Marco Bennati

Noise Limits of CMOS Current Interfaces for Biosensors: A Review

Current sensing readout is one of the most frequent techniques used in biosensing due to the charge-transfer phenomena occurring at solid-liquid interfaces. The development of novel nanodevices for biosensing determines new challenges for electronic interface design based on current sensing, especially when compact and efficient arrays need to be organized, such as in recent trends of rapid label-free electronic detection of DNA synthesis. This paper will review the basic noise limitations of current sensing interfaces with particular emphasis on integrated CMOS technology. Starting from the basic theory, the paper presents, investigates and compares charge-sensitive amplifier architectures used in both continuous-time and discrete-time approaches, along with their design trade-offs involving noise floor, sensitivity to stray capacitance and bandwidth. The ultimate goal of this review is providing analog designers with helpful design rules and analytical tools. Also, in order to present a comprehensive overview of the state-of-the-art, the most relevant papers recently appeared in the literature about this topic are discussed and compared.

Parallel Recording of Single Ion Channels: A Heterogeneous System Approach

The convergence of integrated electronic devices with nanotechnology structures on heterogeneous systems presents promising opportunities for the development of new classes of rapid, sensitive, and reliable sensors. The main advantage of embedding microelectronic readout structures with sensing elements is twofold. On the one hand, the SNR is increased as a result of scaling. On the other, readout miniaturization allows organization of sensors into arrays. The latter point will improve sensing accuracy by using statistical methods. However, accurate interface design is required to establish efficient communication between ionic-based and electronic-based signals. This paper shows a first example of a concurrent readout system with single-ion channel resolution, using a compact and scalable architecture. An array of biological nanosensors is organized on different layers stacked together in a mixed structure: fluidics, printed circuit board, and microelectronic readout. More specifically, an array of microholes machined into a polyoxymethylene homopolymer (POMH or Delrin) device coupled with ultralow noise sigma-delta converters current amplifiers, is used to form bilayer membranes within which ion channels are embedded. It is shown how formation of multiple artificial bilayer lipid membranes (BLMs) is automatically monitored by the interface. The system is used to detect current signals in the pA range, from noncovalent binding between single, BLM-embedded ¿-hemolysin pores and ß-cyclodextrin molecules. The current signals are concurrently processed by the readout structure.

20.5 A Sub-pA ΔΣ Current Amplifier for Single-Molecule Nanosensors

Current readout has been a known technique since the inception of electronic sensors and is widely used, for example, in radiation detectors, impedance spectroscopy, and mechanical sensors. Recently, new challenges have emerged for current sensing in the upcoming era of nanosensors. Nanowires, carbon nanotubes and nanopores are emerging devices that have been proven to be effective in sensing ultra-low concentrations of target molecules [1]. For those devices, current sensing becomes challenging since outputs consist of signals in the pA range or less, in the kHz band. To measure these values, very low-noise front-end amplifiers are needed such as the one in [2]. It achieves a noise floor as low as 20fArms at 1kHz and it is designed for electrophysiology experiments, such as in patch clamp techniques, where single-ion channel recordings from cell membranes are required. However, the instrument is bulky and needs a cooled headstage to boost performance. An integrated solution offering quad current-input 20b analog-to-digital converters is reported in [3]. However, its measured equivalent input noise is above 700fArms at 1kHz.

A Distributed Amplifier System for Bilayer Lipid Membrane (BLM) Arrays With Noise and Individual Offset Cancellation

Lipid bilayer membrane (BLM) arrays are required for high throughput analysis, for example drug screening or advanced DNA sequencing. Complex microfluidic devices are being developed but these are restricted in terms of array size and structure or have integrated electronic sensing with limited noise performance. We present a compact and scalable multichannel electrophysiology platform based on a hybrid approach that combines integrated state-of-the-art microelectronics with low-cost disposable fluidics providing a platform for high-quality parallel single ion channel recording. Specifically, we have developed a new integrated circuit amplifier based on a novel noise cancellation scheme that eliminates flicker noise derived from devices under test and amplifiers. The system is demonstrated through the simultaneous recording of ion channel activity from eight bilayer membranes. The platform is scalable and could be extended to much larger array sizes, limited only by electronic data decimation and communication capabilities.

Combined action potential- and dynamic-clamp for accurate computational modelling of the cardiac IKr current

In the present work Action-Potential clamp (APC) and Dynamic clamp (DC) were used in combination in order to optimize the Luo-Rudy (LRd) mathematical formulation of the guinea-pig rapid delayed rectifier K(+) current (IKr), and to validate the optimized model. To this end, IKr model parameters were adjusted to fit the experimental E4031-sensitive current (IE4031) recorded under APC in guinea-pig myocytes. Currents generated by LRd model (ILRd) and the optimized one (IOpt) were then compared by testing their suitability to replace IE4031 under DC. Under APC, ILRd was significantly larger than IE4031 (mean current densities 0.51±0.01 vs 0.21±0.05pA/pF; p<0.001), mainly because of different rectification. IOpt mean density (0.17±0.01pA/pF) was similar to the IE4031 one (NS); moreover, IOpt accurately reproduced IE4031 distribution along the different AP phases. Models were then compared under DC by blocking native IKr (5μM E4031) and replacing it with ILRd or IOpt. Whereas injection of ILRd overshortened AP duration (APD90) (by 25% of its pre-block value), IOpt injection restored AP morphology and duration to overlap pre-block values. This study highlights the power of APC and DC for the identification of reliable formulations of ionic current models. An optimized model of IKr has been obtained which fully reversed E4031 effects on the AP. The model strongly diverged from the widely used Luo-Rudy formulation; this can be particularly relevant to the in silico analysis of AP prolongation caused by IKr blocking or alterations.

A nanosensor interface based on delta-sigma Arrays

An emerging area of biosensors is based on the use of structures provided by recent advances of Nanotechnology such as nanowires, nanotubes and nanopores. Among them, the integration of natural nanopores such as ion channels with electronics is a promising approach to develop rapid, sensitive and reliable biosensors able to detect low concentration of target molecules or DNA sequencing. This paper presents a compact and low-cost system able to readout, process and record current in the pA range, provided by biological or synthetic nanopores. The approach is based on the idea that by processing the outputs of a large amount of single-molecule nanosensors would result in a significant increase of resolution and signal-to-noise ratio. The approach consists of an electronic interface able to detect current-based array of nanosensors, where the management of very large amount of data is critical for the readout process. As working example, we acquired the single molecule signals derived from non-covalent bindings between single a-hemolysin pores, embedded into an artificial lipid bilayer, and β-cyclodextrin molecules. The system embeds the electronic readout with the microfluidic where is placed the nanosensor array. The electronic interface is a 0.5mm2 current amplifier based on an array of ΣΔ converters. Then the high rate data streams are processed and downsampled by a DSP that communicates with a PC via a USB interface for data processing and storage.

A High Resolution Interface for Kelvin Impedance Sensing

Impedance sensing, together with impedance spectroscopy is a powerful tool detecting charge and mass transfer phenomena at complex interfaces between materials. It is widely used in electrochemical interfaces characterization and biosensing techniques. Recently, it has been proposed as a reliable readout technique to probe biomolecular interactions on modified electrodes in enzyme biosensors, DNA biosensors and immunosensors. Unfortunately, the requirements of impedance characterization accuracy, precision and dynamic range demanded by some specific application is usually accomplished by using cumbersome laboratory instrumentation. In this paper we present a fully integrated standalone, high precision, low power, 4-core impedance sensing interface to be implemented in the fast-growing application field of the ubiquitous sensing. The interface is based on a fully digital approach based on a ΔΣ demodulation that is able to achieve 15 bit of resolution, 150 ppm of temperature accuracy and dynamic ranges varying from 86 dB to 95 dB according to the impedance configuration. The 4-core chip has been implemented in 0.35 μm CMOS technology and occupies an area of 9 mm 2.

Concurrent Acquisition Approach for High Resolution Sensor Arrays

An increasing amount of sensor applications require multiple data acquisition with high resolution in truly parallel fashion. This requirement is particularly useful in the field of Nanotechnology where concurrent acquisition is required to understand the correlation between weak stochastic events. In this paper, we will propose a sensor array readout approach where synchronous sigma-delta converters are interfacing each sensing point and whose outputs are concurrently downsampled by dedicated hardware for decimation processing. The approach shows the following advantages: on the one hand the sigma-delta conversion ensures high resolution and linearity (>12 bits), on the other, the 1-bit output allows easier routing access to the array. The approach is particularly useful in the presence of very low signals where direct raster-mode switching access to the array would compromise the signal-to-noise ratio of the readout process. As a proof of this concept, the approach is applied to an array of lipid bilayer membranes (BLMs) permitting to acquire and display single molecule event data by means of a PC-based graphical user interface (GUI).

Ultra low-noise electrophysiology amplifier on a chip

This paper presents a novel continuous time (CT) - discrete time (DT) current amplifier for electrophysiology. The architecture aims to bring together advantages from both CT and DT approaches, which are high bandwidth and low noise, respectively. The low-noise current amplifier has been implemented in 0.35 μm CMOS technology, showing input-referred noise as low as 4 fA/√Hz. It allows current recording up to 10 kHz consuming about 35 mW. The system has been tested and demonstrated through recording of ion-channels activity.

A Low-Noise Transimpedance Amplifier for BLM-Based Ion Channel Recording

High-throughput screening (HTS) using ion channel recording is a powerful drug discovery technique in pharmacology. Ion channel recording with planar bilayer lipid membranes (BLM) is scalable and has very high sensitivity. A HTS system based on BLM ion channel recording faces three main challenges: (i) design of scalable microfluidic devices; (ii) design of compact ultra-low-noise transimpedance amplifiers able to detect currents in the pA range with bandwidth >10 kHz; (iii) design of compact, robust and scalable systems that integrate these two elements. This paper presents a low-noise transimpedance amplifier with integrated A/D conversion realized in CMOS 0.35 μm technology. The CMOS amplifier acquires currents in the range ±200 pA and ±20 nA, with 100 kHz bandwidth while dissipating 41 mW. An integrated digital offset compensation loop balances any voltage offsets from Ag/AgCl electrodes. The measured open-input input-referred noise current is as low as 4 fA/√Hz at ±200 pA range. The current amplifier is embedded in an integrated platform, together with a microfluidic device, for current recording from ion channels. Gramicidin-A, α-haemolysin and KcsA potassium channels have been used to prove both the platform and the current-to-digital converter.