Multisite Dopamine Sensing With Femtomolar Resolution Using a CMOS Enabled Aptasensor Chip.

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 diagnostics in a minimally invasive way. Here, we present the hybrid integration of bottom-up silicon-nanowire Schottky-junction FETs (SiNW SJ-FETs) with complementary-metal-oxide-semiconductor (CMOS) readout and amplification electronics to establish a robust biosensing platform with 32 × 32 aptasensor measurement sites at a 100 µm pitch. The applied hetero-junctions yield a selective biomolecular detection down to femtomolar concentrations. Selective and multi-site detection of dopamine is demonstrated at an outstanding sensitivity of ∼1 V/fM. The integrated platform offers great potential for detecting biomarkers at high dilution levels and could be applied, for example, to diagnosing neurodegenerative diseases or monitoring therapy progress based on patient samples, such as tear liquid, saliva, or eccrine sweat.

Development and Characterization of a PCB-Based Microfluidic YChannel.

Since the introduction of microfluidics in the 1990s, the community has investigated numerous methods for their fabrication. However, there is interest for their inexpensive rapid prototyping. PCB technology as a low-cost, massfabrication approach for the realization of sensors has attracted attention, while its use for microfluidics is also gaining ground. In this paper the development and characterization of a microfluidic Y-channel is presented. The proposed design and assembly process for realizing the device is described in detail and the flow rate and mixing within the microchannel are characterized, demonstrating the feasibility of the proposed novel technology for lab-on-PCB devices.

Liquid seal for compact micropiston actuation at the capillary tip.

Actuators at the tip of a submillimetric catheter could facilitate in vivo interventional procedures at cellular scales by enabling tissue biopsy and manipulation or supporting active micro-optics. However, the dominance of frictional forces at this scale makes classical mechanism problematic. Here, we report the design of a microscale piston, with a maximum dimension of 150 µm, fabricated with two-photon lithography onto the tip of 140-µm-diameter capillaries. An oil drop method is used to create a seal between the piston and the cylinder that prevents any leakage below 185-mbar pressure difference while providing lubricated friction between moving parts. This piston generates forces that increase linearly with pressure up to 130 µN without breaking the liquid seal. The practical value of the design is demonstrated with its integration with a microgripper that can grasp, move, and release 50-µm microspheres. Such a mechanism opens the way to micrometer-size catheter actuation.

Induced neural stem cell differentiation on a drawn fiber scaffold-toward peripheral nerve regeneration.

To achieve regeneration of long sections of damaged nerves, restoration methods such as direct suturing or autologous grafting can be inefficient. Solutions involving biohybrid implants, where neural stem cells are grown in vitro on an active support before implantation, have attracted attention. Using such an approach, combined with recent advancements in microfabrication technology, the chemical and physical environment of cells can be tailored in order to control their behaviors. Herein, a neural stem cell polycarbonate fiber scaffold, fabricated by 3D printing and thermal drawing, is presented. The combined effect of surface microstructure and chemical functionalization using poly-L-ornithine (PLO) and double-walled carbon nanotubes (DWCNTs) on the biocompatibility of the scaffold, induced differentiation of the neural stem cells (NSCs) and channeling of the neural cells was investigated. Upon treatment of the fiber scaffold with a suspension of DWCNTs in PLO (0.039 g l-1) and without recombinants a high degree of differentiation of NSCs into neuronal cells was confirmed by using nestin, galactocerebroside and doublecortin immunoassays. These findings illuminate the potential use of this biohybrid approach for the realization of future nerve regenerative implants.

Monolithic CMOS sensor platform featuring an array of 9'216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry.

We present the design and characterization of a monolithic complementary metal-oxide-semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9'216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)-based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl.

Floating magnetic microrobots for fiber functionalization.

Because minimally invasive surgery is increasingly used to target small lesions, demand is growing for miniaturized tools-such as microcatheters, articulated microforceps, or tweezers-that incorporate sensing and actuation for precision surgery. Although existing microfabrication techniques have addressed the construction of these devices, accurate integration and functionalization of chemical and physical sensors represent major challenges. This paper presents a microrobotic platform for the functionalization of fibers of diameters from 140 to 830 micrometers, with a patterning precision of 5 micrometers and an orientation error below 0.4°. To achieve this, we developed two 2 millimeter-by-3 millimeter, 200-micrometer-thick microrobots to align floating electronic circuits on a fiber during a wet transfer process. The position and orientation of the microrobots were controlled at the air/water interface by a permanent magnet. The stiffness of the position controlled was 0.2 newton millimeter, leading to an average force of 0.5 newton. The nonhomogeneous magnetic field of the magnet, associated with different preferred magnetization directions recorded in the microrobots, allowed the distance between the two microrobots to be precisely controlled. This extra degree of freedom was used to control the microrobot pair as a tweezer to grab and release floating electronic patterns, whereas the others were used to align the pattern position and orientation with the fiber. A model of this control, as well as the microrobots' interaction through surface tension, is proposed. Detailed performance validation is provided, and various exemplar sensor embodiments on a 200-micrometer-diameter fiber and three-dimensional devices are demonstrated.

A bio-inspired 3D micro-structure for graphene-based bacteria sensing.

Nature is a great source of inspiration for the development of solutions for biomedical problems. We present a novel biosensor design utilizing two-photon polymerisation and graphene to fabricate an enhanced biosensing platform for the detection of motile bacteria. A cage comprising venous valve-inspired directional micro-structure is fabricated around graphene-based sensing electronics. The asymmetric 3D micro-structure promotes motile cells to swim from outside the cage towards the inner-most chamber, resulting in concentrated bacteria surrounding the central sensing region, thus enhancing the sensing signal. The concentrating effect is proved across a range of cell cultures - from 101 CFU/ml to 109 CFU/ml. Fluorescence analysis shows a 3.38-3.5 times enhanced signal. pH sensor presents a 2.14-3.08 times enhancement via the detection of cellar metabolite. Electrical measurements demonstrate an 8.8-26.7 times enhanced current. The proposed platform provides a new way of leveraging bio-inspired 3D printing and 2D materials for the development of sensing devices for biomedical applications.

Dielectrophoresis-Assisted Integration of 1024 Carbon Nanotube Sensors into a CMOS Microsystem.

Carbon-nanotube (CNT)-based sensors offer the potential to detect single-molecule events and picomolar analyte concentrations. An important step toward applications of such nanosensors is their integration in large arrays. The availability of large arrays would enable multiplexed and parallel sensing, and the simultaneously obtained sensor signals would facilitate statistical analysis. A reliable method to fabricate an array of 1024 CNT-based sensors on a fully processed complementary-metal-oxide-semiconductor microsystem is presented. A high-yield process for the deposition of CNTs from a suspension by means of liquid-coupled floating-electrode dielectrophoresis (DEP), which yielded 80% of the sensor devices featuring between one and five CNTs, is developed. The mechanism of floating-electrode DEP on full arrays and individual devices to understand its self-limiting behavior is studied. The resistance distributions across the array of CNT devices with respect to different DEP parameters are characterized. The CNT devices are then operated as liquid-gated CNT field-effect-transistors (LG-CNTFET) in liquid environment. Current dependency to the gate voltage of up to two orders of magnitude is recorded. Finally, the sensors are validated by studying the pH dependency of the LG-CNTFET conductance and it is demonstrated that 73% of the CNT sensors of a given microsystem show a resistance decrease upon increasing the pH value.

Large-scale assembly of single nanowires through capillary-assisted dielectrophoresis.

An innovative technique is proposed for the precise and scalable placement of 1D nanostructures in an affordable manner. This approach combines the dielectrophoresis phenomenon and capillary assembly to successfully align thousands of single nanowires at specific locations at the wafer. The nanowires are selectively trapped by taking advantage of the material--specific frequence dependence.

Elucidation of the role of carbon nanotube patterns on the development of cultured neuronal cells.

Carbon nanotubes (CNTs) promise various novel neural biomedical applications for interfacing neurons with electronic devices or to design appropriate biomaterials for tissue regeneration. In this study, we use a new methodology to pattern SiO(2) cell culture surfaces with double-walled carbon nanotubes (DWNTs). In contrast to homogeneous surfaces, patterned surfaces allow us to investigate new phenomena about the interactions between neural cells and CNTs. Our results demonstrate that thin layers of DWNTs can serve as effective substrates for neural cell culture. Growing neurons sense the physical and chemical properties of the local substrate in a contact-dependent manner and retrieve essential guidance cues. Cells exhibit comparable adhesion and differentiation scores on homogeneous CNT layers and on a homogeneous control SiO(2) surface. Conversely, on patterned surfaces, it is found that cells preferentially grow on CNT patterns and that neurites are guided by micrometric CNT patterns. To further elucidate this observation, we investigate the interactions between CNTs and proteins that are contained in the cell culture medium by using quartz crystal microbalance measurements. Finally, we show that protein adsorption is enhanced on CNT features and that this effect is thickness dependent. CNTs seem to act as a sponge for culture medium elements, possibly explaining the selectivity in cell growth localization and differentiation.

A combination of capillary and dielectrophoresis-driven assembly methods for wafer scale integration of carbon-nanotube-based nanocarpets.

The wafer scale integration of carbon nanotubes (CNT) remains a challenge for electronic and electromechanical applications. We propose a novel CNT integration process relying on the combination of controlled capillary assembly and buried electrode dielectrophoresis (DEP). This process enables us to monitor the precise spatial localization of a high density of CNTs and their alignment in a pre-defined direction. Large arrays of independent and low resistivity (4.4 × 10(-5) Ω m) interconnections were achieved using this hybrid assembly with double-walled carbon nanotubes (DWNT). Finally, arrays of suspended individual CNT carpets are realized and we demonstrate their potential use as functional devices by monitoring their resonance frequencies (ranging between 1.7 and 10.5 MHz) using a Fabry-Perot interferometer.