Systems and Methods for the Spectral Calibration of Swept Source Optical Coherence Tomography Systems

This dissertation relates to the transition of the state of the art of swept source optical coherence tomography (SS-OCT) systems to a new realm in which the image acquisition speed is improved by an order of magnitude. With the aid of a better quality imaging technology, the speed-up factor will considerably shorten the eye-exam clinical visits which in turn improves the patient and doctor interaction experience. These improvements will directly lower associated medical costs for eye-clinics and patients worldwide. There are several other embodiments closely related to Optical Coherence Tomography (OCT) that could benefit from the ideas presented in this dissertation including: optical coherence microscopy (OCM), full-field OCT (FF-OCT), optical coherence elastography (OCE), optical coherence tomography angiography (OCT-A), anatomical OCT (aOCT), optical coherence photoacoustic microscopy (OC-PAM), micro optical coherence tomography (µ OCT), among others. In recent decades, OCT has established itself as the de-facto imaging process that most ophthalmologists refer to in their clinical practices. In a broader sense, optical coherence tomography is used in applications when low penetration and high resolution are desired. These applications include different fields of biomedical sciences including cardiology, dermatology, and pulmonary related sciences. Many other industrial applications including quality control and precise measurements have also been reported that are related to the OCT technology. Every new iteration of OCT technology has always come about with advanced signal processing and data acquisition algorithms using mixed-signal architectures, calibration and signal processing techniques. The existing industrial practices towards data acquisition, processing, and image creation relies on conventional signal processing design flows, which extensively employ continuous/discrete techniques that are both time-consuming and costly. The ideas presented in this dissertation can take the technology to a new dimension of quality of service

Simulation and Design of an UWB Imaging System for Breast Cancer Detection

Breast cancer is the most frequently diagnosed cancer among women. In recent years, the mortality rate due to this disease is greatly decreased thanks to both enormous progress in cancer research, and screening campaigns which have allowed the increase in the number of early diagnoses of the disease. In fact, if the tumor is identied in its early stage, e.g. when it has a diameter of less than one centimeter, the possibility of a cure can reach 93%. However, statistics show that more young aged women are suered breast cancer. The goal of screening exams for early breast cancer detection is to nd cancers before they start to cause symptoms. Regular mass screening of all women at risk is a good option to achieve that. Instead of meeting very high diagnostic standards, it is expected to yield an early warning, not a denitive diagnosis. In the last decades, X-ray mammography is the most ecient screening technique. However, it uses ionizing radiation and, therefore, should not be used for frequent check-ups. Besides, it requires signicant breast compression, which is often painful. In this scenario many alternative technologies were developed to overcome the limitations of mammography. Among these possibilities, Magnetic Resonance Imaging (MRI) is too expensive and time-consuming, Ultrasound is considered to be too operatordependent and low specicity, which are not suitable for mass screening. Microwave imaging techniques, especially Ultra WideBand (UWB) radar imaging, is the most interesting one. The reason of this interest relies on the fact that microwaves are non-ionizing thus permitting frequent examinations. Moreover, it is potentially lowcost and more ecient for young women. Since it has been demonstrated in the literatures that the dielectric constants between cancerous and healthy tissues are quite dierent, the technique consists in illuminating these biological tissues with microwave radiations by one or more antennas and analyzing the re ected signals. An UWB imaging system consists of transmitters, receivers and antennas for the RF part, the transmission channel and of a digital backend imaging unit for processing the received signals. When an UWB pulse strikes the breast, the pulse is re ected due to the dielectric discontinuity in tissues, the bigger the dierence, the bigger the backscatter. The re ected signals are acquired and processed to create the energy maps. This thesis aims to develop an UWB system at high resolution for the detection of carcinoma breast already in its initial phase. To favor the adoption of this method in screening campaigns, it is necessary to replace the expensive and bulky RF instrumentation used so far with ad-hoc designed circuits and systems. In order to realize that, at the very beginning, the overall system environment must be built and veried, which mainly consists of the transmission channel{the breast model and the imaging unit. The used transmission channel data come from MRI of the prone patient. In order to correctly use this numerical model, a simulator was built, which was implemented in Matlab, according to the Finite-Dierence-Time- Domain (FDTD) method. FDTD algorithm solves the electric and magnetic eld both in time and in space, thus, simulates the propagation of electromagnetic waves in the breast model. To better understand the eect of the system non-idealities, two 2D breast models are investigated, one is homogeneous, the other is heterogeneous. Moreover, the modeling takes into account all critical aspects, including stability and medium dispersion. Given the types of tissues under examination, the frequency dependence of tissue dielectric properties is incorporated into wideband FDTD simulations using Debye dispersion parameters. A performed further study is in the implementation of the boundary conditions. The Convolution Perfectly Matched Layer (CPML) is used to implement the absorbing boundaries. The objective of the imaging unit is to obtain an energy map representing the amount of energy re ected from each point of the breast, by recombining the sampled backscattered signals. For this purpose, the study has been carried out on various beamforming in the literature. The basic idea is called as "delay and sum", which is to align the received signals in such a way as to focus a given point in space and then add up all the contributions, so as to obtain a constructive interference at that point if this is a diseased tissue. In this work, Microwave Imaging via Space Time (MIST) Beamforming algorithm is applied, which is based on the above principle and add more elaborations of the signals in order to make the algorithm less sensitive to propagation phenomena in the medium and to the non-idealities of the system. It is divided into two distinct steps: the rst step, called SKin Artifact Removal (SKAR), takes care of removing the contributions from the signal caused by the direct path between the transmitter and receiver, the re ection of skin, as they are orders of magnitude higher compared to the re ections caused by cancers; the second step, which is BEAmForming (BEAF), performs the algorithm of reconstruction by forming a weighted combination of time delayed version of the calibrated re ected signals. As discussed above, more attention must be paid on the implementation of the ad-hoc integration circuits. In this scenario, due to the strict requirements on the RF receiver component, two dierent approaches of the implementation of the RF front-end, Direct Conversion (DC) receiver and Coherent Equivalent Time Sampling (CETS) receiver are compared. They are modeled behaviorally and the eects of various impairments, such as thermal, jitter, and phase noise, as well as phase inaccuracies, non-linearity, ADC quantization noise and distortion, on energy maps and on quantitative metrics such as SCR and SMR are evaluated. Dierential Gaussian pulse is chosen as the exciting source. Results show that DC receiver performs higher sensitivity to phase inaccuracies, which makes it less robust than the CETS receiver. Another advantage of the CETS receiver is that it can work in time domain with UWB pulses, other than in frequency domain with stepped frequency continuous waves like the DC one, which reduces the acquisition time without impacting the performance. Based on the results of the behavioral simulations, low noise amplier (LNA) and Track and Hold Amplier (THA) can be regarded as the most critical parts for the proposed CETS receiver, as well as the UWB antenna. This work therefore focuses on their hardware implementations. The LNA, which shows critical performance limitation at bandwidth and noise gure of receiver, has been developed based on common-gate conguration. And the THA based on Switched Source Follower (SSF) scheme has been presented and improved to obtain high input bandwidth, high sampling rate, high linearity and low power consumption. LNA and THA are implemented in CMOS 130nm technology and the circuit performance evaluation has been taken place separately and together. The small size UWB wide-slot antenna is designed and simulated in HFSS. Finally, in order to evaluate the eect of the implemented transistor level components on system performance, a multi-resolution top-down system methodology is applied. Therfore, the entire ow is analyzed for dierent levels of the RF frontend. Initially the system components are described behaviorally as ideal elements. The main activity consists in the analysis and development of the entire frontend system, observing and complementing each other blocks in a single ow simulation, clear and well-dened in its various interfaces. To achieve that the receiver is modeled and analyzed using VHDL-AMS language block by block, moreover, the impact of quantization, noise, jitter, and non-linearity is also evaluated. At last, the behavioral description of antenna, LNA and THA is replaced with a circuit-level one without changing the rest of the system, which permits a system-level assessment of low-level issues

Portable Ultrasound Imaging

This PhD project investigates hardware strategies and imaging methods for hand-held ultrasound systems. The overall idea is to use a wireless ultrasound probe linked to general-purpose mobile devices for the processing and visualization. The approach has the potential to reduce the upfront costs of the ultrasound system and, consequently, to allow for a wide-scale utilization of diagnostic ultrasound in any medical specialties and out of the radiology department. The first part of the contribution deals with the study of hardware solutions for the reduction of the system complexity. Analog and digital beamforming strategies are simulated from a system-level perspective. The quality of the B-mode image is evaluated and the minimum specifications are derived for the design of a portable probe with integrated electronics in-handle. The system is based on a synthetic aperture sequential beamforming approach that allows to significantly reduce the data rate between the probe and processing unit. The second part investigates the feasibility of vector flow imaging in a hand-held ultrasound system. Vector flow imaging overcomes the limitations of conventional imaging methods in terms of flow angle compensation. Furthermore, high frame rate can be obtained by using synthetic aperture focusing techniques. A method is developed combining synthetic aperture sequential beamforming and directional transverse oscillation to achieve the wireless transmission of the data along with a relatively inexpensive 2-D velocity estimation. The performance of the method is thoroughly assessed through simulations and measurements, and in vivo investigations are carried out to show its potential in presence of complex flow dynamics. A sufficient frame rate is achieved to allow for the visualization of vortices in the carotid bifurcation. Furthermore, the method is implemented on a commercially available tablet to evaluate the real-time processing performance in the built-in GPU with concurrent wireless transmission of the data. Based on the demonstrations in this thesis, a flexible framework can be implemented with performance that can be scaled to the needs of the user and according to the computing resources available. The integration of high-frame-rate vector flow imaging in a hand-held ultrasound scanner, in addition, has the potential to improve the operator’s workflow and opens the way to new possibilities in the clinical practice

Electrical Impedance Tomography for Biomedical Applications: Circuits and Systems Review

There has been considerable interest in electrical impedance tomography (EIT) to provide low-cost, radiation-free, real-time and wearable means for physiological status monitoring. To be competitive with other well-established imaging modalities, it is important to understand the requirements of the specific application and determine a suitable system design. This paper presents an overview of EIT circuits and systems including architectures, current drivers, analog front-end and demodulation circuits, with emphasis on integrated circuit implementations. Commonly used circuit topologies are detailed, and tradeoffs are discussed to aid in choosing an appropriate design based on the application and system priorities. The paper also describes a number of integrated EIT systems for biomedical applications, as well as discussing current challenges and possible future directions

Experiential Learning in Computer Engineering using Medium Complexity Logic Design Circuits

Abstract- One of the main tracks of research is about Low-cost computing devices in engineering educations. This track face the problem that conventual methods are either too trivial demonstrative educational examples, or too abstracted that it hides away the necessary details students should learn, or too complex industry grade demonstrations. This research targets to utilize lost cost computing devices, and produce medium complexity educational component using analog to digital, digital to analogy circuits integrated with Field Programmable Gate Array (FPGA) devices. A medium level complexity example is illustrated in this paper using Analog to Digital and Digital to Analog converter board attached to FPGA development board. A comparison between conventional methods and proposed methods is also presented showing advantages of FPGA based logic design implementations.A medium level complexity example is illustrated in this paper using Analog to Digital and Digital to Analog converter board attached to FPGA development board. A comparison between conventional methods and proposed methods is also presented showing advantages of FPGA based logic design implementations

3D fusion of histology to multi-parametric MRI for prostate cancer imaging evaluation and lesion-targeted treatment planning

Multi-parametric magnetic resonance imaging (mpMRI) of localized prostate cancer has the potential to support detection, staging and localization of tumors, as well as selection, delivery and monitoring of treatments. Delineating prostate cancer tumors on imaging could potentially further support the clinical workflow by enabling precise monitoring of tumor burden in active-surveillance patients, optimized targeting of image-guided biopsies, and targeted delivery of treatments to decrease morbidity and improve outcomes. Evaluating the performance of mpMRI for prostate cancer imaging and delineation ideally includes comparison to an accurately registered reference standard, such as prostatectomy histology, for the locations of tumor boundaries on mpMRI. There are key gaps in knowledge regarding how to accurately register histological reference standards to imaging, and consequently further gaps in knowledge regarding the suitability of mpMRI for tasks, such as tumor delineation, that require such reference standards for evaluation. To obtain an understanding of the magnitude of the mpMRI-histology registration problem, we quantified the position, orientation and deformation of whole-mount histology sections relative to the formalin-fixed tissue slices from which they were cut. We found that (1) modeling isotropic scaling accounted for the majority of the deformation with a further small but statistically significant improvement from modeling affine transformation, and (2) due to the depth (mean±standard deviation (SD) 1.1±0.4 mm) and orientation (mean±SD 1.5±0.9°) of the sectioning, the assumption that histology sections are cut from the front faces of tissue slices, common in previous approaches, introduced a mean error of 0.7 mm. To determine the potential consequences of seemingly small registration errors such as described above, we investigated the impact of registration accuracy on the statistical power of imaging validation studies using a co-registered spatial reference standard (e.g. histology images) by deriving novel statistical power formulae that incorporate registration error. We illustrated, through a case study modeled on a prostate cancer imaging trial at our centre, that submillimeter differences in registration error can have a substantial impact on the required sample sizes (and therefore also the study cost) for studies aiming to detect mpMRI signal differences due to 0.5 – 2.0 cm3 prostate tumors. With the aim of achieving highly accurate mpMRI-histology registrations without disrupting the clinical pathology workflow, we developed a three-stage method for accurately registering 2D whole-mount histology images to pre-prostatectomy mpMRI that allowed flexible placement of cuts during slicing for pathology and avoided the assumption that histology sections are cut from the front faces of tissue slices. The method comprised a 3D reconstruction of histology images, followed by 3D–3D ex vivo–in vivo and in vivo–in vivo image transformations. The 3D reconstruction method minimized fiducial registration error between cross-sections of non-disruptive histology- and ex-vivo-MRI-visible strand-shaped fiducials to reconstruct histology images into the coordinate system of an ex vivo MR image. We quantified the mean±standard deviation target registration error of the reconstruction to be 0.7±0.4 mm, based on the post-reconstruction misalignment of intrinsic landmark pairs. We also compared our fiducial-based reconstruction to an alternative reconstruction based on mutual-information-based registration, an established method for multi-modality registration. We found that the mean target registration error for the fiducial-based method (0.7 mm) was lower than that for the mutual-information-based method (1.2 mm), and that the mutual-information-based method was less robust to initialization error due to multiple sources of error, including the optimizer and the mutual information similarity metric. The second stage of the histology–mpMRI registration used interactively defined 3D–3D deformable thin-plate-spline transformations to align ex vivo to in vivo MR images to compensate for deformation due to endorectal MR coil positioning, surgical resection and formalin fixation. The third stage used interactively defined 3D–3D rigid or thin-plate-spline transformations to co-register in vivo mpMRI images to compensate for patient motion and image distortion. The combined mean registration error of the histology–mpMRI registration was quantified to be 2 mm using manually identified intrinsic landmark pairs. Our data set, comprising mpMRI, target volumes contoured by four observers and co-registered contoured and graded histology images, was used to quantify the positive predictive values and variability of observer scoring of lesions following the Prostate Imaging Reporting and Data System (PI-RADS) guidelines, the variability of target volume contouring, and appropriate expansion margins from target volumes to achieve coverage of histologically defined cancer. The analysis of lesion scoring showed that a PI-RADS overall cancer likelihood of 5, denoting “highly likely cancer”, had a positive predictive value of 85% for Gleason 7 cancer (and 93% for lesions with volumes \u3e0.5 cm3 measured on mpMRI) and that PI-RADS scores were positively correlated with histological grade (ρ=0.6). However, the analysis also showed interobserver differences in PI-RADS score of 0.6 to 1.2 (on a 5-point scale) and an agreement kappa value of only 0.30. The analysis of target volume contouring showed that target volume contours with suitable margins can achieve near-complete histological coverage for detected lesions, despite the presence of high interobserver spatial variability in target volumes. Prostate cancer imaging and delineation have the potential to support multiple stages in the management of localized prostate cancer. Targeted biopsy procedures with optimized targeting based on tumor delineation may help distinguish patients who need treatment from those who need active surveillance. Ongoing monitoring of tumor burden based on delineation in patients undergoing active surveillance may help identify those who need to progress to therapy early while the cancer is still curable. Preferentially targeting therapies at delineated target volumes may lower the morbidity associated with aggressive cancer treatment and improve outcomes in low-intermediate-risk patients. Measurements of the accuracy and variability of lesion scoring and target volume contouring on mpMRI will clarify its value in supporting these roles

Quantitative evaluation of 10 tractography algorithms on a realistic diffusion MR phantom.

International audienceAs it provides the only method for mapping white matter fibers in vivo, diffusion MRI tractography is gaining importance in clinical and neuroscience research. However, despite the increasing availability of different diffusion models and tractography algorithms, it remains unclear how to select the optimal fiber reconstruction method, given certain imaging parameters. Consequently, it is of utmost importance to have a quantitative comparison of these models and algorithms and a deeper understanding of the corresponding strengths and weaknesses. In this work, we use a common dataset with known ground truth and a reproducible methodology to quantitatively evaluate the performance of various diffusion models and tractography algorithms. To examine a wide range of methods, the dataset, but not the ground truth, was released to the public for evaluation in a contest, the "Fiber Cup". 10 fiber reconstruction methods were evaluated. The results provide evidence that: 1. For high SNR datasets, diffusion models such as (fiber) orientation distribution functions correctly model the underlying fiber distribution and can be used in conjunction with streamline tractography, and 2. For medium or low SNR datasets, a prior on the spatial smoothness of either the diffusion model or the fibers is recommended for correct modelling of the fiber distribution and proper tractography results. The phantom dataset, the ground truth fibers, the evaluation methodology and the results obtained so far will remain publicly available on: http://www.lnao.fr/spip.php?rubrique79 to serve as a comparison basis for existing or new tractography methods. New results can be submitted to [email protected] and updates will be published on the webpage

Data Conversion Within Energy Constrained Environments

Within scientific research, engineering, and consumer electronics, there is a multitude of new discrete sensor-interfaced devices. Maintaining high accuracy in signal quantization while staying within the strict power-budget of these devices is a very challenging problem. Traditional paths to solving this problem include researching more energy-efficient digital topologies as well as digital scaling.;This work offers an alternative path to lower-energy expenditure in the quantization stage --- content-dependent sampling of a signal. Instead of sampling at a constant rate, this work explores techniques which allow sampling based upon features of the signal itself through the use of application-dependent analog processing. This work presents an asynchronous sampling paradigm, based off the use of floating-gate-enabled analog circuitry. The basis of this work is developed through the mathematical models necessary for asynchronous sampling, as well the SPICE-compatible models necessary for simulating floating-gate enabled analog circuitry. These base techniques and circuitry are then extended to systems and applications utilizing novel analog-to-digital converter topologies capable of leveraging the non-constant sampling rates for significant sample and power savings

Inhibiitorid ja fotoluminestsents-sondid proteiinkinaaside PKA ja PIM in vitro uuringuteks

Väitekirja elektrooniline versioon ei sisalda publikatsiooneProteiinkinaasid (PK-d) katalüüsivad valkude fosforüülimist. PK-de ebanormaalne aktiivsus rakkudes on korrelatsioonis keeruliste haigustega. Seetõttu teeb farmaatsiatööstus märkimisväärseid jõupingutusi, et reguleerida PK-de aktiivsust inhibiitoritega ja jälgida nende aktiivsust luminestsents-sondidega. Käesolevas töös kasutatud ARC-inhibiitorid on keemiliselt struktuurilt adenosiini matkivate heteroaromaatsete fragmentide ja peptiidide analoogide konjugaadid, neid ühendeid on pikemalt uuritud Tartu Ülikooli keemia instituudis. Käesolevas uuringus näidati, et PK PKA katalüütilise alaühiku α-isovormi (PKAcα) monoklonaalse antikeha (kloon D38C6) seondumine sihtvalguga on konkurentne ARC-Lum(Fluo) sondiga ja see antikeha inhibeerib substraadi fosforüülimist. Proovi järjestikust töötlemist nende konkureerivate PKAcα ligandidega kasutati tundliku AbARC immuunanalüüsi-meetodi väljatöötamiseks, mis võimaldas määrata väikseid koguseid (alates 93 pg) PKAcα rakulüsaatides. Hiljuti avastati Cushingi sündroomiga patsiendil S54L mutatsiooniga PRKACB geen. See mutatsioon viib PK glütsiinirikka aasa struktuuri muutumiseni. Käesolevas uuringus konstrueeriti muteerunud PK suhtes kuuekordse selektiivsusega inhibiitor. Lisaks töötati välja luminestsents-meetod PKAcβ-valgu kaubanduslike ja väljatöötatud inhibiitorite afiinsuse määramiseks. Koostöös Oxfordi ülikooliga viidi läbi ARC-inhibiitorite ja proteiinkinaasi PIM-1 komplekside röntgenstruktuuranalüüs. Saadud struktuurimudelitest lähtuvalt konstrueeriti lihtsustatud keemilise ehitusega ained. Uued inhibiitorid derivatiseeriti biotiiniga või fluorestsentsvärviga Cy5 ja neid aineid kasutati PIM-kinaasidetuvastamiseks biokeemilistes lahustes ja bioloogilistes proovides. Analüüsimeetod, milles kasutati ARC-sonde koos PIM-2-selektiivse antikehaga , võimaldas määrata sihtvalgu väikseid koguseid (alates 44 pg PIM-2). Konfokaalmikroskoopia abil tuvastati, et uued fluorestsents-sondid tungivad kiiresti U2OS-rakkudesse, kus nende paiknemine kattub PIM-1 ja fluorestsentsvalgu konjugaadi paiknemisega.Protein kinases (PKs) catalyze the phosphorylation of proteins. Abnormal activity of PKs in cells is correlated to complex diseases. Therefore, the pharma industry is making significant efforts to regulate the activity of PKs with inhibitors and to monitor the activity of PKs with luminescent probes. ARC inhibitors are conjugates of adenosine analogues and peptide mimetic moieties; they have been studied at length at the Institute of Chemistry of the University of Tartu. In the present study, it was shown that the binding of monoclonal antibody (clone D38C6) to α-isoform of the catalytic subunit of PKA (PKAcα) was competitive with binding of ARC-Lum(Fluo) probes. Sequential treatment of a sample with these competing PKAcα ligands was used to develop a sensitive AbARC immunoassay that allowed the determination of small amounts (from 93 pg) of PKAcα in cell lysates. Recently, PRKACB gene with the S54L mutation was discovered in a patient with the Cushing's syndrome. This mutation leads to a change in the structure of the glycine-rich loop of the PK. In the present study, an inhibitor with six-fold selectivity for the mutated PK was developed. In addition, a luminescence method was worked out for determination of affinity of both commercial and developed inhibitors of the PKAcβ protein. X-ray structure analysis of complexes of ARC inhibitors and PK PIM-1 was performed in collaboration with the University of Oxford. Based on the obtained structural models, compounds with simplified chemical structures were constructed. New inhibitors were derivatized with biotin or fluorescent dye Cy5 and applied for the detection of PIM PKs in biochemical solutions and complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of PIM-2). A confocal microscopy study showed that the fluorescent probes were efficiently taken up by U2OS cells and the probes revealed high extent of co-localization with PIM-1-fused fluorescent proteins.https://www.ester.ee/record=b545989