Michael Weiler

Dynamic deformation characteristics of porcine aortic valve leaflet under normal and hypertensive conditions

Calcific aortic valve (AV) disease has a high prevalence in the United States, and hypertension is correlated to early onset of the disease. The cause of the disease is poorly understood, although biological and remodeling responses to mechanical forces, such as membrane tension, have been hypothesized to play a role. The mechanical behavior of the native AV has, therefore, been the focus of many recent studies. In the present study, the dynamic deformation characteristics of the AV leaflet and the effects of hypertension on leaflet deformation are quantified. Whole porcine aortic roots were trimmed and mounted in an in vitro pulsatile flow loop and subjected to normal (80/120 mmHg), hypertensive (120/160 mmHg), or severe hypertensive (150/190 mmHg) conditions. Local valve leaflet deformations were calculated with dual-camera photogrammetry method: by tracking the motion of markers placed on the AV leaflets in three dimensions and calculating their spatial deformations. The results demonstrate that, first, during diastole, high transvalvular pressure induces a stretch waveform which plateaus over the diastolic duration in both circumferential and radial directions. During systole, the leaflet stretches in the radial direction due to forward flow drag forces but compresses in the circumferential direction in a manner in agreement with Poissons effect. Second, average diastolic and systolic stretch ratios were quantified in the radial and circumferential directions in the base and belly region of the leaflet, and diastolic stretch was found to increase with increasing pressure conditions.

Differential transport function of lymphatic vessels in the rat tail model and the long-term effects of Indocyanine Green as assessed with near-infrared imaging.

Introduction: Near-infrared (NIR) imaging has emerged as a novel imaging modality for assessing lymphatic function in vivo. While the technique has provided quantitative data previously unavailable, questions remain in regards to the spatiotemporal capabilities of the approach. We address three of the more important issues here using the rodent tail, one of the most widely utilized in vivo model systems in the lymphatic literature. Specifically we demonstrate (1) the transient vs. steady state response of lymphatics to tracer injection, (2) the functional characteristics of multiple collecting vessels draining the same tissue space in parallel, and (3) the long-term consequences of fluorescent tracers on lymphatic function to repeated functional measurements. Methods: Rat tails were imaged with NIR and metrics of function were calculated for both collecting vessels that drain the tail. A nitric oxide donor cream (GTNO) was applied to the tail. Additionally, two different NIR dyes, indocyanine green (ICG) and LI-COR IRDye 800CW PEG, were utilized for function imaging at the time of initial injection and at 1, 2, and 4 week follow-up time points after which both draining lymph nodes were harvested. Results and Discussion: Significant differences were found between the two collecting vessels such that the vessel first showing fluorescence (dominant) produced enhanced functional metrics compared to the second vessel (non-dominant). GTNO significantly reduced lymphatic function in the non-dominant vessel compared to the dominant. ICG remained visible in the tail for 2 weeks after injection and was accompanied by significant losses in lymphatic function and enlarged draining lymph nodes. The Licor tracer also remained visible for 2 weeks. However, the dye produced significantly lower effects on lymphatic function than ICG, and lymph nodes were not enlarged at any time point, suggesting that this may be a more appropriate contrast agent for longitudinal lymphatic imaging.

Dual-channel in-situ optical imaging system for quantifying lipid uptake and lymphatic pump function

Nearly all dietary lipids are transported from the intestine to venous circulation through the lymphatic system, yet the mechanisms that regulate this process remain unclear. Elucidating the mechanisms involved in the functional response of lymphatics to changes in lipid load would provide valuable insight into recent implications of lymphatic dysfunction in lipid related diseases. Therefore, we sought to develop an in situ imaging system to quantify and correlate lymphatic function as it relates to lipid transport. The imaging platform provides the capability of dual-channel imaging of both high-speed bright-field video and fluorescence simultaneously. Utilizing post-acquisition image processing algorithms, we can quantify correlations between vessel pump function, lymph flow, and lipid concentration of mesenteric lymphatic vessels in situ. All image analysis is automated with customized LabVIEW virtual instruments; local flow is measured through lymphocyte velocity tracking, vessel contraction through measurements of the vessel wall displacement, and lipid uptake through fluorescence intensity tracking of an orally administered fluorescently labelled fatty acid analogue, BODIPY FL C16. This system will prove to be an invaluable tool for scientists studying intestinal lymphatic function in health and disease, and those investigating strategies for targeting the lymphatics with orally delivered drugs to avoid first pass metabolism.

Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging

The ability to quantify collecting vessel function in a minimally invasive fashion is crucial to the study of lymphatic physiology and the role of lymphatic pump function in disease progression. Therefore, we developed a highly sensitive, minimally invasive research platform for quantifying the pumping capacity of collecting lymphatic vessels in the rodent tail and forelimb. To achieve this, we have integrated a near-infrared lymphatic imaging system with a feedback-controlled pressure cuff to modulate lymph flow. After occluding lymphatic flow by inflating a pressure cuff on the limb or tail, we gradually deflate the cuff while imaging flow restoration proximal to the cuff. Using prescribed pressure applications and automated image processing of fluorescence intensity levels in the vessels, we were able to noninvasively quantify the effective pumping pressure (P(eff), pressure at which flow is restored after occlusion) and vessel emptying rate (rate of fluorescence clearance during flow occlusion) of lymphatics in the rat. To demonstrate the sensitivity of this system to changes in lymphatic function, a nitric oxide (NO) donor cream, glyceryl trinitrate ointment (GTNO), was applied to the tails. GTNO decreased P(eff) of the vessels by nearly 50% and the average emptying rate by more than 60%. We also demonstrate the suitability of this approach for acquiring measurements on the rat forelimb. Thus, this novel research platform provides the first minimally invasive measurements of P(eff) and emptying rate in rodents. This experimental platform holds strong potential for future in vivo studies that seek to evaluate changes in lymphatic health and disease.

Regional analysis of dynamic deformation characteristics of native aortic valve leaflets.

BACKGROUND The mechanical environment of the aortic valve (AV) has a significant impact on valve cellular biology and disease progression, but the regional variation in stretch across the AV leaflet is not well understood. This study, therefore, sought to quantify the regional variation in dynamic deformation characteristics of AV leaflets in the native mechanical environment in order to link leaflet stretch variation to reported AV calcification patterns. METHODS Whole porcine AVs (n=6) were sutured into a physiological left heart simulator and subjected to pulsatile and physiologically normal hemodynamic conditions. A grid of ink dots was marked on the entire ventricular surface of the AV leaflet. Dual camera stereo photogrammetry was used to determine the stretch magnitudes across the entire ventricular surface over the entire diastolic duration. RESULTS Elevated stretch magnitudes were observed along the leaflet base and coaptation line consistent with previously reported calcification patterns suggesting the higher mechanical stretch experienced by the leaflets in these regions may contribute to increased disease propensity. Transient stretch overloads were observed during diastolic closing, predominantly along the leaflet base, indicating the presence of a dynamic fluid hammer effect resulting from retrograde blood flow impacting the leaflet. We speculate the function of the leaflet base to act in cooperation with the sinuses of Valsalva to dampen the fluid hammer effect and reduce stress levels imparted on the rest of the leaflet.

Bridging the divide between pathogenesis and detection in lymphedema.

While our understanding of the lymphatic system has improved substantially in the past few decades, the translation of this knowledge into improved healthcare solutions for patients suffering from secondary lymphedema has been severely limited. The challenge facing clinicians is two-fold. First, there is no reliable, affordable, diagnostic capable of detecting the disease before symptoms of the lymphedema develop and the efficacy of treatment options becomes limited. Second, our understanding of the disease pathogenesis, its risk factors, and the underlying physiologic mechanisms is still in its infancy. These two challenges go hand in hand as limited diagnostic options have hindered our ability to understand lymphedema progression, and the lack of known underlying mechanisms involved in the disease prohibits the development of new diagnostic targets. This review serves to discuss the recent developments in clinical and lab research settings of both lymphedema diagnostic technologies and our understanding of the mechanisms driving disease risk and progression. We will show how these two lines of research are synergistically working with the ultimate goal of improving patient outcomes for those suffering from this horrible disease, identifying key areas of further research that are warranted to move the field forward and provide clinical relief for this neglected patient population.

A fast model of radiation-induced electron trapping in CCDs for implementation in the Gaia data processing

The European Space Agencys Gaia mission1 is scheduled for launch in 2012. It will operate at L2 for 5 years, rotating slowly so that its two optical telescopes will repeatedly observe more than one billion stars. The resulting data set will be iteratively reduced to solve for the relative position, parallax-distance and proper motion of every observed star, yielding a three dimensional dynamical model of our galaxy. The focal plane contains 106 large area silicon CCDs continuously operating in TDI mode at a line rate synchronised with the satellite rotation.2 One of the greatest challenges facing the mission is radiation damage in the CCDs which will cause charge loss and image distortion. This is particularly severe because the large focal plane is difficult to shield and because the launch will coincide with solar maximum. Despite steps taken to minimize the effects of radiation (e.g. regular use of charge injection), the residual distortion will need to be calibrated during the pipeline data processing. Due to the volume of data involved, this requires a trapping model which is physically realistic, yet fast enough and simple enough to implement in the pipeline. The current prototype Charge Distortion Model will be presented. This model was developed specifically for Gaia in TDI mode. However, an imaging mode version has already been applied to other missions, for example, to indicate the potential impact of radiation damage on the proposed Euclid mission.

Comparison of a fast analytical model of radiation damage effects in CCDs with experimental tests

ESAs Gaia mission aims to create a complete and highly accurate stereoscopic map of the Milky Way. The stellar parallaxes will be determined at the micro-arcsecond level, as a consequence the measurement of the stellar image location on the CCD must be highly accurate. The solar wind protons will create charge traps in the CCDs of Gaia, which will induce large charge loss and distort the stellar images causing a degradation of the location measurement accuracy. Accurate modelling of the stellar image distortion induced by radiation is required to mitigate these effects. We assess the capability of a fast physical analytical model of radiation damage effects called the charge distortion model (CDM) to reproduce experimental data. To realize this assessment we developed a rigorous procedure that compares at the sub-pixel level the model outcomes to damaged images extracted from the experimental tests. We show that CDM can reproduce accurately up to a certain level the test data acquired on a highly irradiated device operated in time delay integration mode for different signal levels and different illumination histories. We discuss the potential internal and external factors that contributed to limit the agreement between the data and the charge distortion model. To investigate these limiting factors further, we plan to apply our comparison procedure on a synthetic dataset generated through detailed Monte-Carlo simulations at the CCD electrode level.

Use of a Novel Portable Three-Dimensional Imaging System to Measure Limb Volume and Circumference in Patients with Filarial Lymphedema

The World Health Organizations Global Program to Eliminate Lymphatic Filariasis (LF) has reduced LF transmission worldwide, but millions remain affected by filarial lymphedema. Tools for clinically monitoring lymphedema in developing nations are limited. We tested a novel, portable, infrared three-dimensional imaging system (3DIS) against water displacement (WD) and tape measurement of limb circumference (TMLC) among patients with filarial leg lymphedema in Galle, Sri Lanka. Outcomes were accuracy and reproducibility of imaging system measurements. In parallel, we also tested the reproducibility of skin thickness ultrasound (STU) measurements. We examined 52 patients (104 limbs) with lymphedema of stages 0-6 (N = 28, 19, 20, 21, 2, 4, and 10, respectively). 3DIS measurements correlated nearly perfectly with WD (r2 = 0.9945) and TMLC values (r2 > 0.9801). The median time required to acquire imaging system measurements for both legs was 2.1 minutes, compared with 17, 7, and 29 minutes, respectively, for WD, TMLC, and STU. Median interexaminer coefficients of variation (CVs) for volume measurements were 1.1% (interquartile range [IQR] 0.5-2.1%) for WD and 1.7% (IQR 1.2-2.4%) for the 3DIS. CVs for circumference measurements were 1.4% (IQR 0.8-2.4%) by TMLC and 1.3% (0.8-1.9%) by 3DIS. Median interexaminer CV for STU was 13.7% (IQR 8.5-21.3%). The portable imaging system noninvasively provided accurate and reproducible limb volume and circumference measurements in approximately 2 minutes per patient. This portable technology has the potential to greatly improve assessment and monitoring of lymphedema in the clinic and in the field.

A safe, low-cost, easy-to-use 3D camera platform to assess risk of obstructed labor due to cephalopelvic disproportion

Cephalopelvic disproportion (CPD)-related obstructed labor is accountable for 3–8% of the maternal deaths worldwide. The consequence of CPD-related obstructive labor in the absence of a Caesarian section (C/S) is often maternal or perinatal mortality or morbidity to the mother and/or the infant. Accurate and timely referral of at-risk mothers to health facilities where C/S is a delivery option could reduce maternal mortality in the developing world. The goal of this work was to develop and test the feasibility of a safe, low-cost, easy-to-use, portable tool, using a Microsoft Kinect 3D camera, to identify women at risk for obstructed labor due to CPD. Magnetic resonance imaging (MRI) scans, 3D camera imaging, anthropometry and clinical pelvimetry were collected and analyzed from women 18–40 years of age, at gestational age ≥36+0 weeks with previous C/S due to CPD (n = 43), previous uncomplicated vaginal deliveries (n = 96), and no previous obstetric history (n = 148) from Addis Ababa, Ethiopia. Novel and published CPD risk scores based on anthropometry, clinical pelvimetry, MRI, and Kinect measurements were compared. Significant differences were observed in most anthropometry, clinical pelvimetry, MRI and Kinect measurements between women delivering via CPD-related C/S versus those delivering vaginally. The area under the receiver-operator curve from novel CPD risk scores base on MRI-, Kinect-, and anthropometric-features outperformed novel CPD risk scores based on clinical pelvimetry and previously published indices for CPD risk calculated from these data; e.g., pelvic inlet area, height, and fetal-pelvic index. This work demonstrates the feasibility of a 3D camera-based platform for assessing CPD risk as a novel, safe, scalable approach to better predict risk of CPD in Ethiopia and warrants the need for further blinded, prospective studies to refine and validate the proposed CPD risk scores, which are required before this method can be applied clinically.