Andreas Hierlemann - Academia.edu (original) (raw)

Papers by Andreas Hierlemann

Research paper thumbnail of A Microfluidic Hanging-Drop-Based Islet Perifusion System for Studying Glucose-Stimulated Insulin Secretion From Multiple Individual Pancreatic Islets

Frontiers in Bioengineering and Biotechnology

Islet perifusion systems can be used to monitor the highly dynamic insulin release of pancreatic ... more Islet perifusion systems can be used to monitor the highly dynamic insulin release of pancreatic islets in glucose-stimulated insulin secretion (GSIS) assays. Here, we present a new generation of the microfluidic hanging-drop-based islet perifusion platform that was developed to study the alterations in insulin secretion dynamics from single pancreatic islet microtissues at high temporal resolution. The platform was completely redesigned to increase experimental throughput and to reduce operational complexity. The experimental throughput was increased fourfold by implementing a network of interconnected hanging drops, which allows for performing GSIS assays with four individual islet microtissues in parallel with a sampling interval of 30 s. We introduced a self-regulating drop-height mechanism that enables continuous flow and maintains a constant liquid volume in the chip, which enables simple and robust operation. Upon glucose stimulation, reproducible biphasic insulin release was...

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Research paper thumbnail of A Low-Power Opamp-Less Second-Order Delta-Sigma Modulator for Bioelectrical Signals in 0.18 µm CMOS

Sensors

This article reports on a compact and low-power CMOS readout circuit for bioelectrical signals ba... more This article reports on a compact and low-power CMOS readout circuit for bioelectrical signals based on a second-order delta-sigma modulator. The converter uses a voltage-controlled, oscillator-based quantizer, achieving second-order noise shaping with a single opamp-less integrator and minimal analog circuitry. A prototype has been implemented using 0.18 μm CMOS technology and includes two different variants of the same modulator topology. The main modulator has been optimized for low-noise, neural-action-potential detection in the 300 Hz–6 kHz band, with an input-referred noise of 5.0 μVrms, and occupies an area of 0.0045 mm2. An alternative configuration features a larger input stage to reduce low-frequency noise, achieving 8.7 μVrms in the 1 Hz–10 kHz band, and occupies an area of 0.006 mm2. The modulator is powered at 1.8 V with an estimated power consumption of 3.5 μW.

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Research paper thumbnail of Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology

Frontiers in physiology, 2018

Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important ... more Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse m...

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Research paper thumbnail of Chiral discrimination using piezoelectric and optical gas sensors

Nature

... represents one of the greatest challenges in attempts to devise selective and sensitive gas s... more ... represents one of the greatest challenges in attempts to devise selective and sensitive gas sensors ... detects changes in mass, owing to binding of the compound being analysed (the 'analyte'), by thickness ... you can purchase the article (see below) or access it through a site license ...

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Research paper thumbnail of Analysis Of Complex Gas Mixtures By Pattern Recognition With Polymer Based Quartz Microbalance Sensor Arrays

Proceedings of the International Solid-State Sensors and Actuators Conference - TRANSDUCERS '95

SUMMARY Polymer coated quartz microbalance gas sensor arrays were used to analyse quaternary mixt... more SUMMARY Polymer coated quartz microbalance gas sensor arrays were used to analyse quaternary mixtures of volatile organic compounds. The performance of the sensor arrays in combination with qualitative data evaluation utilising self-organising featuri: maps is described. The concept of context preservation artificial neural networks is compared to standard1 topology preservation with respect to its classification properties for model partitioning. In

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Research paper thumbnail of Development of neural population activity toward self-organized criticality

Neuroscience

Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in netwo... more Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches.

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Research paper thumbnail of A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels

IEEE journal of solid-state circuits, 2017

Biological cells are characterized by highly complex phenomena and processes that are, to a great... more Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm(2)) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 μm electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 ...

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Research paper thumbnail of 2048 action potential recording channels with 2.4 μVrms noise and stimulation artifact suppression

2016 IEEE Biomedical Circuits and Systems Conference (BioCAS), 2016

Here, we present 2048 low-noise, low-offset, and low-power action-potential recording channels, i... more Here, we present 2048 low-noise, low-offset, and low-power action-potential recording channels, integrated in a multi-functional high-density microelectrode array. A resistively loaded open-loop topology has been adapted for the first-stage amplifier to achieve 2.4 µVrms noise levels at low power consumption. Two novel pseudo-resistor structures have been used to realize very low HPF corner frequencies with small variations across all channels. The adjustability of pseudo resistors has been exploited to realize a "soft" reset technique that suppresses stimulation artifacts so that the amplifiers can recover from saturation within 200 µs. The chips were fabricated in a 0.18 µm 6M1P CMOS process, and measurement results are presented to show the performance of the proposed circuit structures and techniques.

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Research paper thumbnail of Towards a “Body on a Chip” using Spherical Microtissues in a Microfluidic Network

ABSTRACT Combining 3-dimensional spherical microtissues and microfluidic technologies lays the fo... more ABSTRACT Combining 3-dimensional spherical microtissues and microfluidic technologies lays the foundation for a modular pharmacological platform for drug development, toxicity testing, and investigations of complex compound-tissue interactions. In this contribution, we present the basic concept of our idea and illustrate how simple 3D tissue structures can be integrated in a continuous-perfusion environment by using basic microfluidic structures. First validations have been performed by optical means and by measuring tissue-specific viability markers.

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Research paper thumbnail of Cortical Axons, Isolated in Channels, Display Activity-Dependent Signal Modulation as a Result of Targeted Stimulation

Frontiers in neuroscience, 2016

Mammalian cortical axons are extremely thin processes that are difficult to study as a result of ... more Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulatio...

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Research paper thumbnail of Microsensor system for monitoring biological and chemical processes

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Research paper thumbnail of Proceedings of the Sixth IASTED International Conference on Biomedical Engineering

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Research paper thumbnail of Seamless Combination of Fluorescence-Activated Cell Sorting and Hanging-Drop Networks for Individual Handling and Culturing of Stem Cells and Microtissue Spheroids

Analytical Chemistry, 2016

Open microfluidic cell culturing devices offer new possibilities to simplify loading, culturing, ... more Open microfluidic cell culturing devices offer new possibilities to simplify loading, culturing, and harvesting of individual cells or microtissues due to the fact that liquids and cells/microtissues are directly accessible. We present a complete workflow for microfluidic handling and culturing of individual cells and microtissue spheroids, which is based on the hanging-drop network concept: The open microfluidic devices are seamlessly combined with fluorescence-activated cell sorting (FACS), so that individual cells, including stem cells, can be directly sorted into specified culturing compartments in a fully automated way and at high accuracy. Moreover, already assembled microtissue spheroids can be loaded into the microfluidic structures by using a conventional pipet. Cell and microtissue culturing is then performed in hanging drops under controlled perfusion. On-chip drop size control measures were applied to stabilize the system. Cells and microtissue spheroids can be retrieved from the chip by using a parallelized transfer method. The presented methodology holds great promise for combinatorial screening of stem-cell and multicellular-spheroid cultures.

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Research paper thumbnail of Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity

Neuron, Jan 16, 2015

Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathwa... more Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease.

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Research paper thumbnail of Microarray-based MALDI-TOF mass spectrometry enables monitoring of monoclonal antibody production in batch and perfusion cell cultures

Methods, 2015

Cell culture process monitoring in monoclonal antibody (mAb) production is essential for efficien... more Cell culture process monitoring in monoclonal antibody (mAb) production is essential for efficient process development and process optimization. Currently employed online, at line and offline methods for monitoring productivity as well as process reproducibility have their individual strengths and limitations. Here, we describe a matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based on a microarray for mass spectrometry (MAMS) technology to rapidly monitor a broad panel of analytes, including metabolites and proteins directly from the unpurified cell supernatant or from host cell culture lysates. The antibody titer is determined from the intact antibody mass spectra signal intensity relative to an internal protein standard spiked into the supernatant. The method allows a semi-quantitative determination of light and heavy chains. Intracellular mass profiles for metabolites and proteins can be used to track cellular growth and cell productivity.

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Research paper thumbnail of Simultaneous impedance spectroscopy and stimulation of human iPS-derived cardiac 3D spheroids in hanging-drop networks

2015 28th Ieee International Conference on Micro Electro Mechanical Systems, 2015

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Research paper thumbnail of Time-lapse electrical impedance spectroscopy for monitoring the cell cycle of single immobilized S. pombe cells

Scientific reports, Jan 26, 2015

As a complement and alternative to optical methods, wide-band electrical impedance spectroscopy (... more As a complement and alternative to optical methods, wide-band electrical impedance spectroscopy (EIS) enables multi-parameter, label-free and real-time detection of cellular and subcellular features. We report on a microfluidics-based system designed to reliably capture single rod-shaped Schizosaccharomyces pombe cells by applying suction through orifices in a channel wall. The system enables subsequent culturing of immobilized cells in an upright position, while dynamic changes in cell-cycle state and morphology were continuously monitored through EIS over a broad frequency range. Besides measuring cell growth, clear impedance signals for nuclear division have been obtained. The EIS system has been characterized with respect to sensitivity and detection limits. The spatial resolution in measuring cell length was 0.25 μm, which corresponds to approximately a 5-min interval of cell growth under standard conditions. The comprehensive impedance data sets were also used to determine the...

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Research paper thumbnail of Mitotic cells contract actomyosin cortex and generate pressure to round against or escape epithelial confinement

Nature communications, Jan 25, 2015

Little is known about how mitotic cells round against epithelial confinement. Here, we engineer m... more Little is known about how mitotic cells round against epithelial confinement. Here, we engineer micropillar arrays that subject cells to lateral mechanical confinement similar to that experienced in epithelia. If generating sufficient force to deform the pillars, rounding epithelial (MDCK) cells can create space to divide. However, if mitotic cells cannot create sufficient space, their rounding force, which is generated by actomyosin contraction and hydrostatic pressure, pushes the cell out of confinement. After conducting mitosis in an unperturbed manner, both daughter cells return to the confinement of the pillars. Cells that cannot round against nor escape confinement cannot orient their mitotic spindles and more likely undergo apoptosis. The results highlight how spatially constrained epithelial cells prepare for mitosis: either they are strong enough to round up or they must escape. The ability to escape from confinement and reintegrate after mitosis appears to be a basic prope...

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Research paper thumbnail of Gas and liquid phase sensing of volatile organics with disk microresonator

2008 IEEE 21st International Conference on Micro Electro Mechanical Systems, 2008

ABSTRACT The sensing of volatile organic compounds (VOCs) using a MEMS resonator with an in-plane... more ABSTRACT The sensing of volatile organic compounds (VOCs) using a MEMS resonator with an in-plane vibrational mode is reported. VOCs are detected in both the gas and liquid phases by a polymer-coated disk microresonator, which is operated as the frequency determining element in an amplifying feedback loop. The functionalized disk microresonators exhibit a short term frequency stability of 1.1 times 10-7 in air and 3.4 times 10-6 in water. Using polymer membranes as chemically sensitive layers, different concentrations of o-xylene, benzene, octane, trichloroethane, and toluene have been detected in the gas phase, with the limit of detection for o-xylene being 2.2 ppm. M-xylene has been detected in the liquid phase with a limit of detection of 1.9 ppm.

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Research paper thumbnail of Microelectronics Technology for Chemo/Biosensors

2006 International Conference on Microtechnologies in Medicine and Biology, 2006

Summary form only given. The aim in utilizing microfabrication techniques and, in particular, CMO... more Summary form only given. The aim in utilizing microfabrication techniques and, in particular, CMOS technology for chemical and biosensors is to devise more intelligent, more integrated, and more reliable sensor systems at potentially low costs in a generic approach. The largely planar integrated circuit (IC) and bio/chemical sensor structures have been extended into the third dimension using microfabrication technologies. Examples

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Research paper thumbnail of A Microfluidic Hanging-Drop-Based Islet Perifusion System for Studying Glucose-Stimulated Insulin Secretion From Multiple Individual Pancreatic Islets

Frontiers in Bioengineering and Biotechnology

Islet perifusion systems can be used to monitor the highly dynamic insulin release of pancreatic ... more Islet perifusion systems can be used to monitor the highly dynamic insulin release of pancreatic islets in glucose-stimulated insulin secretion (GSIS) assays. Here, we present a new generation of the microfluidic hanging-drop-based islet perifusion platform that was developed to study the alterations in insulin secretion dynamics from single pancreatic islet microtissues at high temporal resolution. The platform was completely redesigned to increase experimental throughput and to reduce operational complexity. The experimental throughput was increased fourfold by implementing a network of interconnected hanging drops, which allows for performing GSIS assays with four individual islet microtissues in parallel with a sampling interval of 30 s. We introduced a self-regulating drop-height mechanism that enables continuous flow and maintains a constant liquid volume in the chip, which enables simple and robust operation. Upon glucose stimulation, reproducible biphasic insulin release was...

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Research paper thumbnail of A Low-Power Opamp-Less Second-Order Delta-Sigma Modulator for Bioelectrical Signals in 0.18 µm CMOS

Sensors

This article reports on a compact and low-power CMOS readout circuit for bioelectrical signals ba... more This article reports on a compact and low-power CMOS readout circuit for bioelectrical signals based on a second-order delta-sigma modulator. The converter uses a voltage-controlled, oscillator-based quantizer, achieving second-order noise shaping with a single opamp-less integrator and minimal analog circuitry. A prototype has been implemented using 0.18 μm CMOS technology and includes two different variants of the same modulator topology. The main modulator has been optimized for low-noise, neural-action-potential detection in the 300 Hz–6 kHz band, with an input-referred noise of 5.0 μVrms, and occupies an area of 0.0045 mm2. An alternative configuration features a larger input stage to reduce low-frequency noise, achieving 8.7 μVrms in the 1 Hz–10 kHz band, and occupies an area of 0.006 mm2. The modulator is powered at 1.8 V with an estimated power consumption of 3.5 μW.

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Research paper thumbnail of Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology

Frontiers in physiology, 2018

Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important ... more Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse m...

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Research paper thumbnail of Chiral discrimination using piezoelectric and optical gas sensors

Nature

... represents one of the greatest challenges in attempts to devise selective and sensitive gas s... more ... represents one of the greatest challenges in attempts to devise selective and sensitive gas sensors ... detects changes in mass, owing to binding of the compound being analysed (the 'analyte'), by thickness ... you can purchase the article (see below) or access it through a site license ...

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Research paper thumbnail of Analysis Of Complex Gas Mixtures By Pattern Recognition With Polymer Based Quartz Microbalance Sensor Arrays

Proceedings of the International Solid-State Sensors and Actuators Conference - TRANSDUCERS '95

SUMMARY Polymer coated quartz microbalance gas sensor arrays were used to analyse quaternary mixt... more SUMMARY Polymer coated quartz microbalance gas sensor arrays were used to analyse quaternary mixtures of volatile organic compounds. The performance of the sensor arrays in combination with qualitative data evaluation utilising self-organising featuri: maps is described. The concept of context preservation artificial neural networks is compared to standard1 topology preservation with respect to its classification properties for model partitioning. In

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Research paper thumbnail of Development of neural population activity toward self-organized criticality

Neuroscience

Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in netwo... more Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches.

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Research paper thumbnail of A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels

IEEE journal of solid-state circuits, 2017

Biological cells are characterized by highly complex phenomena and processes that are, to a great... more Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm(2)) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 μm electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 ...

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Research paper thumbnail of 2048 action potential recording channels with 2.4 μVrms noise and stimulation artifact suppression

2016 IEEE Biomedical Circuits and Systems Conference (BioCAS), 2016

Here, we present 2048 low-noise, low-offset, and low-power action-potential recording channels, i... more Here, we present 2048 low-noise, low-offset, and low-power action-potential recording channels, integrated in a multi-functional high-density microelectrode array. A resistively loaded open-loop topology has been adapted for the first-stage amplifier to achieve 2.4 µVrms noise levels at low power consumption. Two novel pseudo-resistor structures have been used to realize very low HPF corner frequencies with small variations across all channels. The adjustability of pseudo resistors has been exploited to realize a "soft" reset technique that suppresses stimulation artifacts so that the amplifiers can recover from saturation within 200 µs. The chips were fabricated in a 0.18 µm 6M1P CMOS process, and measurement results are presented to show the performance of the proposed circuit structures and techniques.

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Research paper thumbnail of Towards a “Body on a Chip” using Spherical Microtissues in a Microfluidic Network

ABSTRACT Combining 3-dimensional spherical microtissues and microfluidic technologies lays the fo... more ABSTRACT Combining 3-dimensional spherical microtissues and microfluidic technologies lays the foundation for a modular pharmacological platform for drug development, toxicity testing, and investigations of complex compound-tissue interactions. In this contribution, we present the basic concept of our idea and illustrate how simple 3D tissue structures can be integrated in a continuous-perfusion environment by using basic microfluidic structures. First validations have been performed by optical means and by measuring tissue-specific viability markers.

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Research paper thumbnail of Cortical Axons, Isolated in Channels, Display Activity-Dependent Signal Modulation as a Result of Targeted Stimulation

Frontiers in neuroscience, 2016

Mammalian cortical axons are extremely thin processes that are difficult to study as a result of ... more Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulatio...

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Research paper thumbnail of Microsensor system for monitoring biological and chemical processes

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Research paper thumbnail of Proceedings of the Sixth IASTED International Conference on Biomedical Engineering

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Research paper thumbnail of Seamless Combination of Fluorescence-Activated Cell Sorting and Hanging-Drop Networks for Individual Handling and Culturing of Stem Cells and Microtissue Spheroids

Analytical Chemistry, 2016

Open microfluidic cell culturing devices offer new possibilities to simplify loading, culturing, ... more Open microfluidic cell culturing devices offer new possibilities to simplify loading, culturing, and harvesting of individual cells or microtissues due to the fact that liquids and cells/microtissues are directly accessible. We present a complete workflow for microfluidic handling and culturing of individual cells and microtissue spheroids, which is based on the hanging-drop network concept: The open microfluidic devices are seamlessly combined with fluorescence-activated cell sorting (FACS), so that individual cells, including stem cells, can be directly sorted into specified culturing compartments in a fully automated way and at high accuracy. Moreover, already assembled microtissue spheroids can be loaded into the microfluidic structures by using a conventional pipet. Cell and microtissue culturing is then performed in hanging drops under controlled perfusion. On-chip drop size control measures were applied to stabilize the system. Cells and microtissue spheroids can be retrieved from the chip by using a parallelized transfer method. The presented methodology holds great promise for combinatorial screening of stem-cell and multicellular-spheroid cultures.

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Research paper thumbnail of Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity

Neuron, Jan 16, 2015

Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathwa... more Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease.

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Research paper thumbnail of Microarray-based MALDI-TOF mass spectrometry enables monitoring of monoclonal antibody production in batch and perfusion cell cultures

Methods, 2015

Cell culture process monitoring in monoclonal antibody (mAb) production is essential for efficien... more Cell culture process monitoring in monoclonal antibody (mAb) production is essential for efficient process development and process optimization. Currently employed online, at line and offline methods for monitoring productivity as well as process reproducibility have their individual strengths and limitations. Here, we describe a matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based on a microarray for mass spectrometry (MAMS) technology to rapidly monitor a broad panel of analytes, including metabolites and proteins directly from the unpurified cell supernatant or from host cell culture lysates. The antibody titer is determined from the intact antibody mass spectra signal intensity relative to an internal protein standard spiked into the supernatant. The method allows a semi-quantitative determination of light and heavy chains. Intracellular mass profiles for metabolites and proteins can be used to track cellular growth and cell productivity.

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Research paper thumbnail of Simultaneous impedance spectroscopy and stimulation of human iPS-derived cardiac 3D spheroids in hanging-drop networks

2015 28th Ieee International Conference on Micro Electro Mechanical Systems, 2015

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Research paper thumbnail of Time-lapse electrical impedance spectroscopy for monitoring the cell cycle of single immobilized S. pombe cells

Scientific reports, Jan 26, 2015

As a complement and alternative to optical methods, wide-band electrical impedance spectroscopy (... more As a complement and alternative to optical methods, wide-band electrical impedance spectroscopy (EIS) enables multi-parameter, label-free and real-time detection of cellular and subcellular features. We report on a microfluidics-based system designed to reliably capture single rod-shaped Schizosaccharomyces pombe cells by applying suction through orifices in a channel wall. The system enables subsequent culturing of immobilized cells in an upright position, while dynamic changes in cell-cycle state and morphology were continuously monitored through EIS over a broad frequency range. Besides measuring cell growth, clear impedance signals for nuclear division have been obtained. The EIS system has been characterized with respect to sensitivity and detection limits. The spatial resolution in measuring cell length was 0.25 μm, which corresponds to approximately a 5-min interval of cell growth under standard conditions. The comprehensive impedance data sets were also used to determine the...

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Research paper thumbnail of Mitotic cells contract actomyosin cortex and generate pressure to round against or escape epithelial confinement

Nature communications, Jan 25, 2015

Little is known about how mitotic cells round against epithelial confinement. Here, we engineer m... more Little is known about how mitotic cells round against epithelial confinement. Here, we engineer micropillar arrays that subject cells to lateral mechanical confinement similar to that experienced in epithelia. If generating sufficient force to deform the pillars, rounding epithelial (MDCK) cells can create space to divide. However, if mitotic cells cannot create sufficient space, their rounding force, which is generated by actomyosin contraction and hydrostatic pressure, pushes the cell out of confinement. After conducting mitosis in an unperturbed manner, both daughter cells return to the confinement of the pillars. Cells that cannot round against nor escape confinement cannot orient their mitotic spindles and more likely undergo apoptosis. The results highlight how spatially constrained epithelial cells prepare for mitosis: either they are strong enough to round up or they must escape. The ability to escape from confinement and reintegrate after mitosis appears to be a basic prope...

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Research paper thumbnail of Gas and liquid phase sensing of volatile organics with disk microresonator

2008 IEEE 21st International Conference on Micro Electro Mechanical Systems, 2008

ABSTRACT The sensing of volatile organic compounds (VOCs) using a MEMS resonator with an in-plane... more ABSTRACT The sensing of volatile organic compounds (VOCs) using a MEMS resonator with an in-plane vibrational mode is reported. VOCs are detected in both the gas and liquid phases by a polymer-coated disk microresonator, which is operated as the frequency determining element in an amplifying feedback loop. The functionalized disk microresonators exhibit a short term frequency stability of 1.1 times 10-7 in air and 3.4 times 10-6 in water. Using polymer membranes as chemically sensitive layers, different concentrations of o-xylene, benzene, octane, trichloroethane, and toluene have been detected in the gas phase, with the limit of detection for o-xylene being 2.2 ppm. M-xylene has been detected in the liquid phase with a limit of detection of 1.9 ppm.

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Research paper thumbnail of Microelectronics Technology for Chemo/Biosensors

2006 International Conference on Microtechnologies in Medicine and Biology, 2006

Summary form only given. The aim in utilizing microfabrication techniques and, in particular, CMO... more Summary form only given. The aim in utilizing microfabrication techniques and, in particular, CMOS technology for chemical and biosensors is to devise more intelligent, more integrated, and more reliable sensor systems at potentially low costs in a generic approach. The largely planar integrated circuit (IC) and bio/chemical sensor structures have been extended into the third dimension using microfabrication technologies. Examples

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