Micromolar Metabolite Measurement in an Electronically Multiplexed Format.

OBJECTIVE: The detection of metabolites such as choline in blood are important in clinical care for patients with cancer and cardiovascular disease. Choline is only present in human blood at low concentrations hence accurate measurement in an affordable point-of-care format is extremely challenging. Although complementary metal-oxide semiconductor (CMOS) and microfluidics are individually mature technologies, their integration has presented challenges that we overcome in a novel, cost-effective, single-step process. METHODS: To demonstrate the process, we present the microfluidic integration of a metabolomics-on-CMOS point-of-care platform with four capillary microfluidic channels on top of a CMOS optical sensor array. RESULTS: The fabricated device was characterised to verify the required structural profile, mechanical strength, optical spectra, and fluid flow. As a proof of concept, we used the device for the in-vitro quantification of choline in human blood plasma with a limit of detection of 3.2 µM and a resolution of 1.6 µM. SIGNIFICANCE: Integration of microfluidics on to CMOS technology has the potential to enable advanced sensing technologies with extremely low limit of detection that are well suited to multiple clinical metabolite measurements.

Negative Refraction in Time-Varying Strongly Coupled Plasmonic-Antenna-Epsilon-Near-Zero Systems.

Time-varying metasurfaces are emerging as a powerful instrument for the dynamical control of the electromagnetic properties of a propagating wave. Here we demonstrate an efficient time-varying metasurface based on plasmonic nano-antennas strongly coupled to an epsilon-near-zero (ENZ) deeply subwavelength film. The plasmonic resonance of the metal resonators strongly interacts with the optical ENZ modes, providing a Rabi level spitting of ∼30%. Optical pumping at frequency ω induces a nonlinear polarization oscillating at 2ω responsible for an efficient generation of a phase conjugate and a negative refracted beam with a conversion efficiency that is more than 4 orders of magnitude greater compared to the bare ENZ film. The introduction of a strongly coupled plasmonic system therefore provides a simple and effective route towards the implementation of ENZ physics at the nanoscale.

Video-rate terahertz digital holographic imaging system.

Terahertz (THz) imaging has been demonstrated in numerous applications from medical to non-destructive evaluation (NDE), but current systems require expensive components, provide slow frame-rates and low resolutions. THz holography offers a potentially low-cost, high-performance alternative. Here we demonstrate the first full video-rate THz digital holography system at 2.52 THz (118.8 µm) using low-cost optical components. 2D digital reconstructions of samples are performed at frame-rates of 50 Hz - an order of magnitude higher than previous systems, whilst imaging of samples concealed in common packaging types demonstrates suitability for NDE applications. A lateral resolution of 250 µm was determined using a 1951 USAF target.

Dynamic acoustic field activated cell separation (DAFACS).

Advances in diagnostics, cell and stem cell technologies drive the development of application-specific tools for cell and particle separation. Acoustic micro-particle separation offers a promising avenue for high-throughput, label-free, high recovery, cell and particle separation and isolation in regenerative medicine. Here, we demonstrate a novel approach utilizing a dynamic acoustic field that is capable of separating an arbitrary size range of cells. We first demonstrate the method for the separation of particles with different diameters between 6 and 45 µm and secondly particles of different densities in a heterogeneous medium. The dynamic acoustic field is then used to separate dorsal root ganglion cells. The shearless, label-free and low damage characteristics make this method of manipulation particularly suited for biological applications. Advantages of using a dynamic acoustic field for the separation of cells include its inherent safety and biocompatibility, the possibility to operate over large distances (centimetres), high purity (ratio of particle population, up to 100%), and high efficiency (ratio of separated particles over total number of particles to separate, up to 100%).

Cell patterning with a heptagon acoustic tweezer--application in neurite guidance.

Accurate control over positioning of cells is a highly desirable feature in tissue engineering applications since it allows, for example, population of substrates in a controlled fashion, rather than relying on random seeding. Current methods to achieve a differential distribution of cells mostly use passive patterning methods to change chemical, mechanical or topographic properties of surfaces, making areas differentially permissive to the adhesion of cells. However, these methods have no ad hoc control over the actual deposition of cells. Direct patterning methods like bioprinting offer good control over cell position, but require sophisticated instrumentation and are often cost- and time-intensive. Here, we present a novel electronically controlled method of generating dynamic cell patterns by acoustic trapping of cells at a user-determined position, with a heptagonal acoustic tweezer device. We demonstrate the capability of the device to create complex patterns of cells using the device's ability to re-position acoustic traps by using a phase shift in the acoustic wave, and by switching the configuration of active piezoelectric transducers. Furthermore, we show that by arranging Schwann cells from neonatal rats in a linear pattern we are able to create Bands of Büngner-like structures on a non-structured surface and demonstrate that these features are able to guide neurite outgrowth from neonatal rat dorsal root ganglia.

Multispectral metamaterial absorber.

We present the simulation, implementation, and measurement of a multispectral metamaterial absorber (MSMMA) and show that we can realize a simple absorber structure that operates in the mid-IR and terahertz (THz) bands. By embedding an IR metamaterial absorber layer into a standard THz metamaterial absorber stack, a narrowband resonance is induced at a wavelength of 4.3 µm. This resonance is in addition to the THz metamaterial absorption resonance at 109 µm (2.75 THz). We demonstrate the inherent scalability and versatility of our MSMMA by describing a second device whereby the MM-induced IR absorption peak frequency is tuned by varying the IR absorber geometry. Such a MSMMA could be coupled with a suitable sensor and formed into a focal plane array, enabling multispectral imaging.

Controlling acoustic streaming in an ultrasonic heptagonal tweezers with application to cell manipulation.

Acoustic radiation force has been demonstrated as a method for manipulating micron-scale particles, but is frequently affected by unwanted streaming. In this paper the streaming in a multi-transducer quasi-standing wave acoustic particle manipulation device is assessed, and found to be dominated by a form of Eckart streaming. The experimentally observed streaming takes the form of two main vortices that have their highest velocity in the region where the standing wave is established. A finite element model is developed that agrees well with experimental results, and shows that the Reynolds stresses that give rise to the fluid motion are strongest in the high velocity region. A technical solution to reduce the streaming is explored that entails the introduction of a biocompatible agar gel layer at the bottom of the chamber so as to reduce the fluid depth and volume. By this means, we reduce the region of fluid that experiences the Reynolds stresses; the viscous drag per unit volume of fluid is also increased. Particle Image Velocimetry data is used to observe the streaming as a function of agar-modified cavity depth. It was found that, in an optimised structure, Eckart streaming could be reduced to negligible levels so that we could make a sonotweezers device with a large working area of up to 13 mm × 13 mm.

Patterning of microspheres and microbubbles in an acoustic tweezers.

We describe the construction of an ultrasonic device capable of micro-patterning a range of microscopic particles for bioengineering applications such as targeted drug delivery. The device is formed from seven ultrasonic transducers positioned around a heptagonal cavity. By exciting two or three transducers simultaneously, lines or hexagonal shapes can be formed with microspheres, emulsions and microbubbles. Furthermore, phase control of the transducers allows patterning at any desired position in a controlled manner. The paper discusses in detail direct positioning of functionalised microspheres, emulsions and microbubbles. With the advantages of miniaturization, rapid and simple fabrication, ultrasonic tweezers is a potentially useful tool in many biomedical applications.

Narrowband multispectral filter set for visible band.

We design, fabricate and characterise a narrowband Fabry-Pérot multispectral filter set for the visible range (400-750 nm) that is suitable for integration onto complementary-metal oxide-semiconductor image sensors. We reduce the fabrication steps by fixing the physical cavity length and altering the effective optical length instead. Using electron-beam lithography, a sub-wavelength hole array is patterned in a silicon nitride cavity layer, backfilled with poly(methyl methacrylate), and bounded by aluminium mirrors to create 23 filters with full-width half-maximums of 22-46 nm. Additionally, for colourmetric reproduction applications, using as few as 10 filters gives a colour difference (CIEDE2000) of 0.072, better than trichromatic filters.

Direct patterning of mammalian cells in an ultrasonic heptagon stencil.

We describe the construction of a ultrasonic device suitable for micro patterning particles and cells for tissue engineering applications. The device is formed by seven transducers shaped into a heptagon cavity. By exciting two and three transducers simultaneously, lines or hexagonal shapes can be formed with beads and cells. Furthermore, phase control of the transducers allows shifting the standing waves and thus patterning at different positions on a surface in a controlled manner. The paper discusses direct patterning of mammalian cells by ultrasound "stencil".

Polarization insensitive terahertz metamaterial absorber.

We present the simulation, implementation, and measurement of a polarization insensitive resonant metamaterial absorber in the terahertz region. The device consists of a metal/dielectric-spacer/metal structure allowing us to maximize absorption by varying the dielectric material and thickness and, hence, the effective electrical permittivity and magnetic permeability. Experimental absorption of 77% and 65% at 2.12 THz (in the operating frequency range of terahertz quantum cascade lasers) is observed for a spacer of polyimide or silicon dioxide respectively. These metamaterials are promising candidates as absorbing elements for thermally based terahertz imaging.

A Wireless Biomedical Signal Interface System-on-Chip for Body Sensor Networks.

Recent years have seen the rapid development of biosensor technology, system-on-chip design, wireless technology. and ubiquitous computing. When assembled into an autonomous body sensor network (BSN), the technologies become powerful tools in well-being monitoring, medical diagnostics, and personal connectivity. In this paper, we describe the first demonstration of a fully customized mixed-signal silicon chip that has most of the attributes required for use in a wearable or implantable BSN. Our intellectual-property blocks include low-power analog sensor interface for temperature and pH, a data multiplexing and conversion module, a digital platform based around an 8-b microcontroller, data encoding for spread-spectrum wireless transmission, and a RF section requiring very few off-chip components. The chip has been fully evaluated and tested by connection to external sensors, and it satisfied typical system requirements.

Measured and simulated performance of a ceramic micromechanical beam steering device at 94 GHz.

We report the first experimental demonstration of a transmission-mode micromechanical beam steering device for use in standoff terahertz imaging and spectroscopy. The device was constructed by laminating laser-cut 96% alumina sheets to form two plates with interlocking rectangular gratings of 762 microm period and was characterized at 94 GHz in a free-space measurement setup with an automated elevation scan. Plate tilts as great as 6 degrees deflected the transmitted beam by 6 degrees for the transverse electric (TE) polarization and by 4 degrees for the transverse magnetic polarization. Finite-difference time-domain simulations of the TE performance were in good agreement with the measurements.

Imprinted diffractive optics for terahertz radiation.

Terahertz diffractive optic elements have been fabricated in polypropylene by imprinting with a silicon master. A silicon master is created with eight phase levels for high diffraction efficiency and etched using inductively coupled plasma reactive ion etching. This technique enables the rapid replication of complex optical structures in a high transmission material. Excellent replication of multilevel high efficiency Fresnel lenses is shown. The resulting lenses were tested with a 2 THz quantum cascade laser. The signal strength at the focus was 70 times the base signal strength.

Effects of changes to the stable environment on the exhalation of ethane, carbon monoxide and hydrogen peroxide by horses with respiratory inflammation.

The aim of this study was to assess the effects of changes to the stable environment on exhaled markers of respiratory inflammation in six horses with clinical histories of recurrent airway obstruction. The horses were maintained for two weeks under conventional stable management (straw bedding and hay) and for two weeks on a reduced-dust regimen (paper bedding and ensiled grass), in a crossover study design. Exhaled ethane and carbon monoxide (CO) and exhaled breath condensate hydrogen peroxide (H(2)O(2)) were measured every three days under each regimen. The presence of clinical signs of airway inflammation (nasal discharge and cough) was monitored daily. The reduced-dust regimen was associated with fewer clinical signs of airway inflammation than the conventional regimen. Exhaled ethane and CO were significantly lower on the reduced-dust regimen and these markers were correlated with clinical signs of respiratory inflammation, but exhaled H(2)O(2) was not affected by the management regimen.

Current and future uses of breath analysis as a diagnostic tool.

The analysis of exhaled breath is a potentially useful method for application in veterinary diagnostics. Breath samples can be easily collected from animals by means of a face mask or collection chamber with minimal disturbance to the animal. After the administration of a 13C-labelled compound the recovery of 13C in breath can be used to investigate gastrointestinal and digestive functions. Exhaled hydrogen can be used to assess orocaecal transit time and malabsorption, and exhaled nitric oxide, carbon monoxide and pentane can be used to assess oxidative stress and inflammation. The analysis of compounds dissolved in the aqueous phase of breath (the exhaled breath condensate) can be used to assess airway inflammation. This review summarises the current status of breath analysis in veterinary medicine, and analyses its potential for assessing animal health and disease.

Validation of a method for collection and assay of pentane in the exhaled breath of the horse.

Oxidative stress refers to an imbalance between the production of oxidising free radicals and the antioxidant defenses of the cell, and is associated with many pathogenic processes. Oxidative damage to cellular lipids results in the evolution of pentane and ethane gas, and detection of these hydrocarbons in the exhaled breath can be used to monitor in vivo oxidative stress. The aim of this study was to validate a gas chromatography (GC) method for measurement of breath pentane in the horse. The GC-system developed showed good specificity for discrimination of pentane from other breath hydrocarbons, and was sensitive to 0.5 ppb pentane. Pentane was detected in the exhaled breath of five horses investigated on two occasions. The results of this preliminary study demonstrate that breath pentane can be measured in the horse, and further work is now justified to investigate the feasibility of applying this method for monitoring in vivo oxidative stress in the horse.

Characterization of T-ray binary lenses.

Multilevel phase-shift Fresnel diffractive zone plates fabricated on silicon wafers have been used as T-ray imaging lenses. The imaging results, including spatial and temporal distribution of T-rays measured at the focal planes in the frequency range from 0.5 to 1.5 THz, indicate that the performance of the diffractive terahertz (THz) lens is comparable with or better than that of conventional refractive THz lenses. The unique properties of the T-ray binary lens make it possible to fabricate excellent optics for narrow-band THz applications.