Formation and Stability of Smooth Thin Films with Soft Microgels Made of Poly(N-Isopropylacrylamide) and Poly(Acrylic Acid).

In this work, soft microgels of Poly(N-Isopropylacrylamide) (PNIPAm) at two different sizes and of interpenetrated polymer network (IPN) composed of PNIPAm and Poly(Acrylic Acid) (PAAc) were synthesized. Then, solutions of these different types of microgels have been spin-coated on glass substrates with different degrees of hydrophobicity. PNIPAm particles with a larger diameter form either patches or a continuous layer, where individual particles are still distinct, depending on the dispersion concentration and spin speed. On the other, PNIPAm particles with a smaller diameter and IPN particles form a continuous and smooth film, with a thickness depending on the dispersion concentration and spin-speed. The difference in morphology observed can be explained if one considers that the microgels may behave as colloidal particles or macromolecules, depending on their size and composition. Additionally, the microgel size and composition can also affect the stability of the depositions when rinsed in water. In particular, we find that the smooth and continuous films show a stimuli-dependent stability on parameters such as temperature and pH, while large particle layers are stable under any condition except on hydrophilic glass by washing at 50 °C.

Author Correction: Memristive synapses connect brain and silicon spiking neurons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Poly(N-isopropylacrylamide) based thin microgel films for use in cell culture applications.

Poly(N-isopropylacrylamide) (PNIPAm) is widely used to fabricate cell sheet surfaces for cell culturing, however copolymer and interpenetrated polymer networks based on PNIPAm have been rarely explored in the context of tissue engineering. Many complex and expensive techniques have been employed to produce PNIPAm-based films for cell culturing. Among them, spin coating has demonstrated to be a rapid fabrication process of thin layers with high reproducibility and uniformity. In this study, we introduce an innovative approach to produce anchored smart thin films both thermo- and electro-responsive, with the aim to integrate them in electronic devices and better control or mimic different environments for cells in vitro. Thin films were obtained by spin coating of colloidal solutions made by PNIPAm and PAAc nanogels. Anchoring the films to the substrates was obtained through heat treatment in the presence of dithiol molecules. From analyses carried out with AFM and XPS, the final samples exhibited a flat morphology and high stability to water washing. Viability tests with cells were finally carried out to demonstrate that this approach may represent a promising route to integrate those hydrogels films in electronic platforms for cell culture applications.

Memristive synapses connect brain and silicon spiking neurons.

Brain function relies on circuits of spiking neurons with synapses playing the key role of merging transmission with memory storage and processing. Electronics has made important advances to emulate neurons and synapses and brain-computer interfacing concepts that interlink brain and brain-inspired devices are beginning to materialise. We report on memristive links between brain and silicon spiking neurons that emulate transmission and plasticity properties of real synapses. A memristor paired with a metal-thin film titanium oxide microelectrode connects a silicon neuron to a neuron of the rat hippocampus. Memristive plasticity accounts for modulation of connection strength, while transmission is mediated by weighted stimuli through the thin film oxide leading to responses that resemble excitatory postsynaptic potentials. The reverse brain-to-silicon link is established through a microelectrode-memristor pair. On these bases, we demonstrate a three-neuron brain-silicon network where memristive synapses undergo long-term potentiation or depression driven by neuronal firing rates.

Impact of Line Edge Roughness on ReRAM Uniformity and Scaling.

We investigate the effects of Line Edge Roughness (LER) of electrode lines on the uniformity of Resistive Random Access Memory (ReRAM) device areas in cross-point architectures. To this end, a modeling approach is implemented based on the generation of 2D cross-point patterns with predefined and controlled LER and pattern parameters. The aim is to evaluate the significance of LER in the variability of device areas and their performances and to pinpoint the most critical parameters and conditions. It is found that conventional LER parameters may induce >10% area variability depending on pattern dimensions and cross edge/line correlations. Increased edge correlations in lines such as those that appeared in Double Patterning and Directed Self-assembly Lithography techniques lead to reduced area variability. Finally, a theoretical formula is derived to explain the numerical dependencies of the modeling method.

Microstructured hybrid scaffolds for aligning neonatal rat ventricular myocytes.

In cardiac tissue engineering (TE), in vitro models are essential for the study of healthy and pathological heart tissues in order to understand the underpinning mechanisms. In this scenario, scaffolds are platforms that can realistically mimic the natural architecture of the heart, and they add biorealism to in vitro models. This paper reports a novel and robust technique to fabricate cardiovascular-mimetic scaffolds based on Parylene C and Polydimethylsiloxane (PDMS). Parylene C is employed as a mask material for inducing hybrid and non-hybrid micropatterns to the PDMS layer. Hybrid architectures present striped hydrophobic/hydrophilic surfaces, whereas non-hybrid scaffolds only corrugated topographies. Herein, we demonstrate that wavy features on PDMS can be obtained at the micro- and nanoscale and that PDMS can be integrated into the microfabrication process without changing its intrinsic physical properties. A study of the effects of these scaffolds on the growth of Neonatal Rat Ventricular Myocytes (NRVMs) cultures reveals that cell alignment occurs only for the case of hybrid architectures made of hydrophilic PDMS and hydrophobic Parylene C.

Modular Pressure and Flow Rate-Balanced Microfluidic Serial Dilution Networks for Miniaturised Point-of-Care Diagnostic Platforms.

Fast, efficient and more importantly accurate serial dilution is a necessary requirement for most biochemical microfluidic-based quantitative diagnostic applications. Over the last two decades, a multitude of microfluidic devices has been proposed, each one demonstrating either a different type of dilution technique or complex system architecture based on various flow source and valving combinations. In this work, a novel serial dilution network architecture is demonstrated, implemented on two entirely different substrates for validation and performance characterisation. The single layer, stepwise serial diluter comprises an optimised microfluidic network, where identical dilution ratios per stage are ensured, either by applying equal pressure or equal flow rates at both inlets. The advantages of this serial diluter are twofold: Firstly, it is structured as a modular unit cell, simplifying the required fluid driving mechanism to a single source for both sample and buffer solution. Thus, this unit cell can be used as a fundamental microfluidic building block, forming multistage serial dilution cascades, once combined appropriately with itself or other similar unit cells. Secondly, the serial diluter can tolerate the inevitable flow source fluctuations, ensuring constant dilution ratios without the need to employ damping mechanisms, making it ideal for Point of Care (PoC) platforms. Proof-of-concept experiments with glucose have demonstrated good agreement between simulations and measurements, highlighting the validity of our serial diluter.

Spike sorting using non-volatile metal-oxide memristors.

Electrophysiological techniques have improved substantially over the past years to the point that neuroprosthetics applications are becoming viable. This evolution has been fuelled by the advancement of implantable microelectrode technologies that have followed their own version of Moore's scaling law. Similarly to electronics, however, excessive data-rates and strained power budgets require the development of more efficient computation paradigms for handling neural data in situ; in particular the computationally heavy task of events classification. Here, we demonstrate how the intrinsic analogue programmability of memristive devices can be exploited to perform spike-sorting on single devices. Leveraging the physical properties of nanoscale memristors allows us to demonstrate that these devices can capture enough information in neural signal for performing spike detection (shown previously) and spike sorting at no additional power cost.

A Novel Microfluidic Point-of-Care Biosensor System on Printed Circuit Board for Cytokine Detection.

Point of Care (PoC) diagnostics have been the subject of considerable research over the last few decades driven by the pressure to detect diseases quickly and effectively and reduce healthcare costs. Herein, we demonstrate a novel, fully integrated, microfluidic amperometric enzyme-linked immunosorbent assay (ELISA) prototype using a commercial interferon gamma release assay (IGRA) as a model antibody binding system. Microfluidic assay chemistry was engineered to take place on Au-plated electrodes within an assay cell on a printed circuit board (PCB)-based biosensor system. The assay cell is linked to an electrochemical reporter cell comprising microfluidic architecture, Au working and counter electrodes and a Ag/AgCl reference electrode, all manufactured exclusively via standard commercial PCB fabrication processes. Assay chemistry has been optimised for microfluidic diffusion kinetics to function under continual flow. We characterised the electrode integrity of the developed platforms with reference to biological sampling and buffer composition and subsequently we demonstrated concentration-dependent measurements of H2O2 depletion as resolved by existing FDA-validated ELISA kits. Finally, we validated the assay technology in both buffer and serum and demonstrate limits of detection comparable to high-end commercial systems with the addition of full microfluidic assay architecture capable of returning diagnostic analyses in approximately eight minutes.

Seamlessly fused digital-analogue reconfigurable computing using memristors.

As the world enters the age of ubiquitous computing, the need for reconfigurable hardware operating close to the fundamental limits of energy consumption becomes increasingly pressing. Simultaneously, scaling-driven performance improvements within the framework of traditional analogue and digital design become progressively more restricted by fundamental physical constraints. Emerging nanoelectronics technologies bring forth new prospects yet a significant rethink of electronics design is required for realising their full potential. Here we lay the foundations of a design approach that fuses analogue and digital thinking by combining digital electronics with analogue memristive devices for achieving charge-based computation; information processing where every dissipated charge counts. This is realised by introducing memristive devices into standard logic gates, thus rendering them reconfigurable and capable of performing analogue computation at a power cost close to digital. The versatility and benefits of our approach are experimentally showcased through a hardware data clusterer and an analogue NAND gate.

Sub 100 nW Volatile Nano-Metal-Oxide Memristor as Synaptic-Like Encoder of Neuronal Spikes.

Advanced neural interfaces mediate a bioelectronic link between the nervous system and microelectronic devices, bearing great potential as innovative therapy for various diseases. Spikes from a large number of neurons are recorded leading to creation of big data that require online processing under most stringent conditions, such as minimal power dissipation and on-chip space occupancy. Here, we present a new concept where the inherent volatile properties of a nano-scale memristive device are used to detect and compress information on neural spikes as recorded by a multielectrode array. Simultaneously, and similarly to a biological synapse, information on spike amplitude and frequency is transduced in metastable resistive state transitions of the device, which is inherently capable of self-resetting and of continuous encoding of spiking activity. Furthermore, operating the memristor in a very high resistive state range reduces its average in-operando power dissipation to less than 100 nW, demonstrating the potential to build highly scalable, yet energy-efficient on-node processors for advanced neural interfaces.

A Sub-30 mpH Resolution Thin Film Transistor-Based Nanoribbon Biosensing Platform.

We present a complete biosensing system that comprises a Thin Film Transistor (TFT)-based nanoribbon biosensor and a low noise, high-performance bioinstrumentation platform, capable of detecting sub-30 mpH unit changes, validated by an enzymatic biochemical reaction. The nanoribbon biosensor was fabricated top-down with an ultra-thin (15 nm) polysilicon semiconducting channel that offers excellent sensitivity to surface potential changes. The sensor is coupled to an integrated circuit (IC), which combines dual switched-capacitor integrators with high precision analog-to-digital converters (ADCs). Throughout this work, we employed both conventional pH buffer measurements as well as urea-urease enzymatic reactions for benchmarking the overall performance of the system. The measured results from the urea-urease reaction demonstrate that the system can detect urea in concentrations as low as 25 µM, which translates to a change of 27 mpH, according to our initial pH characterisation measurements. The attained accuracy and resolution of our system as well as its low-cost manufacturability, high processing speed and portability make it a competitive solution for applications requiring rapid and accurate results at remote locations; a necessity for Point-of-Care (POC) diagnostic platforms.

Parylene C topographic micropattern as a template for patterning PDMS and Polyacrylamide hydrogel.

Parylene C is a well-known polymer and it has been mainly employed as a protective layer for implantable electronics. In this paper, we propose a new approach to use Parylene C as a versatile template for patterning soft materials potentially applicable as scaffolds in cardiac tissue engineering (TE). Parylene C substrates were anisotropically patterned through standard lithographic process with hydrophilic channels separating raised hydrophobic strips. Ridges and grooves of the template are 10 µm width and depth ranging from 1 to 17 µm. Polydimethylsiloxane (PDMS) and Polyacrylamide (PAm) hydrogel have been chosen as soft polymers to be moulded. Thanks to their chemical and physical properties PDMS and PAm hydrogel mimic the extracellular matrix (ECM). PDMS was spin coated on micropatterned Parylene C obtaining composite substrates with 460 nm and 1.15 µm high grooves. The Young's modulus of the composite Parylene C/PDMS was evaluated and it was found to be almost half when compared to PDMS. PAm hydrogel was also printed using collagen coated micro-grooved Parylene C. Optical micrographs and fluorescence analysis show the successful topographic and protein pattern transfer on the hydrogel.

An Assay System for Point-of-Care Diagnosis of Tuberculosis using Commercially Manufactured PCB Technology.

Rapid advances in clinical technologies, detection sensitivity and analytical throughput have delivered a significant expansion in our knowledge of prognostic and diagnostic biomarkers in many common infectious diseases, such as Tuberculosis (TB). During the last decade, a significant number of approaches to TB diagnosis have been attempted at Point-of-Care (PoC), exploiting a large variation of techniques and materials. In this work, we describe an electronics-based Enzyme-Linked ImmunoSorbent Assay (eELISA), using a Lab-on-a-Printed Circuit Board (LoPCB) approach, for TB diagnosis based on cytokine detection. The test relies upon an electrochemical (amperometric) assay, comprising a high-precision bioinstrumentation board and amperometric sensors, produced exclusively using standard PCB manufacturing processes. Electrochemical detection uses standard Au and Ag electrodes together with a bespoke, low-power, multichannel, portable data-acquisition system. We demonstrate high-performance assay chemistry performed at microfluidic volumes on Au pads directly at the PCB surface with improved limit of detection (~10 pg/mL) over standard colorimetric ELISA methods. The assay has also been implemented in plasma, showing the utility of the system for medical applications. This work is a significant step towards the development of a low-cost, portable, high-precision diagnostic and monitoring technology, which once combined with appropriate PCB-based microfluidic networks will provide complete LoPCB platforms.

High-performance PCB-based capillary pumps for affordable point-of-care diagnostics.

Capillary pumps are integral components of passive microfluidic devices. They can displace precise volumes of liquid, avoiding the need for external active components, providing a solution for sample preparation modules in Point-of-Care (PoC) diagnostic platforms. In this work, we describe a variety of high-performance capillary pump designs, suitable for the Lab-on-Printed-Circuit-Board technology (LoPCB). Pumps are fabricated entirely on Printed Circuit Board (PCB) substrates via commercially available manufacturing processes. We demonstrate the concept of LoPCB technology and detail the fabrication method of different architectures of PCB-based capillary pumps. The capillary pumps are combined with microfluidic channels of various hydraulic resistances and characterised experimentally for different micropillar shapes and minimum feature size. Their performance in terms of flow rate is reported. Due to the superhydrophilic properties of oxygen plasma treated FR-4 PCB substrate, the capillary pump flow rates are much higher (138 µL/min, for devices comprising micropillar arrays without preceding microchannel) than comparable devices based on glass, silicon or polymers. Finally, we comment on the technology's prospects, such as incorporating more complicated microfluidic networks that can be tailored for assays.

Resistive switching of Pt/TiO x /Pt devices fabricated on flexible Parylene-C substrates.

Pt/TiO x /Pt resistive switching (RS) devices are considered to be amongst the most promising candidates in memristor family and the technology transfer to flexible substrates could open the way to new opportunities for flexible memory implementations. Hence, an important goal is to achieve a fully flexible RS memory technology. Nonetheless, several fabrication challenges are present and must be solved prior to achieving reliable device fabrication and good electronic performances. Here, we propose a fabrication method for the successful transfer of Pt/TiO x /Pt stack onto flexible Parylene-C substrates. The devices were electrically characterised, exhibiting both digital and analogue memory characteristics, which are obtained by proper adjustment of pulsing schemes during tests. This approach could open new application possibilities of these devices in neuromorphic computing, data processing, implantable sensors and bio-compatible neural interfaces.

Real-time encoding and compression of neuronal spikes by metal-oxide memristors.

Advanced brain-chip interfaces with numerous recording sites bear great potential for investigation of neuroprosthetic applications. The bottleneck towards achieving an efficient bio-electronic link is the real-time processing of neuronal signals, which imposes excessive requirements on bandwidth, energy and computation capacity. Here we present a unique concept where the intrinsic properties of memristive devices are exploited to compress information on neural spikes in real-time. We demonstrate that the inherent voltage thresholds of metal-oxide memristors can be used for discriminating recorded spiking events from background activity and without resorting to computationally heavy off-line processing. We prove that information on spike amplitude and frequency can be transduced and stored in single devices as non-volatile resistive state transitions. Finally, we show that a memristive device array allows for efficient data compression of signals recorded by a multi-electrode array, demonstrating the technology's potential for building scalable, yet energy-efficient on-node processors for brain-chip interfaces.

High Density Crossbar Arrays with Sub- 15 nm Single Cells via Liftoff Process Only.

Emerging nano-scale technologies are pushing the fabrication boundaries at their limits, for leveraging an even higher density of nano-devices towards reaching 4F(2)/cell footprint in 3D arrays. Here, we study the liftoff process limits to achieve extreme dense nanowires while ensuring preservation of thin film quality. The proposed method is optimized for attaining a multiple layer fabrication to reliably achieve 3D nano-device stacks of 32 × 32 nanowire arrays across 6-inch wafer, using electron beam lithography at 100 kV and polymethyl methacrylate (PMMA) resist at different thicknesses. The resist thickness and its geometric profile after development were identified to be the major limiting factors, and suggestions for addressing these issues are provided. Multiple layers were successfully achieved to fabricate arrays of 1 Ki cells that have sub- 15 nm nanowires distant by 28 nm across 6-inch wafer.

Amperometric IFN-γ immunosensors with commercially fabricated PCB sensing electrodes.

Lab-on-a-Chip (LoC) technology has the potential to revolutionize medical Point-of-Care diagnostics. Currently, considerable research efforts are focused on innovative production technologies that will make commercial upscaling of lab-on-chip products financially viable. Printed circuit board (PCB) manufacturing techniques have several advantages in this field. In this paper we focus on transferring a complete IFN-γ enzyme-linked immune-sorbent assay (ELISA) onto a commercial PCB electrochemical biosensing platform, We adapted a commercially available ELISA to detect the enzyme product TMB/H2O2 using amperometry, successfully reproducing the colorimetry-obtained ELISA standard curve. The results demonstrate the potential for the integration of these components into an automated, disposable, electronic ELISA Lab-on-PCB diagnostic platform.

Investigation of the Switching Mechanism in TiO2-Based RRAM: A Two-Dimensional EDX Approach.

The next generation of nonvolatile memory storage may well be based on resistive switching in metal oxides. TiO2 as transition metal oxide has been widely used as active layer for the fabrication of a variety of multistate memory nanostructure devices. However, progress in their technological development has been inhibited by the lack of a thorough understanding of the underlying switching mechanisms. Here, we employed high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) combined with two-dimensional energy dispersive X-ray spectroscopy (2D EDX) to provide a novel, nanoscale view of the mechanisms involved. Our results suggest that the switching mechanism involves redistribution of both Ti and O ions within the active layer combined with an overall loss of oxygen that effectively render conductive filaments. Our study shows evidence of titanium movement in a 10 nm TiO2 thin-film through direct EDX mapping that provides a viable starting point for the improvement of the robustness and lifetime of TiO2-based resistive random access memory (RRAM).