@article{Krol2015,
title = {A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture.},
author = {Jacek Krol and Ilona Krol and Claudia Patricia Patino Alvarez and Michele Fiscella and Andreas Hierlemann and Botond Roska and Witold Filipowicz},
url = {https://www.nature.com/articles/ncomms8305},
doi = {10.1038/ncomms8305},
issn = {2041-1723},
year = {2015},
date = {2015-06-04},
journal = {Nature Communications},
volume = {6},
pages = {7305},
publisher = {Nature Publishing Group},
abstract = {Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia-neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Takahashi2015,
title = {Chronic Co-Variation of Neural Network Configuration and Activity in Mature Dissociated Cultures},
author = {Satoru Okawa and Takeshi Mita and Douglas J Bakkum and Urs Frey and Andreas Hierlemann and Ryohei Kanzaki and Hirokazu Takahashi},
url = {http://onlinelibrary.wiley.com/doi/10.1002/ecj.11736/abstract;jsessionid=791557FA80CF36B1F78DC538C1618924.f03t02},
doi = {10.1002/ecj.11736},
issn = {1942-9541},
year = {2015},
date = {2015-04-08},
journal = {Electronics and Communications in Japan},
volume = {98},
number = {5},
pages = {34-42},
abstract = {Spatiotemporal neural patterns depend on the physical structure of neural circuits. Neural plasticity can thus be associated with changes in the circuit structure. For example, newborn neurons migrate toward existing, already matured, neural networks in order to participate in neural computation. In the present study, we have conducted two experiments to investigate how neural migration is associated with the development of neural activity in primary dissociated cultures of neuronal cells. In Experiment 1, using a mature culture, a high-density CMOS microelectrode array was used to continuously monitor neural migration and activity for more than two weeks. Consequently, we found that even in mature neuronal cultures neurons moved 2.0 ± 1.0 mum a day and that the moving distance was negatively correlated with their firing rate, suggesting that neurons featuring low firing rates tend to migrate actively. In Experiment 2 using a co-culture of mature and immature neurons, we found that immature neurons moved more actively than matured neurons to achieve functional connections to other neurons. These findings suggest that neurons with low firing rates as well as newborn neurons actively migrate in order to establish their connections and function in a neuronal network.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Lewandowska2015,
title = {Recording large extracellular spikes in microchannels along many axonal sites from individual neurons},
author = {Marta K Lewandowska and Douglas J Bakkum and Santiago B Rompani and Andreas Hierlemann},
url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118514},
doi = {10.1371/journal.pone.0118514},
issn = {19326203},
year = {2015},
date = {2015-03-03},
journal = {PLoS ONE},
volume = {10},
number = {3},
pages = {1-24},
abstract = {The numerous connections between neuronal cell bodies, made by their dendrites and axons, are vital for information processing in the brain. While dendrites and synapses have been extensively studied, axons have remained elusive to a large extent. We present a novel platform to study axonal physiology and information processing based on combining an 11,011-electrode high-density complementary metal-oxide semiconductor microelectrode array with a poly(dimethylsiloxane) channel device, which isolates axons from somas and, importantly, significantly amplifies recorded axonal signals. The combination of the microelectrode array with recording and stimulation capability with the microfluidic isolation channels permitted us to study axonal signal behavior at great detail. The device, featuring two culture chambers with over 30 channels spanning in between, enabled long-term recording of single spikes from isolated axons with signal amplitudes of 100 uV up to 2 mV. Propagating signals along axons could be recorded with 10 to 50 electrodes per channel. We (i) describe the performance and capabilities of our device for axonal electrophysiology, and (ii) present novel data on axonal signals facilitated by the device. Spontaneous action potentials with characteristic shapes propagated from somas along axons between the two compartments, and these unique shapes could be used to identify individual axons within channels that contained many axonal branches. Stimulation through the electrode array facilitated the identification of somas and their respective axons, enabling interfacing with different compartments of a single cell. Complex spike shapes observed in channels were traced back to single cells, and we show that more complicated spike shapes originate from a linear superposition of multiple axonal signals rather than signal distortion by the channels.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dragas2015,
title = {Complexity Optimization and High-Throughput Low-Latency Hardware Implementation of a Multi-Electrode Spike-Sorting Algorithm},
author = {Jelena Dragas and David Jäckel and Andreas Hierlemann and Felix Franke},
url = {http://ieeexplore.ieee.org/document/6955847/},
doi = {10.1109/TNSRE.2014.2370510},
issn = {15344320},
year = {2015},
date = {2015-03-01},
journal = {IEEE Transactions on Neural Systems and Rehabilitation Engineering},
volume = {23},
number = {2},
pages = {149--158},
abstract = {Reliable real-time low-latency spike sorting with large data throughput is essential for studies of neural network dynamics and for brain-machine interfaces (BMIs), in which the stimulation of neural networks is based on the networks' most recent activity. However, the majority of existing multi-electrode spike-sorting algorithms are unsuited for processing high quantities of simultaneously recorded data. Recording from large neuronal networks using large high-density electrode sets (thousands of electrodes) imposes high demands on the data-processing hardware regarding computational complexity and data transmission bandwidth; this, in turn, entails demanding requirements in terms of chip area, memory resources and processing latency. This paper presents computational complexity optimisation techniques, which facilitate the use of spike-sorting algorithms in large multi-electrode-based recording systems. The techniques are then applied to a previously published algorithm, on its own, unsuited for large electrode set recordings. Further, a real-time low-latency high-performance VLSI hardware architecture of the modified algorithm is presented, featuring a folded structure capable of processing the activity of hundreds of neurons simultaneously. The hardware is reconfigurable “on-the-fly” and adaptable to the non-stationarities of neuronal recordings. By transmitting exclusively spike time stamps and/or spike waveforms, its real-time processing offers the possibility of data bandwidth and data storage reduction.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Obien2015,
title = {Revealing neuronal function through microelectrode array recordings},
author = {Marie Engelene J Obien and Kosmas Deligkaris and Torsten Bullmann and Douglas J Bakkum and Urs Frey},
url = {https://www.frontiersin.org/articles/10.3389/fnins.2014.00423/full},
doi = {10.3389/fnins.2014.00423},
issn = {1662453X},
year = {2015},
date = {2015-01-06},
journal = {Frontiers in Neuroscience},
volume = {9},
pages = {423},
abstract = {Microelectrode arrays and microprobes have been widely utilized to measure neuronal activity, both in vitro and in vivo. The key advantage is the capability to record and stimulate neurons at multiple sites simultaneously. However, unlike the single-cell or single-channel resolution of intracellular recording, microelectrodes detect signals from all possible sources around every sensor. Here, we review the current understanding of microelectrode signals and the techniques for analyzing them. We introduce the ongoing advancements in microelectrode technology, with focus on achieving higher resolution and quality of recordings by means of monolithic integration with on-chip circuitry. We show how recent advanced microelectrode array measurement methods facilitate the understanding of single neurons as well as network function.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Ballini2014,
title = {A 1024-channel CMOS microelectrode array with 26,400 electrodes for recording and stimulation of electrogenic cells in vitro},
author = {Marco Ballini and Jan Müller and Paolo Livi and Yihui Chen and Urs Frey and Alexander Stettler and Amir Shadmani and Vijay Viswam and Ian L Jones and David Jäckel and Milos Radivojevic and Marta K Lewandowska and Wei Gong and Michele Fiscella and Douglas J Bakkum and Flavio Heer and Andreas Hierlemann},
url = {http://ieeexplore.ieee.org/document/6923484/},
doi = {10.1109/JSSC.2014.2359219},
issn = {00189200},
year = {2014},
date = {2014-10-14},
journal = {IEEE Journal of Solid-State Circuits},
volume = {49},
number = {11},
pages = {2705-2719},
abstract = {To advance our understanding of the functioning of neuronal ensembles, systems are needed to enable simultaneous recording from a large number of individual neurons at high spa-tiotemporal resolution and good signal-to-noise ratio. Moreover, stimulation capability is highly desirable for investigating, for example, plasticity and learning processes. Here, we present a microelectrode array (MEA) system on a single CMOS die for in vitro recording and stimulation. The system incorporates 26,400 platinum electrodes, fabricated by in-house post-processing, over a large sensing area (3.85 2.10 mm) with sub-cellular spatial resolution (pitch of 17.5 µm). Owing to an area and power efficient implementation, we were able to integrate 1024 readout channels on chip to record extracellular signals from a user-specified selection of electrodes. These channels feature noise values of 2.4 µV in the action-potential band (300 Hz–10 kHz) and 5.4 µV in the local-field-potential band (1 Hz–300 Hz), and provide programmable gain (up to 78 dB) to accommodate various biological preparations. Amplified and filtered signals are digitized by 10 bit parallel single-slope ADCs at 20 kSamples/s. The system also includes 32 stimulation units, which can elicit neural spikes through either current or voltage pulses. The chip consumes only 75 mW in total, which obviates the need of active cooling even for sensitive cell cultures.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Bakkum2014,
title = {Parameters for burst detection},
author = {Douglas J Bakkum and Milos Radivojevic and Urs Frey and Felix Franke and Andreas Hierlemann and Hirokazu Takahashi},
url = {http://journal.frontiersin.org/article/10.3389/fncom.2013.00193/abstract},
doi = {10.3389/fncom.2013.00193},
issn = {1662-5188},
year = {2014},
date = {2014-01-13},
journal = {Frontiers in Computational Neuroscience},
volume = {7},
pages = {1-12},
abstract = {Bursts of action potentials within neurons and throughout networks are believed to serve roles in how neurons handle and store information, both in vivo and in vitro. Accurate detection of burst occurrences and durations are therefore crucial for many studies. A number of algorithms have been proposed to do so, but a standard method has not been adopted. This is due, in part, to many algorithms requiring the adjustment of multiple ad-hoc parameters and further post-hoc criteria in order to produce satisfactory results. Here, we broadly catalog existing approaches and present a new approach requiring the selection of only a single parameter: the number of spikes N comprising the smallest burst to consider. A burst was identified if N spikes occurred in less than T ms, where the threshold T was automatically determined from observing a probability distribution of inter-spike-intervals. Performance was compared vs. different classes of detectors on data gathered from in vitro neuronal networks grown over microelectrode arrays. Our approach offered a number of useful features including: a simple implementation, no need for ad-hoc or post-hoc criteria, and precise assignment of burst boundary time points. Unlike existing approaches, detection was not biased toward larger bursts, allowing identification and analysis of a greater range of neuronal and network dynamics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Bakkum2013,
title = {Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites},
author = {Douglas J Bakkum and Urs Frey and Milos Radivojevic and Thomas L Russell and Jan Müller and Michele Fiscella and Hirokazu Takahashi and Andreas Hierlemann},
url = {http://www.nature.com/doifinder/10.1038/ncomms3181},
doi = {10.1038/ncomms3181},
issn = {2041-1723},
year = {2013},
date = {2013-07-19},
journal = {Nature Communications},
volume = {4},
pages = {1-12},
abstract = {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 neuron's output may contribute to neuronal information processing.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Muller2012,
title = {Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons.},
author = {Jan Müller and Douglas J Bakkum and Andreas Hierlemann},
url = {https://www.frontiersin.org/articles/10.3389/fncir.2012.00121/full},
doi = {10.3389/fncir.2012.00121},
issn = {1662-5110},
year = {2013},
date = {2013-01-10},
journal = {Frontiers in Neural Circuits},
volume = {6},
pages = {121},
abstract = {We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal-oxide-semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a "knob" to tune information processing in the network.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Hierlemann2012,
title = {High-density microelectrode array recordings and real-time spike sorting for closed-loop experiments: an emerging technology to study neural plasticity},
author = {Felix Franke and David Jackel and Jelena Dragas and Jan Muller and Milos Radivojevic and Douglas J Bakkum and Andreas Hierlemann},
url = {https://www.frontiersin.org/article/10.3389/fncir.2012.00105},
doi = {10.3389/fncir.2012.00105},
issn = {1662-5110},
year = {2012},
date = {2012-12-20},
journal = {Frontiers in Neural Circuits},
volume = {6},
pages = {105},
abstract = {Understanding plasticity of neural networks is a key to comprehending their development and function. A powerful technique to study neural plasticity includes recording and control of pre- and postsynaptic neural activity, e.g., by using simultaneous intracellular recording and stimulation of several neurons. Intracellular recording is, however, a demanding technique and has its limitations in that only a small number of neurons can be stimulated and recorded from at the same time. Extracellular techniques offer the possibility to simultaneously record from larger numbers of neurons with relative ease, at the expenses of increased efforts to sort out single neuronal activities from the recorded mixture, which is a time consuming and error prone step, referred to as spike sorting. In this mini-review, we describe recent technological developments in two separate fields, namely CMOS-based high-density microelectrode arrays, which also allow for extracellular stimulation of neurons, and real-time spike sorting. We argue that these techniques, when combined, will provide a powerful tool to study plasticity in neural networks consisting of several thousand neurons in vitro.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Fiscella2012,
title = {Recording from defined populations of retinal ganglion cells using a high-density CMOS-integrated microelectrode array with real-time switchable electrode selection},
author = {Michele Fiscella and Karl Farrow and Ian L Jones and David Jäckel and Jan Müller and Urs Frey and Douglas J Bakkum and Péter Hantz and Botond Roska and Andreas Hierlemann},
url = {http://www.sciencedirect.com/science/article/pii/S0165027012003287?via%3Dihub},
doi = {10.1016/j.jneumeth.2012.08.017},
issn = {01650270},
year = {2012},
date = {2012-08-16},
journal = {Journal of Neuroscience Methods},
volume = {211},
number = {1},
pages = {103-113},
publisher = {Elsevier B.V.},
abstract = {In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic-configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14 ± 7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Jackel2012,
title = {Applicability of independent component analysis on high-density microelectrode array recordings},
author = {David Jäckel and Urs Frey and Michele Fiscella and Felix Franke and Andreas Hierlemann},
url = {http://jn.physiology.org/cgi/doi/10.1152/jn.01106.2011},
doi = {10.1152/jn.01106.2011},
issn = {0022-3077},
year = {2012},
date = {2012-04-04},
journal = {Journal of Neurophysiology},
volume = {108},
number = {1},
pages = {334-348},
abstract = {Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Jones2011,
title = {The potential of microelectrode arrays and microelectronics for biomedical research and diagnostics},
author = {Ian L Jones and Paolo Livi and Marta K Lewandowska and Michele Fiscella and Branka Roscic and Andreas Hierlemann},
url = {https://link.springer.com/article/10.1007%2Fs00216-010-3968-1},
doi = {10.1007/s00216-010-3968-1},
issn = {1618-2650},
year = {2011},
date = {2011-07-31},
journal = {Analytical and Bioanalytical Chemistry},
volume = {399},
number = {7},
pages = {2313-2329},
abstract = {Planar microelectrode arrays (MEAs) are devices that can be used in biomedical and basic in vitro research to provide extracellular electrophysiological information about biological systems at high spatial and temporal resolution. Complementary metal oxide semiconductor (CMOS) is a technology with which MEAs can be produced on a microscale featuring high spatial resolution and excellent signal-to-noise characteristics. CMOS MEAs are specialized for the analysis of complete electrogenic cellular networks at the cellular or subcellular level in dissociated cultures, organotypic cultures, and acute tissue slices; they can also function as biosensors to detect biochemical events. Models of disease or the response of cellular networks to pharmacological compounds can be studied in vitro, allowing one to investigate pathologies, such as cardiac arrhythmias, memory impairment due to Alzheimer's disease, or vision impairment caused by ganglion cell degeneration in the retina.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Hierlemann2011,
title = {Growing cells atop microelectronic chips: Interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays},
author = {Andreas Hierlemann and Urs Frey and Sadik Hafizovic and Flavio Heer},
url = {http://ieeexplore.ieee.org/document/5594982/},
doi = {10.1109/JPROC.2010.2066532},
issn = {00189219},
year = {2011},
date = {2011-02-01},
journal = {Proceedings of the IEEE},
volume = {99},
number = {2},
pages = {252-284},
abstract = {Complementary semiconductor-metal-oxide (CMOS) technology is a very powerful technology that can be more or less directly interfaced to electrogenic cells, like heart or brain cells in vitro. To this end, the cells are cultured directly atop the CMOS chips, which usually undergo dedicated postprocessing to obtain a reliable bidirectional interface via noble-metal microelectrodes or high-k dielectrics. The big advantages of using CMOS integrated circuits (ICs) include connectivity, the possibility to address a large number of microelectrodes on a tiny chip, and signal quality, the possibility to condition small signals right at the spot of their generation. CMOS will be demonstrated to constitute an enabling technology that opens a route to high-spatio-temporal-resolution and low-noise electrophysiological recordings from a variety of biological preparations, such as brain slices, or cultured cardiac and brain cells. The recording technique is extracellular and noninvasive, and the CMOS chips do not leak out any toxic compounds, so that the cells remain viable for extended times. In turn, the CMOS chips have been demonstrated to survive several months of culturing while being fully immersed in saline solution and being exposed to cellular metabolic products. The latter requires dedicated passivation and packaging techniques as will be shown. Fully integrated, monolithic microelectrode systems, which feature large numbers of tightly spaced microelectrodes and the associated circuitry units for bidirectional interaction (stimulation and recording), will be in the focus of this review. The respective dense microelectrode arrays (MEAs) with small pixels enable subcellular-resolution investigation of regions of interest in, e.g., neurobiological preparations, and, at the same time, the large number of electrodes allows for studying the activity of entire neuronal networks . Application areas include neuroscience, as the devices enable fundamental neurophysiological insights at the cellular and circuit level, as well as medical diagnostics and pharmacology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Livi2010,
title = {Compact voltage and current stimulation buffer for high-density microelectrode arrays},
author = {Paolo Livi and Flavio Heer and Urs Frey and Douglas J Bakkum and Andreas Hierlemann},
url = {http://ieeexplore.ieee.org/document/5617318/},
doi = {10.1109/TBCAS.2010.2080676},
issn = {19324545},
year = {2010},
date = {2010-11-01},
journal = {IEEE Transactions on Biomedical Circuits and Systems},
volume = {4},
number = {6},
pages = {372-378},
abstract = {We report on a compact (0.02 mm2 ) buffer for both voltage and current stimulation of electrogenic cells on a complementary metal-oxide semiconductor microelectrode array. In voltage mode, the circuit is a high-current class-AB voltage follower, based on a local common-mode feedback (LCMFB) amplifier. In current mode, the circuit is a current conveyor of type II, using the same LCMFB amplifier with cascode stages to increase the gain. The circuit shows good linearity in the 0.5-3.5 V input range and has extensively been used for stimulation of neuronal cultures.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Frey2010,
title = {Switch-matrix-based high-density microelectrode array in CMOS technology},
author = {Urs Frey and Jan Sedivy and Flavio Heer and Rene Pedron and Marco Ballini and Jan Müller and Douglas J Bakkum and Sadik Hafizovic and Francesca D Faraci and Frauke Greve and Kay Uwe Kirstein and Andreas Hierlemann},
url = {http://ieeexplore.ieee.org/document/5405139/},
doi = {10.1109/JSSC.2009.2035196},
issn = {00189200},
year = {2010},
date = {2010-02-02},
journal = {IEEE Journal of Solid-State Circuits},
volume = {45},
number = {2},
pages = {467-482},
abstract = {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 um, electrode pitch 18 um); (ii) a reconflgurable routing of the recording sites to the 126 channels; and (iii) low noise levels.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Frey2009,
title = {Microelectronic system for high-resolution mapping of extracellular electric fields applied to brain slices},
author = {Urs Frey and Ulrich Egert and Flavio Heer and Sadik Hafizovic and Andreas Hierlemann},
url = {http://www.sciencedirect.com/science/article/pii/S095656630800643X?via%3Dihub},
doi = {10.1016/j.bios.2008.11.028},
issn = {09565663},
year = {2009},
date = {2009-03-15},
journal = {Biosensors and Bioelectronics},
volume = {24},
number = {7},
pages = {2191-2198},
abstract = {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 mm2), 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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Weber2009,
title = {A synthetic mammalian electro-genetic transcription circuit},
author = {Wilfried Weber and Stefan Luzi and Maria Karlsson and Carlota Diaz Sanchez-Bustamante and Urs Frey and Andreas Hierlemann and Martin Fussenegger},
url = {https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkp014},
doi = {10.1093/nar/gkp014},
issn = {03051048},
year = {2009},
date = {2009-02-03},
journal = {Nucleic Acids Research},
volume = {37},
number = {4},
pages = {1-8},
abstract = {Electric signal processing has evolved to manage rapid information transfer in neuronal networks and muscular contraction in multicellular organisms and controls the most sophisticated man-built devices. Using a synthetic biology approach to assemble electronic parts with genetic control units engineered into mammalian cells, we designed an electric power-adjustable transcription control circuit able to integrate the intensity of a direct current over time, to translate the amplitude or frequency of an alternating current into an adjustable genetic readout or to modulate the beating frequency of primary heart cells. Successful miniaturization of the electro-genetic devices may pave the way for the design of novel hybrid electrogenetic implants assembled from electronic and genetic parts.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Sanchez-Bustamante2008,
title = {Modulation of cardiomyocyte electrical properties using regulated bone morphogenetic protein-2 expression.},
author = {Carlota Diaz Sanchez-Bustamante and Urs Frey and Jens M Kelm and Andreas Hierlemann and Martin Fussenegger},
url = {http://online.liebertpub.com/doi/abs/10.1089/ten.tea.2007.0302?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed},
doi = {10.1089/ten.tea.2007.0302},
issn = {1937-3341},
year = {2008},
date = {2008-11-19},
journal = {Tissue Engineering. Part A},
volume = {14},
number = {12},
pages = {1969-1988},
abstract = {Because cardiomyocytes lose their ability to divide after birth, any subsequent cell loss or dysfunction results in pathologic cardiac rhythm initiation or impulse conduction. Strategies to restore and control the electrophysiological activity of the heart may, therefore, greatly affect the regeneration of cardiac tissue functionality. Using lentivirus-derived particles to regulate the bone morphogenetic protein-2 (BMP-2) gene expression in a pristinamycin- or gaseous acetaldehyde-inducible manner, we demonstrated the adjustment of cardiomyocyte electrophysiological characteristics. Complementary metal oxide semiconductor-based high-density microelectrode arrays (HD-MEAs) were used to monitor the electrophysiological activity of neonatal rat cardiomyocytes (NRCs) cultured as monolayers (NRCml) or as microtissues (NRCmt). NRCmt more closely resembled heart tissue physiology than did NRCml and could be conveniently monitored using HD-MEAs because of their ability to detect low-signal events and to sub-select the region of interest, namely, areas where the microtissues were placed. Cardiomyocyte-forming microtissues, transduced using lentiviral vectors encoding BMP-2, were capable of restoring myocardial microtissue electrical activity. We also engineered NRCmt to functionally couple within a cardiomyocyte monolayer, thus showing pacemaker-like activity upon local regulation of transgenic BMP-2 expression. The controlled expression of therapeutic transgenes represents a crucial advance for clinical interventions and gene-function analysis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Hierlemann2007,
title = {A CMOS-based microelectrode array for interaction with neuronal cultures},
author = {Sadik Hafizovic and Flavio Heer and T Ugniwenko and Urs Frey and Axel Blau and Christiane Ziegler and Andreas Hierlemann},
url = {http://linkinghub.elsevier.com/retrieve/pii/S0165027007001781},
doi = {10.1016/j.jneumeth.2007.04.006},
issn = {0165-0270},
year = {2007},
date = {2007-04-19},
journal = {Journal of Neuroscience Methods},
volume = {164},
number = {1},
pages = {93-106},
abstract = {We report on the system integration of a CMOS chip that is capable of bidirectionally communicating (stimulation and recording) with electrogenic cells such as neurons or cardiomyocytes and that is targeted at investigating electrical signal propagation within cellular networks in vitro. The overall system consists of three major subunits: first, the core component is a 6.5 mm × 6.5 mm CMOS chip, on top of which the cells are cultured. It features 128 bidirectional electrodes, each equipped with dedicated analog filters and amplification stages and a stimulation buffer. The electrodes are sampled at 20 kHz with 8-bit resolution. The measured input-referred circuitry noise is 5.9 muV root mean square (10 Hz to 100 kHz), which allows to reliably detect the cell signals ranging from 1 mVpp down to 40 muVpp. Additionally, temperature sensors, a digital-to-analog converter for stimulation, and a digital interface for data transmission are integrated. Second, there is a reconfigurable logic device, which provides chip control, event detection, data buffering and an USB interface, capable of processing the 2.56 million samples per second. The third element includes software that is running on a standard PC performing data capturing, processing, and visualization. Experiments involving the stimulation of neurons with two different spatio-temporal patterns and the recording of the triggered spiking activity have been carried out. The response patterns have been successfully classified (83% correct) with respect to the different stimulation patterns. The advantages over current microelectrode arrays, as has been demonstrated in the experiments, include the capability to stimulate (voltage stimulation, 8 bit, 60 kHz) spatio-temporal patterns on arbitrary sets of electrodes and the fast stimulation reset mechanism that allows to record neuronal signals on a stimulating electrode 5 ms after stimulation (instantaneously on all other electrodes). Other advantages of the overall system include the small number of needed electrical connections due to the digital interface and the short latency time that allows to initiate a stimulation less than 2 ms after the detection of an action potential in closed-loop configurations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}