Andreas Hierlemann

ETH Zurich | ETH Zürich · Department of Biosystems Science and Engineering (BSSE)

Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. Yet, the precise relationship between synaptic input patterns and the spiking output of individual neurons remains largely unresolved. Here, we developed, validated and applied a novel in v...

Bio-signal sensing is pivotal in medical bioelectronics. Traditional methods focus on high sampling rates, leading to large amounts of irrelevant data and high energy consumption. We introduce a self-clocked microelectrode array (MEA) that digitizes bio-signals at the pixel level by encoding changes as asynchronous digital address-events only when...

In recent years, high-density microelectrode arrays (HD-MEAs) have emerged as a valuable tool in preclinical research for characterizing the electrophysiology of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). HD-MEAs enable the capturing of both extracellular and intracellular signals on a large scale, while minimizing poten...

Transwell‐based airway models have become increasingly important in studying the effects of respiratory diseases and drug treatment at the air–liquid interface of the lung epithelial barrier. However, the underlying mechanisms at the tissue and cell level often remain unclear, as transwell inserts feature limited live‐cell imaging compatibility. He...

In computational neuroscience, multicompartment models are among the most biophysically realistic representations of single neurons. Constructing such models usually involves the use of the patch-clamp technique to record somatic voltage signals under different experimental conditions. The experimental data are then used to fit the many parameters...

Neural information processing requires accurately timed action potentials arriving from presynaptic neurons at the postsynaptic neuron. However, axons of ganglion cells in the human retina feature low axonal conduction speeds and vastly different lengths, which poses a challenge to the brain for constructing a temporally coherent image over the vis...

Probing the architecture of neuronal circuits and the principles that underlie their functional organization remains an important challenge of modern neurosciences. This holds true, in particular, for the inference of neuronal connectivity from large-scale extracellular recordings. Despite the popularity of this approach and a number of elaborate m...

With the use of high density multi electrode recording devices, electrophysiological signals resulting from action potentials of individual neurons can now be reliably detected on multiple adjacent recording electrodes both in vivo and in vitro. Spike sorting assigns these signals to putative neural sources. However, until now, spike sorting can on...

Evaluation of novel therapeutics often fails to reliably predict severe complications in patients, especially when circulating cells are involved. The reasons may include inter-species differences upon using animal models or the lack of relevant in vitro systems. Moreover, existing in vitro systems mostly rely on static investigations of different...

A growing consensus that the brain is a mechanosensitive organ is driving the need for tools that mechanically stimulate and simultaneously record the electrophysiological response of neurons within neuronal networks. Here we introduce a synchronized combination of atomic force microscopy, high-density microelectrode array and fluorescence microsco...

The multifactorial nature of inflammatory bowel disease (IBD) necessitates reliable and practical experimental models to elucidate its etiology and pathogenesis. To model the intestinal microenvironment at the onset of IBD in vitro, it is important to incorporate relevant cellular and noncellular components before inducing stepwise pathogenic devel...

Probing the architecture of neuronal circuits and the principles that underlie their functional organization remains an important challenge of modern neurosciences. This holds true, in particular, for the inference of neuronal connectivity from large-scale extracellular recordings. Despite the popularity of this approach and a number of elaborate m...

Reproducible functional assays to study in vitro neuronal networks represent an important cornerstone in the quest to develop physiologically relevant cellular models of human diseases. Here, we introduce DeePhys, a MATLAB-based analysis tool for data-driven functional phenotyping of in vitro neuronal cultures recorded by high-density microelectrod...

Neuronal firing sequences are thought to be the basic building blocks of neural coding and information broadcasting within the brain. However, when sequences emerge during neurodevelopment remains unknown. We demonstrate that structured firing sequences are present in spontaneous activity of human brain organoids and ex vivo neonatal brain slices f...

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven...

Transwell-based airway models have become increasingly important to study the effects of respiratory diseases and drug treatment at the air-liquid interface of the lung epithelial barrier. However, the underlying mechanisms at tissue and cell level often remain unclear, as transwell inserts feature limited live-cell imaging compatibility. Here, we...

Bio-signal sensing represents a pivotal domain in the medical applications of bioelectronics. Traditional methods have, so far, focused on capturing these signals as accurately as possible, leading to high sampling rates in clocked synchronous architectures. Given the sparse activity of bio-signals, this approach often results in large amounts of d...

Integrating flowing cells, such as immune cells or circulating tumor cells, within a microphysiological system is crucial for body-on-a-chip applications. However, ensuring unimpeded recirculation of cells is a significant challenge....

We present a high-resolution impedance imaging and electrophysiological recording platform and demonstrate its capabilities with brain slices. The platform is easy to operate featuring an efficient data acquisition system and user-friendly software that runs on a host computer. The data acquisition platform relies on an FPGA system that enables bid...

We present a novel method for inferring connectivity from large-scale neuronal networks with synchronous activity. Our approach leverages Dynamic Differential Covariance to address the associated computational challenges. First, we analyze spike trains generated from Leaky Integrate-and-Fire network simulations and evaluate the performance of sever...

Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array tha...

Silicon-based planar microelectronics is a powerful tool for scalably recording and modulating neural activity at high spatiotemporal resolution, but it remains challenging to target neural structures in three dimensions (3D). We present a method for directly fabricating 3D arrays of tissue-penetrating microelectrodes onto silicon microelectronics....

Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. Yet, the precise relationship between the synaptic input patterns and the spiking output of individual neurons remains largely unresolved. Here, we developed, validated and applied a novel...

Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. Yet, the precise relationship between the synaptic input patterns and the spiking output of individual neurons remains largely unresolved. Here, we developed, validated and applied a novel...

CMOS neural interfaces are aimed at studying the electrical activity of neurons and may help to restore lost functions of the nervous system in the future. The central function of most neural interfaces is the detection of extracellular electrical potentials by means of numerous microelectrodes positioned in close vicinity to the neurons. Modern ne...

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, novel catalytically-d...

Blood‐brain‐barrier (BBB) disruption has been associated with a variety of central‐nervous‐system diseases. In vitro BBB models enable to investigate how the barrier reacts to external injury events, commonly referred to as insults. Here, a human‐cell‐based BBB platform with integrated, transparent electrodes to monitor barrier tightness in real ti...

Despite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient‐derived leukemia samples provide important information to tailor treatments for high‐risk patients. However, currently used well‐based drug screening pl...

Modern Graph Neural Networks (GNNs) provide opportunities to study the determinants underlying the complex activity patterns of biological neuronal networks. In this study, we applied GNNs to a large-scale electrophysiological dataset of rodent primary neuronal networks obtained by means of high-density microelectrode arrays (HD-MEAs). HD-MEAs allo...

Self-sustained recurrent activity in cortical networks is thought to be important for multiple crucial processes, including circuit development and homeostasis. However, the precise relationship between synaptic input patterns and spiking output of individual neurons remains unresolved during spontaneous network activity. Here, using whole-network...

Chimeric antigen receptors (CARs) consist of an antigen-binding region fused to intracellular signaling domains, enabling customized T cell responses against targets. Despite their major role in T cell activation, effector function and persistence, only a small set of immune signaling domains have been explored. Here we present speedingCARs, an int...

Despite being composed of highly plastic neurons with extensive positive feedback, the nervous system maintains stable overall function. To keep activity within bounds, it relies on a set of negative feedback mechanisms that can induce stabilizing adjustments and that are collectively termed “homeostatic plasticity.” Recently, a highly excitable mi...

Pharmaceutical compounds may have cardiotoxic properties, triggering potentially life-threatening arrhythmias. To investigate proarrhythmic effects of drugs, the patch clamp technique has been used as the gold standard for characterizing the electrophysiology of cardiomyocytes in vitro. However, the applicability of this technology for drug screeni...

The blood-brain-barrier (BBB) prevents that harmful substances in the blood enter the brain, and barrier disruption has been associated with a variety of central-nervous-system diseases. In vitro BBB models enable to recapitulate the BBB behavior in a controlled environment to investigate how the barrier reacts to stress events and external insults...

To enable accurate, high-throughput and longer-term studies of the immunopathogenesis of type 1 diabetes (T1D), we established three in-vitro islet-immune injury models by culturing spheroids derived from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cyt...

Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic...

In computational neuroscience, multicompartment models are among the most biophysically realistic representations of single neurons. Constructing such models usually involves the use of the patch-clamp technique to record somatic voltage signals under different experimental conditions. The experimental data are then used to fit the many parameters...

Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiology of neuronal circuits within organoids remains under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we captured spontaneous extracellular activity from brain organoids derived from human i...

Microfluidic-drop networks consist of several stable drops—interconnected through microfluidic channels—in which organ models can be cultured long-term. Drop networks feature a versatile configuration and an air–liquid interface (ALI). This ALI provides ample oxygenation, rapid liquid turnover, passive degassing, and liquid-phase stability through...

Spike sorting is an essential procedure to extract single-neuron spiking activity from extracellular electrical recordings, which is a mixture of signals from multiple neurons. To assess the performance of spike sorting algorithms, ground-truth data – where the true spiking times of individual underlying neurons are known – are necessary. However,...

Studies have provided evidence that human cerebral organoids (hCOs) recapitulate fundamental milestones of early brain development, but many important questions regarding their functionality and electrophysiological properties persist. High-density microelectrode arrays (HD-MEAs) represent an attractive analysis platform to perform functional studi...

Many biomarkers including neurotransmitters are found in external body fluids, such as sweat or saliva, but at lower titration levels than they are present in blood. Efficient detection of such biomarkers thus requires, on the one hand, to use techniques offering high sensitivity, and, on the other hand, to use a miniaturized format to carry out di...

Due to their label-free and noninvasive nature, impedance measurements have attracted increasing interest in biological research. Advances in microfabrication and integrated-circuit technology have opened a route to using large-scale microelectrode arrays for real-time, high-spatiotemporal-resolution impedance measurements of biological samples. In...

Despite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient-derived leukemia samples provides important information to tailor treatments for high-risk patients. However, currently used well-based drug screening p...

Parkinson's disease (PD) is a common debilitating neurodegenerative disorder, characterized by a progressive loss of dopaminergic (DA) neurons. Mutations, gene dosage increase, and single nucleotide polymorphisms in the α-synuclein-encoding gene SNCA either cause or increase the risk for PD. However, neither the function of α-synuclein in health an...

Economical efficiency has been a popular explanation for how networks organize themselves within the developing nervous system. However, the precise nature of the economic negotiations governing this self- organization remain unclear. We approach this problem by combining high-density microelectrode array (HD-MEA) recordings, which allow for detail...

Objective: Neurons communicate with each other by sending action potentials through their axons. The velocity of axonal signal propagation describes how fast electrical action potentials can travel. This velocity can be affected in a human brain by several pathologies, including multiple sclerosis, traumatic brain injury and channelopathies. High-...

Schistosomiasis is a neglected tropical disease that affects over 200 million people annually. As the antischistosomal drug pipeline is currently empty, repurposing of compound libraries has become a source for accelerating drug development, which demands the implementation of high-throughput and efficient screening strategies. Here, we present a p...

Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic...

As 3D in vitro tissue models become more pervasive, their built-in nutrient, metabolite, compound, and waste gradients increase biological relevance at the cost of analysis simplicity. Investigating these gradients and the resulting metabolic heterogeneity requires invasive and time-consuming methods. An alternative is using electrochemical biosens...

Existing first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited clinical applications of ACT, despite its advantages...

More than 20 years ago, electrical impedance spectroscopy (EIS) was proposed as a potential characterization method for flow cytometry. As the setup is comparably simple and the method is label-free, EIS has attracted considerable interest from the research community as a potential alternative to standard optical methods, such as fluorescence-activ...

The selective permeability of the blood-brain barrier (BBB) is a major obstacle to delivery of drugs to the central nervous system (CNS), so that in vitro BBB models are needed for drug permeability studies. Here, we present a pump-free, hanging-drop-based microfluidic BBB model that recapitulates key BBB structural features and functions. BBB func...

In extracellular neural electrophysiology, individual spikes have to be assigned to their cell of origin in a procedure called "spike sorting". Spike sorting is an unsupervised problem, since no ground-truth information is generally available. Here, we focus on improving spike sorting performance, particularly during periods of high synchronous act...

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 usi...