Development of a Smart Wireless Multisensor Platform for an Optogenetic Brain Implant.

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments.

Peptide-Based Sensor and Microfluidic Platform for IgG Antibody Detection by Differential Impedance Sensing.

Serological assays enable infection screening as relatively easy-to-operate approaches compared with standard methods. In addition, to be relevant for early diagnosis, specific antibody detection is important for epidemiological surveillance and quantitative detection has potential significance for evaluating the severity and prognosis of different diseases.Here, we describe the detection process based on differential impedance sensing of IgG antibodies labeled with polystyrene nanoparticles. The electrode differential configuration, the amplification with nanoparticle functionalization, the electronic reading, and the microfluidic protocol allow to reach a limit of detection below 100 pg/mL for commercial IgG antibody spiked in buffer.

Temperature and wavelength drift tolerant WDM transmission and routing in on-chip silicon photonic interconnects.

We demonstrate a temperature and wavelength shift resilient silicon transmission and routing interconnect system suitable for multi-socket interconnects, utilizing a dual-strategy CLIPP feedback circuitry that safeguards the operating point of the constituent photonic building blocks along the entire on-chip transmission-multiplexing-routing chain. The control circuit leverages a novel control power-independent and calibration-free locking strategy that exploits the 2nd derivative of ring resonator modulators (RMs) transfer function to lock them close to the point of minimum transmission penalty. The system performance was evaluated on an integrated Silicon Photonics 2-socket demonstrator, enforcing control over a chain of RM-MUX-AWGR resonant structures and stressed against thermal and wavelength shift perturbations. The thermal and wavelength stress tests ranged from 27°C to 36°C and 1309.90 nm to 1310.85 nm and revealed average eye diagrams Q-factor values of 5.8 and 5.9 respectively, validating the system robustness to unstable environments and fabrication variations.

Active Opto-Magnetic Biosensing with Silicon Microring Resonators.

Integrated optical biosensors are gaining increasing attention for their exploitation in lab-on-chip platforms. The standard detection method is based on the measurement of the shift of some optical quantity induced by the immobilization of target molecules at the surface of an integrated optical element upon biomolecular recognition. However, this requires the acquisition of said quantity over the whole hybridization process, which can take hours, during which any external perturbation (e.g., temperature and mechanical instability) can seriously affect the measurement and contribute to a sizeable percentage of invalid tests. Here, we present a different assay concept, named Opto-Magnetic biosensing, allowing us to optically measure off-line (i.e., post hybridization) tiny variations of the effective refractive index seen by microring resonators upon immobilization of magnetic nanoparticles labelling target molecules. Bound magnetic nanoparticles are driven in oscillation by an external AC magnetic field and the corresponding modulation of the microring transfer function, due to the effective refractive index dependence on the position of the particles above the ring, is recorded using a lock-in technique. For a model system of DNA biomolecular recognition we reached a lowest detected concentration on the order of 10 pm, and data analysis shows an expected effective refractive index variation limit of detection of 7.5×10-9 RIU, in a measurement time of just a few seconds.

High-sensitivity transparent photoconductors in voltage-controlled silicon waveguides.

On-chip optical power monitors are essential elements to calibrate, stabilize, and reconfigure photonic integrated circuits. Many applications require in-line waveguide detectors, where a trade-off has to be found between large sensitivity and high transparency to the guided light. In this work, we demonstrate a transparent photoconductor integrated on standard low-doped silicon-on-insulator waveguides that reaches a photoconductive gain of more than 106 and an in-line sensitivity as high as -60 dBm. This performance is achieved by compensating the effect of electric charges in the cladding oxide through a bias voltage applied to the chip substrate or locally through a gate electrode on top of the waveguide, allowing one to tune on demand the conductivity of the core to the optimum level.

Differential Impedance Sensing platform for high selectivity antibody detection down to few counts: A case study on Dengue Virus.

We developed a biosensing system for serological detection of viruses based on the impedance variation between gold microelectrodes upon the capture of the target antibodies hybridized with nanobeads for signal amplification. The microfluidic platform core features a Differential Impedance Sensing (DIS) architecture between a reference and an active sensor able to reach nanoparticle resolution of few tens. The biosensor, functionalized with a copoly layer housing a synthetic peptide probe, has shown a limit of detection (LOD) below 100 pg/mL using a model IgG antibody spiked in a buffer. The biosensor was also tested with human serum samples for quantitative counts of anti-Dengue Virus antibodies, reaching a sensitivity that outperforms commercial ELISA kit. The system is perfectly suited to be easily reconfigured for novel probes by simply modifying the preparation of the biosensor chip surface, thus addressing a wide range of pathogens and diseases with clinically relevant concentrations for rapid immunoassays in a point of care setting.

Polarization-transparent silicon photonic add-drop multiplexer with wideband hitless tuneability.

Flexible optical networks require reconfigurable devices with operation on a wavelength range of several tens of nanometers, hitless tuneability (i.e. transparency to other channels during reconfiguration), and polarization independence. All these requirements have not been achieved yet in a single photonic integrated device and this is the reason why the potential of integrated photonics is still largely unexploited in the nodes of optical communication networks. Here we report on a fully-reconfigurable add-drop silicon photonic filter, which can be tuned well beyond the extended C-band (almost 100 nm) in a complete hitless (>35 dB channel isolation) and polarization transparent (1.2 dB polarization dependent loss) way. This achievement is the result of blended strategies applied to the design, calibration, tuning and control of the device. Transmission quality assessment on dual polarization 100 Gbit/s (QPSK) and 200 Gbit/s (16-QAM) signals demonstrates the suitability for dynamic bandwidth allocation in core networks, backhaul networks, intra- and inter-datacenter interconnects.

A Lab-On-chip Tool for Rapid, Quantitative, and Stage-selective Diagnosis of Malaria.

Malaria remains the most important mosquito-borne infectious disease worldwide, with 229 million new cases and 409.000 deaths in 2019. The infection is caused by a protozoan parasite which attacks red blood cells by feeding on hemoglobin and transforming it into hemozoin. Despite the WHO recommendation of prompt malaria diagnosis, the quality of microscopy-based diagnosis is frequently inadequate while rapid diagnostic tests based on antigens are not quantitative and still affected by non-negligible false negative/positive results. PCR-based methods are highly performant but still not widely used in endemic areas. Here, a diagnostic tool (TMek), based on the paramagnetic properties of hemozoin nanocrystals in infected red blood cells (i-RBCs), is reported on. Exploiting the competition between gravity and magnetic forces, i-RBCs in a whole blood specimen are sorted and electrically detected in a microchip. The amplitude and time evolution of the electrical signal allow for the quantification of i-RBCs (in the range 10-105 i-RBC µL-1) and the distinction of the infection stage. A preliminary validation study on 75 patients with clinical suspect of malaria shows on-field operability, without false negative and a few false positive results. These findings indicate the potential of TMek as a quantitative, stage-selective, rapid test for malaria.

Platinum diimine-dithiolate complexes as a new class of photoconducting compounds for pristine photodetectors: case study on [Pt(bipy)(Naph-edt)] (bipy = 2,2'-bipyridine; Naph-edt2- = 2-naphthylethylene-1,2-dithiolate).

The photoconducting properties of platinum diimine-dithiolate complex [Pt(bipy)(Naph-edt)] (1; bipy = 2,2'-bipyridine; Naph-edt2- = 2-naphthylethylene-1,2-dithiolate) were investigated. DFT calculations on a model assembly with four complex units suggest that the high external quantum efficency measured on a prototype photodetector correlates with the intermolecular character of electronic excitations in the visible region.

Electrical conductance of silicon photonic waveguides.

Many optoelectronic devices embedded in a silicon photonic chip, like photodetectors, modulators, and attenuators, rely on waveguide doping for their operation. However, the doping level of a waveguide is not always reflecting in an equal amount of free carriers available for conduction because of the charges and trap energy states inevitably present at the Si/SiO2 interface. In a silicon-on-insulator technology with 1015cm-3p-doped native waveguides, this can lead to a complete depletion of the core from free carriers and to a consequently very high electrical resistance. This Letter experimentally quantifies this effect and shows how the amount of free carriers in a waveguide can be modified and restored to the original doping value with a proper control of the chip substrate potential. A similar capability is also demonstrated by means of a specific metal gate integrated above the waveguide that allows fine control of the conductance with high locality level. This paper highlights the linearity achievable in the conductance modulation that can be exploited in a number of possible applications.

Monitoring cell endocytosis of liposomes by real-time electrical impedance spectroscopy.

Evaluation and understanding the effect of drug delivery in in vitro systems is fundamental in drug discovery. We present an assay based on real-time electrical impedance spectroscopy (EIS) measurements that can be used to follow the internalisation and cytotoxic effect of a matrix metalloproteinase (MMP)-sensitive liposome formulation loaded with oxaliplatin (OxPt) on colorectal cancer cells. The EIS response identified two different cellular processes: (i) a negative peak in the cell index (CI) within the first 5 h, due to onset of liposome endocytosis, followed by (ii) a subsequent CI increase, due to the reattachment of cells until the onset of cytotoxicity with a decrease in CI. Free OxPt or OxPt-loaded Stealth liposomes did not show this two-stage EIS response; the latter can be due to the fact that Stealth cannot be cleaved by MMPs and thus is not taken up by the cells. Real-time bright-field imaging supported the EIS data, showing variations in cell adherence and cell morphology after exposure to the different liposome formulations. A drastic decrease in cell coverage as well as rounding up of cells during the first 5 h of exposure to OxPt-loaded (MMP)-sensitive liposome formulation is reflected by the first negative EIS response, which indicates the onset of liposome endocytosis. Graphical abstract.

Photoconducting Devices with Response in the Visible-Near-Infrared Region Based on Neutral Ni Complexes of Aryl-1,2-dithiolene Ligands.

Metal bis(1,2-dithiolene) complexes belonging to the class [Ni(Ar-edt)2]x- [Ar-edt2- = arylethylene-1,2-dithiolate; Ar = phenyl, (1x-), 2-naphthyl (2x-); x = 0 and 1] were fully characterized by NMR, UV-visible-near-infrared (UV-vis-NIR), diffuse reflectance, and FT-IR spectroscopy, as well as cyclic voltammetry and single-crystal X-ray diffraction analysis. These complexes have emerged as new photoconducting materials that allowed for the development of a prototype of photodetectors with response in the vis-NIR region. The photodetecting devices showed in some cases quantum efficiencies orders of magnitude higher than those of previously reported 1,2-dithiolene systems.

Miniaturized Impedance Flow Cytometer: Design Rules and Integrated Readout.

A dual-channel credit-card-sized impedance cell counter featuring a throughput of 2000 cell/s and detection of single yeast cells (5 µm) with a signal-to-noise ratio of 20 dB is presented. Its compactness is achieved by a CMOS ASIC combining a lock-in impedance demodulator with an oversampling 20-bit ΣΔ ADC and real-time peak detection embedded in field-programmable gate array. The module is coupled to a dielectrophoretic cell-sorting microfluidic device, offering compact and label-free electrical readout that replaces the need for a fluorescence microscope and, thus, is suitable for point-of-care diagnostics. The independent role of each dimension of the planar sensing microelectrodes is demonstrated, with simulations and experiments, along with its relevant effect on the spectrum of thin channels, deriving useful design guidelines.

Unscrambling light-automatically undoing strong mixing between modes.

Propagation of light beams through scattering or multimode systems may lead to the randomization of the spatial coherence of the light. Although information is not lost, its recovery requires a coherent interferometric reconstruction of the original signals, which have been scrambled into the modes of the scattering system. Here we show that we can automatically unscramble optical beams that have been arbitrarily mixed in a multimode waveguide, undoing the scattering and mixing between the spatial modes through a mesh of silicon photonics tuneable beam splitters. Transparent light detectors integrated in a photonic chip are used to directly monitor the evolution of each mode along the mesh, allowing sequential tuning and adaptive individual feedback control of each beam splitter. The entire mesh self-configures automatically through a progressive tuning algorithm and resets itself after significantly perturbing the mixing, without turning off the beams. We demonstrate information recovery by the simultaneous unscrambling, sorting and tracking of four mixed modes, with residual cross-talk of -20 dB between the beams. Circuit partitioning assisted by transparent detectors enables scalability to meshes with a higher port count and to a higher number of modes without a proportionate increase in the control complexity. The principle of self-configuring and self-resetting in optical systems should be applicable in a wide range of optical applications.

On-Chip Magnetic Platform for Single-Particle Manipulation with Integrated Electrical Feedback.

Methods for the manipulation of single magnetic particles have become very interesting, in particular for in vitro biological studies. Most of these studies require an external microscope to provide the operator with feedback for controlling the particle motion, thus preventing the use of magnetic particles in high-throughput experiments. In this paper, a simple and compact system with integrated electrical feedback is presented, implementing in the very same device both the manipulation and detection of the transit of single particles. The proposed platform is based on zig-zag shaped magnetic nanostructures, where transverse magnetic domain walls are pinned at the corners and attract magnetic particles in suspension. By applying suitable external magnetic fields, the domain walls move to the nearest corner, thus causing the step by step displacement of the particles along the nanostructure. The very same structure is also employed for detecting the bead transit. Indeed, the presence of the magnetic particle in suspension over the domain wall affects the depinning field required for its displacement. This characteristic field can be monitored through anisotropic magnetoresistance measurements, thus implementing an integrated electrical feedback of the bead transit. In particular, the individual manipulation and detection of single 1-µm sized beads is demonstrated.

The role of micro-scale current sensing in biomedicine: A unifying view and design guidelines.

The electrical activity of cells is regulated by ion fluxes and chemical signaling between them is sustained by redox-reactive molecules. Consequently, current sensing represents a straightforward way to interface electronics with biology and a common detection tool in several applications spanning from patch-clamp and nanopores to micro-scale impedance tracking. Reaching pA resolution at the ms timescale represents a challenge for the readout circuit and here all the criticalities involved in the optimal design of the sensing electrode are reviewed. Advantages vs. drawbacks and risks of the use of silicon as active vs. passive substrate respectively are illustrated by means of experimental examples.

All-organic and fully-printed semitransparent photodetectors based on narrow bandgap conjugated molecules.

All-organic, fully-printed and semitransparent photodetectors with a broad wavelength band response, based on a ternary blend comprising narrow band-gap small molecules, are demonstrated. The ternary blend with a semiconducting polymer allows for the optimal printing of small molecules, suppressing strong phase segregation, and uncontrolled crystallization. The insertion of a suitable interlayer enables the adoption of polymer, transparent, top and bottom printed electrodes, thus making light detection possible from both device sides.

Integration of an organic photodetector onto a plastic optical fiber by means of spray coating technique.

A working prototype of integrated fiber/receiver system for optical data transmission is realized. The prototype is made by directly depositing an organic photodetector onto a plastic optical fiber. For the deposition of the organic layers, spray coating is successfully exploited. Operation over four orders of magnitude range of light intensities as well as photoresponse to pulsed stimulation are demonstrated.

Doped overoxidized polypyrrole microelectrodes as sensors for the detection of dopamine released from cell populations.

A surface modification of interdigitated gold microelectrodes (IDEs) with a doped polypyrrole (PPy) film for detection of dopamine released from populations of differentiated PC12 cells is presented. A thin PPy layer was potentiostatically electropolymerized from an aqueous pyrrole solution onto electrode surfaces. The conducting polymer film was doped during electropolymerization by introducing counter-ions in the monomer solution. Several counter-ions were tested and the resulting electrode modifications were characterized electrochemically to find the optimal dopant that increases sensitivity in dopamine detection. Overoxidation of the PPy films was shown to contribute to a significant enhancement in sensitivity to dopamine. The changes caused by overoxidation in the electrochemical behavior and electrode morphology were investigated using cyclic voltammetry and SEM as well as AFM, respectively. The optimal dopant for dopamine detection was found to be polystyrene sulfonate anion (PSS(-)). Rat pheochromocytoma (PC12) cells, a suitable model to study exocytotic dopamine release, were differentiated on IDEs functionalized with an overoxidized PSS(-)-doped PPy film. The modified electrodes were used to amperometrically detect dopamine released by populations of cells upon triggering cellular exocytosis with an elevated K(+) concentration. A comparison between the generated current on bare gold electrodes and gold electrodes modified with overoxidized doped PPy illustrates the clear advantage of the modification, yielding 2.6-fold signal amplification. The results also illustrate how to use cell population based dopamine exocytosis measurements to obtain biologically significant information that can be relevant in, for instance, the study of neural stem cell differentiation into dopaminergic neurons.

Multichannel bipotentiostat integrated with a microfluidic platform for electrochemical real-time monitoring of cell cultures.

An electrochemical detection system specifically designed for multi-parameter real-time monitoring of stem cell culturing/differentiation in a microfluidic system is presented. It is composed of a very compact 24-channel electronic board, compatible with arrays of microelectrodes and coupled to a microfluidic cell culture system. A versatile data acquisition software enables performing amperometry, cyclic voltammetry and impedance spectroscopy in each of the 12 independent chambers over a 100 kHz bandwidth with current resolution down to 5 pA for 100 ms measuring time. The design of the platform, its realization and experimental characterization are reported, with emphasis on the analysis of impact of input capacitance (i.e., microelectrode size) and microfluidic pump operation on current noise. Programmable sequences of successive injections of analytes (ferricyanide and dopamine) and rinsing buffer solution as well as the impedimetric continuous tracking for seven days of the proliferation of a colony of PC12 cells are successfully demonstrated.