynamics and biofilm density.

Non-invasive assessment of corneal endothelial permeability by means of electrical impedance measurements

The permeability of the corneal endothelial layer has an important role in the correct function of the cornea. Since ionic permeability has a fundamental impact on the passive electrical properties of living tissues, here it is hypothesized that impedance methods can be employed for assessing the permeability of the endothelial layer in a minimally invasive fashion. Precisely, the main objective of the present study is to develop and to analyze a minimally invasive method for assessing the electrical properties of the corneal endothelium, as a possible diagnostic tool for the evaluation of patients with endothelial dysfunction. A bidimensional model consisting of the main corneal layers and a four-electrode impedance measurement setup placed on the epithelium has been implemented and analyzed by means of the finite elements method (FEM). In order to obtain a robust indicator of the permeability of the endothelium layer, the effect of the endothelium electrical properties on the measured impedance has been studied together with reasonable variations of the other model layers. Simulation results show that the impedance measurements by means of external electrodes are indeed sufficiently sensitive to the changes in the electrical properties of the endothelial layer. It is concluded that the method presented here can be employed as non-invasive method for assessing endothelial layer function.

Cancer Prognostics by Direct Detection of p53-Antibodies on Gold Surfaces by Impedance Measurements

The identification and measurement of biomarkers is critical to a broad range of methods that diagnose and monitor many diseases. Serum auto-antibodies are rapidly becoming interesting targets because of their biological and medical relevance. This paper describes a highly sensitive, label-free approach for the detection of p53-antibodies, a prognostic indicator in ovarian cancer as well as a biomarker in the early stages of other cancers. This approach uses impedance measurements on gold microelectrodes to measure antibody concentrations at the picomolar level in undiluted serum samples. The biosensor shows high selectivity as a result of the optimization of the epitopes responsible for the detection of p53-antibodies and was validated by several techniques including microcontact printing, self-assembled-monolayer desorption ionization (SAMDI) mass spectrometry, and adhesion pull-off force by atomic force microscopy (AFM). This transduction method will lead to fast and accurate diagnostic tools for the early detection of cancer and other diseases.