Chirped guided-mode resonance biosensor

Advanced biomedical diagnostic technologies fulfill an important role in improving health and well-being in society. A large number of excellent technologies have already been introduced and have given rise to the "lab-on-a-chip" paradigm. Most of these technologies, however, require additional instrumentation for interfacing and readout, so they are often confined to the laboratory and are not suitable for use in the field or in wider clinical practice. Other technologies require a light coupling element, such as a grating coupler or a fiber coupler, which complicates packaging. Here, we introduce a novel biosensor based on a chirped guided-mode resonant grating. The chirped grating combines the sensing function with the readout function by translating spectral information into spatial information that is easily read out with a simple CMOS camera. We demonstrate a refractive index sensitivity of 137 nm/RIU and an extrapolated limit of detection of 267 pM for the specific binding of an immunoglobulin G antibody. The chirped guided-mode resonance approach introduces a new degree of freedom for sensing biomedical information that combines high sensitivity with autonomous operation. We estimate that the cost of components is U.S. $10 or less when mass manufactured, so the technology has the potential to truly transform point-of-care applications

Chirped guided-mode resonance biosensor

Advanced biomedical diagnostic technologies fulfill an important role in improving health and well-being in society. A large number of excellent technologies have already been introduced and have given rise to the "lab-on-a-chip" paradigm. Most of these technologies, however, require additional instrumentation for interfacing and readout, so they are often confined to the laboratory and are not suitable for use in the field or in wider clinical practice. Other technologies require a light coupling element, such as a grating coupler or a fiber coupler, which complicates packaging. Here, we introduce a novel biosensor based on a chirped guided-mode resonant grating. The chirped grating combines the sensing function with the readout function by translating spectral information into spatial information that is easily read out with a simple CMOS camera. We demonstrate a refractive index sensitivity of 137 nm/RIU and an extrapolated limit of detection of 267 pM for the specific binding of an immunoglobulin G antibody. The chirped guided-mode resonance approach introduces a new degree of freedom for sensing biomedical information that combines high sensitivity with autonomous operation. We estimate that the cost of components is U.S. $10 or less when mass manufactured, so the technology has the potential to truly transform point-of-care applications

HYPERPOLARIZED CARBON-13 MAGNETIC RESONANCE MEASUREMENTS OF TISSUE PERFUSION AND METABOLISM

Hyperpolarized Magnetic Resonance Imaging (HP MRI) is an emerging modality that enables non-invasive interrogation of cells and tissues with unprecedented biochemical detail. This technology provides rapid imaging measurements of the activity of a small quantity of molecules with a strongly polarized nuclear magnetic moment. This polarization is created in a polarizer separate from the imaging magnet, and decays continuously towards a non-detectable thermal equilibrium once the imaging agent is removed from the polarizer and administered by intravenous injection. Specialized imaging strategies are therefore needed to extract as much information as possible from the HP signal during its limited lifetime. In this work, we present innovative strategies for measurement of tissue perfusion and metabolism with HP MRI. These techniques include the capacity to sensitize the imaging signal to the diffusive motion of HP molecules, providing improved accuracy and reproducibility for assessment of agent uptake in tissue. The proposed methods were evaluated in numerical simulations, implemented on a preclinical MRI system and demonstrated in vivo in rodents through imaging of HP 13C urea. Using the simulation and imaging infrastructure developed in this work, established methods for encoding HP chemical signals were compared quantitatively. Lastly, our method was adapted for imaging of [2-13C]dihydroxyacetone, a novel HP agent that probes enzymatic flux through multiple biochemical pathways in vivo. Our results demonstrate the capacity of HP MRI to measure tissue perfusion and metabolism in ways not possible with the imaging modalities currently available in the clinic. As the use of HP MRI advances in clinical investigations of human disease, these imaging measurements can offer real-time and individualized information on disease states for early detection and therapeutic guidance

Double volumetric navigators for real-time simultaneous shim and motion measurement and correction in Glycogen Chemical Exchange Saturation Transfer (GlycoCEST) MRI

Glycogen is the primary glucose storage mechanism in in living systems and plays a central role in systemic glucose homeostasis. The study of muscle glycogen concentrations in vivo still largely relies on tissue sampling methods via needle biopsy. However, muscle biopsies are invasive and limit the frequency of measurements and the number of sites that can be assessed. Non-invasive methods for quantifying glycogen in vivo are therefore desirable in order to understand the pathophysiology of common diseases with dysregulated glycogen metabolism such as obesity, insulin resistance, and diabetes, as well as glycogen metabolism in sports physiology. Chemical Exchange Saturation Transfer (CEST) MRI has emerged as a non-invasive contrast enhancement technique that enables detection of molecules, like glycogen, whose concentrations are too low to impact the contrast of standard MR imaging. CEST imaging is performed by selectively saturating hydrogen nuclei of the metabolites that are in chemical exchange with those of water molecules and detecting a reduction in MRI signal in the water pool resulting from continuous chemical exchange. However, CEST signal can easily be compromised by artifacts. Since CEST is based on chemical shift, it is very sensitive to field inhomogeneity which may arise from poor initial shimming, subject respiration, heating of shim iron, mechanical vibrations or subject motion. This is a particular problem for molecules that resonate close to water, such as - OH protons in glycogen, where small variations in chemical shift cause misinterpretation of CEST data. The purpose of this thesis was to optimize the CEST MRI sequence for glycogen detection and implement a real-time simultaneous motion and shim correction and measurement method. First, analytical solution of the Bloch-McConnell equations was used to find optimal continuous wave RF pulse parameters for glycogen detection, and results were validated on a phantom with varying glycogen concentrations and in vivo on human calf muscle. Next, the CEST sequence was modified with double volumetric navigators (DvNavs) to measure pose changes and update field of view and zero- and first-order shim parameters. Finally, the impact of B0 field fluctuations on the scan-rescan reproducibility of CEST was evaluated in vivo in 9 volunteers across 10 different scans. Simulation results showed an optimal RF saturation power of 1.5µT and duration of 1s for glycoCEST. These parameters were validated experimentally in vivo and the ability to detect varying glycogen concentrations was demonstrated in a phantom. Phantom data showed that the DvNav-CEST sequence accurately estimates system frequency and linear shim gradient changes due to motion and corrects resulting image distortions. In addition, DvNav-CEST was shown to yield improved CEST quantification in vivo in the presence of motion and motion-induced field inhomogeneity. B0 field fluctuations were found to lower the reproducibility of CEST measures: the mean coefficient of variation (CoV) for repeated scans was 83.70 ± 70.79 % without shim correction. However, the DvNav-CEST sequence was able to measure and correct B0 variations, reducing the CoV to 2.6 ± 1.37 %. The study confirms the possibility of detecting glycogen using CEST MRI at 3 T and shows the potential of the real-time shim and motion navigated CEST sequence for producing repeatable results in vivo by reducing the effect of B0 field fluctuations

Accelerating MRI Data Acquisition Using Parallel Imaging and Compressed Sensing

Magnetic Resonance Imaging (MRI) scanners are one of important medical instruments, which can achieve more information of soft issues in human body than other medical instruments, such as Ultrasound, Computed Tomography (CT), Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), etc. But MRI\u27s scanning is slow for patience of doctors and patients. In this dissertation, the author proposes some methods of parallel imaging and compressed sensing to accelerate MRI data acquisition. Firstly, a method is proposed to improve the conventional GRAPPA using cross-sampled auto-calibration data. This method use cross-sampled auto-calibration data instead of the conventional parallel-sampled auto-calibration data to estimate the linear kernel model of the conventional GRAPPA. The simulations and experiments show that the cross-sampled GRAPPA can decrease the quantity of ACS lines and reduce the aliasing artifacts comparing to the conventional GRAPPA under same reduction factors. Secondly, a Hybrid encoding method is proposed to accelerate the MRI data acquisition using compressed sensing. This method completely changes the conventional Fourier encoding into Hybrid encoding, which combines the benefits of Fourier and Circulant random encoding, under 2D and 3D situation, through the proposed special hybrid encoding pulse sequences. The simulations and experiments illustrate that the images can be reconstructed by the proposed Hybrid encoding method to reserve more details and resolutions than the conventional Fourier encoding method. Thirdly, a pseudo 2D random sampling method is proposed by dynamically swapping the gradients of x and y axes on pulse sequences, which can be implemented physically as the convention 1D random sampling method. The simulations show that the proposed method can reserve more details than the convention 1D random sampling method. These methods can recover images to achieve better qualities under same situations than the conventional methods. Using these methods, the MRI data acquisitions can be accelerated comparing to the conventional methods

Electron multiplying CCD – based detection in Fluorescence Correlation Spectroscopy and measurements in living zebrafish embryos

Fluorescence correlation spectroscopy (FCS) is an ultra-sensitive optical technique to investigate the dynamic properties of ensembles of single fluorescent molecules in solution. It is in particular suited for measurements in biological samples. High sensitivity is obtained by employing confocal microscopy setups with diffraction limited small detection volumes, and by using single-photon sensitive detectors, for example avalanche photo diodes (APD). However, fluorescence signal is hence typically collected from a single focus position in the sample only, and several measurements at different positions have to be performed successively. To overcome the time-consuming successive FCS measurements, we introduce electron multiplying CCD (EMCCD) camera-based spatially resolved detection for FCS. With this new detection method, multiplexed FCS measurements become feasible. Towards this goal, we perform FCS measurements with two focal volumes. As an application, we demonstrate spatial cross-correlation measurements between the two detection volumes, which allow to measure calibration-free diffusion coefficients and direction-sensitive processes like molecular flow in microfluidic channels. FCS is furthermore applied to living zebrafish embryos, to investigate the concentration gradient of the morphogen fibroblast growth factor 8 (Fgf8). It is shown by one-focus APD-based and two-focus EMCCD-based FCS, that Fgf8 propagates largely by random diffusion through the extracellular space in developing tissue. The stable concentration gradient is shown to arise from the equilibrium between a local morphogen production and the sink function of the receiving cells by receptor-mediated removal from the extracellular space. The study shows the applicability of FCS to whole model organisms. Especially in such dynamically changing systems in vivo, the perspective of fast parallel FCS measurements is of great importance. In this work, we exemplify parallel, spatially resolved FCS by utilizing an EMCCD camera. The approach, however, can be easily adapted to any other class of two-dimensional array detector. Novel generations of array detectors might become available in the near future, so that multiplexed spatial FCS could then emerge as a standard extension to classical one-focus FCS.Fluoreszenz-Korrelations-Spektroskopie (FCS) ist eine hochempfindliche optische Methode, um die dynamischen Eigenschaften eines Ensembles von einzelnen, fluoreszierenden Molekülen in Lösung zu erforschen. Sie ist insbesondere geeignet für Messungen in biologischen Proben. Die hohe Empfindlichkeit wird erreicht durch Verwendung konfokaler Mikroskop-Aufbauten mit beugungsbegrenztem Detektionsvolumen, und durch Messung der Fluoreszenz mit Einzelphotonen-empfindlichen Detektoren, zum Beispiel Avalanche-Photodioden (APD). Dadurch wird das Fluoreszenzsignal allerdings nur von einer einzelnen Fokusposition in der Probe eingesammelt, und mehrfache Messungen an verschiedenen Positionen in der Probe müssen nacheinander durchgeführt werden. Um die zeitaufwendigen, aufeinanderfolgenden FCS-Einzelmessungen zu überwinden, entwickeln wir in dieser Arbeit Elektronenvervielfachungs-CCD (EMCCD) Kamera-basierte räumlich aufgelöste Detektion für FCS. Mit dieser neuartigen Detektionsmethode werden Multiplex-FCS Messungen möglich. Darauf abzielend führen wir FCS Messungen mit zwei Detektionsvolumina durch. Als Anwendung nutzen wir die räumliche Kreuzkorrelation zwischen dem Signal beider Fokalvolumina. Sie ermöglicht die kalibrationsfreie Bestimmung von Diffusionskoeffizienten und die Messung von gerichteter Bewegung, wie zum Beispiel laminarem Fluss in mikrostrukturierten Kanälen. FCS wird darüber hinaus angewendet auf Messungen in lebenden Zebrafischembryonen, um den Konzentrationsgradienten des Morphogens Fibroblasten-Wachstumsfaktor 8 (Fgf8) zu untersuchen. Mit Hilfe von APD-basierter ein-Fokus FCS und EMCCD-basierter zwei-Fokus FCS zeigen wir, dass Fgf8 hauptsächlich frei diffffundiert im extrazellulären Raum des sich entwickelnden Embryos. Der stabile Konzentrationsgradient entsteht durch ein Gleichgewicht von lokaler Morphogenproduktion und globalem Morphogenabbau durch Rezeptor vermittelte Entfernung aus dem extrazellulären Raum. Die Studie zeigt die Anwendbarkeit von FCS in ganzen Modell-Organismen. Gerade in diesen sich dynamisch ändernden Systemen in vivo ist die Perspektive schneller, paralleler FCS-Messungen von großer Bedeutung. In dieser Arbeit wird räumlich aufgelöste FCS am Beispiel einer EMCCD Kamera durchgeführt. Die Herangehensweise ist jedoch einfach übertragbar auf jede andere Art von zwei-dimensionalem Flächendetektor. Neuartige Flächendetektoren könnten in naher Zukunft verfügbar sein. Dann könnte räumlich aufgelöste Multiplex-FCS eine standardisierte Erweiterung zur klassischen ein-Fokus FCS werden

Absolute Quantitation for MR Molecular Imaging of Angiogenesis

Medical imaging is undergoing a transition from an art that is used to make static images of human physiology into a scientific tool that employs advanced techniques to measure clinically relevant data. Recently, the role of magnetic resonance imaging in cardiovascular and oncological research has grown, largely due to the implementation of new quantitative techniques in the clinic. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are particularly rich in their capability to quantify both physiology and disease via biomarker detection. While this is true for many applications of MRI in cardiovascular and oncological research, 19F MR molecular imaging is particularly useful when coupled to the use of emerging site-targeted molecular imaging agents for diagnosis and therapy, such as αvβ3 integrin-targeted perfluorocarbon (PFC) nanoparticle (NP) emulsions. Unfortunately, the radiological world is realizing that although image quality may be consistently high, the absolute quantitative values being calculated vary widely across time, techniques, laboratories, and imaging platforms. The overall objective of this work is to advance the state of the art for 19F MR molecular imaging of perfluorocarbon nanoparticle emulsion contrast agents. To reach this objective, three specific aims have been identified: (1) to create new tools and techniques for 19F MR molecular imaging of PFC nanoparticles, (2) to develop translatable procedures for absolute quantification of 19F nuclei with MR molecular imaging, and (3) to evaluate the potential for clinical translation with ex vivo and in vivo preclinical experiments. Robust, standardized techniques are developed in this work to improve the accuracy of in vivo quantitative 19F MR molecular imaging, validate system performance, calibrate measurements to ensure repeatability of these quantitative metrics, and evaluate the potential for clinical translation. As these quantitative metrics become routine in medical imaging procedures, these standardized calibrations and techniques are expected to be critical for accurate interpretation of underlying pathophysiology. This will also impact the development of new therapies and diagnostic techniques/agents by reducing the variability of image-based measurements, thereby increasing the impact of the studies and reducing the overall time and cost to translate new technologies into the clinic

Toward Magnetic Resonance Only Treatment Planning: Distortion Mitigation And Image-Guided Radiation Therapy Validation

While MR-only treatment planning has shown promise, there are still several well-known challenges that are currently limiting widespread clinical implementation. Firstly, MR images are affected by both patient-induced and system-level geometric distortions that can significantly degrade treatment planning accuracy. . In addition, the availability of comprehensive distortion analysis software is currently limited. Also while many groups have been working toward a synthetic CT solution, further study is needed on the implementation of synCTs as the reference datasets for linac-based image-guided radiation therapy (IGRT) to help determine their robustness in an MR-only workflow. A 36×43×2 cm3 phantom with 255 known landmarks (~1 mm3) was scanned using 1.0T high-field open MR-SIM at isocenter in the transverse, sagittal, and coronal axes, and a 465x350x168mm 3D phantom was scanned by stepping in the superior-inferior direction in 3 overlapping positions to achieve a total 465x350x400mm sampled FOV yielding \u3e13,800 landmarks(3D Gradient-Echo, TE/TR/α = 5.54 ms/30 ms/28°, voxel size =1×1×2mm3). A binary template (reference) was generated from a phantom schematic. An automated program converted MR images to binary via masking, thresholding, and testing for connectivity to identify landmarks. Distortion maps were generated by centroid mapping. Images were corrected via warping with inverse distortion maps, and temporal stability was assessed. To determine candidate materials for phantom and software development, 1.0 T MR and CT images were acquired of twelve urethane foam samples of various densities and strengths. Samples were precision machined to accommodate 6 mm diameter paintballs used as landmarks. Final material candidates were selected by balancing strength, machinability, weight, and cost. Bore sizes and minimum aperture width resulting from couch position were tabulated from the literature (14 systems, 5 vendors). Bore geometry and couch position were simulated using MATLAB to generate machine-specific models to optimize the phantom build. Previously developed software for distortion characterization was modified for several magnet geometries (1.0 T, 1.5 T, 3.0 T), compared against previously published 1.0 T results, and integrated into the 3DSlicer application platform. To evaluate the performance of synthetic CTs in an image guided workflow, magnetic resonance simulation and CT simulation images were acquired of an anthropomorphic skull phantom and 12 patient brain cancer cases. SynCTs were generated using fluid attenuation inversion recovery, ultrashort echo time, and Dixon data sets through a voxel-based weighted summation of 5 tissue classifications. The DRRs were generated from the phantom synCT, and geometric fidelity was assessed relative to CT-generated DRRs through bounding box and landmark analysis. An offline retrospective analysis was conducted to register cone beam CTs to synCTs and CTs using automated rigid registration in the treatment planning system. Planar MV and KV images were rigidly registered to synCT and CT DRRs using an in-house script. Planar and volumetric registration reproducibility was assessed and margin differences were characterized by the van Herk formalism. Over the sampled FOV, non-negligible residual gradient distortions existed as close as 9.5 cm from isocenter, with a maximum distortion of 7.4mm as close as 23 cm from isocenter. Over 6 months, average gradient distortions were -0.07±1.10 mm and 0.10±1.10 mm in the x and y-directions for the transverse plane, 0.03±0.64 and -0.09±0.70 mm in the sagittal plane, and 0.4±1.16 and 0.04±0.40 mm in the coronal plane. After implementing 3D correction maps, distortions were reduced to \u3c 1 pixel width (1mm) for all voxels up to 25 cm from magnet isocenter. All foam samples provided sufficient MR image contrast with paintball landmarks. Urethane foam (compressive strength ∼1000psi, density ~20lb/ft3) was selected for its accurate machinability and weight characteristics. For smaller bores, a phantom version with the following parameters was used: 15 foam plates, 55×55×37.5 cm3 (L×W×H), 5,082 landmarks, and weight ~30 kg. To accommodate \u3e70 cm wide bores, an extended build used 20 plates spanning 55×55×50 cm3 with 7,497 landmarks and weight ~44 kg. Distortion characterization software was implemented as an external module into 3DSlicer’s plugin framework and results agreed with the literature. Bounding box and landmark analysis of phantom synCT DRRs were within 1 mm of CT DRRs. Absolute planar registration shift differences ranged from 0.0 to 0.7 mm for phantom DRRs on all treatment platforms and from 0.0 to 0.4 mm for volumetric registrations. For patient planar registrations, the mean shift differences were 0.4±0.5 mm (range, 0.6 to 1.6 mm), 0.0±0.5 mm (range, 0.9 to 1.2 mm), and 0.1±0.3 mm (range, 0.7 to 0.6 mm) for the superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) axes, respectively. The mean shift differences in volumetric registrations were 0.6±0.4 mm (range, 0.2 to 1.6 mm), 0.2±0.4 mm (range, 0.3 to 1.2 mm), and 0.2±0.3 mm (range, 0.2 to 1.2 mm) for the S-I, L-R, and A-P axes, respectively. The CT-SIM and synCT derived margins were \u3c0.3mm different. This work has characterized the inaccuracies related to GNL distortion for a previously uncharacterized MR-SIM system at large FOVs, and established that while distortions are still non-negligible after current vendor corrections are applied, simple post-processing methods can be used to further reduce these distortions to less than 1mm for the entire field of view. Additionally, it was important to not only establish effective corrections, but to establish the previously uncharacterized temporal stability of these corrections. This work also developed methods to improve the accessibility of these distortion characterizations and corrections. We first tested the application of a more readily available 2D phantom as a surrogate for 3D distortion characterization by stepping the table with an integrated batch script file. Later we developed and constructed a large modular distortion phantom using easily obtainable materials, and showed and constructed a large modular distortion phantom using easily obtainable materials, and used it to characterize the distortion on several widely available MR systems. To accompany this phantom, open source software was also developed for easy characterization of system-dependent distortions. Finally, while the dosimetric equivalence of synCT with CT has been well established, it was necessary to characterize any differences that may exist between synCT and CT in an IGRT setting. This work has helped to establish the geometric equivalence of these two modalities, with some caveats that have been discussed at length

New techniques for imaging photon-counting and particle detectors

Since the advent of space-based astronomy in the early 1960's, there has been a need for space-qualified detectors with sufficient sensitivity and resolution to detect and image single photons, ions or electrons. This thesis describes a research programme to develop detectors that fulfil these requirements. I begin by describing the role of detectors in space astronomy and follow with a review of detector technologies, with particular emphasis on imaging techniques. Conductive charge division image readouts offer high performance, simplicity, and flexibility and their potential is investigated in both theory and practice. I introduce the basic design concept and discuss the fundamental factors limiting performance in relation to physical design and to underlying physical processes. Readout manufacturing techniques are reviewed and a novel method presented. I describe specific space and ground-based readout applications which proved valuable in teaching lessons and raising questions. These questions initiated an experimental programme, whose goals were to understand limiting physical processes and find techniques to overcome them. Results are presented, and the innovation of the progressive geometry readout technique, which this programme also spawned, is described. Progressive geometry readout devices, such as the Vernier anode, offer dramatically improved performance and have been successfully flight-proven. I describe the development of a Vernier readout for the J-PEX sounding rocket experiment, and discuss the instrument calibration and the flight programme. First investigations into a next generation of charge division readout design are presented. These devices will use charge comparison instead of amplitude measurement to further enhance resolution and count rate capability. In conclusion, I summarize the advances made during the course of this research, and discuss ongoing technological developments and further work which will enable MCP detectors to continue to excel where characteristics such as true photon-counting ability, high spatial resolution, format flexibility, and high temporal resolution are required