95 research outputs found
Quantifying the effects of cerebral capillary flow disruptions with two photon microscopy
The cerebral capillary network performs the critical role of delivering oxygen to tissue with a rich supply of oxygen bound red blood cells. Disruptions in this steady flow have been observed in healthy brains, but also at elevated levels in a number of disease models such as Alzheimer’s disease and stroke, both of which lack good treatment options. Reductions in these “stalls” in blood flow have been shown to improve cortical blood flow as well as disease outcomes in preclinical models. But the assessment of capillary stalling, and its potential as a therapeutic target, have been limited, in part due to limitations in technology.
To address this, we develop and apply tools using two-photon microscopic imaging for improved estimation of stalling and its impact. We first utilize a custom built Bessel beam two photon microscope for extended depth of field imaging. We show that its high volumetric imaging rate allows for improved detection of capillary stalling events, and develop an algorithm for semi-automated analysis of stalls to increase analysis throughout and reliability. Next, we develop and validate a novel scanning strategy for estimation of red blood cell flow speed, for simultaneous estimation of capillary flow speeds across many capillaries. Our approach is easy to implement and readily adaptable to any researchers interested in capillary flow.
Finally, we utilize phosphorescent lifetime imaging (PLIM) to measure changes in local oxygen around individual stalling events and demonstrate a rapid and consistent drop in oxygen as a result of stalled flow. Our measurements show that this drop likely extends to the local tissue, and in some cases reaches critically hypoxic levels
Non-invasive ultrasound monitoring of regional carotid wall structure and deformation in atherosclerosis
Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001.Includes bibliographical references (p. 223-242).Atherosclerosis is characterized by local remodeling of arterial structure and distensibility. Developing lesions either progress gradually to compromise tissue perfusion or rupture suddenly to cause catastrophic myocardial infarction or stroke. Reliable measurement of changes in arterial structure and composition is required for assessment of disease progression. Non-invasive carotid ultrasound can image the heterogeneity of wall structure and distensibility caused by atherosclerosis. However, this capability has not been utilized for clinical monitoring because of speckle noise and other artifacts. Clinical measures focus instead on average wall thickness and diameter distension in the distal common carotid to reduce sensitivity to noise. The goal of our research was to develop an effective system for reliable regional structure and deformation measurements since these are more sensitive indicators of disease progression. We constructed a system for freehand ultrasound scanning based on custom software which simultaneously acquires real-time image sequences and 3D frame localization data from an electromagnetic spatial localizer. With finite element modeling, we evaluated candidate measures of regional wall deformation.(cont.) Finally, we developed a multi-step scheme for robust estimation of local wall structure and deformation. This new strategy is based on a directionally-sensitive segmentation functional and a motion-region-of-interest constrained optical flow algorithm. We validated this estimator with simulated images and clinical ultrasound data. The results show structure estimates that are accurate and precise, with inter- and intra-observer reproducibility surpassing existing methods. Estimates of wall velocity and deformation likewise show good overall accuracy and precision. We present results from a proof-of-principle evaluation conducted in a pilot study of normal subjects and clinical patients. For one example, we demonstrate the combination of 2D image processing with 3D frame localization for visualization of the carotid volume. With slice localization, estimates of carotid wall structure and deformation can be derived for all axial positions along the carotid artery. The elements developed here provide the tools necessary for reliable quantification of regional wall structure and composition changes which result from atherosclerosis.by Raymond C. Chan.Ph.D
Acoustic Standing Wave Manipulation of Particles and Cells in Microfluidic Chips
The rise of MEMS and µTAS techniques has created a whole new family of microfluidic devices for a wide range of chemical and biomedical analyses to be performed on small Lab-on-a-chip platforms. The operations often include small samples of particle or cell suspensions on which separation, mixing, trapping or sorting is performed. External fields and forces are used for these operations, and this thesis is specifically focused the development of ultrasonic standing wave technology and the use of acoustic force fields to perform bioanalytical unit operations. The combination of acoustic standing waves and the laminar flow in microfluidics has proven to be well suited for performing particle and cell separation. The fundamental acoustic separator used in this thesis consists of a microfluidic flow channel with a three way flow splitter (trifurcation) in the end of the channel. An acoustic standing wave field is applied to the main flow channel by attaching the transducer underneath the chip. The acoustic standing wave is however obtained perpendicular to the axial propagation of the wave field and the direction of the flow. The half wavelength resonance affects rigid particles or cells driving them into the acoustic pressure node while liquid spheres having other density and compressibility properties may move to the pressure antinode. This enables acoustic separation of different particle types. Blood has proven to be very suitable for acoustic cell manipulation. An application where lipid particles can be removed acoustically from shed blood from open heart surgery is demonstrated. An application for acoustic plasmapheresis is also shown where high quality blood plasma is generated. Different separator designs, device material, and the influence of the separation channel cross-section design are also investigated
Analysis of myocardial contractility with magnetic resonance
Heart failure has considerable morbidity and poor prognosis. An understanding of the underlying mechanics governing myocardial contraction is a prerequisite for interpreting and predicting changes induced by heart disease. Gross changes in contractile behaviour of the myocardium are readily detected with existing techniques. For more subtle changes during early stages of cardiac dysfunction, however, it requires a sensitive method for measuring, as well as a precise criterion for quantifying, normal and impaired myocardial function. Cardiovascular Magnetic Resonance (CMR) imaging is emerging as an important clinical tool because of its safety, versatility, and the high quality images it produces that allow accurate and reproducible quantification of cardiac structure and function. Traditional CMR approaches for measuring contractility rely on tagging of the myocardium with fiducial markers and require a lengthy and often subjective dependant post-processing procedure. The aim of this research is to develop a new technique, which uses velocity as a marker for the visualisation and assessment of myocardial contractility. Two parallel approaches have been investigated for the assessment of myocardial velocity. The first of these is haimonic phase (HARP) imaging. HARP imaging allows direct derivation of myocardial velocity and strain without the need of further user interaction. We investigated the effect of respiration on the accuracy of the derived contractility, and assessed the clinical applicability and potential pitfalls of the technique by analysing results from a group of patients with hypertrophic cardiomyopathy. The second technique we have investigated is the direct measurement of myocardial velocity with phase contrast myocardial velocity mapping. The imaging sequence used employs effective blood saturation for reducing flow induced phase errors within the myocardium. View sharing was used to improve the temporal resolution, which permitted acquisition of 3D velocity information throughout the cardiac cycle in a single breath-hold, enabling a comprehensive assessment of strain rate of the left ventricle.
One key factor that affects the derivation of myocardial contractility based on myocardial velocity is the practical inconsistency of the velocity data. A novel iterative optimisation scheme by incorporating the incompressibility constraint was developed for the restoration of myocardial velocity data. The method allowed accurate assessment of both in-plane and through-plan strain rates, as demonstrated with both synthetic and in vivo data acquired from normal subjects and ischaemic patients. To further enhance the clinical potential of the technique and facilitate the visual assessment of contractile abnormality with myocardial velocity mapping, a complementary analysis framework, named Virtual Tagging, has been developed. The method used velocity data in all directions combined with a finite element mesh incorporating geometrical and physical constraints. The Virtual Tagging framewoik allowed velocity measurements to be used for calculating strain distribution within the 3D volume. It also permitted easy visualisation of the displacement of the tissue, akin to traditional CMR tagging. Detailed validation of the technique is provided, which involves both numerical simulation and in vitro phantom experiments.
The main contribution of this thesis is in the improvement of the effectiveness and quality of quantitative myocardial contractility analysis from both sequence design and medical image computing perspectives. It is aimed at providing a sensitive means of detecting subtle as well as gross changes in contractile behaviour of the myocardium. The study is expected to provide a clinically viable platform for functional correlation with other functional measures such as myocardial perfusion and diffusion, and to serve as an aid for further understanding of the links between intrinsicOpen acces
Measuring blood flow and pro-inflammatory changes in the rabbit aorta
Atherosclerosis is a chronic inflammatory disease that develops as a consequence of progressive entrapment of low density lipoprotein, fibrous proteins and inflammatory cells in the arterial intima. Once triggered, a myriad of inflammatory and atherogenic factors mediate disease progression. However, the role of pro-inflammatory activity in the initiation of atherogenesis and its relation to altered mechanical stresses acting on the arterial wall is unclear. Estimation of wall shear stress (WSS) and the inflammatory mediator NF-κB is consequently useful. In this thesis novel ultrasound tools for accurate measurement of spatiotemporally varying 2D and 3D blood flow, with and without the use of contrast agents, have been developed. This allowed for the first time accurate, broad-view quantification of WSS around branches of the rabbit abdominal aorta. A thorough review of the evidence for a relationship between flow, NF-κB and disease was performed which highlighted discrepancies in the current literature and was used to guide the study design. Subsequently, methods for the measurement and colocalization of the spatial distribution of NF-κB, arterial permeability and nuclear morphology in the aorta of New Zealand White rabbits were developed. It was demonstrated that endothelial pro-inflammatory changes are spatially correlated with patterns of WSS, nuclear morphology and arterial permeability in vivo in the rabbit descending and abdominal aorta. The data are consistent with a causal chain between WSS, macromolecule uptake, inflammation and disease, and with the hypothesis that lipids are deposited first, through flow-mediated naturally occurring transmigration that, in excessive amounts, leads to subsequent inflammation and disease.Open Acces
Transport in complex systems : a lattice Boltzmann approach
Celem niniejszej pracy jest zbadanie możliwości efektywnego modelowania procesów transportu w złożonych systemach z zakresu dynamiki płynów za pomocą metody siatkowej Boltzmanna (LBM). Złożoność systemu została potraktowana wieloaspektowo i konkretne układy, które poddano analizie pokrywały szeroki zakres zagadnień fizycznych, m.in. przepływy wielofazowe, hemodynamikę oraz turbulencje. We wszystkich
przypadkach szczególna uwaga została zwrócona na aspekty numeryczne — dokładność używanych modeli, jak również szybkość z jaką pozwalają one uzyskać zadowalające rozwiązanie.
W ramach pracy rozwinięty został pakiet oprogramowania Sailfish, będący otwarta implementacja
metody siatkowej Boltzmanna na procesory kart graficznych (GPU). Po analizie szybkości jego działania, walidacji oraz omówieniu założeń projektowych, pakiet ten został użyty do symulacji trzech typów przepływów.
Pierwszym z nich były przepływy typu Brethertona/Taylora w dwu- i trójwymiarowych geometriach, do symulacji których zastosowano model energii swobodnej. Analiza otrzymanych wyników pokazała dobra zgodność z danymi dostępnymi w literaturze, zarówno eksperymentalnymi, jak i otrzymanymi za pomocą innych metod numerycznych. Drugim badanym problemem były przepływy krwi w realistycznych geometriach tętnic dostarczających krew do ludzkiego mózgu. Wyniki symulacji zostały dokładnie porównane z rozwiązaniem otrzymanym metoda objętości skończonych z wykorzystaniem pakietu OpenFOAM, przyspieszonego komercyjna biblioteka pozwalająca na wykonywanie obliczeń na GPU. Otrzymano dobra zgodność między badanymi metodami oraz pokazano, że metoda siatkowa Boltzmanna pozwala na wykonywanie symulacji do ok. 20 razy szybciej. Trzecim przeanalizowanym zagadnieniem były turbulentne przepływy w prostych geometriach. Po zwalidowaniu wszystkich zaimplementowanych modeli relaksacji na przypadku wiru Kidy, zbadano przepływy w pustym kanale oraz w obecności przeszkód. Do symulacji wykorzystano zarówno siatki zapewniające pełną rozdzielczość aż do skal Kolmogorova, jak i siatki o mniejszej rozdzielczości. Również w tym kontekście pokazano dobrą zgodność wyników otrzymanych metodą siatkową Boltzmanna z wynikami innych symulacji oraz badaniami eksperymentalnymi. Pokazano również, że implementacja LBM w pakiecie Sailfish zapewnia większą stabilność obliczeń niż ta opisana w literaturze dla tych samych przepływów i modeli relaksacji
A cumulative index to the 1976 issues of a continuing bibliography on Aerospace Medicine and Biology
This publication is a cumulative index to the abstracts contained in Supplements 151 through 162 of Aerospace Medicine and Biology: A continuing bibliography. It includes three indexes - subject, personal author, and corporate source
Image analysis and modeling of cellular organization in micropatterned environments
In experimental cellular biophysics, it has become standard practice to control the shape and organization of adherent cells. For this purpose, micropatterned environments are being used, which are fabricated using techniques from materials science. Thereby, cell variability can be reduced, which facilitates statistical analysis and allows for a detailed comparison to mathematical models. In this thesis we combine image processing with computational modeling and use the normalization properties of micropatterned environments to investigate cellular organization. In the first part, we apply image analysis techniques to study cell shape and internal organization. For this, we first analyze how contractile polymer bundles, so-called stress fibers, determine the shape of adherent cells in two and three dimensions. Next, we investigate the detailed structure of such bundles and quantify their influence on cellular contraction dynamics. In the second part of the thesis we develop different computational modeling approaches to gain deeper understanding into the interplay between cell shape and the microtubule network. We propose models that are based either on stochastic simulations of polymers or on an effective continuum theory for liquid crystals. With these models we can explain experimental results and predict the internal architecture of cells adhering to micropatterned substrates
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Ultrasonic Pulse Wave Imaging for in vivo Assessment of Vascular Wall Dynamics and Characterization of Arterial Pathologies
Arterial diseases such as hypertension, carotid stenosis, and abdominal aortic aneurysm (AAA) may progress silently without symptoms and contribute to acute cardiovascular events such as heart attack, stroke, and aneurysm rupture, which are consistently among the leading causes of death worldwide. The arterial pulse wave, regarded as one of the fundamental vital signs of clinical medicine, originates from the heart and propagates throughout the arterial tree as a pressure, flow velocity, and wall displacement wave, giving rise to the natural pulsation of the arteries. The dynamic properties of the pulse wave are intimately related to the physical state of the cardiovascular system. Thus, the assessment of the arterial wall dynamics driven by the pulse wave may provide valuable insights into vascular mechanical properties for the early detection and characterization of arterial pathologies.
The focus of this dissertation was to develop and clinically implement Pulse Wave Imaging (PWI), an ultrasound elasticity imaging-based method for the visualization and spatio-temporal mapping of the pulse wave propagation at any accessible arterial location. Motion estimation algorithms based on cross-correlation of the ultrasound radio-frequency (RF) signals were used to track the arterial walls and capture the pulse wave-induced displacements over the cardiac cycle. PWI facilitates the image-guided measurement of clinically relevant pulse wave features such as propagation speed (pulse wave velocity, or PWV), uniformity, and morphology as well as derivation of the pulse pressure waveform.
A parametric study investigating the performance of PWI in two canine aortas ex vivo and 10 normal, healthy human arteries in vivo established the optimal image acquisition and signal processing parameters for reliable measurement of the PWV and wave propagation uniformity. Using this framework, three separate clinical feasibility studies were conducted in patients diagnosed with hypertension, AAA, and carotid stenosis.
In a pilot study comparing hypertensive and aneurysmal abdominal aortas with normal controls, the AAA group exhibited significantly higher PWV and lower wave propagation uniformity. A “teetering” motion upon pulse wave arrival was detected in the smaller aneurysms ( 5.5 cm in diameter). While no significant difference in PWV or propagation uniformity was observed between normal and hypertensive aortas, qualitative differences in the pulse wave morphology along the imaged aortic segment may be an indicator of increased wave reflection caused by elevated blood pressure and/or arterial stiffness.
Pulse Wave Ultrasound Manometry (PWUM) was introduced as an extension of the PWI method for the derivation of the pulse pressure (PP) waveform in large central arteries. A feasibility study in 5 normotensive, 9 pre-hypertensive, and 5 hypertensive subjects indicated that a significantly higher PP in the hypertensive group was detected in the abdominal aorta by PWUM but not in the peripheral arteries by alternative devices (i.e. a radial applanation tonometer and the brachial sphygmomanometer cuff). A relatively strong positive correlation between aortic PP and both radial and brachial PP was observed in the hypertensive group but not in the normal and pre-hypertensive groups, confirming the notion that PP variation throughout the arterial tree may not be uniform in relatively compliant arteries.
The application of PWI in 10 stenotic carotid arteries identified phenomenon such as wave convergence, elevated PWV, and decreased cumulative displacement around and/or within regions of atherosclerotic plaque. Intra-plaque mapping of the PWV and cumulative strain demonstrated the potential to quantitatively differentiate stable (i.e. calcified) and vulnerable (i.e. lipid) plaque components. The lack of correlation between quantitative measurements (PWV, modulus, displacement, and strain) and expected plaque stiffness illuminates to need to consider several physiological and imaging-related factors such as turbulent flow, wave reflection, imaging location, and the applicability of established theoretical models in vivo.
PWI presents a highly translational method for visualization of the arterial pulse wave and the image-guided measurement of several clinically relevant pulse wave features. The aforementioned findings collectively demonstrated the potential of PWI to detect, diagnose, and characterize vascular disease based on qualitative and quantitative information about arterial wall dynamics under pathological conditions
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