Micro and nanostructured impedance sensors for biological and biomedical applications

This thesis work covered the fabrication and characterisation of impedance sensors for biological applications aiming in particular to the cytotoxicity monitoring of cultured cells exposed to different kind of chemical compounds and drugs and to the identification of different types of biological tissue (fat, muscles, nerves) using a sensor fabricated on the tip of a commercially available needle during peripheral nerve block procedures. Gold impedance electrodes have been successfully fabricated for impedance measurement on cells cultured on the electrode surface which was modified with the fabrication of gold nanopillars. These nanostructures have a height of 60nm or 100nm and they have highly ordered layout as they are fabricated through the e-beam technique. The fabrication of the threedimensional structures on the interdigitated electrodes was supposed to improve the sensitivity of the ECIS (electric cell-substrate impedance sensing) measurement while monitoring the cytotoxicity effects of two different drugs (Antrodia Camphorata extract and Nicotine) on three different cell lines (HeLa, A549 and BALBc 3T3) cultured on the impedance devices and change the morphology of the cells growing on the nanostructured electrodes. The fabrication of the nanostructures was achieved combining techniques like UV lithography, metal lift-off, evaporation and e-beam lithography techniques. The electrodes were packaged using a pressure sensitive, medical grade adhesive double-sided tape. The electrodes were then characterised with the aid of AFM and SEM imaging which confirmed the success of the fabrication processes showing the nanopillars fabricated with the right layout and dimensions figures. The introduction of nanopillars on the impedance electrodes, however, did not improve much the sensitivity of the assay with the exception of tests carried out with Nicotine. HeLa and A549 cells appeared to grow in a different way on the two surfaces, while no differences where noticed on the BALBc 3T3 cells. Impedance measurements obtained with the dead cells on the negative control electrodes or the test electrodes with the drugs can be compared to those done on the electrodes containing just media in the tested volume (as no cells are attached and cover the electrode surface). The impedance figures recorded using these electrodes were between 1.5kΩ and 2.5 kΩ, while the figures recorded on confluent cell layers range between 4kΩ and 5.5kΩ with peaks of almost 7 kΩ if there was more than one layer of cells growing on each other. There was then a very clear separation between the values of living cell compared to the dead ones which was almost 2.5 - 3kΩ. In this way it was very easy to determine whether the drugs affected the cells normal life cycle on not. However, little or no differences were noticed in the impedance analysis carried out on the two different kinds of electrodes using cultured cells. An increase of sensitivity was noticed only in a couple of experiments carried out on A549 cells growing on the nanostructured electrodes and exposed to different concentration of a solution containing Nicotine. More experiments to achieve a higher number of statistical evidences will be needed to prove these findings with an absolute confidence. The smart needle project aimed to reduce the limitations of the Electrical Nerve Stimulation (ENS) and the Ultra Sound Guided peripheral nerve block techniques giving the clinicians an additional tool for performing correctly the peripheral nerve block. Bioimpedance, as measured at the needle tip, provides additional information on needle tip location, thereby facilitating detection of intraneural needle placement. Using the needle as a precision instrument and guidance tool may provide additional information as to needle tip location and enhance safety in regional anaesthesia. In the time analysis, with the frequency fixed at 10kHz and the samples kept at 12°C, the approximate range for muscle bioimpedance was 203 – 616 Ω, the approximate bioimpedance range for fat was 5.02 - 17.8 kΩ and the approximate range for connective tissue was 790 Ω – 1.55 kΩ. While when the samples were heated at 37°C and measured again at 10kHz, the approximate bioimpedance range for muscle was 100-175Ω. The approximate bioimpedance range of fat was 627 Ω - 3.2 kΩ and the range for connective tissue was 221-540Ω. In the experiments done on the fresh slaughtered lamb carcass, replicating a scenario close to the real application, the impedance values recorded for fat were around 17 kΩ, for muscle and lean tissue around 1.3 kΩ while the nervous structures had an impedance value of 2.9 kΩ. With the data collected during this research, it was possible to conclude that measurements of bioimpedance at the needle tip location can give valuable information to the clinicians performing a peripheral nerve block procedure as the separation (in terms of impedance figures) was very marked between the different type of tissues. It is then feasible to use an impedance electrode fabricated on the needle tip to differentiate several tissues from the nerve tissue. Currently, several different methods are being studied to fabricate an impedance electrode on the surface of a commercially available needle used for the peripheral nerve block procedure.

Algorithms for indoor localization based on IEEE 802.15.4-2011 UWB and inertial sensors

In this thesis, extensive experiments are firstly conducted to characterize the performance of using the emerging IEEE 802.15.4-2011 ultra wideband (UWB) for indoor localization, and the results demonstrate the accuracy and precision of using time of arrival measurements for ranging applications. A multipath propagation controlling technique is synthesized which considers the relationship between transmit power, transmission range and signal-to-noise ratio. The methodology includes a novel bilateral transmitter output power control algorithm which is demonstrated to be able to stabilize the multipath channel, and enable sub 5cm instant ranging accuracy in line of sight conditions. A fully-coupled architecture is proposed for the localization system using a combination of IEEE 802.15.4-2011 UWB and inertial sensors. This architecture not only implements the position estimation of the object by fusing the UWB and inertial measurements, but enables the nodes in the localization network to mutually share positional and other useful information via the UWB channel. The hybrid system has been demonstrated to be capable of simultaneous local-positioning and remote-tracking of the mobile object. Three fusion algorithms for relative position estimation are proposed, including internal navigation system (INS), INS with UWB ranging correction, and orientation plus ranging. Experimental results show that the INS with UWB correction algorithm achieves an average position accuracy of 0.1883m, and gets 83% and 62% improvements on the accuracy of the INS (1.0994m) and the existing extended Kalman filter tracking algorithm (0.5m), respectively.

Harmonic source wavefront aberration correction for ultrasound imaging.

A method is proposed which uses a lower-frequency transmit to create a known harmonic acoustical source in tissue suitable for wavefront correction without a priori assumptions of the target or requiring a transponder. The measurement and imaging steps of this method were implemented on the Duke phased array system with a two-dimensional (2-D) array. The method was tested with multiple electronic aberrators [0.39π to 1.16π radians root-mean-square (rms) at 4.17 MHz] and with a physical aberrator 0.17π radians rms at 4.17 MHz) in a variety of imaging situations. Corrections were quantified in terms of peak beam amplitude compared to the unaberrated case, with restoration between 0.6 and 36.6 dB of peak amplitude with a single correction. Standard phantom images before and after correction were obtained and showed both visible improvement and 14 dB contrast improvement after correction. This method, when combined with previous phase correction methods, may be an important step that leads to improved clinical images.

Compressive video sensors using multichannel imagers.

We explore the possibilities of obtaining compression in video through modified sampling strategies using multichannel imaging systems. The redundancies in video streams are exploited through compressive sampling schemes to achieve low power and low complexity video sensors. The sampling strategies as well as the associated reconstruction algorithms are discussed. These compressive sampling schemes could be implemented in the focal plane readout hardware resulting in drastic reduction in data bandwidth and computational complexity.

Boosting high-intensity focused ultrasound-induced anti-tumor immunity using a sparse-scan strategy that can more effectively promote dendritic cell maturation.

BACKGROUND: The conventional treatment protocol in high-intensity focused ultrasound (HIFU) therapy utilizes a dense-scan strategy to produce closely packed thermal lesions aiming at eradicating as much tumor mass as possible. However, this strategy is not most effective in terms of inducing a systemic anti-tumor immunity so that it cannot provide efficient micro-metastatic control and long-term tumor resistance. We have previously provided evidence that HIFU may enhance systemic anti-tumor immunity by in situ activation of dendritic cells (DCs) inside HIFU-treated tumor tissue. The present study was conducted to test the feasibility of a sparse-scan strategy to boost HIFU-induced anti-tumor immune response by more effectively promoting DC maturation. METHODS: An experimental HIFU system was set up to perform tumor ablation experiments in subcutaneous implanted MC-38 and B16 tumor with dense- or sparse-scan strategy to produce closely-packed or separated thermal lesions. DCs infiltration into HIFU-treated tumor tissues was detected by immunohistochemistry and flow cytometry. DCs maturation was evaluated by IL-12/IL-10 production and CD80/CD86 expression after co-culture with tumor cells treated with different HIFU. HIFU-induced anti-tumor immune response was evaluated by detecting growth-retarding effects on distant re-challenged tumor and tumor-specific IFN-gamma-secreting cells in HIFU-treated mice. RESULTS: HIFU exposure raised temperature up to 80 degrees centigrade at beam focus within 4 s in experimental tumors and led to formation of a well-defined thermal lesion. The infiltrated DCs were recruited to the periphery of lesion, where the peak temperature was only 55 degrees centigrade during HIFU exposure. Tumor cells heated to 55 degrees centigrade in 4-s HIFU exposure were more effective to stimulate co-cultured DCs to mature. Sparse-scan HIFU, which can reserve 55 degrees-heated tumor cells surrounding the separated lesions, elicited an enhanced anti-tumor immune response than dense-scan HIFU, while their suppressive effects on the treated primary tumor were maintained at the same level. Flow cytometry analysis showed that sparse-scan HIFU was more effective than dense-scan HIFU in enhancing DC infiltration into tumor tissues and promoting their maturation in situ. CONCLUSION: Optimizing scan strategy is a feasible way to boost HIFU-induced anti-tumor immunity by more effectively promoting DC maturation.

Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors.

Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release and bioactivity characterization of tubular, porous dexamethasone (Dex)-releasing polyurethane coatings designed to attenuate local inflammation at the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy and micro-computed tomography (micro-CT) showed controlled porosity and coating thickness. In vitro drug release from coatings monitored over 2 weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.

Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors

© 2014 Acta Materialia Inc.Commercially available implantable needle-type glucose sensors for diabetes management are robust analytically but can be unreliable clinically primarily due to tissue-sensor interactions. Here, we present the physical, drug release and bioactivity characterization of tubular, porous dexamethasone (Dex)-releasing polyurethane coatings designed to attenuate local inflammation at the tissue-sensor interface. Porous polyurethane coatings were produced by the salt-leaching/gas-foaming method. Scanning electron microscopy and micro-computed tomography (micro-CT) showed controlled porosity and coating thickness. In vitro drug release from coatings monitored over 2 weeks presented an initial fast release followed by a slower release. Total release from coatings was highly dependent on initial drug loading amount. Functional in vitro testing of glucose sensors deployed with porous coatings against glucose standards demonstrated that highly porous coatings minimally affected signal strength and response rate. Bioactivity of the released drug was determined by monitoring Dex-mediated, dose-dependent apoptosis of human peripheral blood derived monocytes in culture. Acute animal studies were used to determine the appropriate Dex payload for the implanted porous coatings. Pilot short-term animal studies showed that Dex released from porous coatings implanted in rat subcutis attenuated the initial inflammatory response to sensor implantation. These results suggest that deploying sensors with the porous, Dex-releasing coatings is a promising strategy to improve glucose sensor performance.

Multicomponent gas-mixture measurements using an array of gas sensors and an artificial neural-network

An Electronic Nose is being jointly developed between the University of Greenwich and the Institute of Intelligent Machines to detect the gases given off from an oil filled transformer when it begins to break down. The gas sensors being used are very simple, consisting of a layer of Tin Oxide (SnO2) which is heated to approximately 640 K and the conductivity varies with the gas concentrations. Some of the shortcomings introduced by the commercial gas sensors available are being overcome by the use of an integrated array of gas sensors and the use of artificial neural networks which can be 'taught' to recognize when the gas contains several components. At present simulated results have achieved up to a 94% success rate of recognizing two component gases and future work will investigate alternative neural network configurations to maintain this success rate with practical measurements.

Solid phase velocity measurements utilising electrostatic sensors and cross correlation signal processing

Gas-solids two phase systems are widely employed within process plant in the form of pneumatic conveyors, dust extraction systems and solid fuel injection systems. The measurement of solids phase velocity therefore has wide potential application in flow monitoring and, in conjunction with density measurement instrumentation, solids mass flow rate measurement. Historically, a number of authors have detailed possible measurement techniques, and some have published limited test results. It is, however, apparent that none of these technologies have found wide application in industry. Solids phase velocity measurements were undertaken using real time cross correlation of signals from two electrostatic sensors spaced axially along a pipeline conveying pulverised coal (PF). Details of the measurement equipment, the pilot scale test rig and the test results are presented.

Velocity measurement of pneumatically conveyed solids using electrodynamic sensors

Theoretical and experimental studies of cross correlation techniques applied to non-restrictive velocity measurement of pneumatically conveyed solids using ring-shaped electrodynamic flow sensors are presented. In-depth studies of the electrodynamic sensing mechanism, and also of the spatial sensitivity and spatial filtering properties of the sensor are included, together with their relationships to measurement accuracy and the effects of solids' velocity profiles. The experimental evaluation of a 53 mm bore sensing head is described, including trials using a calibrated pneumatic conveyor circulating pulverized fuel and cement. Comparisons of test results with the mathematical models of the sensor are used to identify important aspects of the instrument design. Off-line test results obtained using gravity-fed solids flow show that the system repeatability is within +/-0.5% over the velocity range of 2-4 m s(-1) for volumetric concentrations of solids no greater than 0.2%. Results obtained in the pilot-plant trials demonstrate that the system is capable of achieving repeatability better than +/-2% and linearity within +/-2% over the velocity range 20-40 m s(-1) for volumetric concentrations of solids in the range 0.01-0.44%.

On the temporal consistency of chlorophyll products derived from three ocean-colour sensors

Satellite ocean-colour sensors have life spans lasting typically five-to-ten years. Detection of long-term trends in chlorophyll-a concentration (Chl-a) using satellite ocean colour thus requires the combination of different ocean-colour missions with sufficient overlap to allow for cross-calibration. A further requirement is that the different sensors perform at a sufficient standard to capture seasonal and inter-annual fluctuations in ocean colour. For over eight years, the SeaWiFS, MODIS-Aqua and MERIS ocean-colour sensors operated in parallel. In this paper, we evaluate the temporal consistency in the monthly Chl-a time-series and in monthly inter-annual variations in Chl-a among these three sensors over the 2002–2010 time period. By subsampling the monthly Chl-a data from the three sensors consistently, we found that the Chl-a time-series and Chl-a anomalies among sensors were significantly correlated for >90% of the global ocean. These correlations were also relatively insensitive to the choice of three Chl-a algorithms and two atmospheric-correction algorithms. Furthermore, on the subsampled time-series, correlations between Chl-a and time, and correlations between Chl-a and physical variables (sea-surface temperature and sea-surface height) were not significantly different for >92% of the global ocean. The correlations in Chl-a and physical variables observed for all three sensors also reflect previous theories on coupling between physical processes and phytoplankton biomass. The results support the combining of Chl-a data from SeaWiFS, MODIS-Aqua and MERIS sensors, for use in long-term Chl-a trend analysis, and highlight the importance of accounting for differences in spatial sampling among sensors when combining ocean-colour observations.

Hand arthritis in systemic lupus erythematosus: an ultrasound pictorial essay.

A small minority of systemic lupus erythematosus (SLE) patients may develop a deforming arthritis, typically with a non-erosive (Jaccoud's) pattern, although erosive features indistinguishable from rheumatoid arthritis may also occur. High-resolution ultrasonography (HRUS) allows detailed 'real time' imaging of joint and tendon morphostructural changes involving the hand in patients with several rheumatic diseases. The main aim of this pictorial essay is to provide the first descriptive HRUS and power Doppler (PD) findings of joint and tendon involvement of the hand and wrist in patients with SLE arthritis. Seventeen patients with SLE and hand involvement were examined. HRUS of the wrist, 2nd and 3rd MCP joints, 3rd PIP joint and 2nd, 3rd and 4th finger flexor tendons were studied in the dominant hand for each patient. Sixteen (94%) patients had joint effusion or synovial hypertrophy in the wrist. Twelve (71%) patients had joint effusion or synovial hypertrophy in 2nd or 3rd MCPJs. Eight (47%) patients had erosion at 2nd or 3rd MCPJs. In three cases erosions were not present radiologically. Eleven (65%) patients had evidence of tenosynovitis. In SLE, HRUS with PD detects a high prevalence of inflammatory pathology in the tendons and synovium of the hand and wrist, and a high prevalence of MCP joint erosions. HRUS offers a sensitive, real-time and readily repeatable assessment of soft-tissue, inflammatory and bony changes in SLE hands.

Economic modelling of antenatal screening and ultrasound scanning programmes for identification of fetal abnormalities

Objective Within the framework of a health technology assessment and using an economic model, to determine the most clinically and cost effective policy of scanning and screening for fetal abnormalities in early pregnancy. Design A discrete event simulation model of 50,000 singleton pregnancies. Setting Maternity services in Scotland. Population Women during the first 24 weeks of their pregnancy. Methods The mathematical model was populated with data on uptake of screening, prevalence, detection and false positive rates for eight fetal abnormalities and with costs for ultrasound scanning and serum screening. Inclusion of abnormalities was based on the relative prevalence and clinical importance of conditions and the availability of data. Six strategies for the identification of abnormalities prenatally including combinations of first and second trimester ultrasound scanning and first and second trimester screening for chromosomal abnormalities were compared. Main outcome measures The number of abnormalities detected and missed, the number of iatrogenic losses resulting from invasive tests, the total cost of strategies and the cost per abnormality detected were compared between strategies. Results First trimester screening for chromosomal abnormalities costs more than second trimester screening but results in fewer iatrogenic losses. Strategies which include a second trimester ultrasound scan result in more abnormalities being detected and have lower costs per anomaly detected. Conclusions The preferred strategy includes both first and second trimester ultrasound scans and a first trimester screening test for chromosomal abnormalities. It has been recommended that this policy is offered to all women in Scotland.