BACKGROUND:As myocardial blood flow measurement (MBF) in SPECT systems became recently available, significant effort has been devoted to its validation. For that purpose, we have developed a cardiac phantom that is able to mimic physiological radiotracer variation in the left ventricle cavity and in the myocardium, while performing beating-like motion. The new phantom is integrated inside a standard anthropomorphic torso allowing a realistic tissue attenuation and gamma-ray scattering METHODS AND RESULTS: A mechanical cardiac phantom was integrated in a commercially available anthropomorphic torso. Using a GE Discovery 530c SPECT, measurements were performed. It was found that gamma-ray attenuation effects are significant and limit the MBF measurements to global/three-vessel resolution. Dynamic SPECT experiments were performed to validate MBF accuracy and showed mean relative error of 14%. Finally, the effect of varying radiotracer dose on the accuracy of dynamic SPECT was studied CONCLUSIONS: A dynamic cardiac phantom has been developed and successfully integrated in a standard SPECT torso. A good agreement was found between SPECT-reported MBF values and the expected results. Despite increased noise-to-signal ratio when radiotracer doses were reduced, MBF uncertainty did not increase significantly down to very low doses, thanks to the temporal integration of the activity during the measurement.

Coronary artery obstruction (CAO), a fatal complication of transcatheter aortic valve replacement (TAVR), is commonly found after Valve-in-Valve implantation inside a degenerated bioprosthetic valve. Leaflet laceration (BASILICA technique) has been proposed to prevent CAO and to potentially reduce the risk of leaflet thrombosis. We have previously demonstrated that this technique can reduce the anchorage forces of the TAVR device, which may lead to future complications. In this short communication, we hypothesize that the anchorage force reduction can be minimized by implanting a TAVR with a larger diameter, if two sizes are clinically recommended. We evaluated this hypothesis by employing finite element models of the deployments of the Evolut 26 and 29 mm inside a 27 mm Mitroflow valve, with and without leaflet lacerations. The results show that a laceration substantially decreases the contact area between the Evolut stent and the Mitroflow valve. The larger Evolut has a larger contact area and stronger anchorage forces. Additionally, the anchorage forces are less sensitive to additional lacerations in the larger Evolut (29 case). The results suggest that a larger self-expending device can ensure stronger anchorage and can lower the risk of possible migration, when TAVR is performed in a lacerated bioprosthesis.

The human conjunctival epithelial cells (HCEC) line the inner sides of the eyelids and the anterior part of the sclera. They include goblet cells that secret mucus into the tear film that protects the ocular surface. The conjunctival epithelium is subjected to mechano-physical stimuli due to eyelid movement during blinking, during wiping and rubbing the eyes, and when exposed to wind and air currents. We cultured primary HCEC under air–liquid interface (ALI) conditions in custom-designed wells that can be disassembled for installation of the in vitro model in a flow chamber. We exposed the HCEC after ALI culture of 8–10 days to steady and oscillatory airflows. The in vitro model of HCEC was exposed to steady wall shear stresses (sWSS) of 0.5 and 1.0 dyne/cm2 for lengths of 30 and 60 min and to oscillatory wall shear stresses (oWSS) of 0.5 and 0.77 dyne/cm2 amplitudes for a length of 10 min. Cytoskeletal alterations and MUC5AC mucin secretion in response to WSS were investigated using immunohistochemically fluorescent staining and enzyme-linked lectin assay (ELLA), respectively. The results revealed that both exposure times and sWSS values increased the polymerization of F-actin filaments while mucin secretion decreased. However, after a recovery of 24 h in the incubator we observed a decrease of F-actin fibers and mucin secretion only for exposure of 30 min. The length of exposure was more influential on cytoskeletal alterations than the level of sWSS. The very small effect of sWSS on mucin secretion is most likely related to the much smaller amount of goblet cell than in other mucus-secreting tissue. The results for both oWSS amplitudes revealed similar trends regarding F-actin and mucin secretion. Immediately post-exposure we observed an increase in polymerization of F-actin filaments while mucin secretion decreased. However, after 24-h recovery we observed that both F-actin and mucin secretion returned to the same values as for unexposed cultures. The results of this study suggest that WSS should be considered while exploring the physiological characteristics of HCEC.

The arterial intima is continuously under pulsatile wall shear stresses (WSS) imposed by the circulating blood. The knowledge of the contribution of smooth muscle cells (SMC) to the response of endothelial cell (EC) to WSS is still incomplete. We developed a co-culture model of EC on top of SMC that mimics the inner in vivo structure of the arterial intima of large arteries. The co-cultured model, as well as a mono layer model of EC, were developed in custom-designed wells that allowed for mechanobiology experiments. Both the monolayer and co-culture models were exposed to steady flow induced WSS of up to 24 dyne/cm(2) and for lengths of 60 min. Quantification of WSS induced alterations in the cytoskeletal actin filaments (F-actin) and vascular endothelial cadherin (VE-cadherin) junctions were utilized from confocal images and flow cytometry. High confluency of both models was observed even after exposure to the high WSS. The quantitive analysis revealed larger post WSS amounts of EC F-actin polymerization in the monolayer, which may be explained by the relative help of the SMC to resist the external load of WSS. The VE-cadherin demonstrated morphological alterations in the monolayer model, but without significant changes in their content. The SMC in the co-culture maintained their contractile phenotype post high WSS which is more physiological, but not post low WSS. Generally, the results of this work demonstrate the active role of SMC in the intima performance to resist flow induced WSS.

Short peripheral catheters are ubiquitous in today's healthcare environment, enabling effective and direct delivery of fluids and medications intravenously. A commonly associated complication of their use is thrombophlebitis-thrombus formation-involved inflammation of the vein wall. A novel design of a very short peripheral catheter showed promising results in a pig model in reducing the mechanical irritation to the vein wall. Here, the kinetics of drug release through the novel catheter was compared to a standard commercial catheter using experimental and computational models. In a good agreement, in vitro and in silico models reveal the superiority of the novel catheter design with faster washout time, favorable spatial distribution within the vein, and substantially lower wall shear stress. We submit therefore that the novel design has an improved drug removal profile compared to the conventional catheter and can potentially reduce chemical irritation to the vein wall and minimize the risk for thrombophlebitis. CLINICAL RELEVANCE: Short peripheral catheters are ubiquitous in today's healthcare environment, allowing effective and direct delivery of fluids and medications intravenously. It is well known, however, that prolonged exposure to an irritant drug may lead to its absorption in the endothelial layer lining the vein wall, promoting among other, thrombophlebitis that may lead to increased morbidity, delayed treatment, and prolonged hospitalization. There have been multiple calls to consider low infusion rates with various infusion protocols and to place the catheter tip as central as possible to promote faster drug clearance and reduce the potential vessel damage, but the requisite device had not been available, and the short peripheral catheter is still, and for decades, the standard of care. Towards this end, we recently introduced a novel very short peripheral catheter design, and here, we demonstrate using experimental and computational models its favorable spatial and temporal drug-releasing profiles compared with the standard catheter. The clinically potential relevance is underscore both by the more efficient perfusion of IV drugs and lower irritation to the vein wall at the site of injection. Graphical abstract.

Cyclic myometrial contractions of the non-pregnant uterus induce intra-uterine peristaltic flows, which have important roles in transport of sperm and embryos during early stages of reproduction. Hyperperistalsis in young females may lead to migration of endometrial cells and development of adenomyosis or endometriosis. We conducted an in vitro study of the biological response of a tissue engineered endometrial barrier exposed to peristaltic wall shear stresses (PWSSs). The endometrial barrier model was co-cultured of endometrial epithelial cells on top of myometrial smooth muscle cells (MSMCs) in custom-designed wells that can be disassembled for mechanobiology experiments. A new experimental setup was developed for exposing the uterine wall in vitro model to PWSSs that mimic the in vivo intra-uterine environment. Peristaltic flow was induced by moving a belt with bulges to deform the elastic cover of a fluid filled chamber that held the uterine wall model at the bottom. The in vitro biological model was exposed to peristaltic flows for 60 and 120 min and then stained for immunofluorescence studies of alternations in the cytoskeleton. Quantification of the F-actin mass in both layers revealed a significant increase with the length of exposure to PWSSs. Moreover, the inner layer of MSMCs that were not in direct contact with the fluid also responded with an increase in the F-actin mass. This new experimental approach can be expanded to in vitro studies of multiple structural changes and genetic expressions, while the tissue engineered uterine wall models are tested under conditions that mimic the in vivo physiological environment.

BACKGROUND:In recent years, with the advance of myocardial blood flow (MBF) measurement capability in dynamic single photon emission computerized tomography (SPECT) systems, significant effort has been devoted to validation of the new capability. Unfortunately, the mechanical phantoms available for the validation process lack essential features-they either have a constant radiotracer concentration or they have rigid (static) walls unable to simulate cardiac beating.METHODS AND RESULTS:We have developed a mechanical cardiac phantom that is able to mimic physiological radiotracer variation in the left ventricle (LV) cavity and in the myocardium (M), while performing beating-like motion. We have also developed a mathematical model of the phantom, allowing a description of the radiotracer concentrations in both regions (LV, M) as a function of time, which served as a tool for experiment planning and to accurately mimic physiological-like time-activity curves (TACs). A net retention model for the phantom was also developed, which served to compute the theoretical (i.e., expected) MBF of the phantom from measured quantities only, and thus validate the MBF reported by the SPECT system. In this paper, phantom experiments were performed on a GE Discovery NM 530c SPECT system.CONCLUSIONS:A novel dynamic cardiac phantom for emission tomography has been developed. The new phantom is capable of producing a wide range of TACs that can mimic physiological (and potentially in the future, pathological) curves, similar to those observed in dynamic SPECT systems. SPECT-reported MBF values were validated against known (measured) activity of the injected radiotracer from phantom experiments, which allowed to determine the accuracy of the GE Discovery 530c SPECT system.

Introduction:In recent years, with the advance of non-invasive myocardial blood flow (MBF) measurement capability in dynamic SPECT and PET systems, significant effort has been devoted to validation of the new capability in both phantom and clinical studies.Unfortunately, the phantoms used in the validation process lack some of the essential features of an actual heart (e.g., constant radionuclide concentration or rigid walls with no cardiac beating).Therefore, we have developed a novel cardiac phantom that is able to mimic physiological radionuclide variation in the left ventricle cavity and in the myocardium that generates time-activity curves (TACs) similar to those observed in human patients (which are used for the computation of MBF), while performing beating-like motion.A brief description of the phantom design and experimental results of the phantom with a commercial dynamic SPECT system will be presented.Methods: Since dynamic SPECT computes the MBF from TACs, it was envisioned that the phantom must mimic physiological TACs.In this case, radionuclide temporal behavior in both the left ventricle cavity (LV) and in the myocardium regions of the phantom should allow rapid increase and decrease of radiotracer concentration in the left ventricle cavity and monotonic increase of radiotracer concentration in the myocardium region.To achieve these goals, the newly designed phantom consists of the following components: (1) Two nested flexible silicon membranes -the internal volume representing the LV and the intermediate volume between both membranes representing the myocardium region surrounding the LV.(2) The dimensions of the membranes resemble the endocardium and epicardium of an actual human heart.(3) Multiple ports for both regions for injection and flushing of radiotracer and saline/water.(4) A large diameter port representing the aorta connected to the base of the LV region, allowing for significant stroke volume at each "cardiac beating" using a pulsatile pump.Results: Temporal variation of radiotracer concentration in both of the phantom"s volumes was obtained by electronically-controlled syringe injectors, typically injecting 0.1-0.5 mCi of 99mTc-SESTAMIBI directly into the phantom.The injection profiles were designed to resemble the TACs observed in human patients: A high-concentration activity bolus arriving into the LV and rapidly dropping after leaving the heart through the aorta, followed by monotonic increase of the tracer concentration until it reaches its final state.A comparison between dynamic SPECT measurements of the phantom and a human patient is shown in the attached figure.Conclusions: A newly developed cardiac phantom for dynamic SPECT/PET measurements was presented.The phantom is able generate reproducible, reliable results to investigate key parameters of dynamic SPECT/PET systems, namely, the accuracy and reproducibility of TACs and their propagated effect on the computed MBF.

Transcatheter aortic valve implantation (TAVI) is currently recommended in practice guidelines for patients who are at intermediate to high surgical risk for surgical aortic valve replacement. Coronary artery obstruction is a fatal complication of TAVI that occurs in up to 3.5% of the implantations inside a failed surgical bioprosthetic valve (valve-in-valve, ViV). A new technique to address this problem is intentional laceration of the bioprosthetic leaflets, known as BASILICA. In this technique, the leaflets are lacerated to prevent coronary obstruction and may also help in preventing leaflet thrombosis. Our hypothesis is that this technique may harm the circumferential stress in the surgical valve and weaken the anchorage of the TAVI device. This study aims to compare the anchorage post-ViV implantations, with and without lacerations, using numerical modelling. Deployments of TAVI stents (Medtronic Evolut PRO; Edwards SAPIEN 3) inside an externally mounted surgical bioprosthetic valve (Sorin Mitroflow) were modelled by finite element analysis. The results show that each laceration reduces the contact area of the TAVI stent with its landing zone and that the anchorage contact force weakens. The BASILICA technique has lesser effect on the anchorage contact area and forces in the SAPIEN than in the Evolut cases, because the balloon inflation is less sensitive to the deployment region. TAVI stent migration was not found in any of the models. These results can help expanding the use of leaflet laceration by choosing a better matched TAVI devices for the BASILICA technique.

Dust storms are common phenomena in many parts of the world, and significantly increase the level of atmospheric particulate matter (PM). The soil-derived dust is a mixture of organic and inorganic particles and even remnants of pesticides from agricultural areas nearby. The risk of human exposure to atmospheric dust is well documented, but very little is known on the impact of inhaled PM on the biological lining of the nasal cavity, which is the natural filter between the external environment and the respiratory tract. We developed a new system and methodology for in vitro exposure of cultured nasal epithelial cells (NEC) to atmospheric soil-dust pollutants under realistic and controlled laboratory simulations that mimic nasal breathing. We exposed cultured NEC to clean and dust-polluted airflows that mimic physiological conditions. The results revealed that the secretion of mucin and IL-8 from the NEC exposed to clean and dust-polluted airflows was less than the secretion at static conditions under clean air. The secretion of IL-8 from NEC exposed to dust-polluted air was larger than that of clean air, but not larger than in the static case. The experiments with dust air pollution that also contained agricultural pesticides did not reveal differences in the secretion of mucin and IL-8 as compared to the same pollution without pesticides.

Blood pressure drop and arterial distensibility are important, allegedly independent, parameters that are indicative of the coronary arteries patency and atherosclerosis severity. In the present study we show that these two parameters are dependent, allowing to obtain both parameters from a single measurement, and to do so a high-resolution differential pressure measurement system is required. The objective of the study was to unveil the relationship between local fluid pressure drops and tube distensibility, through various scenarios of stenosis severity, tube diameter, and flow rate (for coronary hemodynamic conditions). The investigation was performed using validated Fluid–Structure Interaction (FSI) analysis on silicone mock arteries with intermediate size stenosis (0–65%). Highly accurate pressure drop measurements (±0.05 mmHg) were performed with our in-house fluid-filled double-lumen catheter measurement. The results indicated that our accurate pressure drop measurement method facilitated the differentiation among several levels of the mock arteries’ stiffness, with distensibilities ranging from 1 to 7%. Local pressure drops were markedly affected by the mock arteries’ stiffness and could be best described using a second-order polynomial function. These changes in pressure drop could be detected even when there was no stenosis present, and FFR values remained insensitive at 1.00. The results indicated the clinical potential of a high accuracy pressure drop-based parameter to be superior to FFR. Such a parameter would provide cardiovascular interventionalists with lesion-specific bio-mechanical and functional data, for improved real-time decision-making in the cath-lab.

- The small intestine (SI) is a mechanically active tube-like organ that actuates peristaltic constriction motion. The motion assists capsule endoscopy products to passively travel along the SI tract. The goal of the present study was to design a mechanical simulator of the small intestine. Having such a simulator would allow effective testing of new capsule endoscopic devices, as well as offline practice with endoscopic and other devices. The simulator, loaded with ex-vivo swine SI, was functionally validated using two ingestible capsule products: PillCam® SB3 and SmartPill® (Given Imaging, Ltd.). Excellent agreement was found in comparison to in-vivo recordings, showing the great potential of the simulator.

ObjectivesThe purpose of this study was to develop an ex vivo placental perfusion model to assess changes in the umbilical artery systolic‐to‐diastolic (S/D) ratio due to progressive occlusion of the placental arterial system.MethodsEx vivo human placentas were connected to a computerized pulse duplicator mimicking pulsatile flow from the fetal heart. Doppler sonographic measurements were conducted on the umbilical and chorionic arteries of 25 mature placentas. Simulation of placental occlusion was performed by progressive ligature of the chorionic arteries, including one umbilical artery. The correlation between the umbilical artery S/D ratio and the severity of simulated placental occlusion was analyzed.ResultsThe normal mean S/D ratio ± SD decreased gradually along the chorionic plate from 2.66 ± 0.47 at the cord insertion to 1.90 ± 0.59 in generation IV of the chorionic vessels. The Doppler index initially increased slowly with simulated placental occlusion. Only when all 4 generations were occluded was the umbilical artery S/D ratio elevated. Complete occlusion of one umbilical artery resulted in a 39% increase in the umbilical artery S/D ratio.ConclusionsThis unique model combining Doppler sonography with perfusion of an ex vivo placenta can be used for a better understudying of pathologic placental blood flow circulation.

Coronary artery pressure-drop and distensibility (compliance) are two major, seemingly unrelated, parameters in the cardiovascular clinical setting, which are indicative of coronary arteries patency and atherosclerosis severity. While pressure drop is related to flow, and therefore serves as a functional indicator of a stenosis severity, the arterial distensibility is indicative of the arterial stiffness, and hence the arterial wall composition. In the present study, we hypothesized that local pressure drops are dependent on the arterial distensibility, and hence can provide information on both indices. The clinical significance is that a single measurement of pressure drop could potentially provide both functional and bio-mechanical metrics of lesions, and thus assist in real-time decision making prior to stenting. The goal of the current study was to set the basis for understanding this relationship, and define the accuracy and sensitivity required from the pressure measurement system. The investigation was performed using numerical fluid-structure interaction (FSI) simulations, validated experimentally using our high accuracy differential pressure measurement system. Simplified silicone mock coronary arteries with zero to intermediate size stenoses were used, and various combinations of arterial distensibility, diameter, and flow rate were simulated. Results of hyperemic flow cases were also compared to fractional flow reserve (FFR). The results indicate the potential clinical superiority of a high accuracy pressure drop-based parameter over FFR, by: (i) being more lesion-specific, (ii) the possibility to circumvent the FFR dependency on pharmacologically-induced hyperemia, and, (iii) by providing both functional and biomechanical lesion-specific information.

Conclusions: A simple non-invasive method, based on acoustic analysis of breathing signals, revealed a potential for objective evaluation of differences between the patency of nasal passageways. Objectives: To examine whether acoustic signals of nasal breathing contain information that can differentiate between obstructed and patent nasal passageways. Method: A technical study aimed to examine measurements of nasal airflow acoustic signals, taken, non-invasively, simultaneously from both external sides of the nostrils. The signals were acquired for several breathing cycles, with different respiratory efforts, before and after application of a nasal decongestant to the (narrower) side that yielded lower amplitudes. Data processing of the expiratory phase yielded the power spectrum density (PSD), which was used to compute the ratio of PSD areas between the signals from both sides of the nose. The study group was composed of 20 healthy volunteers. Results: PSD changes were noted in accordance with the rise in expiratory efforts. The ratio of PSD areas between the two sides of the nasal cavity, calculated for maximal expiratory efforts, correlated well with the side that was treated with nasal decongestant in 18 out of the 20. Changes in the opposite direction were noted in two examinees.

Vascular functions are affected by wall shear stresses (WSS) applied on the endothelial cells (EC), as well as by the interactions of the EC with the adjacent smooth muscle cells (SMC). The present study was designed to investigate the effects of WSS on the endothelial interactions with its surroundings. For this purpose we developed and constructed two co-culture models of EC and SMC, and compared their response to that of a single monolayer of cultured EC. In one co-culture model the EC were cultured on the SMC, whereas in the other model the EC and SMC were cultured on the opposite sides of a membrane. We studied EC-matrix interactions through focal adhesion kinase morphology, EC-EC interactions through VE-Cadherin expression and morphology, and EC-SMC interactions through the expression of Cx43 and Cx37. In the absence of WSS the SMC presence reduced EC-EC connectivity but produced EC-SMC connections using both connexins. The exposure to WSS produced discontinuity in the EC-EC connections, with a weaker effect in the co-culture models. In the EC monolayer, WSS exposure (12 and 4 dyne/cm2 for 30 min) increased the EC-EC interaction using both connexins. WSS exposure of 12 dyne/cm2 did not affect the EC-SMC interactions, whereas WSS of 4 dyne/cm2 elevated the amount of Cx43 and reduced the amount of Cx37, with a different magnitude between the models. The reduced endothelium connectivity suggests that the presence of SMC reduces the sealing properties of the endothelium, showing a more inflammatory phenotype while the distance between the two cell types reduced their interactions. These results demonstrate that EC-SMC interactions affect EC phenotype and change the EC response to WSS. Furthermore, the interactions formed between the EC and SMC demonstrate that the 1-side model can simulate better the arterioles, while the 2-side model provides better simulation of larger arteries.

High accuracy differential pressure measurements are required in various biomedical and medical applications, such as in fluid-dynamic test systems, or in the cath-lab. Differential pressure measurements using fluid-filled catheters are relatively inexpensive, yet may be subjected to common mode pressure errors (CMP), which can significantly reduce the measurement accuracy. Recently, a novel correction method for high accuracy differential pressure measurements was presented, and was shown to effectively remove CMP distortions from measurements acquired in rigid tubes. The purpose of the present study was to test the feasibility of this correction method inside compliant tubes, which effectively simulate arteries. Two tubes with varying compliance were tested under dynamic flow and pressure conditions to cover the physiological range of radial distensibility in coronary arteries. A third, compliant model, with a 70% stenosis severity was additionally tested. Differential pressure measurements were acquired over a 3 cm tube length using a fluid-filled double-lumen catheter, and were corrected using the proposed CMP correction method. Validation of the corrected differential pressure signals was performed by comparison to differential pressure recordings taken via a direct connection to the compliant tubes, and by comparison to predicted differential pressure readings of matching fluid-structure interaction (FSI) computational simulations. The results show excellent agreement between the experimentally acquired and computationally determined differential pressure signals. This validates the application of the CMP correction method in compliant tubes of the physiological range for up to intermediate size stenosis severity of 70%.