Left ventricle diastolic vortex ring characterization in ischemic cardiomyopathy: insight into atrio-ventricular interplay.

Diastolic vortex ring (VR) plays a key role in the blood-pumping function exerted by the left ventricle (LV), with altered VR structures being associated with LV dysfunction. Herein, we sought to characterize the VR diastolic alterations in ischemic cardiomyopathy (ICM) patients with systo-diastolic LV dysfunction, as compared to healthy controls, in order to provide a more comprehensive understanding of LV diastolic function. 4D Flow MRI data were acquired in ICM patients (n = 15) and healthy controls (n = 15). The λ2 method was used to extract VRs during early and late diastolic filling. Geometrical VR features, e.g., circularity index (CI), orientation (α), and inclination with respect to the LV outflow tract (ß), were extracted. Kinetic energy (KE), rate of viscous energy loss ( EL ˙ ), vorticity (W), and volume (V) were computed for each VR; the ratios with the respective quantities computed for the entire LV were derived. At peak E-wave, the VR was less circular (p = 0.032), formed a smaller α with the LV long-axis (p = 0.003) and a greater ß (p = 0.002) in ICM patients as compared to controls. At peak A-wave, CI was significantly increased (p = 0.034), while α was significantly smaller (p = 0.016) and ß was significantly increased (p = 0.036) in ICM as compared to controls. At both peak E-wave and peak A-wave, EL ˙ VR / EL ˙ LV , WVR/WLV, and VVR/VLV significantly decreased in ICM patients vs. healthy controls. KEVR/VVR showed a significant decrease in ICM patients with respect to controls at peak E-wave, while VVR remained comparable between normal and pathologic conditions. In the analyzed ICM patients, the diastolic VRs showed alterations in terms of geometry and energetics. These derangements might be attributed to both structural and functional alterations affecting the infarcted wall region and the remote myocardium.

Quantification of anatomical aortic valve area by multi-detector computed tomography: A pilot 3D-morphological modeling of the stenotic aortic valve.

BACKGROUND: Aortic-valve-stenosis (AS) is a frequent degenerative valvular-disease and carries dismal outcome under-medical-treatment. Transvalvular pressure gradient reflects severity of the valve-disease but is highly dependent on flow-conditions and on other valvular/aortic characteristics. Alternatively, aortic-valve-area (AVA) represents a measure of aortic-valve lesion severity conceptually essential and practically widely-recognized but exhibits multiple-limitations. METHODS: We analyzed the 4D multi-detector computed tomography(MDCT) of 20 randomly selected patients with severe AS. For each-patient, we generated the 3D-model of the valve and of its calcifications, and we computed the anatomical AVA accounting for the 3D-morphology of the leaflets in three-different-ways. Finally, we compared our results vs. Doppler-based AVAE measurements and vs. 2D-planimetric AVA-measurements. RESULTS: 3D-reconstruction and identification of the cusps were successful in 90% of the cases. The calcification patterns where highly-variable over patients, ranging from multiple small deposits to wide and c-shaped deposits running from commissure-to-commissure. AVAE was 82 ± 15 mm2. When segmenting 18 image planes, AVATight, AVAProj-Ann, AVAProj-Tip and their average AVAAve were equal to 80 ± 16, 88 ± 20, 93 ± 21 and 87 ± 19 mm2, respectively, while AVAPlan was equal to 143 ± 50 mm2. Linear-regression of the three measurements vs. AVAE yielded regression slopes equal to 1.26, 1.13 and 0.93 for AVAProj-Ann, AVAProj-Tip and AVATight, respectively. The respective Pearson-coefficients were 0.85,0.86 and 0.90. Conversely, when comparing AVAPlan vs. AVAE, linear regression yielded a slope of 1.73 and a Pearson coefficient of 0.53. CONCLUSIONS: We described a new-method to obtain a set of flow-independent quantifications that complement pressure gradient measurements and combine the advantages of previously proposed methods, while bypassing the corresponding-limitations.

Influence of Hematocrit Level and Integrin αIIbßIII Function on vWF-Mediated Platelet Adhesion and Shear-Induced Platelet Aggregation in a Sudden Expansion.

Purpose: Shear-mediated thrombosis is a clinically relevant phenomenon that underlies excessive arterial thrombosis and device-induced thrombosis. Red blood cells are known to mechanically contribute to physiological hemostasis through margination of platelets and vWF, facilitating the unfurling of vWF multimers, and increasing the fraction of thrombus-contacting platelets. Shear also plays a role in this phenomenon, increasing both the degree of margination and the near-wall forces experienced by vWF and platelets leading to unfurling and activation. Despite this, the contribution of red blood cells in shear-induced platelet aggregation has not been fully investigated-specifically the effect of elevated hematocrit has not yet been demonstrated. Methods: Here, a microfluidic model of a sudden expansion is presented as a platform for investigating platelet adhesion at hematocrits ranging from 0 to 60% and shear rates ranging from 1000 to 10,000 s-1. The sudden expansion geometry models nonphysiological flow separation characteristic to mechanical circulatory support devices, and the validatory framework of the FDA benchmark nozzle. PDMS microchannels were fabricated and coated with human collagen. Platelets were fluorescently tagged, and blood was reconstituted at variable hematocrit prior to perfusion experiments. Integrin function of selected blood samples was inhibited by a blocking antibody, and platelet adhesion and aggregation over the course of perfusion was monitored. Results: Increasing shear rates at physiological and elevated hematocrit levels facilitate robust platelet adhesion and formation of large aggregates. Shear-induced platelet aggregation is demonstrated to be dependent on both αIIbßIII function and the presence of red blood cells. Inhibition of αIIbßIII results in an 86.4% reduction in overall platelet adhesion and an 85.7% reduction in thrombus size at 20-60% hematocrit. Hematocrit levels of 20% are inadequate for effective platelet margination and subsequent vWF tethering, resulting in notable decreases in platelet adhesion at 5000 and 10,000 s-1 compared to 40% and 60%. Inhibition of αIIbßIII triggered dramatic reductions in overall thrombus coverage and large aggregate formation. Stability of platelets tethered by vWF are demonstrated to be αIIbßIII-dependent, as adhesion of single platelets treated with A2A9, an anti-αIIbßIII blocking antibody, is transient and did not lead to sustained thrombus formation. Conclusions: This study highlights driving factors in vWF-mediated platelet adhesion that are relevant to clinical suppression of shear-induced thrombosis and in vitro assays of platelet adhesion. Primarily, increasing hematocrit promotes platelet margination, permitting shear-induced platelet aggregation through αIIbßIII-mediated adhesion at supraphysiological shear rates. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00796-0.

Implicit neural representations for unsupervised super-resolution and denoising of 4D flow MRI.

BACKGROUND AND OBJECTIVE: 4D flow magnetic resonance imaging provides time-resolved blood flow velocity measurements, but suffers from limitations in spatio-temporal resolution and noise. In this study, we investigated the use of sinusoidal representation networks (SIRENs) to improve denoising and super-resolution of velocity fields measured by 4D flow MRI in the thoracic aorta. METHODS: Efficient training of SIRENs in 4D was achieved by sampling voxel coordinates and enforcing the no-slip condition at the vessel wall. A set of synthetic measurements were generated from computational fluid dynamics simulations, reproducing different noise levels. The influence of SIREN architecture was systematically investigated, and the performance of our method was compared to existing approaches for 4D flow denoising and super-resolution. RESULTS: Compared to existing techniques, a SIREN with 300 neurons per layer and 20 layers achieved lower errors (up to 50% lower vector normalized root mean square error, 42% lower magnitude normalized root mean square error, and 15% lower direction error) in velocity and wall shear stress fields. Applied to real 4D flow velocity measurements in a patient-specific aortic aneurysm, our method produced denoised and super-resolved velocity fields while maintaining accurate macroscopic flow measurements. CONCLUSIONS: This study demonstrates the feasibility of using SIRENs for complex blood flow velocity representation from clinical 4D flow, with quick execution and straightforward implementation.

A fully automated deep learning approach for coronary artery segmentation and comprehensive characterization.

Coronary computed tomography angiography (CCTA) allows detailed assessment of early markers associated with coronary artery disease (CAD), such as coronary artery calcium (CAC) and tortuosity (CorT). However, their analysis can be time-demanding and biased. We present a fully automated pipeline that performs (i) coronary artery segmentation and (ii) CAC and CorT objective analysis. Our method exploits supervised learning for the segmentation of the lumen, and then, CAC and CorT are automatically quantified. 281 manually annotated CCTA images were used to train a two-stage U-Net-based architecture. The first stage employed a 2.5D U-Net trained on axial, coronal, and sagittal slices for preliminary segmentation, while the second stage utilized a multichannel 3D U-Net for refinement. Then, a geometric post-processing was implemented: vessel centerlines were extracted, and tortuosity score was quantified as the count of branches with three or more bends with change in direction forming an angle >45°. CAC scoring relied on image attenuation. CAC was detected by setting a patient specific threshold, then a region growing algorithm was applied for refinement. The application of the complete pipeline required <5 min per patient. The model trained for coronary segmentation yielded a Dice score of 0.896 and a mean surface distance of 1.027 mm compared to the reference ground truth. Tracts that presented stenosis were correctly segmented. The vessel tortuosity significantly increased locally, moving from proximal, to distal regions (p < 0.001). Calcium volume score exhibited an opposite trend (p < 0.001), with larger plaques in the proximal regions. Volume score was lower in patients with a higher tortuosity score (p < 0.001). Our results suggest a linked negative correlation between tortuosity and calcific plaque formation. We implemented a fast and objective tool, suitable for population studies, that can help clinician in the quantification of CAC and various coronary morphological parameters, which is helpful for CAD risk assessment.

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.

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.

A CT-based deep learning system for automatic assessment of aortic root morphology for TAVI planning.

Accurate planning of transcatheter aortic valve implantation (TAVI) is important to minimize complications, and it requires anatomic evaluation of the aortic root (AR), commonly performed through 3D computed tomography (CT) image analysis. Currently, there is no standard automated solution for this process. Two convolutional neural networks with 3D U-Net architectures (model 1 and model 2) were trained on 310 CT scans for AR analysis. Model 1 performs AR segmentation and model 2 identifies the aortic annulus and sinotubular junction (STJ) contours. After training, the two models were integrated into a fully automated pipeline for geometric analysis of the AR. Results were validated against manual measurements of 178 TAVI candidates. The trained CNNs segmented the AR, annulus, and STJ effectively, resulting in mean Dice scores of 0.93 for the AR, and mean surface distances of 0.73 mm and 0.99 mm for the annulus and STJ, respectively. Automatic measurements were in good agreement with manual annotations, yielding annulus diameters that differed by 0.52 [-2.96, 4.00] mm (bias and 95% limits of agreement for manual minus algorithm). Evaluating the area-derived diameter, bias, and limits of agreement were 0.07 [-0.25, 0.39] mm. STJ and sinuses diameters computed by the automatic method yielded differences of 0.16 [-2.03, 2.34] and 0.1 [-2.93, 3.13] mm, respectively. The proposed tool is a fully automatic solution to quantify morphological biomarkers for pre-TAVI planning. The method was validated against manual annotation from clinical experts and showed to be quick and effective in assessing AR anatomy, with potential for time and cost savings.

Coronary Perfusion After Valve-in-Valve Transcatheter Aortic Valve Implantation in Small Aortic Root: In Vitro Experimental Assessment.

Coronary flow obstruction following transcatheter aortic valve-in-valve implantation (VIV-TAVI) is associated with a high mortality risk. The aim of this work was to quantify the coronary perfusion after VIV-TAVI in a high-risk aortic root anatomy. 3D printed models of small aortic root were used to simulate the implantation of a TAVI prosthesis (Portico 23) into surgical prostheses (Trifecta 19 and 21). The aortic root models were tested in a pulsatile in vitro bench setup with a coronary perfusion simulator. The tests were performed at baseline and post-VIV-TAVI procedure in aligned and misaligned commissural configurations under simulated hemodynamic rest and exercise conditions. The experimental design provided highly controllable and repeatable flow and pressure conditions. The left and right coronary mean flow did not differ significantly at pre- and post-VIV-TAVI procedure in any tested configurations. The commissural misalignment did not induce any significant alterations to the coronary flow. High-risk aortic root anatomy did not trigger coronary ostia obstruction or coronary flow alteration after transcatheter aortic valve implantation in a surgical bioprosthesis as shown from in-vitro flow loop tests.

Data-driven generation of 4D velocity profiles in the aneurysmal ascending aorta.

BACKGROUND AND OBJECTIVE: Numerical simulations of blood flow are a valuable tool to investigate the pathophysiology of ascending thoratic aortic aneurysms (ATAA). To accurately reproduce in vivo hemodynamics, computational fluid dynamics (CFD) models must employ realistic inflow boundary conditions (BCs). However, the limited availability of in vivo velocity measurements, still makes researchers resort to idealized BCs. The aim of this study was to generate and thoroughly characterize a large dataset of synthetic 4D aortic velocity profiles sampled on a 2D cross-section along the ascending aorta with features similar to clinical cohorts of patients with ATAA. METHODS: Time-resolved 3D phase contrast magnetic resonance (4D flow MRI) scans of 30 subjects with ATAA were processed through in-house code to extract anatomically consistent cross-sectional planes along the ascending aorta, ensuring spatial alignment among all planes and interpolating all velocity fields to a reference configuration. Velocity profiles of the clinical cohort were extensively characterized by computing flow morphology descriptors of both spatial and temporal features. By exploiting principal component analysis (PCA), a statistical shape model (SSM) of 4D aortic velocity profiles was built and a dataset of 437 synthetic cases with realistic properties was generated. RESULTS: Comparison between clinical and synthetic datasets showed that the synthetic data presented similar characteristics as the clinical population in terms of key morphological parameters. The average velocity profile qualitatively resembled a parabolic-shaped profile, but was quantitatively characterized by more complex flow patterns which an idealized profile would not replicate. Statistically significant correlations were found between PCA principal modes of variation and flow descriptors. CONCLUSIONS: We built a data-driven generative model of 4D aortic inlet velocity profiles, suitable to be used in computational studies of blood flow. The proposed software system also allows to map any of the generated velocity profiles to the inlet plane of any virtual subject given its coordinate set.

Quantification of paravalvular leaks associated with TAVI implants using 4D MRI in an aortic root phantom made possible by the use of 3D printing.

Introduction: Transcatheter aortic valve implantation (TAVI) has become an alternative to surgical replacement of the aortic valve elderly patients. However, TAVI patients may suffer from paravalvular leaks (PVL). Detecting and grading is usually done by echocardiography, but is limited by resolution, 2D visualization and operator dependency. 4D flow magnetic resonance imaging (MRI) is a promising alternative, which did not reach clinical application in TAVI patients. The aim of this study was applying 3D printing technologies in order to evaluate flow patterns and hemodynamics of PVLs following TAVI, exploiting 4D flow MRI and standard ultrasound. Materials and methods: An MR-compatible, anatomically left ventricle, aortic root, and ascending aorta model was fabricated by combining 3D-printed parts and various soft silicone materials to match physiological characteristics. An Abbott Portico™ valve was used in continuous antegrade flow (12-22 l/min), retrograde flow with varying transvalvular pressures (60-110 mmHg), and physiological pulsatile hemodynamics (aortic pressure: 120/80 mmHg, cardiac output: 5 l/min) Time-resolved MR measurements were performed above and below the TAVI stent and compared with color Doppler ultrasound measurements in exactly the same setup. Results: The continuous antegrade flow measurements from MRI largely agreed with the flowmeter measurements, and a maximum error of only 7% was observed. In the retrograde configuration, visualization of the paravalvular leaks was possible from the MR measurements, but flow was overestimated by up to 33%. The 4D MRI measurement in the pulsatile setup revealed a single main PVL, which was also confirmed by the color Doppler measurements, and velocities were similar (2.0 m/s vs. 1.7 m/s). Discussion: 4D MRI techniques were used to qualitatively assess flow in a patient-specific, MR-compatible and flexible model, which only became possible through the use of 3D printing techniques. Flow patterns in the ascending aorta, identification and quantification of PVLs was possible and the location and extent of PVLs were confirmed by ultrasound measurements. The 4D MRI flow technique allowed evaluation of flow patterns in the ascending aorta and the left ventricle below the TAVI stent with good results in identifying PVLs, demonstrating its capabilities over ultrasound by providing the ability to visualize the paravalvular jets in three dimensions at however, additional expenditure of time and money.

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.

The use of mixed reality for the treatment planning of unruptured intracranial aneurysms.

BACKGROUND: A thorough comprehension of topographic neuroanatomy is paramount in neurosurgery. In recent years, great attention has been raised towards extended reality, which comprises virtual, augmented, and mixed reality (MR) as an aid for surgery. In this paper, we describe our preliminary experience with the use of a new MR platform, aiming to assess its reliability and usefulness in the planning of surgical treatment of unruptured intracranial aneurysms. METHODS: We prospectively enrolled 5 patients, harboring a total of 8 intracranial unruptured aneurysms, undergoing elective surgical clipping. A wearable mixed-reality device (HoloLens; Microsoft Corp., Redmond, WA, USA) was used to display and interact with a holographic model during surgical planning. Afterward, a total of 10 among surgeons and residents filled in a 5-point Likert-Scale evaluation questionnaire. RESULTS: According to the participants' feedback, the main MR platform advantages were considered the educational value, its utility during patients positioning and craniotomy planning, as well as the anatomical and imaging interpretation during surgery. The graphic performance was also deemed very satisfactory. On the other hand, the device was evaluated as not easy to use and pretty uncomfortable when worn for a long time. CONCLUSIONS: We demonstrated that MR could play important role in planning the surgical treatment of intracranial aneurysms by enhancing the visualization and understanding of the patient-specific anatomy.

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.

Predicting human cardiac QT alterations and pro-arrhythmic effects of compounds with a 3D beating heart-on-chip platform.

Determining the potential cardiotoxicity and pro-arrhythmic effects of drug candidates remains one of the most relevant issues in the drug development pipeline (DDP). New methods enabling to perform more representative preclinical in vitro studies by exploiting induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are under investigation to increase the translational power of the outcomes. Here we present a pharmacological campaign conducted to evaluate the drug-induced QT alterations and arrhythmic events on uHeart, a 3D miniaturized in vitro model of human myocardium encompassing iPSC-CM and dermal fibroblasts embedded in fibrin. uHeart was mechanically trained resulting in synchronously beating cardiac microtissues in 1 week, characterized by a clear field potential (FP) signal that was recorded by means of an integrated electrical system. A drug screening protocol compliant with the new International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines was established and uHeart was employed for testing the effect of 11 compounds acting on single or multiple cardiac ion channels and well-known to elicit QT prolongation or arrhythmic events in clinics. The alterations of uHeart's electrophysiological parameters such as the beating period, the FP duration, the FP amplitude, and the detection of arrhythmic events prior and after drug administration at incremental doses were effectively analyzed through a custom-developed algorithm. Results demonstrated the ability of uHeart to successfully anticipate clinical outcome and to predict the QT prolongation with a sensitivity of 83.3%, a specificity of 100% and an accuracy of 91.6%. Cardiotoxic concentrations of drugs were notably detected in the range of the clinical highest blood drug concentration (Cmax), qualifying uHeart as a fit-to-purpose preclinical tool for cardiotoxicity studies.

Computational investigation of the haemodynamics shows criticalities of central venous lines used for chronic haemodialysis in children.

Background: Haemodialysis is a life-saving treatment for children with kidney failure. The majority of children have haemodialysis through central venous lines (CVLs). The use of CVLs in pediatric patients is often associated to complications which can lead to their replacement. The aim of this study is to investigate haemodynamics of pediatric CVLs to highlight the criticalities of different line designs. Methods: Four models of CVLs for pediatric use were included in this study. The selected devices varied in terms of design and sizes (from 6.5 Fr to 14 Fr). Accurate 3D models of CVLs were reconstructed from high-resolution images including venous and arterial lumens, tips and side holes. Computational fluid dynamics (CFD) analyses were carried out to simulate pediatric working conditions of CVLs in ideal and anatomically relevant conditions. Results: The arterial lumens of all tested CVLs showed the most critical conditions with the majority of blood flowing through the side-holes. A zone of low flow was identified at the lines' tip. The highest shear stresses distribution (>10 Pa) was found in the 8 Fr line while the highest platelet lysis index in the 10 Fr model. The analysis on the anatomical geometry showed an increase in wall shear stress measured in the 10 F model compared to the idealised configuration. Similarly, in anatomical models an increased disturbance and velocity of the flow was found inside the vein after line placement. Conclusion: This study provided a numerical characterization of fluid dynamics in pediatric CVLs highlighting performance criticalities (i.e. high shear stresses and areas of stagnation) associated to specific sizes (8 Fr and 10 Fr) and conditions (i.e. anatomical test).

Development and Validation of a Novel Skills Training Model for PCNL, an ESUT project.

BACKGROUND AND AIM: The aim of this study is to validate a totally non biologic training model that combines the use of ultrasound and X ray to train Urologists and Residents in Urology in PerCutaneous NephroLithotripsy (PCNL). METHODS: The training pathway was divided into three modules: Module 1, related to the acquisition of basic UltraSound (US) skill on the kidney; Module 2, consisting of correct Nephrostomy placement; and Module 3, in which a complete PCNL was performed on the model. Trainees practiced on the model first on Module 1, than in 2 and in 3. The pathway was repeated at least three times. Afterward, they rated the performance of the model and the improvement gained using a global rating score questionnaire. RESULTS: A total of 150 Urologists took part in this study. Questionnaire outcomes on this training model showed a mean 4.21 (range 1-5) of positive outcome overall. Individual constructive validity showed statistical significance between the first and the last time that trainees practiced on the PCNL model among the three different modules. Statistical significance was also found between residents, fellows and experts scores. Trainees increased their skills during the training modules. CONCLUSION: This PCNL training model allows for the acquisition of technical knowledge and skills as US basic skill, Nephrostomy placement and entire PCNL procedure. Its structured use could allow a better and safer training pathway to increase the skill in performing a PCNL.

Hybrid fibroin/polyurethane small-diameter vascular grafts: from fabrication toin vivopreliminary assessment.

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very small-calibre grafts (Øin= 1.5 mm) via electrospinning. Bio-hybrid grafts werein vitrocharacterized in terms of morphology and mechanical behaviour, and compared to similar grafts of pure SF. Similarly, two native vessels from a rodent model (abdominal aorta and vena cava) were harvested and characterized. Preliminary implants were performed on Lewis rats to confirm the suitability of Silkothane® grafts for small-calibre applications, specifically as aortic insertion and femoral shunt. The manufacturing process generated pliable grafts consisting of a randomized fibrous mesh and exhibiting similar geometrical features to rat aortas. Both Silkothane® and pure SF grafts showed radial compliances in the range from 1.37 ± 0.86 to 1.88 ± 1.01% 10-2mmHg-1, lower than that of native vessels. The Silkothane® small-calibre devices were also implanted in rats demonstrating to be adequate for vascular applications; all the treated rats survived the surgery for three months after implantation, and 16 rats out of 17 (94%) still showed blood flow inside the graft at sacrifice. The obtained results lay the basis for a deeper investigation of the interaction between the Silkothane® graft and the implant site, which may deal with further analysis on the potentialities in terms of degradability and tissue formation, on longer time-points.

Non-invasive estimation of vascular compliance and distensibility in the arm vessels: a novel ultrasound-based protocol.

Background: Performance and durability of arterio-venous grafts depend on their ability to mimic the mechanical behavior of the anastomized blood vessels. To select the most suitable synthetic graft, in vivo evaluation of the radial deformability of peripheral arteries and veins could be crucial; however, a standardized non-invasive strategy is still missing. Herein, we sought to define a novel and user-friendly clinical protocol for in vivo assessment of the arm vessel deformability. Methods: A dedicated protocol, applied on 30 volunteers, was specifically designed to estimate both compliance and distensibility of the brachial and radial arteries, and of the basilic and cephalic veins. Bi-dimensional ultrasound imaging was used to acquire cross-sectional areas (CSAs) of arteries in clinostatic configuration, and CSAs of veins combining clinostatic and orthostatic configurations. Arterial pulse pressure was measured with a digital sphygmomanometer, while venous hydrostatic pressure was derived from the arm length in orthostatic configuration. Results: For each participant, all CSAs were successfully extracted from ultrasound images. The basilic vein and the radial artery exhibited the largest (21.5±8.9 mm2) and the smallest (3.4±1.0 mm2) CSAs, respectively; CSA measurements were highly repeatable (Bland-Altman bias <10% and Pearson correlation ≥0.90, for both arteries and veins). In veins, compliance and distensibility were higher than in arteries; compliance was significantly higher (P<0.0001) in the brachial than in the radial artery (3.52×10-4 vs. 1.3×10-4 cm2/mmHg); it was three times larger in basilic veins than in cephalic veins (17.4×10-4 vs. 5.6×10-4 cm2/mmHg, P<0.0001). Conclusions: The proposed non-invasive protocol proved feasible, effective and adequate for daily clinical practice, allowing for the estimation of patient-specific compliance and distensibility of peripheral arteries and veins. If further extended, it may contribute to the fabrication of biohybrid arterio-venous grafts, paving the way towards patient-tailored solutions for vascular access.