Jordi Aguiló

Minimally invasive silicon probe for electrical impedance measurements in small animals

It is commonly accepted that electrical impedance provides relevant information about the physiological condition of living tissues. Currently, impedance measurements are performed with relatively large electrodes not suitable for studies in small animals due to their poor spatial resolution and to the damage that they cause to the tissue. A minimally invasive needle shaped probe for electrical impedance measurements of living tissues is presented in this paper. This micro-probe consists of four square platinum electrodes (300 microm x 300 microm) on a silicon substrate (9 mm x 0.6 mm x 0.5 mm) and has been fabricated by using standard Si microelectronic techniques. The electrodes are not equally spaced in order to optimise the signal strength and the spatial resolution. Characterisation data obtained indicate that these probes provide high spatial resolution (measurement radius <4 mm) with a useful wide frequency band going from 100 Hz to 100 kHz. A series of in vivo experiments in rat kidneys subjected to ischemia was performed to demonstrate the feasibility of the probes and the measurement system. The impedance modulus and phase were measured at 1 kHz since this frequency is sufficiently low to permit the study of the extracellular medium. The extracellular pH and K+ were also simultaneously measured by using commercial miniaturised Ion Selective Electrodes. The induced ischemia period (45 min) resulted in significant changes of all measured parameters (Delta/Z/ approximately 65%; DeltapH approximately 0.8; DeltaK+ approximately 30 mM).

Bioimpedance dispersion width as a parameter to monitor living tissues

In the case of living tissues, the spectral width of the electrical bioimpedance dispersions (closely related with the alpha parameter in the Cole equation) evolves during the ischemic periods. This parameter is often ignored in favor of other bioimpedance parameters such as the central frequency or the resistivity at low frequencies. The object of this paper is to analyze the significance of this parameter through computer simulations (in the alpha and beta dispersion regions) and to demonstrate its practical importance through experimental studies performed in rat kidneys during cold preservation. The simulations indicate that the dispersion width could be determined by the morphology of the extra-cellular spaces. The experimental studies show that it is a unique parameter able to detect certain conditions such as a warm ischemia period prior to cold preservation or the effect of a drug (Swinholide A) able to disrupt the cytoskeleton. The main conclusion is that, thanks to the alpha parameter in the Cole equation, the bioimpedance is not only useful to monitor the intra/extra-cellular volume imbalances or the inter-cellular junctions resistance but also to detect tissue structural alterations.

New technology for multi-sensor silicon needles for biomedical applications

Abstract A multi-sensor silicon needle including two ion-sensitive field effect transistor (ISFET) sensors, a platinum pseudo-reference electrode (Pt) and a temperature sensor has been fabricated by using a CMOS-compatible technology and silicon micromachining. This paper presents a summary of the fabrication process and results of the device characterisation. The feasibility of the fabrication technology has been demonstrated and all devices have operated satisfactorily, with a response showing good sensitivity and linearity. The multi-sensor has been developed for the detection of myocardial ischemia during cardiac surgery.

Development of a CMOS-compatible PCR chip: comparison of design and system strategies

In the last decade research in chips for DNA amplification through the polymerase chain reaction (PCR) has been relatively abundant, but has taken very diverse approaches, leaving little common ground for a straightforward comparison of results. Here we report the development of a line of PCR chips that is fully compatible with complementary-metal-oxide-semiconductor (CMOS) technology and its revealing use as a general platform to test and compare a wide range of experimental parameters involved in PCR-chip design and operation. Peltier-heated and polysilicon thin-film driven PCR chips have been produced and directly compared in terms of efficiency, speed and power consumption, showing that thin-film systems run faster and more efficiently than Peltier-based ones, but yield inferior PCR products. Serpentine-like chamber designs have also been compared with standard rectangular designs and with the here reported rhomboidal chamber shape, showing that serpentine-like chambers do not have detrimental effects in PCR efficiency when using non-flow-through schemes, and that chamber design has a strong impact on sample insertion/extraction yields. With an accurate temperature control (±0.2 °C) we have optimized reaction kinetics to yield sound PCR amplifications of 25 µl mixtures in 20 min and with 24.4 s cycle times, confirming that a titrated amount of bovine albumin serum (BSA, 2.5 µg µl−1) is essential to counteract polymerase adsorption at chip walls. The reported use of a CMOS-compatible technological process paves the way for an easy adaption to foundry requirements and for a scalable integration of electro-optic detection and control circuitry.

Hydrogen-selective microelectrodes based on silicon needles

The fabrication of hydrogen-selective microelectrodes on silicon needle-shaped substrates is described. The microelectrodes are based on an ion-selective poly(vinyl chloride) (PVC) membrane with an intrinsically conducting polymer (polypyrrole (PPy)) solid contact layer. The polypyrrole is prepared with the dopant anion cobaltbis(dicarbollide) [3,3 0 -Co(1,2-C2B9H11)2] � , which gives a high stability to the polymer layer. The performance of the resulting solid-contact ion-selective microelectrodes (SCISME) is investigated by using potentiometric measurement and electrochemical impedance spectrometry. The feasibility of the fabrication technology is demonstrated and the devices operate satisfactorily, with a response showing good sensitivity and selectivity against common interfering cations in background solutions. The SCISME has been developed for organ monitoring during cardiac surgery or during transportation for transplants. # 2003 Elsevier Science B.V. All rights reserved.

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.

Instrumentation system for in vivo organ studies

A custom-made instrumentation system to measure multiple physiological parameters such as electrical impedance, temperature and extracellular pH and potassium levels is described. It is oriented to perform in vivo tissue experiments using electrodes and sensors based on Microsystems technologies. In vivo experimentation on rats have been carried out for validating the proposed system.

Design considerations for optimum impedance probes with planar electrodes for bioimpedance measurements

This paper describes the key issues for designing optimum impedance probes for bioimpedance monitoring. The geometrical specification of a silicon-based probe is described and experimental obtained results are also reported. A new model for probes with non-constant inter-electrode distance is also analyzed.

Micro and nano technologies in medical applications: a challenge

This paper is aimed at the analysis of the main characteristics of recent micro-devices for biomedical applications. The massive use of microtechnologies is limited today to a reduced number of fields such as: telemedicine, bioanalysis, patient monitoring, implantable devices for functional regeneration, diseases treatment, signal recording, and minimally invasive surgery. The various aspects of the current tendencies are also analysed. We conclude with the biomedical devices that CNM has developed or is currently developing.

Implementation of multisensor silicon needles for cardiac applications

The technological implementation of needle shaped probes for in vivo medical applications is presented. These probes are characterised by the simultaneous integration of various sensing capabilities: temperature, tissue electrical impedance and extracellular ions (pH and K/sup +/). The paper summarises the fabrication processes and describes the in vitro characterisation results.