Andreas Hierlemann

Impedance characterization and modeling of electrodes for biomedical applications

A low electrode-electrolyte impedance interface is critical in the design of electrodes for biomedical applications. To design low-impedance interfaces a complete understanding of the physical processes contributing to the impedance is required. In this work a model describing these physical processes is validated and extended to quantify the effect of organic coatings and incubation time. Electrochemical impedance spectroscopy has been used to electrically characterize the interface for various electrode materials: platinum, platinum black, and titanium nitride; and varying electrode sizes: 1 cm/sup 2/, and 900 /spl mu/m/sup 2/. An equivalent circuit model comprising an interface capacitance, shunted by a charge transfer resistance, in series with the solution resistance has been fitted to the experimental results. Theoretical equations have been used to calculate the interface capacitance impedance and the solution resistance, yielding results that correspond well with the fitted parameter values, thereby confirming the validity of the equations. The effect of incubation time, and two organic cell-adhesion promoting coatings, poly-L-lysine and laminin, on the interface impedance has been quantified using the model. This demonstrates the benefits of using this model in developing a better understanding of the physical processes occurring at the interface in more complex, biomedically relevant situations.

Higher-Order Chemical Sensing

6.2. Orthogonality versus Independence 584 6.3. Cross-sensitivity and Diversity 585 6.4. Multiple Roles of Redundancy 585 7. Data Preprocessing 586 7.1. Baseline Correction 586 7.2. Scaling 587 7.2.1. Global Techniques 588 7.2.2. Local Techniques 588 7.2.3. Nonlinear Transforms 588 8. Drift Compensation 588 8.1. Univariate Drift Compensation 589 8.2. Multivariate Drift Compensation 589 9. Feature Extraction from Sensor Dynamics 591 9.1. Transient Analysis 591 9.1.1. Oversampling Procedures 592 9.1.2. Ad hoc Transient Parameters 593 9.1.3. Model-Based Parameters 593 9.1.4. Comparative Studies 595 9.2. Temperature-Modulation Analysis 596 10. Multivariate Calibration 599 10.1. Multiway Analysis 599 10.2. Dynamical Models 602 11. Array Optimization 604 11.1. Sensor Selection 604 11.2. Feature Selection 605 11.3. Optimization of Excitation Profiles 607 12. Conclusion and Outlook 608 13. References 609

Microelectronic system for high-resolution mapping of extracellular electric fields applied to brain slices

There is an enduring quest for technologies that provide - temporally and spatially - highly resolved information on electric neuronal or cardiac activity in functional tissues or cell cultures. Here, we present a planar high-density, low-noise microelectrode system realized in microelectronics technology that features 11,011 microelectrodes (3,150 electrodes per mm(2)), 126 of which can be arbitrarily selected and can, via a reconfigurable routing scheme, be connected to on-chip recording and stimulation circuits. This device enables long-term extracellular electrical-activity recordings at subcellular spatial resolution and microsecond temporal resolution to capture the entire dynamics of the cellular electrical signals. To illustrate the device performance, extracellular potentials of Purkinje cells (PCs) in acute slices of the cerebellum have been analyzed. A detailed and comprehensive picture of the distribution and dynamics of action potentials (APs) in the somatic and dendritic regions of a single cell was obtained from the recordings by applying spike sorting and spike-triggered averaging methods to the collected data. An analysis of the measured local current densities revealed a reproducible sink/source pattern within a single cell during an AP. The experimental data substantiated compartmental models and can be used to extend those models to better understand extracellular single-cell potential patterns and their contributions to the population activity. The presented devices can be conveniently applied to a broad variety of biological preparations, i.e., neural or cardiac tissues, slices, or cell cultures can be grown or placed directly atop of the chips for fundamental mechanistic or pharmacological studies.

Microfabrication techniques for chemical/biosensors

Microfabrication processes for chemical and biochemical sensors are reviewed. Standard processing steps originating from semiconductor technology are detailed, and specific micromachining steps to fabricate three-dimensional mechanical structures are described. Fundamental chemical sensor principles are briefly abstracted and corresponding state-of-the-art examples of microfabricated chemical sensors and biosensors are given. The advantages and disadvantages of either fabricating devices in IC fabrication technology with additional microfabrication steps, or of using custom-designed nonstandard microfabrication process flows are debated. Finally, monolithic integrated chemical and biological microsensor systems are presented, which include transducer structures and operation circuitry on a single chip.

Switch-Matrix-Based High-Density Microelectrode Array in CMOS Technology

We report on a CMOS-based microelectrode array (MEA) featuring 11, 011 metal electrodes and 126 channels, each of which comprises recording and stimulation electronics, for extracellular bidirectional communication with electrogenic cells, such as neurons or cardiomyocytes. The important features include: (i) high spatial resolution at (sub)cellular level with 3150 electrodes per mm2 (electrode diameter 7 ¿m, electrode pitch 18 ¿m); (ii) a reconflgurable routing of the recording sites to the 126 channels; and (iii) low noise levels.

CMOS microelectrode array for bidirectional interaction with neuronal networks

A CMOS metal-electrode-based micro system for bidirectional communication (stimulation and recording) with neuronal cells in vitro is presented. The chip overcomes the interconnect challenge that limits todays bidirectional microelectrode arrays. The microsystem has been fabricated in an industrial CMOS technology with several post-CMOS processing steps to realize 128 biocompatible electrodes and to ensure chip stability in physiological saline. The system comprises all necessary control circuitry and on-chip A/D and D/A conversion. A modular design has been implemented, where individual stimulation- and signal-conditioning circuitry units are associated with each electrode. Stimulation signals with a resolution of 8 bits can be sent to any subset of electrodes at a rate of 60 kHz, while all electrodes of the chip are continuously sampled at a rate of 20 kHz. The circuitry at each electrode can be individually reset to its operating point in order to suppress artifacts evoked by the stimulation pulses. Biological measurements from cultured neuronal networks originating from dissociated cortical tissue of fertilized chicken eggs with amplitudes of up to 500 muVpp are presented

Application-specific sensor systems based on CMOS chemical microsensors

Abstract We report on results achieved with three different types of polymer-coated chemical microsensors fabricated in industrial CMOS technology followed by post-CMOS anisotropic etching and film deposition. The first and most extensively studied transducer is a microcapacitor sensitive to changes in dielectric properties of the polymer layer upon analyte absorption. An on-chip integrated ΣΔ-converter allows for detecting the minute capacitance changes. The second transducer is a resonant cantilever sensitive to predominantly mass changes. The cantilever is electrothermally excited; its vibrations are detected using a piezoresistive Wheatstone bridge. In analogy to acoustic wave devices, analyte absorption in the polymer causes resonance frequency shifts as a consequence of changes in the oscillating mass. The last transducer is a microcalorimeter consisting of a polymer-coated sensing thermopile and an uncoated reference thermopile each on micromachined membranes. The measurand is the absorption or desorption heat of organic volatiles in the polymer layer. The difference between the resulting thermovoltages is processed with an on-chip low-noise differential amplifier. Gas test measurements with all three transducer principles will be presented. The goal is to combine the three different transducer principles and vary the polymers in an array type structure to build a new generation of application-specific microsensor systems.

Polymer-based sensor arrays and multicomponent analysis for the detection of hazardous oragnic vapours in the environment

Abstract An array of piezoelectric quartz crystals was used to detect volatile organic compounds such as hydrocarbons, chlorinated compounds and alcohols. Steady-state frequency shifts have been used as the input parameters for multicomponent analysis. The coating materials chosen were side-chain-modified polysiloxanes. The results show clearly that these polymers provide excellent reproducibility over months. In addition, the performance of the array in the presence of humidity up to 70% r.h. does not decrease compared with dry air. In the multicomponent analysis, we compared commercially available partial least-squares regression (PLS) and artificial neural network (ANN) software. The neutral network designed for this application was small in order to avoid overfitting. For low-dimensional problems there is no difference between the two evaluation methods, but for complex ternary mixtures and long-term measurements the ANN offers advantages in predictability. Efforts were made to use a reduced set of calibration points, and here PLS presents the possibility of reducing the calibration time by 90% (use of Factorial and Box-Behnken designs) without loss of resolution, whereas the ANN suffers if a small number of training vectors is chosen.

Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites

Axons are traditionally considered stable transmission cables, but evidence of the regulation of action potential propagation demonstrates that axons may have more important roles. However, their small diameters render intracellular recordings challenging, and low-magnitude extracellular signals are difficult to detect and assign. Better experimental access to axonal function would help to advance this field. Here we report methods to electrically visualize action potential propagation and network topology in cortical neurons grown over custom arrays, which contain 11,011 microelectrodes and are fabricated using complementary metal oxide semiconductor technology. Any neuron lying on the array can be recorded at high spatio-temporal resolution, and simultaneously precisely stimulated with little artifact. We find substantial velocity differences occurring locally within single axons, suggesting that the temporal control of a neurons output may contribute to neuronal information processing.

Performances of Mass-Sensitive Devices for Gas Sensing: Thickness Shear Mode and Surface Acoustic Wave Transducers

In this work we investigated different thickness shear mode resonators (TSMRs) with fundamental frequencies of 10 and 30 MHz and surface acoustic wave devices with fundamental frequencies of 80 and 433 MHz. Four aspects were of primary interest in this comparison:  noise levels and signal-to-noise ratios (S/N), influence of the polymer film thickness, influence of temperature on the transducer signal before and after coating, and minimum threshold values for monitoring different volatile organic compounds in the environment. We limited our investigations to a temperature range between 298 and 308 K, with 303 K the routine measuring temperature. Analyte concentrations (n-octane, tetrachloroethene) were chosen from the minimum detection limit up to 5000 μg/L. The temperature was found to strongly affect the performance of all the devices. The sorption of the analyte vapors into the polymeric films was demonstrated to be transducer-independent (identical partition coefficients for all the devices). The 30 MHz TSMRs showed very satisfying results in terms of S/N and limits of detection.