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Abstract: We present a novel method to monolithically fabricate three-dimensional (3-D) microfluidic networks and based on this fabrication technology, we have constructed the first cell culture device with an integrated combinatorial mixer. The device is designed for screening the combinatorial effects of multiple compound exposure on cultured cells, and a 1cm×1cm proof-of-concept chip having a three-input combinatorial mixer and eight individually isolated micro culture-chambers has been fabricated. The 3-D microfluidic networks are fabricated utilizing the surface micromachining of parylene C (poly(chloro-p-xylylene)), and the monolithic method enables the device to achieve precise alignment in between microchannels and favorably obviates multilayer bonding processes. By incorporating several microfluidic “overpass” structures to allow one microfluidic channel to cross over other microfluidic channels, the combinatorial mixer is able to simultaneously generate all the combinations of the input fluidic streams for output to the microchambers. Cell culturing inside parylene C micro culture-chambers has been successfully performed, and the ability to simultaneously treat arrays of cells with different combinations of compounds has been demonstrated with experiments using three different cell stains. Our scaleable process can enable the fabrication of devices with a high-input combinatorial mixer with applications not only for high-throughput cell-based assays but also for conducting researches in combinatorial chemistry or the pharmaceutical industry. At the same time, the fabrication technique will have general applicability for building complex 3-D microfluidic devices, which can broaden the applications for current lab-on-a-chip systems. [Copyright &y& Elsevier]

Abstract: This work describes a novel design for a potentiometric microsensor for nitrate (NO3 −) ion based on doped polypyrrole (PPy(NO3 −)) films. First, 6–7μm diameter single carbon fiber filaments are coated with a thin (1–10μm) insulating layer of parylene C (poly(o-chloro-p-xylylene)). This preparatory step is followed by electrodeposition of a PPy(NO3 −) sensing layer on the open carbon fiber cross section. Parylene C provides an excellent protective coating for the fiber while maintaining its flexibility at micro-dimensions. Examination by scanning electron microscopy confirms that the sensing material (PPy(NO3 −)) is deposited in the form of micro-beads with diameter of 30–40μm at the fiber tip. The resulting nitrate sensor exhibits an improvement of approximately half an order of magnitude of NO3 − concentration in sensitivity and linear response range relative to a previously reported PPy(NO3 −)-based sensor for which the sensing layer was deposited on the carbon fiber walls. The overall sensor geometry, a micro-dimensioned sensing portion accompanied by a flexible, parylene-insulated body, forms a sensor for nitrate with a unique form factor that can be widely used for in situ measurements of variety of environmental samples. [Copyright &y& Elsevier]

Plaque rupture causes acute coronary syndromes and stroke. Intraplaque oxidized low density lipoprotein (oxLDL) is metabolically unstable and prone to induce rupture. We designed an intravascular ultrasound (IVUS)-guided electrochemical impedance spectroscopy (EIS) sensor to enhance the detection reproducibility of oxLDL-laden plaques. The flexible 2-point micro-electrode array for EIS was affixed to an inflatable balloon anchored onto a co-axial double layer catheter (outer diameter = 2 mm). The mechanically scanning-driven IVUS transducer (45 MHz) was deployed through the inner catheter (diameter = 1.3 mm) to the acoustic impedance matched-imaging window. Water filled the inner catheter to match acoustic impedance and air was pumped between the inner and outer catheters to inflate the balloon. The integrated EIS and IVUS sensor was deployed into the ex vivo aortas dissected from the fat-fed New Zealand White (NZW) rabbits (n = 3 for fat-fed, n = 5 normal diet). IVUS imaging was able to guide the 2-point electrode to align with the plaque for EIS measurement upon balloon inflation. IVUS-guided EIS signal demonstrated reduced variability and increased reproducibility ( p < 0.0001 for magnitude, p < 0.05 for phase at <15 kHz) as compared to EIS sensor alone ( p < 0.07 for impedance, p < 0.4 for phase at <15 kHz). Thus, we enhanced topographic and EIS detection of oxLDL-laden plaques via a catheter-based integrated sensor design to enhance clinical assessment for unstable plaque. [ABSTRACT FROM AUTHOR]

Electrical impedance spectroscopy (EIS) has been recognized to characterize oxidized low-density lipoprotein (oxLDL) in the metabolically active plaque. However, intravascular deployment of 3-D EIS-derived electrical impedance tomography (EIT) for endoluminal mapping of oxLDL-laden arterial walls remains an unmet clinical challenge. To this end, we designed the 6-point microelectrode arrays that were circumferentially configurated onto the balloon catheter for 15 intravascular EIS permutations. In parallel, we created the metabolically active plaques by performing partial ligation of right carotid artery in Yorkshire mini-pigs (n = 6 males), followed by demonstrating the plaque progression at baseline, 8 weeks, and 16 weeks of high-fat diet via computed tomography (CT) angiogram. Next, we deployed the 3-D EIS sensors to the right and left carotid arteries, and we demonstrated 3-D EIS mapping of metabolically active endolumen in the right but not left carotid arteries as evidenced by the positive E06 immunostaining for oxLDL-laden regions. By considering electrical conductivity (σ) and permittivity (ε) properties of collagen, lipid, and smooth muscle presence in the arterial wall, we further validated the 3-D EIS-derived EIT by reconstructing the histology of right and left carotid arteries for the finite element modeling of the oxLDL-laden endolumen, and we accurately predicted 3-D EIS mapping. Thus, we establish the capability of 3-D EIS-derived EIT to detect oxLDL-laden arterial walls with translational implication to predict metabolically active plaques prone to acute coronary syndromes or stroke. • First endoluminal mapping of oxLDL-laden arteries to predict plaques. • 6-point EIS sensors for electrical impedance tomography reconstruction. • 3-D mapping demonstration of endoluminal oxLDL in carotid arteries. • 3-D histology and finite element modeling for the spectroscopy validation. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we demonstrated leukocyte labeling, sensing and differentiation from undiluted human whole blood samples with microfabricated devices. A challenging issue in leukocyte sensing from blood samples is the required high-dilution level, which is used mainly to prevent interference from the overwhelmingly outnumbered erythrocytes. Dilution is undesirable for micro hemacytometers. It not only increases sample volume and processing time, but also requires mixing and buffer storage for on-chip implementation. Unlike commercial bulk instruments and previous efforts by other groups, we completely eliminated the requirement for dilution by staining leukocytes specifically with fluorescent dye acridine orange (AO) in undiluted human whole blood and then sensing them in microfluidic devices. Green fluorescent signal centered at 525nm is used for leukocyte count and red fluorescent signal centered at 650nm is used for leukocyte differentiation. Throughput of 1000 leukocytes per second was achieved. [Copyright &y& Elsevier]

Abstract: Novel flexible parylene-based high-density electrode arrays have been developed for functional electrical stimulation in retinal and spinal cord prosthetics. These arrays are microfabricated according to a single-metal-layer process and a revolutionary dual-metal-layer process that promises to meet the needs of extremely high-density stimulation applications. While in many cases thin-film platinum electrodes in parylene C would be sufficient, high surface-area platinum electroplating has been shown to extend the lifetime of stimulated electrodes to more than 430 million pulses without failing. Iridium electrode arrays with higher charge delivery capacity have also been fabricated using a new high-temperature stabilized parylene variant, parylene HT. In addition, a new heat molding process has been implemented to conform electrode arrays to approximate the curvature of canine retinas, and a chronic implantation study of the mechanical effects of parylene-based electrode arrays on the retina over a 6-month follow-up period has provided excellent results. Retinal stimulation from these parylene-based electrode arrays in an isolated tiger salamander preparation was shown to be comparable to light stimulation in terms of generation of action potentials in the inner retina. Finally, electrode arrays have also been implanted and tested on the spinal cords of murine models, with the ultimate goal of facilitation of locomotion after spinal cord injury; these arrays provide a higher density and better spatial control of stimulation and recording than is typically possible using traditional fine-wire electrodes. Spinal cord stimulation typically elicited three muscle responses, an early (direct), a middle (monosynaptic), and a late (polysynaptic) response, classified based on latency after stimulation. Stimulation at different rostrocaudal levels of the cord yielded markedly different muscle responses, highlighting the need for such high-density arrays. [Copyright &y& Elsevier]

Abstract: We present the first packaging technology for high lead-count retinal prostheses capable of fully scalable interconnection of a high-density electrode array, a radiofrequency (RF) telemetry coil, and other discrete components, such as chip capacitors, with prefabricated, stand-alone driver circuitry. This parylene-based drop-chip technology enables the application-specific integrated circuit (ASIC) to be directly integrated into the fabrication process of the other system components, such that the resulting device is flexible, facilitating surgical implantation. The ASIC-to-electrode interconnects are patterned using standard photolithography and standard microfabrication techniques, enabling the density of interconnects to scale to the limits of the lithographic equipment used to define the etch holes over the on-chip pads. This scheme also enables the simultaneous integration and interconnection of multiple ASICs with the rest of the system in such a way that the best features of chip-level and wafer-level packaging technologies are combined into a single process. Using this technique, standard photolithography and interconnect fabrication has been performed successfully on 10 chips. Electrical test results verify the efficacy of this cost-effective and high-yield packaging scheme, and pave the way for a monolithic implantable parylene-based retinal prosthesis system as well as other systems requiring the capability to perform microfabrication steps on prefabricated chips. [Copyright &y& Elsevier]

The nanofiber shaped NiS@In 2 O 3 crystalline nanocomposite with uniform diameter of 100 ± 10 nm were synthesized via the facile electrospinning and grinding routes. The gas-sensing performance of the composites was studied upon exposure to different concentrations of ethanol gas from 5 ppm to 500 ppm at the optimum temperature (300 °C). Due to the existence of p-n heterojunction, the NiS@In 2 O 3 sensor possesses ultra-high response of 20.41 towards 500 ppm, and excellent selectivity toward ethanol. Specifically, it can effectively work with super long-term stability of as long as 60 days, compared to the pristine In 2 O 3 sensor. • NiS@In 2 O 3 heterojunction was fabricated via electrospinning and calcination processes. • The NiS@In 2 O 3 sensor possesses high response of 20.41 and good selectivity to ethanol. • The sensing mechanism of the p -NiS@ n -In 2 O 3 heterojunction were discussed. Heterostructured semiconductor materials, combining the collective advantages of individuals and synergistic properties, have spurred great interest as a new paradigm toward detecting of volatile organic compounds recently. Direct use of NiS as a sensing material is impractical because the structure of NiS is unstable, exhibiting an undesirable sensing performance. Herein, we firstly report its incorporation into an ethanol gas sensor with a conventional n -type sensitive material of In 2 O 3 , and the gas sensing performance of the NiS@In 2 O 3 nanocomposites has been significantly enhanced. Nanofiber-like NiS and In 2 O 3 were fabricated via a synergetic approach of electrospinning and calcination processes. The diameters of crystalline NiS and In 2 O 3 are about 150 nm and 120 nm, respectively. Then, the NiS@In 2 O 3 nanocomposites were prepared via re-calcination of as-prepared NiS and In 2 O 3 nanofibers. The results show that the sensor based on NiS@In 2 O 3 exhibits a detecting limit of as low as 5 ppm and a short response time of 8 s at the optimum temperature of 300 ºC, which outstripped that (13 s) of pristine In 2 O 3 and pure NiS sensors (21 s) for the detection of ethanol gas. The remarkable improvement of sensing performance can be attributed to the p - n heterojunction in multi-component phases of NiS and In 2 O 3. [ABSTRACT FROM AUTHOR]