Prediction of bird-beak configuration in thoracic endovascular aortic repair preoperatively using patient-specific finite element simulations.

Objectives: Formation of bird-beak configuration in thoracic endovascular aortic repair (TEVAR) has been shown to be correlated with the risk of complications such as type Ia endoleaks, stent graft migration, and collapse. The aim of this study was to use patient-specific computational simulations of TEVAR to predict the formation of bird-beak configuration preoperatively. Methods: Patient-specific TEVAR computational simulations are developed using a retrospective cohort of patients treated for thoracic aortic aneurysm. The preoperative computed tomography images were segmented to develop three-dimensional geometry of the thoracic aorta. These geometries were used in finite element simulations of stent graft deployment during TEVAR. Simulated results were compared against the postoperative computed tomography images to assess the accuracy of simulations in predicting the proximal position of a deployed stent graft and presence of bird-beak. In cases with a bird-beak configuration, the length and angle of the bird-beak were measured and compared between the simulated and postoperative results. Results: Twelve TEVAR patient cases were simulated. Computational simulations were able to accurately predict whether the proximal stent graft was fully apposed, proximal bare stents were protruded, or bird-beak configuration was present. In three cases with bird-beak configuration, simulations predicted the length and angle of the bird-beak with less than 10% and 24% error, respectively. Other factors such as a small aortic arch angle, small oversizing value, and landing zones close to the arch apex may have played a role in formation of bird-beak in these patients. Conclusions: Computational simulations of TEVAR accurately predicted the proximal position of a deployed stent graft and the presence of bird-beak preoperatively. The computational models were able to predict the length and angle of bird-beak configurations with good accuracy. These simulations can provide insight into the surgical planning process with the goal of minimizing bird-beak occurrence.

A Comparison of Vessel Patch Materials in Tetralogy of Fallot Patients Using Virtual Surgery Techniques.

Tetralogy of Fallot (ToF) is characterized by stenosis causing partial obstruction of the right ventricular outflow tract, typically alleviated through the surgical application of a vessel patch made from a biocompatible material. In this study, we use computational simulations to compare the mechanical performance of four patch materials for various stenosis locations. Nine idealized pre-operative ToF geometries were created by imposing symmetrical stenoses on each of three anatomical sub-regions of the pulmonary arteries of three patients with previously repaired ToF. A virtual surgery methodology was implemented to replicate the steps of vessel de-pressurization, surgical patching, and subsequent vessel expansion after reperfusion. Significant differences in patch average stress (p < 0.001) were found between patch materials. Biological patch materials (porcine xenopericardium, human pericardium) exhibited higher patch stresses in comparison to synthetic patch materials (Dacron and PTFE). Observed differences were consistent across the various stenosis locations and were insensitive to patient anatomy.

Identification of geometric and mechanical factors predictive of bird-beak configuration in thoracic endovascular aortic repair using computational models of stent graft deployment.

Objective: Formation of a bird-beak configuration in thoracic endovascular aortic repair (TEVAR) has been shown to be influenced by various factors. However, the main cause of bird-beak formation remains poorly understood. The hypothesis has been that the geometric and mechanical properties of both the aorta and the stent graft contribute to the formation and extent of a bird-beak configuration. The goal of the present study was to use parameter-based computational simulations of TEVAR to predict for bird-beak formation and identify its most significant contributing factors. Methods: In the present study, we considered five parameters for the computational simulations of TEVAR, including aortic curvature, aortic arch angle, age as a surrogate for thoracic aortic tissue properties, TEVAR landing zone, and stent graft oversizing. Using an experimental design approach, computational models for 160 TEVAR scenarios were developed by varying the values of the simulation parameters within clinically relevant ranges. The bird-beak length and angle were used as metrics to evaluate the simulation results. Statistical analysis of the simulation data using a random forest model was conducted to identify significant parameters and interactions. Results: The mean ± standard deviation of the bird-beak length and angle across 160 simulations were 4.32 ± 4.87 mm and 9.16° ± 12.21°, respectively. The largest mean bird-beak length and angle were found in the most distal location in zone 0 (10.04 mm) and zone 2 (21.48°), respectively. An inverse correlation was found between the aortic arch angle and the bird-beak length and angle. In ∼75% of the scenarios, increased stent graft oversizing either fully resolved the presence of the bird-beak configuration or had reduced its size. In the remaining 25%, oversizing minimally changed the bird-beak length and enlarged the bird-beak angle, which mainly occurred in cases with a smaller aortic arch angle and landing zones near the arch apex. This was justified by the mechanism of stent graft bending in the arch angulation. The aortic curvature and tissue properties were shown to be statistically insignificant in relation to bird-beak formation. Conclusions: Significant parameters predictive of a bird-beak configuration in TEVAR were identified, and the trends in which each parameter influenced the bird-beak size were determined. The findings from the present study can inform the surgical planning and device selection process with the goal of minimizing bird-beak formation.

Subject-Specific Alignment and Mass Distribution in Musculoskeletal Models of the Lumbar Spine.

Musculoskeletal modeling is a well-established method in spine biomechanics and generally employed for investigations concerning both the healthy and the pathological spine. It commonly involves inverse kinematics and optimization of muscle activity and provides detailed insight into joint loading. The aim of the present work was to develop and validate a procedure for the automatized generation of semi-subject-specific multi-rigid body models with an articulated lumbar spine. Individualization of the models was achieved with a novel approach incorporating information from annotated EOS images. The size and alignment of bony structures, as well as specific body weight distribution along the spine segments, were accurately reproduced in the 3D models. To ensure the pipeline's robustness, models based on 145 EOS images of subjects with various weight distributions and spinopelvic parameters were generated. For validation, we performed kinematics-dependent and segment-dependent comparisons of the average joint loads obtained for our cohort with the outcome of various published in vivo and in situ studies. Overall, our results agreed well with literature data. The here described method is a promising tool for studying a variety of clinical questions, ranging from the evaluation of the effects of alignment variation on joint loading to the assessment of possible pathomechanisms involved in adjacent segment disease.

Vessel network extraction and analysis of mouse pulmonary vasculature via X-ray micro-computed tomographic imaging.

In this work, non-invasive high-spatial resolution three-dimensional (3D) X-ray micro-computed tomography (µCT) of healthy mouse lung vasculature is performed. Methodologies are presented for filtering, segmenting, and skeletonizing the collected 3D images. Novel methods for the removal of spurious branch artefacts from the skeletonized 3D image are introduced, and these novel methods involve a combination of distance transform gradients, diameter-length ratios, and the fast marching method (FMM). These new techniques of spurious branch removal result in the consistent removal of spurious branches without compromising the connectivity of the pulmonary circuit. Analysis of the filtered, skeletonized, and segmented 3D images is performed using a newly developed Vessel Network Extraction algorithm to fully characterize the morphology of the mouse pulmonary circuit. The removal of spurious branches from the skeletonized image results in an accurate representation of the pulmonary circuit with significantly less variability in vessel diameter and vessel length in each generation. The branching morphology of a full pulmonary circuit is characterized by the mean diameter per generation and number of vessels per generation. The methods presented in this paper lead to a significant improvement in the characterization of 3D vasculature imaging, allow for automatic separation of arteries and veins, and for the characterization of generations containing capillaries and intrapulmonary arteriovenous anastomoses (IPAVA).

Computational fluid dynamics for enhanced tracheal bioreactor design and long-segment graft recellularization.

Successful re-epithelialization of de-epithelialized tracheal scaffolds remains a challenge for tracheal graft success. Currently, the lack of understanding of the bioreactor hydrodynamic environment, and its relation to cell seeding outcomes, serve as major obstacles to obtaining viable tracheal grafts. In this work, we used computational fluid dynamics to (a) re-design the fluid delivery system of a trachea bioreactor to promote a spatially uniform hydrodynamic environment, and (b) improve the perfusion cell seeding protocol to promote homogeneous cell deposition. Lagrangian particle-tracking simulations showed that low rates of rotation provide more uniform circumferential and longitudinal patterns of cell deposition, while higher rates of rotation only improve circumferential uniformity but bias cell deposition proximally. Validation experiments with human bronchial epithelial cells confirm that the model accurately predicts cell deposition in low shear stress environments. We used the acquired knowledge from our particle tracking model, as a guide for long-term tracheal repopulation studies. Cell repopulation using conditions resulting in low wall shear stress enabled enhanced re-epithelialization of long segment tracheal grafts. While our work focuses on tracheal regeneration, lessons learned in this study, can be applied to culturing of any tissue engineered tubular scaffold.

Optimization of porous stents for endovascular repair of abdominal aortic aneurysms.

This study presents a simulation-based methodology to design porous stents to induce suitable hemodynamic environments inside abdominal aortic aneurysm (AAA) sacs. In the proposed methodology, an optimization algorithm iteratively modifies the porosity distribution of the stent and executes a computational fluid dynamics (CFD) simulation to determine the effect of these changes on the hemodynamic conditions inside the aneurysm sac. The optimization iterations proceed until relevant hemodynamic parameters are within ranges prescribed a priori by the user as desirable to control the progression of the AAA. The resulting porosity distribution uniquely describes the porous stent design that can control the hemodynamic environment (eg, shear stress at the aneurysm wall, pressure distribution, residence time), reducing AAA rupture risks and improving treatment efficacy. To demonstrate its potential, the proposed methodology is applied to idealized AAA geometry under steady-state flow conditions, though it may be easily applied to more complex AAA geometries under transient, pulsatile flow conditions. The proposed methodology has the potential to enable the design of a new generation of porous stents tailored to patient-specific geometries and flow conditions, to improve patient outcomes.

Combinatorial screening of 3D biomaterial properties that promote myofibrogenesis for mesenchymal stromal cell-based heart valve tissue engineering.

The physical and chemical properties of a biomaterial integrate with soluble cues in the cell microenvironment to direct cell fate and function. Predictable biomaterial-based control of integrated cell responses has been investigated with two-dimensional (2D) screening platforms, but integrated responses in 3D have largely not been explored systematically. To address this need, we developed a screening platform using polyethylene glycol norbornene (PEG-NB) as a model biomaterial with which the polymer wt% (to control elastic modulus) and adhesion peptide types (RGD, DGEA, YIGSR) and densities could be controlled independently and combinatorially in arrays of 3D hydrogels. We applied this platform and regression modeling to identify combinations of biomaterial and soluble biochemical (TGF-ß1) factors that best promoted myofibrogenesis of human mesenchymal stromal cells (hMSCs) in order to inform our understanding of regenerative processes for heart valve tissue engineering. In contrast to 2D culture, our screens revealed that soft hydrogels (low PEG-NB wt%) best promoted spread myofibroblastic cells that expressed high levels of α-smooth muscle actin (α-SMA) and collagen type I. High concentrations of RGD enhanced α-SMA expression in the presence of TGF-ß1 and cell spreading regardless of whether TGF-ß1 was in the culture medium. Strikingly, combinations of peptides that maximized collagen expression depended on the presence or absence of TGF-ß1, indicating that biomaterial properties can modulate MSC response to soluble signals. This combination of a 3D biomaterial array screening platform with statistical modeling is broadly applicable to systematically identify combinations of biomaterial and microenvironmental conditions that optimally guide cell responses. STATEMENT OF SIGNIFICANCE: We present a novel screening platform and methodology to model and identify how combinations of biomaterial and microenvironmental conditions guide cell phenotypes in 3D. Our approach to systematically identify complex relationships between microenvironmental cues and cell responses enables greater predictive power over cell fate in conditions with interacting material design factors. We demonstrate that this approach not only predicts that mesenchymal stromal cell (MSC) myofibrogenesis is promoted by soft, porous 3D biomaterials, but also generated new insights which demonstrate how biomaterial properties can differentially modulate MSC response to soluble signals. An additional benefit of the process includes utilizing both parametric and non parametric analyses which can demonstrate dominant significant trends as well as subtle interactions between biochemical and biomaterial cues.

A comparison of key aspects of gene regulation in Streptomyces coelicolor and Escherichia coli using nucleotide-resolution transcription maps produced in parallel by global and differential RNA sequencing.

Streptomyces coelicolor is a model for studying bacteria renowned as the foremost source of natural products used clinically. Post-genomic studies have revealed complex patterns of gene expression and links to growth, morphological development and individual genes. However, the underlying regulation remains largely obscure, but undoubtedly involves steps after transcription initiation. Here we identify sites involved in RNA processing and degradation as well as transcription within a nucleotide-resolution map of the transcriptional landscape. This was achieved by combining RNA-sequencing approaches suited to the analysis of GC-rich organisms. Escherichia coli was analysed in parallel to validate the methodology and allow comparison. Previously, sites of RNA processing and degradation had not been mapped on a transcriptome-wide scale for E. coli. Through examples, we show the value of our approach and data sets. This includes the identification of new layers of transcriptional complexity associated with several key regulators of secondary metabolism and morphological development in S. coelicolor and the identification of host-encoded leaderless mRNA and rRNA processing associated with the generation of specialized ribosomes in E. coli. New regulatory small RNAs were identified for both organisms. Overall the results illustrate the diversity in mechanisms used by different bacterial groups to facilitate and regulate gene expression.