In-vitro Major Arterial Cardiovascular Simulator to generate Benchmark Data Sets for in-silico Model Validation

A deeper understanding of the influence of common cardiovascular diseases like stenosis, aneurysm or atherosclerosis on the circulatory mechanism is required, to establish new methods for early diagnosis. Different types of simulators were developed in the past to simulate healthy and pathological conditions of blood flow, often based on computational models, which allow to generate large data sets. However, since computational models often lack some aspects of real world data, hardware simulators are used to close this gap and generate data for model validation. The aim of this study is the development and validation of a hardware simulator to generate benchmark data sets of healthy and pathological conditions. The in-vitro hardware simulator in this study includes the major 33 arteries and is driven by a ventricular assist device generating a parametrised input condition at the heart node. Physiologic flow conditions including heart rate, systolic/diastolic pressure, peripheral resistance and compliance are adjustable in a wide range. The pressure and flow waves at 17+1 different locations are measured by inverted fluid resistant pressure transducers and one ultrasound flow transducer supporting a detailed analysis of the measurement data. The pressure and flow waves show physiological conditions. Furthermore, the influence of stenoses degree and location on blood pressure and flow was investigated. The results indicate decreasing translesional pressure and flow with increasing degree of stenosis, as expected. The benchmark data set is made available to the research community, with the purpose to validate and compare in-silico models of different type.Comment: Data available at Zenodo with doi 10.5281/zenodo.641527

First Steps towards Localized Opening of the Blood-Brain-Barrier by IR Laser Illumination Through the Rodent Skull

Glioblastoma, an aggressive malign tumor of the brain, is one of the most shattering diagnoses due to its very poor prognosis and limited treatment options. These options mainly consist of surgical or radiation therapeutic removal of as much tumor mass as possible, which unfortunately is almost always incomplete. Even worse, chemotherapy is of little use, as the special setup of the brain′s vessels severely limits the transit into the parenchyma of elsewhere efficient cytostatica. This Blood-Brain-Barrier (BBB) is for quite some time the target of sophisticated and nano-particle based transport mechanisms, however it is reported, that a boost of permeability for most of the brain can be achieved based on moderate temperature increase. One means to locally and reversibly increase the brain′s temperature and thus potentially opening the BBB may be achieved by illuminating the skull with infrared laser light, thus causing punctual heating and heat diffusion into the cortex. In extension of the common laser light guiding by glass fibres, we use a micro-positioned simple optics to focus a 1470 nm laser beam of approximately 500 µm in diameter on the skull. The apparent opening of the BBB is evidenced by the localized spread of Evans Blue injected into the tail vein of said rat, binding to Albumin (64,6 kDa) in the body. This marker molecule is usually blocked from passing through the intact BBB, but under IR illumination for half a minute, it appeared in post mortem visible blobs. Temperature profiles and potential tissue damage are now under investigation by high speed thermal camera and post mortem histology

In Vitro Major Arterial Cardiovascular Simulator to Generate Benchmark Data Sets for In Silico Model Validation

Cardiovascular diseases are commonly caused by atherosclerosis, stenosis and aneurysms. Understanding the influence of these pathological conditions on the circulatory mechanism is required to establish methods for early diagnosis. Different tools have been developed to simulate healthy and pathological conditions of blood flow. These simulations are often based on computational models that allow the generation of large data sets for further investigation. However, because computational models often lack some aspects of real-world data, hardware simulators are used to close this gap and generate data for model validation. The aim of this study is to develop and validate a hardware simulator to generate benchmark data sets of healthy and pathological conditions. The development process was led by specific design criteria to allow flexible and physiological simulations. The in vitro hardware simulator includes the major 33 arteries and is driven by a ventricular assist device generating a parametrised in-flow condition at the heart node. Physiologic flow conditions, including heart rate, systolic/diastolic pressure, peripheral resistance and compliance, are adjustable across a wide range. The pressure and flow waves at 17 + 1 locations are measured by inverted fluid-resistant pressure transducers and one ultrasound flow transducer, supporting a detailed analysis of the measurement data even for in silico modelling applications. The pressure and flow waves are compared to in vivo measurements and show physiological conditions. The influence of the degree and location of the stenoses on blood pressure and flow was also investigated. The results indicate decreasing translesional pressure and flow with an increasing degree of stenosis, as expected. The benchmark data set is made available to the research community for validating and comparing different types of computational models. It is hoped that the validation and improvement of computational simulation models will provide better clinical predictions

Neurophotonic Scanning System – Towards Automatic Infrared Neurostimulation

Intraoperative neuromonitoring is without doubt important for all surgical interventions, where nerve structures are at risk. Mapping techniques for the identification of motor nerves and cortex are available. They rely on manual identification using an electrical stimulation probe. A landmark-based visualization of the results is currently not possible. To overcome these limitations, we are developing a system for automatic stimulation and display of functional tissue. Infrared neurostimulation (INS) was proposed to be a feasible alternative to electrical stimulation of nerves. It provides contactless and artifact-free activation of nerves. For our preclinical experiments we used an infrared diode laser system with a wavelength of 1470 nm. For automatic screening, we developed a scanning system and suitable scan-algorithms in order to provide optimal scanning parameters. Recording of compound muscle action potentials (CMAP) was performed with a differential amplifier and appropriate neurophysiologic software. Subunits of the system were combined via multiple interfaces. A control-software merges all relevant functions of the individual parts and parallel use. Marking of tissue was realized with a red pilot laser deflected by the same scanning system. With this work we could show, that a system for automatic laser deflection with parallel neurophysiologic recording and subsequent highlighting of irradiated tissue is possible. This system can serve as a tool for further systematic investigations in the field of INS

Coronary artery plaques: cardiac CT with model-based and adaptive-statistical iterative reconstruction technique

OBJECTIVES: To compare image quality of coronary artery plaque visualization at CT angiography with images reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model based iterative reconstruction (MBIR) techniques. METHODS: The coronary arteries of three ex vivo human hearts were imaged by CT and reconstructed with FBP, ASIR and MBIR. Coronary cross-sectional images were co-registered between the different reconstruction techniques and assessed for qualitative and quantitative image quality parameters. Readers were blinded to the reconstruction algorithm. RESULTS: A total of 375 triplets of coronary cross-sectional images were co-registered. Using MBIR, 26% of the images were rated as having excellent overall image quality, which was significantly better as compared to ASIR and FBP (4% and 13%, respectively, all p<0.001). Qualitative assessment of image noise demonstrated a noise reduction by using ASIR as compared to FBP (p<0.01) and further noise reduction by using MBIR (p<0.001). The contrast-to-noise-ratio (CNR) using MBIR was better as compared to ASIR and FBP (44±19, 29±15, 26±9, respectively; all p<0.001). CONCLUSIONS: Using MBIR improved image quality, reduced image noise and increased CNR as compared to the other available reconstruction techniques. This may further improve the visualization of coronary artery plaque and allow radiation reduction

Computed tomography and histopathological findings after embolization with inherently radiopaque 40μm-microspheres, standard 40μm-microspheres and iodized oil in a porcine liver model.

PURPOSE:The present study compared standard computed tomography (CT) and histopathological findings after endovascular embolization using a prototype of inherently radiopaque 40μm-microspheres with both standard 40μm-microspheres and iodized oil in a porcine liver model. MATERIALS AND METHODS:Twelve pigs were divided into six study groups, of two pigs each. Four pigs were embolized with iodized oil alone and four with radiopaque microspheres; two animals in each group were sacrificed at 2 hours and two at 7 days. Two pigs were embolized with radiopaque microspheres and heparin and sacrificed at 7 days. Two pigs were embolized with standard microspheres and sacrificed at 2 hours. CT was performed before and after segmental embolization and before sacrifice at 7 days. The distribution of embolic agent, inflammatory response and tissue necrosis were assessed histopathologically. RESULTS:Radiopaque microspheres and iodized oil were visible on standard CT 2 hours and 7 days after embolization, showing qualitatively comparable arterial and parenchymal enhancement. Quantitatively, the enhancement was more intense for iodized oil. Standard microspheres, delivered without contrast, were not visible by imaging. Radiopaque and standard microspheres similarly occluded subsegmental and interlobular arteries and, to a lesser extent, sinusoids. Iodized oil resulted in the deepest penetration into sinusoids. Necrosis was always observed after embolization with microspheres, but never after embolization with iodized oil. The inflammatory response was mild to moderate for microspheres and moderate to severe for iodized oil. CONCLUSION:Radiopaque 40μm-microspheres are visible on standard CT with qualitatively similar but quantitatively less intense enhancement compared to iodized oil, and with a tendency towards less of an inflammatory reaction than iodized oil. These microspheres also result in tissue necrosis, which was not observed after embolization with iodized oil. Both radiopaque and standard 40μm-microspheres are found within subsegmental and interlobar arteries, as well as in hepatic sinusoids

Histogram analysis of lipid-core plaques in coronary computed tomographic angiography: Ex vivo validation against histology

PURPOSE: In coronary computed tomographic angiography (CTA), low attenuation of coronary atherosclerotic plaque is associated with lipid-rich plaques. However, an overlap in Hounsfield units (HU) between fibrous and lipid-rich plaque as well as an influence of luminal enhancement on plaque attenuation was observed and may limit accurate detection of lipid-rich plaques by CTA. We sought to determine whether the quantitative histogram analysis improves accuracy of the detection of lipid-core plaque (LCP) in ex vivo hearts by validation against histological analysis. MATERIALS AND METHODS: Human donor hearts were imaged with a 64-slice computed tomographic scanner using a standard coronary CTA protocol, optical coherence tomography (OCT), a histological analysis. Lipid-core plaque was defined in the histological analysis as any fibroatheroma with a lipid/necrotic core diameter of greater than 200 μm and a circumference greater than 60 degrees as well as a cap thickness of less than 450 μm. In OCT, lipid-rich plaque was determined as a signal-poor region with diffuse borders in 2 quadrants or more. In CTA, the boundaries of the noncalcified plaque were manually traced. The absolute and relative areas of low attenuation plaque based on pixels with less than 30, less than 60, and less than 90 HU were calculated using quantitative histogram analysis. RESULTS: From 5 hearts, a total of 446 cross sections were coregistered between CTA and the histological analysis. Overall, 55 LCPs (12%) were identified by the histological analysis. In CTA, the absolute and relative areas of low attenuation plaque less than 30, less than 60, and less than 90 HU were 0.14 (0.31) mm (4.22% [9.02%]), 0.69 (0.95) mm (18.28% [21.22%]), and 1.35 (1.54) mm (35.65% [32.07%]), respectively. The low attenuation plaque area correlated significantly with histological lipid content (lipid/necrotic core size [in square millimeter] and a portion of lipid/necrotic core on the entire plaque) at all thresholds but was the strongest at less than 60 HU (r = 0.53 and r = 0.48 for the absolute and relative areas, respectively). Using a threshold of 1.0 mm or greater, the absolute plaque area of less than 60 HU in CTA yielded 69% sensitivity and 80% specificity to detect LCP, whereas sensitivity and specificity were 73% and 71% for using 25.0% or higher relative area less than 60 HU. The discriminatory ability of CTA for LCP was similar between the absolute and relative areas (the area under the curve, 0.744 versus 0.722; P = 0.37). Notably, the association of the low attenuation plaque area in CTA with LCP was not altered by the luminal enhancement for the relative (P = 0.48) but for the absolute measurement (P = 0.03). Similar results were achieved when validated against lipid-rich plaque by OCT in a subset of 285 cross sections. CONCLUSIONS: In ex vivo conditions, the relative area of coronary atherosclerotic plaque less than 60 HU in CTA as derived from quantitative histogram analysis has good accuracy to detect LCP as compared with a histological analysis independent of differences in luminal contrast enhancement

Classification of coronary atherosclerotic plaques ex vivo with T1, T2, and ultrashort echo time CMR

OBJECTIVES: This study sought to determine whether the classification of human coronary atherosclerotic plaques with T1, T2, and ultrashort echo time (UTE) cardiac magnetic resonance (CMR) would correlate well with atherosclerotic plaque classification by histology. BACKGROUND: CMR has been extensively used to classify carotid plaque, but its ability to characterize coronary plaque remains unknown. In addition, the detection of plaque calcification by CMR remains challenging. Here, we used T1, T2, and UTE CMR to evaluate atherosclerotic plaques in fixed post-mortem human coronary arteries. We hypothesized that the combination of T1, T2, and UTE CMR would allow both calcified and lipid-rich coronary plaques to be accurately detected. METHODS: Twenty-eight plaques from human donor hearts with proven coronary artery disease were imaged at 9.4-T with a T1-weighted 3-dimensional fast low-angle shot (FLASH) sequence (250-μm resolution), a T2-weighted rapid acquisition with refocused echoes (RARE) sequence (in-plane resolution 0.156 mm), and an UTE sequence (300-μm resolution). Plaques showing selective hypointensity on T2-weighted CMR were classified as lipid-rich. Areas of hypointensity on the T1-weighted images, but not the UTE images, were classified as calcified. Hyperintensity on the T1-weighted and UTE images was classified as hemorrhage. Following CMR, histological characterization of the plaques was performed with a pentachrome stain and established American Heart Association criteria. RESULTS: CMR showed high sensitivity and specificity for the detection of calcification (100% and 90%, respectively) and lipid-rich necrotic cores (90% and 75%, respectively). Only 2 lipid-rich foci were missed by CMR, both of which were extremely small. Overall, CMR-based classification of plaque was in complete agreement with the histological classification in 22 of 28 cases (weighted κ = 0.6945, p < 0.0001). CONCLUSIONS: The utilization of UTE CMR allows plaque calcification in the coronary arteries to be robustly detected. High-resolution CMR with T1, T2, and UTE contrast enables accurate classification of human coronary atherosclerotic plaque