Mid-Infrared Integrated Devices for Optical Chemical Sensing

The mid-infrared (MIR) spectral range is of special interest for establishing optical chemical sensor technologies by allowing specific molecular identification and quantification, whether the sample is in a liquid, gas or solid form, in addition to providing highly sensitive, rapid, reagent-free and non-destructive detection. This thesis explores four different liquid- and gas- sensing applications and methods using MIR spectroscopy by integrating it with other technologies, such as microfluidics and fibre-optics. Firstly, fibre-optic integrated microfluidic devices were developed and tested for con- tinuous fluid monitoring. These showed good sensing capabilities for online, continuous and real-time liquid sensing in hard-to-reach locations. Next, this thesis presents the establishment and clinical testing of a novel method for continuous monitoring of the brain chemistry of traumatically brain-injured patients by MIR transmission spectroscopy. Here, the outlet of a cerebral microdialysis catheter is cou- pled to a micro flow-cell and the flowing microdialysate is continuously analysed. Clinical studies were carried out and showed the capability of this system for performing continuous patient monitoring over several hours. With further optimisation, the implementation of this system could lead to improved patient outcome. This thesis also presents a novel method and system based on MIR fibre-optic evanescent- wave spectroscopy, which enables enhanced detection of volatile organic compounds (VOCs). Here, a nanoporous silicon cladding was used to reversibly concentrate molecules close to the fibre surface, thus enhancing VOC detection. A significant increase in sen- sitivity was seen compared to that of an uncoated fibre and successful detection of three different VOCs, both independently and in binary mixtures, was achieved. Finally, this thesis introduces a simple and relatively low-cost fibre-optic sensor for in-line, real-time bioprocess monitoring. The sensor was successfully able to monitor varying concentrations of product (sophorolipids) in fermentation broth and was able to distinguish between the two types of generated product (acidic and lactonic sophorolipids). The work presented in this thesis showed that MIR-integrated sensors have great potential to provide novel and/or enhanced sensing solutions in a wide range of applications, including medical, industrial and environmental

Assessment of a Microfluidic Intravenous Oxygen Generating Platform to Aid Acute Respiratory Failure

Acute respiratory failure is associated with a high mortality rate, despite the advances in conventional treatments. This work presents the development of a proof-of-concept device for assessing the viability of an oxygen-generating catheter, deployed intravenously, to temporarily sustain a patient who is suffering from acute respiratory failure. The assessment device mimics the interface between the catheter and bloodstream (deoxygenated water substitutes the blood), and consists of two parallel channels separated from each other by an oxygen-permeable membrane that simulates the catheter material. Several polydimethylsiloxane membranes with enhanced permeability were developed and tested on the device according to their permeation rates. The highest permeation rate achieved was 3.6×10-7 cm3/s (equivalent in-blood value) considering the device’s surface area and applied pressure. However, the extrapolation of this value to a catheter with increased surface area demonstrated a predicted oxygen permeation rate of 1.6×10-3 cm3/s. Although the oxygen permeation rates achieved here do not yet reach the minimum required rate to sustain a patient with only 30 % of their lungs functional (1.6 cm3/s O2), it may be enhanced further by improving certain parameters such as material permeability, surface area and applied pressure. The ability to administer oxygen or other gases directly into the bloodstream may portray a technique for short-term rescue of severely hypoxemic patients to increase whole body or at-risk organ oxygenation

Cerebral Microdialysate Metabolite Monitoring using Mid-infrared Spectroscopy.

Funder: Wellcome TrustThe brains of patients suffering from traumatic brain-injury (TBI) undergo dynamic chemical changes in the days following the initial trauma. Accurate and timely monitoring of these changes is of paramount importance for improved patient outcome. Conventional brain-chemistry monitoring is performed off-line by collecting and manually transferring microdialysis samples to an enzymatic colorimetric bedside analyzer every hour, which detects and quantifies the molecules of interest. However, off-line, hourly monitoring means that any subhourly neurochemical changes, which may be detrimental to patients, go unseen and thus untreated. Mid-infrared (mid-IR) spectroscopy allows rapid, reagent-free, molecular fingerprinting of liquid samples, and can be easily integrated with microfluidics. We used mid-IR transmission spectroscopy to analyze glucose, lactate, and pyruvate, three relevant brain metabolites, in the extracellular brain fluid of two TBI patients, sampled via microdialysis. Detection limits of 0.5, 0.2, and 0.1 mM were achieved for pure glucose, lactate, and pyruvate, respectively, in perfusion fluid using an external cavity-quantum cascade laser (EC-QCL) system with an integrated transmission flow-cell. Microdialysates were collected hourly, then pooled (3-4 h), and measured consecutively using the standard ISCUSflex analyzer and the EC-QCL system. There was a strong correlation between the compound concentrations obtained using the conventional bedside analyzer and the acquired mid-IR absorbance spectra, where a partial-least-squares regression model was implemented to compute concentrations. This study demonstrates the potential utility of mid-IR spectroscopy for continuous, automated, reagent-free, and online monitoring of the dynamic chemical changes in TBI patients, allowing a more timely response to adverse brain metabolism and consequently improving patient outcomes

OptiJ: Open-source optical projection tomography of large organ samples

The three-dimensional imaging of mesoscopic samples with Optical Projection Tomography (OPT) has become a powerful tool for biomedical phenotyping studies. OPT uses visible light to visualize the 3D morphology of large transparent samples. To enable a wider application of OPT, we present OptiJ, a low-cost, fully open-source OPT system capable of imaging large transparent specimens up to 13 mm tall and 8 mm deep with 50 µm resolution. OptiJ is based on off-the-shelf, easy-to-assemble optical components and an ImageJ plugin library for OPT data reconstruction. The software includes novel correction routines for uneven illumination and sample jitter in addition to CPU/GPU accelerated reconstruction for large datasets. We demonstrate the use of OptiJ to image and reconstruct cleared lung lobes from adult mice. We provide a detailed set of instructions to set up and use the OptiJ framework. Our hardware and software design are modular and easy to implement, allowing for further open microscopy developments for imaging large organ samples

OptiJ: Open-source optical projection tomography of large organ samples

Abstract: The three-dimensional imaging of mesoscopic samples with Optical Projection Tomography (OPT) has become a powerful tool for biomedical phenotyping studies. OPT uses visible light to visualize the 3D morphology of large transparent samples. To enable a wider application of OPT, we present OptiJ, a low-cost, fully open-source OPT system capable of imaging large transparent specimens up to 13 mm tall and 8 mm deep with 50 µm resolution. OptiJ is based on off-the-shelf, easy-to-assemble optical components and an ImageJ plugin library for OPT data reconstruction. The software includes novel correction routines for uneven illumination and sample jitter in addition to CPU/GPU accelerated reconstruction for large datasets. We demonstrate the use of OptiJ to image and reconstruct cleared lung lobes from adult mice. We provide a detailed set of instructions to set up and use the OptiJ framework. Our hardware and software design are modular and easy to implement, allowing for further open microscopy developments for imaging large organ samples

Quantification of pyruvate in-vitro using mid-infrared spectroscopy: Developing a system for microdialysis monitoring in traumatic brain injury patients.

INTRODUCTION: Complex metabolic disruption is a major aspect of the pathophysiology of traumatic brain injury (TBI). Pyruvate is an intermediate in glucose metabolism and considered one of the most clinically informative metabolites during neurocritical care of TBI patients, especially in deducing the lactate/pyruvate ratio (LPR) - a widely-used metric for probing the brain's metabolic redox state. LPR is conventionally measured offline on a bedside analyzer, on hourly accumulations of brain microdialysate. However, there is increasing interest within the field to quantify microdialysate pyruvate and LPR continuously in near-real-time within its pathophysiological range. We have previously measured pure standard pyruvate in-vitro using mid-infrared transmission, employing a commercially available external cavity-quantum cascade laser (EC-QCL) and a microfluidic flow cell and reported a limit of detection (LOD) of 0.1 mM. RESEARCH QUESTION: The present study was to test whether the current commercially available state-of-the-art mid-infrared transmission system, can detect pyruvate levels lower than previously reported. MATERIALS AND METHODS: We measured pyruvate in perfusion fluid on the mid-infrared transmission system also equipped with an EC-QCL and microfluidic flow cells, tested at three pathlengths. RESULTS: We characterised the system to extract its relevant figures-of-merit and report the LOD of 0.07 mM. DISCUSSION AND CONCLUSION: The reported LOD of 0.07 mM represents a clinically recognised threshold and is the lowest value reported in the field for a sensor that can be coupled to microdialysis. While work is ongoing for a definitive evaluation of the system to measuring pyruvate, these preliminary results set a good benchmark and reference against which future developments can be examined

Monitoring Neurochemistry in Traumatic Brain Injury Patients Using Microdialysis Integrated with Biosensors: A Review.

In a traumatically injured brain, the cerebral microdialysis technique allows continuous sampling of fluid from the brain's extracellular space. The retrieved brain fluid contains useful metabolites that indicate the brain's energy state. Assessment of these metabolites along with other parameters, such as intracranial pressure, brain tissue oxygenation, and cerebral perfusion pressure, may help inform clinical decision making, guide medical treatments, and aid in the prognostication of patient outcomes. Currently, brain metabolites are assayed on bedside analysers and results can only be achieved hourly. This is a major drawback because critical information within each hour is lost. To address this, recent advances have focussed on developing biosensing techniques for integration with microdialysis to achieve continuous online monitoring. In this review, we discuss progress in this field, focusing on various types of sensing devices and their ability to quantify specific cerebral metabolites at clinically relevant concentrations. Important points that require further investigation are highlighted, and comments on future perspectives are provided.National Institute for Health Research Invention for Innovation Awards (NIHR i4i Challenge Award and NIHR i4i Product Development Award) and the NIHR Brain Injury MedTech Co-operative. C.Z. is supported by a Research Studentship from the W.D. Armstrong Trust (Uni-versity of Cambridge). F.C.A. is supported by an NIHR i4i Product Development Award. K.L.H.C. is supported by the NIHR Biomedical Research Centre, Cambridge and by an NIHR i4i Product Development Award. P.J.H. is supported by the NIHR Biomedical Research Centre Cambridge, NIHR Senior Investigator Award, and the Royal College of Surgeons of England

Mid-IR Evanescent-field Fiber Sensor with Enhanced Sensitivity for Volatile Organic Compounds

The increasing awareness of the harsh environmental and health risks associated with air pollution has placed volatile organic compounds (VOCs) sensor technologies in elevated demand. While the currently available VOC-monitoring technologies are either bulky and expensive, or only capable of measuring a total VOC concentration, the selective detection of VOCs in the gas-phase remains a challenge. To overcome this, a novel method and device based on mid-IR evanescent-wave fiber-optic spectroscopy, which enables enhanced detection of VOCs, is hereby proposed. This is achieved by increasing the number of analyte molecules in the proximity of the evanescent field via capillary condensation inside nano-porous microparticles coated on the fiber surface. The nano-porous structure of the coating allows the VOC analytes to rapidly diffuse into the pores and become concentrated at the surface of the fiber, thereby allowing the utilization of highly sensitive evanescent-wave spectroscopy. To ascertain the effectiveness and performance of the sensor, different VOCs are measured, and the enhanced sensitivity is analyzed using a custom-built gas cell. According to the results presented here, our VOC sensor shows a significantly increased sensitivity compared to a non-coated fiber.Innovative Research Call in Explosives and Weapons Detection 2016, Henslow Research Fellowship at Darwin College, Cambridge