An evaluation of physical and augmented patient-specific intracranial aneurysm simulators on microsurgical clipping performance and skills: a randomized controlled study.

OBJECTIVE: In the era of flow diversion, there is an increasing demand to train neurosurgeons outside the operating room in safely performing clipping of unruptured intracranial aneurysms. This study introduces a clip training simulation platform for residents and aspiring cerebrovascular neurosurgeons, with the aim to visualize peri-aneurysm anatomy and train virtual clipping applications on the matching physical aneurysm cases. METHODS: Novel, cost-efficient techniques allow the fabrication of realistic aneurysm phantom models and the additional integration of holographic augmented reality (AR) simulations. Specialists preselected suitable and unsuitable clips for each of the 5 patient-specific models, which were then used in a standardized protocol involving 9 resident participants. Participants underwent four sessions of clip applications on the models, receiving no interim training (control), a video review session (video), or a video review session and holographic clip simulation training (video + AR) between sessions 2 and 3. The study evaluated objective microsurgical skills, which included clip selection, number of clip applications, active simulation time, wrist tremor analysis during simulations, and occlusion efficacy. Aneurysm occlusions of the reference sessions were assessed by indocyanine green videoangiography, as well as conventional and photon-counting CT scans. RESULTS: A total of 180 clipping procedures were performed without technical complications. The measurements of the active simulation times showed a 39% improvement for all participants. A median of 2 clip application attempts per case was required during the final session, with significant improvement observed in experienced residents (postgraduate year 5 or 6). Wrist tremor improved by 29% overall. The objectively assessed aneurysm occlusion rate (Raymond-Roy class 1) improved from 76% to 80% overall, even reaching 93% in the extensively trained cohort (video + AR) (p = 0.046). CONCLUSIONS: The authors introduce a newly developed simulator training platform combining physical and holographic aneurysm clipping simulators. The development of exchangeable, aneurysm-comprising housings allows objective radio-anatomical evaluation through conventional and photon-counting CT scans. Measurable performance metrics serve to objectively document improvements in microsurgical skills and surgical confidence. Moreover, the different training levels enable a training program tailored to the cerebrovascular trainees' levels of experience and needs.

Fast Approximate Quantification of Endovascular Stent Graft Displacement Forces in the Bovine Aortic Arch Variant.

PURPOSE: Displacement forces (DFs) identify hostile landing zones for stent graft deployment in thoracic endovascular aortic repair (TEVAR). However, their use in TEVAR planning is hampered by the need for time-expensive computational fluid dynamics (CFD). We propose a novel fast-approximate computation of DFs merely exploiting aortic arch anatomy, as derived from the computed tomography (CT) and a measure of central aortic pressure. MATERIALS AND METHODS: We tested the fast-approximate approach against CFD gold-standard in 34 subjects with the "bovine" aortic arch variant. For each dataset, a 3-dimensional (3D) model of the aortic arch lumen was reconstructed from computed tomography angiography and CFD then employed to compute DFs within the aortic proximal landing zones. To quantify fast-approximate DFs, the wall shear stress contribution to the DF was neglected and blood pressure space-distribution was averaged on the entire aortic wall to reliably approximate the patient-specific central blood pressure. Also, DF values were normalized on the corresponding proximal landing zone area to obtain the equivalent surface traction (EST). RESULTS: Fast-approximate approach consistently reflected (r2=0.99, p<0.0001) the DF pattern obtained by CFD, with a -1.1% and 0.7° bias in DFs magnitude and orientation, respectively. The normalized EST progressively increased (p<0.0001) from zone 0 to zone 3 regardless of the type of arch, with proximal landing zone 3 showing significantly greater forces than zone 2 (p<0.0001). Upon DF normalization to the corresponding aortic surface, fast-approximate EST was decoupled in blood pressure and a dimensionless shape vector (S) reflecting aortic arch morphology. S showed a zone-specific pattern of orientation and proved a valid biomechanical blueprint of DF impact on the thoracic aortic wall. CONCLUSION: Requiring only a few seconds and quantifying clinically relevant biomechanical parameters of proximal landing zones for arch TEVAR, our method suits the real preoperative decision-making process. It paves the way toward analyzing large population of patients and hence to define threshold values for a future patient-specific preoperative TEVAR planning.

Infrared nanospectroscopy depth-dependent study of modern materials: morpho-chemical analysis of polyurethane/fibroin binary meshes.

Infrared scattering-type scanning near-field optical microscopy (IR s-SNOM) and imaging is here exploited together with attenuated total reflection (ATR) IR imaging and scanning electron microscopy (SEM) to depict the chemical composition of fibers in hybrid electrospun meshes. The focus is on a recently developed bio-hybrid material for vascular tissue engineering applications, named Silkothane®, obtained in the form of nanofibrous matrices from the processing of a silk fibroin-polyurethane (SFPU) blend via electrospinning. Morphology and chemistry of single fibers, at both surface and subsurface level, have been successfully characterized with nanoscale resolution, taking advantage of the IR s-SNOM capability to portray the nanoscale depth profile of this modern material working at diverse harmonics of the signal. The applied methodology allowed to describe the superficial characteristics of the mesh up to a depth of about 100 nm, showing that SF and PU do not tend to co-aggregate to form hybrid fibers, at least at the length scale of hundreds of nanometers, and that subdomains other than the fibrillar ones can be present. More generally, in the present contribution, the depth profiling capabilities of IR s-SNOM, so far theoretically predicted and experimentally proven only on model systems, have been corroborated on a real material in its natural conditions with respect to production, opening the room for the exploitation of IR s-SNOM as valuable technique to support the production and the engineering of nanostructured materials by the precise understanding of their chemistry at the interface with the environment.

In Silico Analysis of Nanoplastics' and ß-amyloid Fibrils' Interactions.

Plastic pollution has become a global environmental threat, which leads to an increasing concern over the consequences of plastic exposition on global health. Plastic nanoparticles have been shown to influence the folding of proteins and influence the formation of aberrant amyloid proteins, therefore potentially triggering the development of systemic and local amyloidosis. This work aims to study the interaction between nanoplastics and ß-amyloid fibrils to better understand the potential role of nanoplastics in the outbreak of neurodegenerative disorders. Using microsecond-long coarse-grained molecular dynamics simulations, we investigated the interactions between neutral and charged nanoparticles made of the most common plastic materials (i.e., polyethylene, polypropylene, and polystyrene) and ß-amyloid fibrils. We observe that the occurrence of contacts, region of amyloid fibril involved, and specific amino acids mediating the interaction depend on the type and charge of the nanoparticles.

Comparison of Four-Dimensional Magnetic Resonance Imaging Analysis of Left Ventricular Fluid Dynamics and Energetics in Ischemic and Restrictive Cardiomyopathies.

BACKGROUND: Time-resolved three-directional velocity-encoded (4D flow) magnetic resonance imaging (MRI) enables the quantification of left ventricular (LV) intracavitary fluid dynamics and energetics, providing mechanistic insight into LV dysfunctions. Before becoming a support to diagnosis and patient stratification, this analysis should prove capable of discriminating between clearly different LV derangements. PURPOSE: To investigate the potential of 4D flow in identifying fluid dynamic and energetics derangements in ischemic and restrictive LV cardiomyopathies. STUDY TYPE: Prospective observational study. POPULATION: Ten patients with post-ischemic cardiomyopathy (ICM), 10 patients with cardiac light-chain cardiac amyloidosis (AL-CA), and 10 healthy controls were included. FIELD STRENGTH/SEQUENCE: 1.5 T/balanced steady-state free precession cine and 4D flow sequences. ASSESSMENT: Flow was divided into four components: direct flow (DF), retained inflow, delayed ejection flow, and residual volume (RV). Demographics, LV morphology, flow components, global and regional energetics (volume-normalized kinetic energy [KEV ] and viscous energy loss [ELV ]), and pressure-derived hemodynamic force (HDF) were compared between the three groups. STATISTICAL TESTS: Intergroup differences in flow components were tested by one-way analysis of variance (ANOVA); differences in energetic variables and peak HDF were tested by two-way ANOVA. A P-value of <0.05 was considered significant. RESULTS: ICM patients exhibited the following statistically significant alterations vs. controls: reduced KEV , mostly in the basal region, in systole (-44%) and in diastole (-37%); altered flow components, with reduced DF (-33%) and increased RV (+26%); and reduced basal-apical HDF component on average by 63% at peak systole. AL-CA patients exhibited the following alterations vs. controls: significantly reduced KEV at the E-wave peak in the basal segment (-34%); albeit nonstatistically significant, increased peaks and altered time-course of the HDF basal-apical component in diastole and slightly reduced HDF components in systole. DATA CONCLUSION: The analysis of multiple 4D flow-derived parameters highlighted fluid dynamic alterations associated with systolic and diastolic dysfunctions in ICM and AL-CA patients, respectively. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

A Deep Learning-Based and Fully Automated Pipeline for Thoracic Aorta Geometric Analysis and Planning for Endovascular Repair from Computed Tomography.

Feasibility assessment and planning of thoracic endovascular aortic repair (TEVAR) require computed tomography (CT)-based analysis of geometric aortic features to identify adequate landing zones (LZs) for endograft deployment. However, no consensus exists on how to take the necessary measurements from CT image data. We trained and applied a fully automated pipeline embedding a convolutional neural network (CNN), which feeds on 3D CT images to automatically segment the thoracic aorta, detects proximal landing zones (PLZs), and quantifies geometric features that are relevant for TEVAR planning. For 465 CT scans, the thoracic aorta and pulmonary arteries were manually segmented; 395 randomly selected scans with the corresponding ground truth segmentations were used to train a CNN with a 3D U-Net architecture. The remaining 70 scans were used for testing. The trained CNN was embedded within computational geometry processing pipeline which provides aortic metrics of interest for TEVAR planning. The resulting metrics included aortic arch centerline radius of curvature, proximal landing zones (PLZs) maximum diameters, angulation, and tortuosity. These parameters were statistically analyzed to compare standard arches vs. arches with a common origin of the innominate and left carotid artery (CILCA). The trained CNN yielded a mean Dice score of 0.95 and was able to generalize to 9 pathological cases of thoracic aortic aneurysm, providing accurate segmentations. CILCA arches were characterized by significantly greater angulation (p = 0.015) and tortuosity (p = 0.048) in PLZ 3 vs. standard arches. For both arch configurations, comparisons among PLZs revealed statistically significant differences in maximum zone diameters (p < 0.0001), angulation (p < 0.0001), and tortuosity (p < 0.0001). Our tool allows clinicians to obtain objective and repeatable PLZs mapping, and a range of automatically derived complex aortic metrics.

Assessing the influence of perfusion on cardiac microtissue maturation: A heart-on-chip platform embedding peristaltic pump capabilities.

Heart-on-chip is an unprecedented technology for recapitulating key biochemical and biophysical cues in cardiac pathophysiology. Several designs have been proposed to improve its ability to mimic the native tissue and establish it as a reliable research platform. However, despite mimicking one of most vascularized organs, reliable strategies to deliver oxygen and substrates to densely packed constructs of metabolically demanding cells remain unsettled. Herein, we describe a new heart-on-chip platform with precise fluid control, integrating an on-chip peristaltic pump, allowing automated and fine control over flow on channels flanking a 3D cardiac culture. The application of distinct flow rates impacted on temporal dynamics of microtissue structural and transcriptional maturation, improving functional performance. Moreover, a widespread transcriptional response was observed, suggesting flow-mediated activation of critical pathways of cardiomyocyte structural and functional maturation and inhibition of cardiomyocyte hypoxic injury. In conclusion, the present design represents an important advance in bringing engineered cardiac microtissues closer to the native heart, overcoming traditional bulky off-chip fluid handling systems, improving microtissue performance, and matching oxygen and energy substrate requirements of metabolically active constructs, avoiding cellular hypoxia. Distinct flow patterns differently impact on microtissue performance and gene expression program.

Differential Effects of Aortic Valve Replacement on Aortic Circumferential Strain in Aortic Stenosis and Aortic Insufficiency.

OBJECTIVES: Aortic valve replacement (AVR) potentially can modify pulse-wave propagation to the distal aorta. Echo-derived global circumferential strain (GCS) was used to test whether AVR for aortic stenosis (AS) or aortic insufficiency (AI) resulted in differential aortic biomechanics in the descending thoracic aorta. DESIGN: This was a prospective observational study of patients who underwent cardiac surgery between 2016 and 2019. SETTING: Weill Cornell Medicine, a single large academic medical center. PARTICIPANTS: The population comprised 48 patients undergoing AVR (62 ± 15 y/o, 79% male; 22 with AI and 26 with AS) and 11 patients undergoing coronary bypass surgery as controls. INTERVENTIONS: Elective cardiac surgery, transesophageal echocardiography (TEE), pulmonary artery catheter. MEASUREMENTS AND MAIN RESULTS: Pre- and postprocedural TEEs were collected. Descending aorta short-axis images were analyzed for GCS, time-to-peak strain, aortic end-diastolic, end-systolic area, and fractional area changes. Pulse pressure (PP) and stroke volume were quantified. Preprocedural GCS significantly differed between patients with AI and AS, with AI patients having greater GCS (median/interquartile range, 9.6 95.3,13.6) than patients with AS (4.3 [3.4-5.1]). After AVR, in AI patients, strain significantly decreased (5.5 [3.8,8.2], p = 0.001), along with PP (mean ± standard deviation) (66.4 ± 0.8 to 54.1 ± 13.7, p < 0.001), and PP corrected strain did not (GCS/PP = 14.8 [6.9-19.9] v 12.7[8.2-18.6], p = 0.34). In AS patients, GCS significantly increased after AVR to (5.45 [4.2-6.8], p = 0.003), as did PP-corrected strain (6.9 [5.8-9.2] v 9.7 [6.5-13.4], p = 0.016). Surgical AVR produced decrements in time-to-peak strain in AI and AS groups (both p < 0.001). CONCLUSIONS: After AVR for AI and AS, the direction of change in distal aortic strain from baseline depends on valve pathology. This finding may have important clinical implications in terms of indication for surgery and postoperative surveillance, especially in patients with aortopathies.

Rational backbone redesign of a fructosyl peptide oxidase to widen its active site access tunnel.

Fructosyl peptide oxidases (FPOXs) are enzymes currently used in enzymatic assays to measure the concentration of glycated hemoglobin and albumin in blood samples, which serve as biomarkers of diabetes. However, since FPOX are unable to work directly on glycated proteins, current enzymatic assays are based on a preliminary proteolytic digestion of the target proteins. Herein, to improve the speed and costs of the enzymatic assays for diabetes testing, we applied a rational design approach to engineer a novel enzyme with a wider access tunnel to the catalytic site, using a combination of Rosetta design and molecular dynamics simulations. Our final design, L3_35A, shows a significantly wider and shorter access tunnel, resulting from the deletion of five-amino acids lining the gate structures and from a total of 35 point mutations relative to the wild-type (WT) enzyme. Indeed, upon experimental testing, our engineered enzyme shows good structural stability and maintains significant activity relative to the WT.

Platelet Adhesion and Thrombus Formation in Microchannels: The Effect of Assay-Dependent Variables.

Microfluidic flow chambers (MFCs) allow the study of platelet adhesion and thrombus formation under flow, which may be influenced by several variables. We developed a new MFC, with which we tested the effects of different variables on the results of platelet deposition and thrombus formation on a collagen-coated surface. METHODS: Whole blood was perfused in the MFC over collagen Type I for 4 min at different wall shear rates (WSR) and different concentrations of collagen-coating solutions, keeping blood samples at room temperature or 37 °C before starting the experiments. In addition, we tested the effects of the antiplatelet agent acetylsalicylic acid (ASA) (antagonist of cyclooxygenase-1, 100 µM) and cangrelor (antagonist of P2Y12, 1 µM). RESULTS: Platelet deposition on collagen (I) was not affected by the storage temperature of the blood before perfusion (room temperature vs. 37 °C); (II) was dependent on a shear rate in the range between 300/s and 1700/s; and (III) was influenced by the collagen concentration used to coat the microchannels up to a value of 10 µg/mL. ASA and cangrelor did not cause statistically significant inhibition of platelet accumulation, except for ASA at low collagen concentrations. CONCLUSIONS: Platelet deposition on collagen-coated surfaces is a shear-dependent process, not influenced by the collagen concentration beyond a value of 10 µg/mL. However, the inhibitory effect of antiplatelet drugs is better observed using low concentrations of collagen.

The MICELI (MICrofluidic, ELectrical, Impedance): Prototyping a Point-of-Care Impedance Platelet Aggregometer.

As key cellular elements of hemostasis, platelets represent a primary target for thrombosis and bleeding management. Currently, therapeutic manipulations of platelet function (antithrombotic drugs) and count (platelet transfusion) are performed with limited or no real-time monitoring of the desired outcome at the point-of-care. To address the need, we have designed and fabricated an easy-to-use, accurate, and portable impedance aggregometer called "MICELI" (MICrofluidic, ELectrical, Impedance). It improves on current platelet aggregation technology by decreasing footprint, assay complexity, and time to obtain results. The current study aimed to optimize the MICELI protocol; validate sensitivity to aggregation agonists and key blood parameters, i.e., platelet count and hematocrit; and verify the MICELI operational performance as compared to commercial impedance aggregometry. We demonstrated that the MICELI aggregometer could detect platelet aggregation in 250 µL of whole blood or platelet-rich plasma, stimulated by ADP, TRAP-6, collagen, epinephrine, and calcium ionophore. Using hirudin as blood anticoagulant allowed higher aggregation values. Aggregation values obtained by the MICELI strongly correlated with platelet count and were not affected by hematocrit. The operational performance comparison of the MICELI and the Multiplate® Analyzer demonstrated strong correlation and similar interdonor distribution of aggregation values obtained between these devices. With the proven reliability of the data obtained by the MICELI aggregometer, it can be further translated into a point-of-care diagnostic device aimed at monitoring platelet function in order to guide pharmacological hemostasis management and platelet transfusions.

Immediate Impact of Prosthetic Graft Replacement of the Ascending Aorta on Circumferential Strain in the Descending Aorta.

OBJECTIVES: Prosthetic replacement of the ascending aorta (AA) can potentially modify energy propagation to the distal aorta and contribute to adverse aortic remodelling. This preliminary study employed intra-operative transoesophageal echocardiography (TOE) to assess the immediate impact of prosthetic graft replacement of the AA on circumferential strain in the descending aorta. METHODS: Intra-operative TOEs in patients undergoing AA graft replacement were analysed for circumferential strain, fractional area change (FAC), dimensions (end diastolic area [EDA], and end systolic area [ESA]) in the descending aorta immediately before and after graft replacement. Deformation was assessed via global peak circumferential aortic strain (CAS), together with pulse pressure corrected strain, time to peak strain (TTP), and aortic distensibility. RESULTS: Forty-five patients undergoing AA replacement with prosthetic graft (91% elective) were studied. Following grafting, descending thoracic aortic circumferential strain increased (6.3 ± 2.8% vs. 8.9 ± 3.4%, p = .001) paralleling distensibility (5.7 [3.7-8.6] 10-3 mmHg vs. 8.5 [6.4-12.4] 10-3 mmHg, p < .001). Despite slight increments in post graft left ventricular ejection fraction (LVEF) (52.3 ± 10.8% vs. 55.0 ± 11.9, p < .001), stroke volume was similar (p = .41), and magnitude of increased strain did not correlate with change in stroke volume (r = -.03, p = .86), LVEF (r = .18, p = .28), or pulse pressure (r = .28, p = .06). Descending aortic size (EDA 4 [2.7-4.6] cm2vs. 3.7 [2.5-5] cm2, p = .89; ESA 4.3 [3.2-5.3] cm2vs. 4.5 [3.3-5.8] cm2, p = .14) was similar pre- and post graft. In subgroup analysis, patients with cystic medial necrosis had a significantly higher post procedure CAS than patients with atherosclerotic aneurysms (9.7 ± 3.5% vs. 7.0 ± 2.3%, p = .03). CONCLUSIONS: Prosthetic graft replacement of the AA increases immediate aortic circumferential strain of the descending aorta, particularly in patients with cystic medial necrosis. Our findings suggest that grafts augment energy transfer to the distal aorta, a potential mechanism for progressive distal aortic dilation and/or dissection.

Fluid-Structure Interaction and In Vitro Analysis of a Real Bileaflet Mitral Prosthetic Valve to Gain Insight Into Doppler-Silent Thrombosis.

Prosthetic valve thrombosis (PVT) is a serious complication affecting prosthetic heart valves. The transvalvular mean pressure gradient (MPG) derived by Doppler echocardiography is a crucial index to diagnose PVT but may result in false negatives mainly in case of bileaflet mechanical valves (BMVs) in mitral position. This may happen because MPG estimation relies on simplifying assumptions on the transvalvular fluid dynamics or because Doppler examination is manual and operator dependent. A deeper understanding of these issues may allow for improving PVT diagnosis and management. To this aim, we used in vitro and fluid-structure interaction (FSI) modeling to simulate the function of a real mitral BMV in different configurations: normally functioning and stenotic with symmetric and completely asymmetric leaflet opening, respectively. In each condition, the MPG was measured in vitro, computed directly from FSI simulations and derived from the corresponding velocity field through a Doppler-like postprocessing approach. Following verification versus in vitro data, MPG computational data were analyzed to test their dependency on the severity of fluid-dynamic derangements and on the measurement site. Computed MPG clearly discriminated between normally functioning and stenotic configurations. They did not depend markedly on the site of measurement, yet differences below 3 mmHg were found between MPG values at the central and lateral orifices of the BMV. This evidence suggests a mild uncertainty of the Doppler-based evaluation of the MPG due to probe positioning, which yet may lead to false negatives when analyzing subjects with almost normal MPG.

Nanostructure and stability of calcitonin amyloids.

Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel ß-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel ß-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp15 and Phe19 aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel ß-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel ß-sheet packing.

Toward the Virtual Benchmarking of Pneumatic Ventricular Assist Devices: Application of a Novel Fluid-Structure Interaction-Based Strategy to the Penn State 12 cc Device.

The pediatric use of pneumatic ventricular assist devices (VADs) as a bridge to heart transplant still suffers for short-term major complications such as bleeding and thromboembolism. Although numerical techniques are increasingly exploited to support the process of device optimization, an effective virtual benchmark is still lacking. Focusing on the 12 cc Penn State pneumatic VAD, we developed a novel fluid-structure interaction (FSI) model able to capture the device functioning, reproducing the mechanical interplay between the diaphragm, the blood chamber, and the pneumatic actuation. The FSI model included the diaphragm mechanical response from uniaxial tensile tests, realistic VAD pressure operative conditions from a dedicated mock loop system, and the behavior of VAD valves. Our FSI-based benchmark effectively captured the complexity of the diaphragm dynamics. During diastole, the initial slow diaphragm retraction in the air chamber was followed by a more rapid phase; asymmetries were noticed in the diaphragm configuration during its systolic inflation in the blood chamber. The FSI model also captured the major features of the device fluid dynamics. In particular, during diastole, a rotational wall washing pattern is promoted by the penetrating inlet jet with a low-velocity region located in the center of the device. Our numerical analysis of the 12 cc Penn State VAD points out the potential of the proposed FSI approach well resembling previous experimental evidences; if further tested and validated, it could be exploited as a virtual benchmark to deepen VAD-related complications and to support the ongoing optimization of pediatric devices.

On the Use of the Platelet Activity State Assay for the In Vitro Quantification of Platelet Activation in Blood Recirculating Devices for Extracorporeal Circulation.

We designed an experimental setup to characterize the thrombogenic potential associated with blood recirculating devices (BRDs) used in extracorporeal circulation (ECC). Our methodology relies on in vitro flow loop platelet recirculation experiments combined with the modified-prothrombinase platelet activity state (PAS) assay to quantify the bulk thrombin production rate of circulated platelets, which correlates to the platelet activation (PA) level. The method was applied to a commercial neonatal hollow fiber membrane oxygenator. In analogous hemodynamic environment, we compared the PA level resulting from multiple passes of platelets within devices provided with phosphorylcholine (PC)-coated and noncoated (NC) fibers to account for flow-related mechanical factors (i.e., fluid-induced shear stress) together with surface contact activation phenomena. We report for the first time that PAS assay is not significantly sensitive to the effect of material coating under clinically pertinent flow conditions (500 mL/min), while providing straightforward information on shear-mediated PA dynamics in ECC devices. Being that the latter is intimately dependent on local flow dynamics, according to our results, the rate of thrombin production as measured by the PAS assay is a valuable biochemical marker of the selective contribution of PA in BRDs induced by device design features. Thus, we recommend the use of PAS assay as a means of evaluating the effect of modification of specific device geometrical features and/or different design solutions for developing ECC devices providing flow conditions with reduced thrombogenic impact.

Opening-closing pattern of four pericardial prostheses: results from an in vitro study of leaflet kinematics.

Pericardial and porcine stented aortic valves have different leaflet kinematics. To study the biomechanics of a prosthesis thoroughly, the in vitro setting is the most appropriate. The aim of our study was to find out whether the prosthesis design in which the pericardial sheet is outside the stent post might influence the opening and closing patterns of the leaflets. Four pericardial prostheses (Magna Ease [MG] 21, Trifecta [TRI] 21, Soprano-Armonia [SA] 20 and Mitroflow [MF] 23) that fitted aortic roots with a native annulus diameter of 2.1 cm were implanted and their leaflet kinematics was studied by a high-speed digital camera. In the opening phase, MG showed the shortest RVOT and the highest RVOVI, with values of 12 ± 2 and 209 ± 17 ms, respectively. The RVOT of MG was significantly shorter than that of MF (p < 0.01), but not than that of TRI (p = 0.286). Both TRI and SA showed similar opening patterns (TRI: RVOT of 15 ± 3 ms and RVOVI of 132 ± 25 ms; SA: 17 ± 2 ms and 126 ± 19 ms), without statistically significant difference. Conversely, MF showed the slowest profile, with an RVOT of 23 ± 3 ms and an RVOVI of 94 ± 8 ms (Table 1; Fig. 3). The opening/closing profile is not influenced by the position of the pericardial leaflets, but depends on other intrinsic structural characteristics related to the material used for the stent and leaflets. Moreover, the kinematics does not affect the valve performance. Table 1 Kinematics and hydrodynamic results, reported as means and standard deviations, evaluated over the tested heart samples TRI SA MG MF ANOVA TRI versus SA TRI versus MG TRI versus MF SA versus MG SA versus MF MG versus MF p Value p Value p Value p Value p Value p Value p Value ET (ms) 1.0 1.0 1.0 1.0 RVOT (ms) 15 ± 3 17 ± 2 12 ± 2 23 ± 3 <0.01 1.0 0.286 <0.01 0.03 <0.01 <0.01 SVCT (ms) 247 ± 14 231 ± 15 256 ± 26 241 ± 11 0.170 0.463 0.853 0.931 0.213 1.0 1.0 RVCT (ms) 35 ± 19 52 ± 13 32 ± 17 52 ± 4 0.07 0.474 1.0 0.494 0.236 1.0 0.247 TVCT (ms) 283 ± 10 283 ± 19 289 ± 10 293 ± 11 0.584 1.00 1.0 1.0 1.0 1.0 1.0 RVOVI (ms-1) 132 ± 25 126 ± 19 209 ± 17 94 ± 8 <0.01 0.959 <0.01 0.02 <0.01 0.07 <0.01 SVCVI (ms-1) -0.9 ± 0.3 -1.1 ± 0.4 -0.57 ± 0.1 -0.55 ± 0.1 <0.01 1.0 0.353 0.292 0.045 0.04 1.0 RVCVI (ms-1) -16 ± 4 -10 ± 2 -18 ± 6 -10 ± 1 <0.01 0.396 1.0 0.513 0.025 1.0 0.03 Δp (mmHg) 6.7 ± 3.6 10.6 ± 5.5 15.2 ± 7.9 10.7 ± 6.1 <0.01 0.01 <0.01 0.01 0.04 1.0 <0.01 EOA (cm2) 2.2 ± 1.2 1.7 ± 0.9 1.5 ± 0.8 1.7 ± 0.9 <0.01 0.03 <0.01 0.01 0.261 0.617 0.11 El  % 7.3 ± 1 11.9 ± 1 15.4 ± 2 11.8 ± 3 <0.01 <0.01 <0.01 <0.01 0.04 1.00 0.03 CO (L/min) 3.1 ± 0.4 2.8 ± 0.5 3.1 ± 0.3 3.0 ± 0.5 0.534 0.282 0.792 0.702 0.106 0.552 0.559 ET ejection time, RVOT rapid valve-opening time, SVCT slow valve-closing time, RVCT rapid valve-closing time, TVCT total valve-closing time, RVOVI rapid valve-opening velocity index, SVCVI slow valve-closing velocity index, RVCVI rapid valve-closing velocity index, Δp mean pressure drop, EOA effective orifice area, El % energy loss, CO cardiac output.

Hemolysate-mediated platelet aggregation: an additional risk mechanism contributing to thrombosis of continuous flow ventricular assist devices.

Despite the clinical success and growth in the utilization of continuous flow ventricular assist devices (cfVADs) for the treatment of advanced heart failure, hemolysis and thrombosis remain major limitations. Inadequate and/or ineffective anticoagulation regimens, combined with high pump speed and non-physiological flow patterns, can result in hemolysis which often is accompanied by pump thrombosis. An unexpected increase in cfVADs thrombosis was reported by multiple major VAD implanting centers in 2014, highlighting the association of hemolysis and a rise in lactate dehydrogenase (LDH) presaging thrombotic events. It is well established that thrombotic complications arise from the abnormal shear stresses generated by cfVADs. What remains unknown is the link between cfVAD-associated hemolysis and pump thrombosis. Can hemolysis of red blood cells (RBCs) contribute to platelet aggregation, thereby, facilitating prothrombotic complications in cfVADs? Herein, we examine the effect of RBC-hemolysate and selected major constituents, i.e., lactate dehydrogenase (LDH) and plasma free hemoglobin (pHb) on platelet aggregation, utilizing electrical resistance aggregometry. Our hypothesis is that elements of RBCs, released as a result of shear-mediated hemolysis, will contribute to platelet aggregation. We show that RBC hemolysate and pHb, but not LDH, are direct contributors to platelet aggregation, posing an additional risk mechanism for cfVAD thrombosis.

Microfluidic emulation of mechanical circulatory support device shear-mediated platelet activation.

Thrombosis of ventricular assist devices (VADs) compromises their performance, with associated risks of systemic embolization, stroke, pump stop and possible death. Anti-thrombotic (AT) drugs, utilized to limit thrombosis, are largely dosed empirically, with limited testing of their efficacy. Further, such testing, if performed, typically examines efficacy under static conditions, which is not reflective of actual shear-mediated flow. Here we adopted our previously developed Device Thrombogenicity Emulation methodology to design microfluidic platforms able to emulate representative shear stress profiles of mechanical circulatory support (MCS) devices. Our long-term goal is to utilize these systems for point-of-care (POC) personalized testing of AT efficacy under specific, individual shear profiles. First, we designed different types of microfluidic channels able to replicate sample shear stress patterns observed in MCS devices. Second, we explored the flexibility of microfluidic technology in generating dynamic shear stress profiles by modulating the geometrical features of the channels. Finally, we designed microfluidic channel systems able to emulate the shear stress profiles of two commercial VADs. From CFD analyses, the VAD-emulating microfluidic systems were able to replicate the main characteristics of the shear stress waveforms of the macroscale VADs (i.e., shear stress peaks and duration). Our results establish the basis for development of a lab-on-chip POC system able to perform device-specific and patient-specific platelet activation state assays.

An anatomy-based lumped parameter model of cerebrospinal venous circulation: can an extracranial anatomical change impact intracranial hemodynamics?

BACKGROUND: The relationship between extracranial venous system abnormalities and central nervous system disorders has been recently theorized. In this paper we delve into this hypothesis by modeling the venous drainage in brain and spinal column areas and simulating the intracranial flow changes due to extracranial morphological stenoses. METHODS: A lumped parameter model of the cerebro-spinal venous drainage was created based on anatomical knowledge and vessels diameters and lengths taken from literature. Each vein was modeled as a hydraulic resistance, calculated through Poiseuille's law. The inputs of the model were arterial flow rates of the intracranial, vertebral and lumbar districts. The effects of the obstruction of the main venous outflows were simulated. A database comprising 112 Multiple Sclerosis patients (Male/Female = 42/70; median age ± standard deviation = 43.7 ± 10.5 years) was retrospectively analyzed. RESULTS: The flow rate of the main veins estimated with the model was similar to the measures of 21 healthy controls (Male/Female = 10/11; mean age ± standard deviation = 31 ± 11 years), obtained with a 1.5 T Magnetic Resonance scanner. The intracranial reflux topography predicted with the model in cases of internal jugular vein diameter reduction was similar to those observed in the patients with internal jugular vein obstacles. CONCLUSIONS: The proposed model can predict physiological and pathological behaviors with good fidelity. Despite the simplifications introduced in cerebrospinal venous circulation modeling, the key anatomical feature of the lumped parameter model allowed for a detailed analysis of the consequences of extracranial venous impairments on intracranial pressure and hemodynamics.