A novel approach to in vivo mitral valve stress analysis

Three-dimensional (3-D) echocardiography allows the generation of anatomically correct and time-resolved geometric mitral valve (MV) models. However, as imaged in vivo, the MV assumes its systolic geometric configuration only when loaded. Customarily, finite element analysis (FEA) is used to predict material stress and strain fields rendered by applying a load on an initially unloaded model. Therefore, this study endeavors to provide a framework for the application of in vivo MV geometry and FEA to MV physiology, pathophysiology, and surgical repair. We hypothesize that in vivo MV geometry can be reasonably used as a surrogate for the unloaded valve in computational (FEA) simulations, yielding reasonable and meaningful stress and strain magnitudes and distributions. Three experiments were undertaken to demonstrate that the MV leaflets are relatively nondeformed during systolic loading: 1) leaflet strain in vivo was measured using sonomicrometry in an ovine model, 2) hybrid models of normal human MVs as constructed using transesophageal real-time 3-D echocardiography (rt-3DE) were repeatedly loaded using FEA, and 3) serial rt-3DE images of normal human MVs were used to construct models at end diastole and end isovolumic contraction to detect any deformation during isovolumic contraction. The average linear strain associated with isovolumic contraction was 0.02 ± 0.01, measured in vivo with sonomicrometry. Repeated loading of the hybrid normal human MV demonstrated little change in stress or geometry: peak von Mises stress changed by <4% at all locations on the anterior and posterior leaflets. Finally, the in vivo human MV deformed minimally during isovolumic contraction, as measured by the mean absolute difference calculated over the surfaces of both leaflets between serial MV models: 0.53 ± 0.19 mm. FEA modeling of MV models derived from in vivo high-resolution truly 3-D imaging is reasonable and useful for stress prediction in MV pathologies and repairs.     

Personalized Computational Modeling of Mitral Valve Prolapse: Virtual Leaflet Resection

Posterior leaflet prolapse following chordal elongation or rupture is one of the primary valvular diseases in patients with degenerative mitral valves (MVs). Quadrangular resection followed by ring annuloplasty is a reliable and reproducible surgical repair technique for treatment of posterior leaflet prolapse. Virtual MV repair simulation of leaflet resection in association with patient-specific 3D echocardiographic data can provide quantitative biomechanical and physiologic characteristics of pre- and post-resection MV function. We have developed a solid personalized computational simulation protocol to perform virtual MV repair using standard clinical guidelines of posterior leaflet resection with annuloplasty ring implantation. A virtual MV model was created using 3D echocardiographic data of a patient with posterior chordal rupture and severe mitral regurgitation. A quadrangle-shaped leaflet portion in the prolapsed posterior leaflet was removed, and virtual plication and suturing were performed. An annuloplasty ring of proper size was reconstructed and virtual ring annuloplasty was performed by superimposing the ring and the mitral annulus. Following the quadrangular resection and ring annuloplasty simulations, patient-specific annular motion and physiologic transvalvular pressure gradient were implemented and dynamic finite element simulation of MV function was performed. The pre-resection MV demonstrated a substantial lack of leaflet coaptation which directly correlated with the severe mitral regurgitation. Excessive stress concentration was found along the free marginal edge of the posterior leaflet involving the chordal rupture. Following the virtual resection and ring annuloplasty, the severity of the posterior leaflet prolapse markedly decreased. Excessive stress concentration disappeared over both anterior and posterior leaflets, and complete leaflet coaptation was effectively restored. This novel personalized virtual MV repair strategy has great potential to help with preoperative selection of the patient-specific optimal MV repair techniques, allow innovative surgical planning to expect improved efficacy of MV repair with more predictable outcomes, and ultimately provide more effective medical care for the patient.     

On the in vivo function of the mitral heart valve leaflet: insights into tissue–interstitial cell biomechanical coupling

There continues to be a critical need for developing data-informed computational modeling techniques that enable systematic evaluations of mitral valve (MV) function. This is important for a better understanding of MV organ-level biomechanical performance, in vivo functional tissue stresses, and the biosynthetic responses of MV interstitial cells (MVICs) in the normal, pathophysiological, and surgically repaired states. In the present study, we utilized extant ovine MV population-averaged 3D fiducial marker data to quantify the MV anterior leaflet (MVAL) deformations in various kinematic states. This approach allowed us to make the critical connection between the in vivo functional and the in vitro experimental configurations. Moreover, we incorporated the in vivo MVAL deformations and pre-strains into an enhanced inverse finite element modeling framework (Path 1) to estimate the resulting in vivo tissue prestresses \((\sigma _\mathrm{CC}\cong \sigma _\mathrm{RR}\cong \, 30\,\hbox {kPa})\) and the in vivo peak functional tissue stresses \((\sigma _\mathrm{CC}\cong 510\, \hbox {kPa}, \sigma _\mathrm{RR}\cong 740\, \hbox {kPa})\). These in vivo stress estimates were then cross-verified with the results obtained from an alternative forward modeling method (Path 2), by taking account of the changes in the in vitro and in vivo reference configurations. Moreover, by integrating the tissue-level kinematic results into a downscale MVIC microenvironment FE model, we were able to estimate, for the first time, the in vivo layer-specific MVIC deformations and deformation rates of the normal and surgically repaired MVALs. From these simulations, we determined that the placement of annuloplasty ring greatly reduces the peak MVIC deformation levels in a layer-specific manner. This suggests that the associated reductions in MVIC deformation may down-regulate MV extracellular matrix maintenance, ultimately leading to reduction in tissue mechanical integrity. These simulations provide valuable insight into MV cellular mechanobiology in response to organ- and tissue-level alternations induced by MV disease or surgical repair. They will also assist in the future development of computer simulation tools for guiding MV surgery procedure with enhanced durability and improved long-term surgical outcomes.     

A three-dimensional insight into the complexity of flow convergence in mitral regurgitation: adjunctive benefit of anatomic regurgitant orifice area

Mitral effective regurgitant orifice area (EROA) using the flow convergence (FC) method is used to quantify the severity of mitral regurgitation (MR). However, it is challenging and prone to interobserver variability in complex valvular pathology. We hypothesized that real-time three-dimensional (3D) transesophageal echocardiography (RT3D TEE) derived anatomic regurgitant orifice area (AROA) can be a reasonable adjunct, irrespective of valvular geometry. Our goals were to 1) to determine the regurgitant orifice morphology and distance suitable for FC measurement using 3D computational flow dynamics and finite element analysis (FEA), and (2) to measure AROA from RT3D TEE and compare it with 2D FC derived EROA measurements. We studied 61 patients. EROA was calculated from 2D TEE images using the 2D-FC technique, and AROA was obtained from zoomed RT3DE TEE acquisitions using prototype software. 3D computational fluid dynamics by FEA were applied to 3D TEE images to determine the effects of mitral valve (MV) orifice geometry on FC pattern. 3D FEA analysis revealed that a central regurgitant orifice is suitable for FC measurements at an optimal distance from the orifice but complex MV orifice resulting in eccentric jets yielded nonaxisymmetric isovelocity contours close to the orifice where the assumptions underlying FC are problematic. EROA and AROA measurements correlated well (r = 0.81) with a nonsignificant bias. However, in patients with eccentric MR, the bias was larger than in central MR. Intermeasurement variability was higher for the 2D FC technique than for RT3DE-based measurements. With its superior reproducibility, 3D analysis of the AROA is a useful alternative to quantify MR when 2D FC measurements are challenging.     

Material properties of the ovine mitral valve anterior leaflet in vivo from inverse finite element analysis

We measured leaflet displacements and used inverse finite-element analysis to define, for the first time, the material properties of mitral valve (MV) leaflets in vivo. Sixteen miniature radiopaque markers were sewn to the MV annulus, 16 to the anterior MV leaflet, and 1 on each papillary muscle tip in 17 sheep. Four-dimensional coordinates were obtained from biplane videofluoroscopic marker images (60 frames/s) during three complete cardiac cycles. A finite-element model of the anterior MV leaflet was developed using marker coordinates at the end of isovolumic relaxation (IVR; when the pressure difference across the valve is approximately 0), as the minimum stress reference state. Leaflet displacements were simulated during IVR using measured left ventricular and atrial pressures. The leaflet shear modulus (G(circ-rad)) and elastic moduli in both the commisure-commisure (E(circ)) and radial (E(rad)) directions were obtained using the method of feasible directions to minimize the difference between simulated and measured displacements. Group mean (+/-SD) values (17 animals, 3 heartbeats each, i.e., 51 cardiac cycles) were as follows: G(circ-rad) = 121 +/- 22 N/mm2, E(circ) = 43 +/- 18 N/mm2, and E(rad) = 11 +/- 3 N/mm2 (E(circ) > E(rad), P < 0.01). These values, much greater than those previously reported from in vitro studies, may result from activated neurally controlled contractile tissue within the leaflet that is inactive in excised tissues. This could have important implications, not only to our understanding of mitral valve physiology in the beating heart but for providing additional information to aid the development of more durable tissue-engineered bioprosthetic valves.     

In vitro dynamic strain behavior of the mitral valve posterior leaflet

Knowledge of mitral valve (MV) mechanics is essential for the understanding of normal MV function, and the design and evaluation of new surgical repair procedures. In the present study, we extended our investigation of MV dynamic strain behavior to quantify the dynamic strain on the central region of the posterior leaflet. Native porcine MVs were mounted in an in-vitro physiologic flow loop. The papillary muscle (PM) positions were set to the normal, taut, and slack states to simulate physiological and pathological PM positions. Leaflet deformation was measured by tracking the displacements of 16 small markers placed in the central region of the posterior leaflet. Local leaflet tissue strain and strain rates were calculated from the measured displacements under dynamic loading conditions. A total of 18 mitral valves were studied. Our findings indicated the following: (1) There was a rapid rise in posterior leaflet strain during valve closure followed by a plateau where no additional strain (i.e., no creep) occurred. (2) The strain field was highly anisotropic with larger stretches and stretch rates in the radial direction. There were negligible stretches, or even compression (stretch < 1) in the circumferential direction at the beginning of valve closure. (3) The areal strain curves were similar to the stretches in the trends. The posterior leaflet showed no significant differences in either peak stretches or stretch rates during valve closure between the normal, taut, and slack PM positions. (4) As compared with the anterior leaflet, the posterior leaflet demonstrated overall lower stretch rates in the normal PM position. However, the slack and taut PM positions did not demonstrate the significant difference in the stretch rates and areal strain rates between the posterior leaflet and the anterior leaflet. The MV posterior leaflet exhibited pronounced mechanically anisotropic behavior Loading rates of the MV posterior leaflet were very high. The PM positions influenced neither peak stretch nor stretch rates in the central area of the posterior leaflet. The stretch rates and areal strain rates were significantly lower in the posterior leaflet than those measured in the anterior leaflet in the normal PM position. However, the slack and taut PM positions did not demonstrate the significant differences between the posterior leaflet and the anterior leaflet. We conclude that PM positions may influence the posterior strain in a different way as compared to the anterior leaflet.     

High-resolution subject-specific mitral valve imaging and modeling: experimental and computational methods

The diversity of mitral valve (MV) geometries and multitude of surgical options for correction of MV diseases necessitates the use of computational modeling. Numerical simulations of the MV would allow surgeons and engineers to evaluate repairs, devices, procedures, and concepts before performing them and before moving on to more costly testing modalities. Constructing, tuning, and validating these models rely upon extensive in vitro characterization of valve structure, function, and response to change due to diseases. Micro-computed tomography (\(\mu \)CT) allows for unmatched spatial resolution for soft tissue imaging. However, it is still technically challenging to obtain an accurate geometry of the diastolic MV. We discuss here the development of a novel technique for treating MV specimens with glutaraldehyde fixative in order to minimize geometric distortions in preparation for \(\mu \)CT scanning. The technique provides a resulting MV geometry which is significantly more detailed in chordal structure, accurate in leaflet shape, and closer to its physiological diastolic geometry. In this paper, computational fluid–structure interaction (FSI) simulations are used to show the importance of more detailed subject-specific MV geometry with 3D chordal structure to simulate a proper closure validated against \(\mu \)CT images of the closed valve. Two computational models, before and after use of the aforementioned technique, are used to simulate closure of the MV.     

Regional stiffening of the mitral valve anterior leaflet in the beating ovine heart

Left atrial muscle extends into the proximal third of the mitral valve (MV) anterior leaflet and transient tensing of this muscle has been proposed as a mechanism aiding valve closure. If such tensing occurs, regional stiffness in the proximal anterior mitral leaflet will be greater during isovolumic contraction (IVC) than isovolumic relaxation (IVR) and this regional stiffness difference will be selectively abolished by β-receptor blockade. We tested this hypothesis in the beating ovine heart. Radiopaque markers were sewn around the MV annulus and on the anterior MV leaflet in 10 sheep hearts. Four-dimensional marker coordinates were obtained from biplane videofluoroscopy before (CRTL) and after administration of esmolol (ESML). Heterogeneous finite element models of each anterior leaflet were developed using marker coordinates over matched pressures during IVC and IVR for CRTL and ESML. Leaflet displacements were simulated using measured left ventricular and atrial pressures and a response function was computed as the difference between simulated and measured displacements. Circumferential and radial elastic moduli for ANNULAR, BELLY and EDGE leaflet regions were iteratively varied until the response function reached a minimum. The stiffness values at this minimum were interpreted as the in vivo regional material properties of the anterior leaflet. For all regions and all CTRL beats IVC stiffness was 40–58% greater than IVR stiffness. ESML reduced ANNULAR IVC stiffness to ANNULAR IVR stiffness values. These results strongly implicate transient tensing of leaflet atrial muscle during IVC as the basis of the ANNULAR IVC–IVR stiffness difference.     

Annulus tension of the prolapsed mitral valve corrected by edge-to-edge repair

BackgroundMitral valve (MV) performance after edge-to-edge repair (ETER) without ring annuloplasty is suboptimal. ETER efficacy needs to be evaluated from annulus tension (AT) of a prolapsed MV corrected by ETER to understand annular dilatation.MethodsTen porcine MVs were harvested and mounted on a MV closure test rig. The MV annulus tissue rested on top of a saddle-shaped plastic ring on which the annulus could slide freely. The annulus was held by strings in the periphery during MV closure under a hydrostatic trans-mitral pressure. String tensions were measured and further divided by string spacing to obtain AT. The MVs were then prolapsed by shifting split papillary muscles to simulate mono-leaflet prolapse due to elongation of chords, which insert into a single leaflet. Last, MV prolapse was corrected by ETER applied in the central leaflet region and AT was measured.ResultsAT in both anterior and posterior leaflet prolapse corrected by ETER was less than that of normal MVs. AT in the anterior leaflet prolapse corrected by ETER was less than that in the posterior leaflet prolapse corrected by ETER.ConclusionETER does not restore the normal AT and therefore leads potential of annular dilatation. The anterior leaflet prolapse has a greater potential of annular dilatation than the posterior leaflet prolapse after ETER. Annuloplasty is recommended to maintain long-term ETER efficacy.     

Isolated effect of geometry on mitral valve function for in silico model development

Computational models for the heart's mitral valve (MV) exhibit several uncertainties that may be reduced by further developing these models using ground-truth data-sets. This study generated a ground-truth data-set by quantifying the effects of isolated mitral annular flattening, symmetric annular dilatation, symmetric papillary muscle (PM) displacement and asymmetric PM displacement on leaflet coaptation, mitral regurgitation (MR) and anterior leaflet strain. MVs were mounted in an in vitro left heart simulator and tested under pulsatile haemodynamics. Mitral leaflet coaptation length, coaptation depth, tenting area, MR volume, MR jet direction and anterior leaflet strain in the radial and circumferential directions were successfully quantified at increasing levels of geometric distortion. From these data, increase in the levels of isolated PM displacement resulted in the greatest mean change in coaptation depth (70% increase), tenting area (150% increase) and radial leaflet strain (37% increase) while annular dilatation resulted in the largest mean change in coaptation length (50% decrease) and regurgitation volume (134% increase). Regurgitant jets were centrally located for symmetric annular dilatation and symmetric PM displacement. Asymmetric PM displacement resulted in asymmetrically directed jets. Peak changes in anterior leaflet strain in the circumferential direction were smaller and exhibited non-significant differences across the tested conditions. When used together, this ground-truth data-set may be used to parametrically evaluate and develop modelling assumptions for both the MV leaflets and subvalvular apparatus. This novel data may improve MV computational models and provide a platform for the development of future surgical planning tools.     

Automatic system for 3D reconstruction of the chick eye based on digital photographs

The geometry of anatomical specimens is very complex and accurate 3D reconstruction is important for morphological studies, finite element analysis (FEA) and rapid prototyping. Although magnetic resonance imaging, computed tomography and laser scanners can be used for reconstructing biological structures, the cost of the equipment is fairly high and specialised technicians are required to operate the equipment, making such approaches limiting in terms of accessibility. In this paper, a novel automatic system for 3D surface reconstruction of the chick eye from digital photographs of a serially sectioned specimen is presented as a potential cost-effective and practical alternative. The system is designed to allow for automatic detection of the external surface of the chick eye. Automatic alignment of the photographs is performed using a combination of coloured markers and an algorithm based on complex phase order likelihood that is robust to noise and illumination variations. Automatic segmentation of the external boundaries of the eye from the aligned photographs is performed using a novel level-set segmentation approach based on a complex phase order energy functional. The extracted boundaries are sampled to construct a 3D point cloud, and a combination of Delaunay triangulation and subdivision surfaces is employed to construct the final triangular mesh. Experimental results using digital photographs of the chick eye show that the proposed system is capable of producing accurate 3D reconstructions of the external surface of the eye. The 3D model geometry is similar to a real chick eye and could be used for morphological studies and FEA.     

Optimization of three-dimensional modeling for geometric precision and efficiency for healthy and diseased aortas

The study purpose is to optimize modeling parameters, specifically segmentation spacing and centerline extraction, to efficiently construct accurate 3D aortic models. Models are constructed by centerline extraction and orthogonal 2D segmentations. We examine the effect of segmentation interval spacing (2, 1, 0.5, 0.25 cm) and orthogonal segmentation and centerline extraction iteration (one, two, three iterations) for constructing models of Healthy, Tortuous, Aneurysmal, and Dissected human thoracic aortas. Aortic arclength, curvature, and cross-sectional axis ratio were computed to compare variations in modeling parameters. Centerline arclength is precisely characterized for all aortas with a single iteration of centerline extraction (≤1% deviation), however, complex anatomies required 1 cm segmentation intervals whereas the Healthy aorta only required 2 cm intervals. Centerline curvature is more sensitive to modeling methods, requiring 1 cm intervals for ≤5% deviation in peak curvature for the three diseased anatomies, and two iterations of segmentation and centerline extraction for the Aneurysmal and Dissected aortas. Accurate lumen cross-sectional characterization required 1 or 0.5 cm segmentation intervals, and two or three segmentation and centerline iterations, with greater refinement needed for more complex geometries. Depending on the geometric characteristic and complexity of anatomy and pathology, different levels of segmentation interval refinement and iterations of segmentation and centerline extraction are required.     

Engineering tumors with 3D scaffolds

Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.     

Localization of 1,25-(OH)2D3-responsive alkaline phosphatase in osteoblast-like cells (ROS 17/2.8, MG 63, and MC 3T3) and growth cartilage cells in culture

Previous studies have shown 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-responsive alkaline phosphatase in cultured growth zone cartilage chondrocytes is localized in extracellular matrix vesicles (MV). Since osteoblast-like cells also have 1,25-(OH)2D3-responsive alkaline phosphatase, this study determined whether the 1,25-(OH)2D3-responsive enzyme activity is localized to MV produced by these cells as well. Osteoblast-like cells from rat (ROS 17/2.8), mouse (MC 3T3), human (MG 63), and rat growth zone cartilage were cultured in Dulbecco's modified Eagle's medium containing 10(-7)-10(-12) M 1,25-(OH)2D3. Alkaline phosphatase total activity and specific activity were measured in the cell layer, MV, and plasma membrane (PM) fractions. MV and PM purity were verified by electron microscopy and MV alkaline phosphatase specific activity compared to PM (MV versus PM: ROS 17/2.8 6 x; MG 63, 5.5 x; MC 3T3, 33 x; GC, 2 x). There was a dose-dependent stimulation of MV alkaline phosphatase (5- to 15-fold increase at 10(-7)-10(-9) M) in all cell types in response to the 1,25-(OH)2D3. The PM enzyme was stimulated in a parallel fashion in the osteoblast cultures. No effect of 1,25-(OH)2D3 was observed in growth cartilage PM. Although MV accounted for less than 20% of the total activity they contributed 50% of the increase in alkaline phosphatase activity in the cell layer in response to 1,25-(OH)2D3 and MV specific activity was enriched 10 times over that of the cell layer. These are common features of MV produced by cells which calcify their matrix and suggest that hormonal regulation of MV enzymes may be important in primary calcification.     

Biview Learning for Human Posture Segmentation from 3D Points Cloud

Posture segmentation plays an essential role in human motion analysis. The state-of-the-art method extracts sufficiently high-dimensional features from 3D depth images for each 3D point and learns an efficient body part classifier. However, high-dimensional features are memory-consuming and difficult to handle on large-scale training dataset. In this paper, we propose an efficient two-stage dimension reduction scheme, termed biview learning, to encode two independent views which are depth-difference features (DDF) and relative position features (RPF). Biview learning explores the complementary property of DDF and RPF, and uses two stages to learn a compact yet comprehensive low-dimensional feature space for posture segmentation. In the first stage, discriminative locality alignment (DLA) is applied to the high-dimensional DDF to learn a discriminative low-dimensional representation. In the second stage, canonical correlation analysis (CCA) is used to explore the complementary property of RPF and the dimensionality reduced DDF. Finally, we train a support vector machine (SVM) over the output of CCA. We carefully validate the effectiveness of DLA and CCA utilized in the two-stage scheme on our 3D human points cloud dataset. Experimental results show that the proposed biview learning scheme significantly outperforms the state-of-the-art method for human posture segmentation.     

New head models extracted from thermal infrared (IR) images for dosimetry computations

In electromagnetic dosimetry, anatomical human models are commonly obtained by segmentation of magnetic resonance imaging or computed tomography scans. In this paper, a human head model extracted from thermal infrared images is examined in terms of its applicability to specific absorption rate (SAR) calculations. Since thermal scans are two-dimensional (2D) representation of surface temperature, this allows researchers to overcome the extensive computational demand associated with 3D simulation. The numerical calculations are performed using the finite-difference time-domain method with mesh sizes of 2 mm at 900 MHz plane wave irradiation. The power density of the incident plane wave is assumed to be 10 W/m(2). Computations were compared with a realistic anatomical head model. The results show that although there were marked differences in the local SAR distribution in the various tissues in the two models, the 1 g peak SAR values are approximately similar in the two models.     

Application of a semi-automatic cartilage segmentation method for biomechanical modeling of the knee joint

Manual segmentation of articular cartilage from knee joint 3D magnetic resonance images (MRI) is a time consuming and laborious task. Thus, automatic methods are needed for faster and reproducible segmentations. In the present study, we developed a semi-automatic segmentation method based on radial intensity profiles to generate 3D geometries of knee joint cartilage which were then used in computational biomechanical models of the knee joint. Six healthy volunteers were imaged with a 3T MRI device and their knee cartilages were segmented both manually and semi-automatically. The values of cartilage thicknesses and volumes produced by these two methods were compared. Furthermore, the influences of possible geometrical differences on cartilage stresses and strains in the knee were evaluated with finite element modeling. The semi-automatic segmentation and 3D geometry construction of one knee joint (menisci, femoral and tibial cartilages) was approximately two times faster than with manual segmentation. Differences in cartilage thicknesses, volumes, contact pressures, stresses, and strains between segmentation methods in femoral and tibial cartilage were mostly insignificant (p > 0.05) and random, i.e. there were no systematic differences between the methods. In conclusion, the devised semi-automatic segmentation method is a quick and accurate way to determine cartilage geometries; it may become a valuable tool for biomechanical modeling applications with large patient groups.     

Computer modeling of deployment and mechanical expansion of neurovascular flow diverter in patient-specific intracranial aneurysms

Flow diverter (FD) is an emerging neurovascular device based on self-expandable braided stent for treating intracranial aneurysms. Variability in FD outcome has underscored a need for investigating the hemodynamic effect of fully deployed FD in patient-specific aneurysms. Image-based computational fluid dynamics, which can provide important hemodynamic insight, requires accurate representation of FD in deployed states. We developed a finite element analysis (FEA) based workflow for simulating mechanical deployment of FD in patient-specific aneurysms. We constructed FD models of interlaced wires emulating the Pipeline Embolization Device, using 3D finite beam elements to account for interactions between stent strands, and between the stent and other components. The FEA analysis encompasses all steps that affect the final deployed configuration including stent crimping, delivery and expansion. Besides the stent, modeling also includes key components of the FD delivery system such as microcatheter, pusher, and distal coil. Coordinated maneuver of these components allowed the workflow to mimic clinical operation of FD deployment and to explore clinical strategies. The workflow was applied to two patient-specific aneurysms. Parametric study indicated consistency of the deployment result against different friction conditions, but excessive intra-stent friction should be avoided. This study demonstrates for the first time mechanical modeling of braided FD stent deployment in cerebral vasculature to produce realistic deployed configuration, thus paving the way for accurate CFD analysis of flow diverters for reliable prediction and optimization of treatment outcome.     

Inhibition of ubiquitination and stabilization of human ubiquitin E3 ligase PIRH2 by measles virus phosphoprotein

Using a C-terminal domain (PCT) of the measles virus (MV) phosphoprotein (P protein) as bait in a yeast two-hybrid screen, a cDNA identical to the recently described human p53-induced-RING-H2 (hPIRH2) cDNA was isolated. A glutathione S-transferase-hPIRH2 fusion protein expressed in bacteria was able to pull down P protein when mixed with an extract from P-expressing HeLa cells in vitro, and myc-tagged hPIRH2 could be reciprocally co-immunoprecipitated with MV P protein from human cells. Additionally, immunoprecipitation experiments demonstrated that hPIRH2-myc, MV P, and nucleocapsid (N) proteins form a ternary complex. The hPIRH2 binding site was mapped to the C-terminal X domain region of the P protein by using a yeast two-hybrid assay. The PCT binding site was mapped on hPIRH2 by using a novel yeast two-hybrid tagged PCR approach and by co-immunoprecipitation of hPIRH2 cysteine mutants and mouse/human PIRH2 chimeras. The hPIRH2 C terminus could mediate the interaction with MV P which was favored by the RING-H2 motif. When coexpressed with an enhanced green fluorescent protein-tagged hPIRH2 protein, MV P alone or in a complex with MV N was able to redistribute hPIRH2 to outside the nucleus, within intracellular aggregates. Finally, MV P efficiently stabilized hPIRH2-myc expression and prevented its ubiquitination in vivo but had no effect on the stability or ubiquitination of an alternative ubiquitin E3 ligase, Mdm2. Thus, MV P protein is the first protein from a pathogen that is able to specifically interact with and stabilize the ubiquitin E3 ligase hPIRH2 by preventing its ubiquitination.