Influence of vortical structures on fibrin clot formation in cerebral aneurysms: A two-dimensional computational study.

Thrombosis is an important contributor to cerebral aneurysm growth and progression. A number of sophisticated multiscale and multiphase in silico models have been developed with a view towards interventional planning. Many of these models are able to account for clotting outcomes, but do not provide detailed insight into the role of flow during clot development. In this study, we present idealised, two-dimensional in silico cerebral fibrin clot model based on computational fluid dynamics (CFD), biochemical modelling and variable porosity, permeability, and diffusivity. The model captures fibrin clot growth in cerebral aneurysms over a period at least 1000 s in five different geometries. The fibrin clot growth results were compared to an experiment presented in literature. The biochemistry was found to be more sensitive to mesh size compared to the haemodynamics, while larger timesteps overpredicted clot size in pulsatile flow. When variable diffusivity was used, the predicted clot size was 25.4% lesser than that with constant diffusivity. The predicted clot size in pulsatile flow was 14.6% greater than in plug flow. Different vortex modes were observed in plug and pulsatile flow; the latter presented smaller intermediate modes where the main vortex was smaller and less likely to disrupt the growing fibrin clot. Furthermore, smaller vortex modes were seen to support fibrin clot propagation across geometries. The model clearly demonstrates how the growing fibrin clot alters vortical structures within the aneurysm sac and how this changing flow, in turn, shapes the growing fibrin clot.

Computational Fluid Dynamics (CFD) Model for Analysing the Role of Shear Stress in Angiogenesis in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by an attack on healthy cells in the joints. Blood flow and wall shear stress are crucial in angiogenesis, contributing to RA's pathogenesis. Vascular endothelial growth factor (VEGF) regulates angiogenesis, and shear stress is a surrogate for VEGF in this study. Our objective was to determine how shear stress correlates with the location of new blood vessels and RA progression. To this end, two models were developed using computational fluid dynamics (CFD). The first model added new blood vessels based on shear stress thresholds, while the second model examined the entire blood vessel network. All the geometries were based on a micrograph of RA blood vessels. New blood vessel branches formed in low shear regions (0.840-1.260 Pa). This wall-shear-stress overlap region at the junctions was evident in all the models. The results were verified quantitatively and qualitatively. Our findings point to a relationship between the development of new blood vessels in RA, the magnitude of wall shear stress and the expression of VEGF.

Conceptual Tools to Inform Course Design and Teaching for Ethical Engineering Engagement for Diverse Student Populations.

Contemporary engineering education recognises the need for engineering ethics content in undergraduate programmes to extend beyond concepts that form the basis of professional codes to consider relationality and context of engineering practice. Yet there is debate on how this might be done, and we argue that the design and pedagogy for engineering ethics has to consider what and to whom ethics is taught in a particular context. Our interest is in the possibilities and challenges of pursuing the dual imperatives of socialization and critique. Socialization involves creating opportunities for all, in a diverse cohort of students, to access and engage with the dominant professional engineering ethics knowledge, while critique involves engaging with a range of ways of knowing, valuing, being and using language as relevant in contemporary engineering practice. We identify conceptual tools from engineering ethics and ethical pedagogy in education scholarship for our context. We illustrate how we use these tools systematically to strengthen our reflective practice in a first-year university engineering ethics module to a deeper form of reflexivity. Specifically, we explore the ways in which we attend to the dual imperatives and also highlight opportunities that we miss. We identify as key opportunities design choices such as how we formulated questions and prompts, and how we attended to content, context and language in selecting classroom texts. Other key opportunities were pedagogical choices of when and how to use student contributions in discussion, and what was made explicit in the classroom and assessment. We share our plans to take our learnings forward in our practice and consider the generative possibilities of these learnings and the concepts in other contexts.

PROTEA, A Southern African Multicenter Congenital Heart Disease Registry and Biorepository: Rationale, Design, and Initial Results.

Objectives: The PartneRships in cOngeniTal hEart disease (PROTEA) project aims to establish a densely phenotyped and genotyped Congenital Heart Disease (CHD) cohort for southern Africa. This will facilitate research into the epidemiology and genetic determinants of CHD in the region. This paper introduces the PROTEA project, characterizes its initial cohort, from the Western Cape Province of South Africa, and compares the proportion or "cohort-prevalences" of CHD-subtypes with international findings. Methods: PROTEA is a prospective multicenter CHD registry and biorepository. The initial cohort was recruited from seven hospitals in the Western Cape Province of South Africa from 1 April 2017 to 31 March 2019. All patients with structural CHD were eligible for inclusion. Descriptive data for the preliminary cohort are presented. In addition, cohort-prevalences (i.e., the proportion of patients within the cohort with a specific CHD-subtype) of 26 CHD-subtypes in PROTEA's pediatric cohort were compared with the cohort-prevalences of CHD-subtypes in two global birth-prevalence studies. Results: The study enrolled 1,473 participants over 2 years, median age was 1.9 (IQR 0.4-7.1) years. Predominant subtypes included ventricular septal defect (VSD) (339, 20%), atrial septal defect (ASD) (174, 11%), patent ductus arteriosus (185, 11%), atrioventricular septal defect (AVSD) (124, 7%), and tetralogy of Fallot (121, 7%). VSDs were 1.8 (95% CI, 1.6-2.0) times and ASDs 1.4 (95% CI, 1.2-1.6) times more common in global prevalence estimates than in PROTEA's pediatric cohort. AVSDs were 2.1 (95% CI, 1.7-2.5) times more common in PROTEA and pulmonary stenosis and double outlet right ventricle were also significantly more common compared to global estimates. Median maternal age at delivery was 28 (IQR 23-34) years. Eighty-two percent (347/425) of mothers used no pre-conception supplementation and 42% (105/250) used no first trimester supplements. Conclusions: The cohort-prevalence of certain mild CHD subtypes is lower than for international estimates and the cohort-prevalence of certain severe subtypes is higher. PROTEA is not a prevalence study, and these inconsistencies are unlikely the result of true differences in prevalence. However, these findings may indicate under-diagnosis of mild to moderate CHD and differences in CHD management and outcomes. This reemphasizes the need for robust CHD epidemiological research in the region.

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.

Thrombin-Fibrinogen In Vitro Flow Model of Thrombus Growth in Cerebral Aneurysms.

Cerebral aneurysms are balloon-like structures that develop on weakened areas of cerebral artery walls, with a significant risk of rupture. Thrombi formation is closely associated with cerebral aneurysms and has been observed both before and after intervention, leading to a wide variability of outcomes in patients with the condition. The attempt to manage the outcomes has led to the development of various computational models of cerebral aneurysm thrombosis. In the current study, we developed a simplified thrombin-fibrinogen flow system, based on commercially available purified human-derived plasma proteins, which enables thrombus growth and tracking in an idealized cerebral aneurysm geometry. A three-dimensional printed geometry of an idealized cerebral aneurysm and parent vessel configuration was developed. An unexpected outcome was that this phantom-based flow model allowed us to track clot growth over a period of time, by using optical imaging to record the progression of the growing clot into the flow field. Image processing techniques were subsequently used to extract important quantitative metrics from the imaging dataset, such as end point intracranial thrombus volume. The model clearly demonstrates that clot formation, in cerebral aneurysms, is a complex interplay between mechanics and biochemistry. This system is beneficial for verifying computational models of cerebral aneurysm thrombosis, particularly those focusing on initial angiographic occlusion outcomes, and will also assist manufacturers in optimizing interventional device designs.

The evolving mechanical response of curly hair fibres subject to fatigue testing.

Cyclic testing of human hair reveals important details about the behaviour of fibres over many cycles of loading. Phenomena which are observed under static tensile tests give important clues about the form and behaviour of hair fibres, but these do not necessarily remain constant on the inevitable march to failure. In previous work, we demonstrated that curly fibres exhibited a toe-region during tensile tests. The form of curly fibres could be altered by mechanical manipulation but the curl could be recovered upon immersion in water. In this study, where straight and curly fibres are subject to cyclic loading, this characteristic toe-region was shown to be present in the first cycle of loading (for curly fibres). As the number of cycles increased (and the curly fibres progressively became straighter), the stress-strain response of curly fibres started to resemble that of straight fibres. This observation supports our previous hypothesis, which states that the toe-region can be attributed to the presence of a hydrogen bonding mechanism, which is present in curly fibres only, and can be altered by mechanical force. Interestingly, the alteration in load-bearing pattern in curly fibres did not necessarily translate to increased endurance, demonstrating that the relationship between fatigue and strength is a complex one in hair fibres.

A Patient-Specific CFD Pipeline Using Doppler Echocardiography for Application in Coarctation of the Aorta in a Limited Resource Clinical Context.

Congenital heart disease (CHD) is the most common birth defect globally and coarctation of the aorta (CoA) is one of the commoner CHD conditions, affecting around 1/1800 live births. CoA is considered a CHD of critical severity. Unfortunately, the prognosis for a child born in a low and lower-middle income country (LLMICs) with CoA is far worse than in a high-income country. Reduced diagnostic and interventional capacities of specialists in these regions lead to delayed diagnosis and treatment, which in turn lead to more cases presenting at an advanced stage. Computational fluid dynamics (CFD) is an important tool in this context since it can provide additional diagnostic data in the form of hemodynamic parameters. It also provides an in silico framework, both to test potential procedures and to assess the risk of further complications arising post-repair. Although this concept is already in practice in high income countries, the clinical infrastructure in LLMICs can be sparse, and access to advanced imaging modalities such as phase contrast magnetic resonance imaging (PC-MRI) is limited, if not impossible. In this study, a pipeline was developed in conjunction with clinicians at the Red Cross War Memorial Children's Hospital, Cape Town and was applied to perform a patient-specific CFD study of CoA. The pipeline uses data acquired from CT angiography and Doppler transthoracic echocardiography (both much more clinically available than MRI in LLMICs), while segmentation is conducted via SimVascular and simulation is realized using OpenFOAM. The reduction in cost through use of open-source software and the use of broadly available imaging modalities makes the methodology clinically feasible and repeatable within resource-constrained environments. The project identifies the key role of Doppler echocardiography, despite its disadvantages, as an intrinsic component of the pipeline if it is to be used routinely in LLMICs.

Understanding Curly Hair Mechanics: Fiber Strength.

The relationship between the geometric and mechanical profiles of hair fibers has been studied, with special focus on curly samples. Incidental observations pointed to a significantly different viscoelastic character with varying curliness. Further investigations confirmed initial observations, showing an initial distinct toe region behavior for curly fibers on the stress-strain plot, which is absent for straight fibers. This behavior suggested a difference in the viscoelastic nature of the curly fiber that is linked to mechanical energy stored in the fiber. Results also suggest that the strength of hair depends on two main components, and further pointed out that de facto methods of tensile testing may erode curly fiber strength during preparation. The main outcome of this study is that the tensile strength (σT) of hair fibers is composed of two (rather than one main) components, namely the toe region (σt) and the elastic region (σε), so that: σT=σt+σε. For noncurly fibers, the greatest part of fiber strength is derived from σε, while σt ≈ 0. For curly fibers, σt (i.e., springiness) adds significantly to the overall strength, even though σε remains the major contributor. Although these results require validation in larger studies, they are significant in the current understanding of curly hair. Also, they may represent a fundamental shift from the current understanding of tensile testing of human hair in general.

The what, why and how of curly hair: a review.

An attempt to understand and explain a peculiarity that was observed for curly fibres during experimentation revealed disparate literature reporting on several key issues. The phenotypical nature of curly fibres is only accurately understood within the larger scope of hair fibres, which are highly complex biological structures. A brief literature search produced thousands of research items. Besides the large amount of information on the topic, there was also great variability in research focus. From our review, it appeared that the complexity of hair biology, combined with the variety of research subtopics, often results in uncertainty when relating different aspects of investigation. During the literature investigation, we systematically categorized elements of curly hair research into three basic topics: essentially asking why fibres curl, what the curly fibre looks like and how the curly fibre behaves. These categories were subsequently formalized into a curvature fibre model that is composed of successive but distinctive tiers comprising the elements in curly hair research. The purpose of this paper is twofold: namely to present (i) a literature review that explores the different aspects of curly human scalp hair and (ii) the curvature fibre model as a systemized approach to investigating curly hair.

A Preliminary Computational Investigation Into the Flow of PEG in Rat Myocardial Tissue for Regenerative Therapy.

Myocardial infarction (MI), a type of cardiovascular disease, affects a significant proportion of people around the world. Traditionally, non-communicable chronic diseases were largely associated with aging populations in higher income countries. It is now evident that low- to middle-income countries are also affected and in these settings, younger individuals are at high risk. Currently, interventions for MI prolong the time to heart failure. Regenerative medicine and stem cell therapy have the potential to mitigate the effects of MI and to significantly improve the quality of life for patients. The main drawback with these therapies is that many of the injected cells are lost due to the vigorous motion of the heart. Great effort has been directed toward the development of scaffolds which can be injected alongside stem cells, in an attempt to improve retention and cell engraftment. In some cases, the scaffold alone has been seen to improve heart function. This study focuses on a synthetic polyethylene glycol (PEG) based hydrogel which is injected into the heart to improve left ventricular function following MI. Many studies in literature characterize PEG as a Newtonian fluid within a specified shear rate range, on the macroscale. The aim of the study is to characterize the flow of a 20 kDa PEG on the microscale, where the behavior is likely to deviate from macroscale flow patterns. Micro particle image velocimetry (µPIV) is used to observe flow behavior in microchannels, representing the gaps in myocardial tissue. The fluid exhibits non-Newtonian, shear-thinning behavior at this scale. Idealized two-dimensional computational fluid dynamics (CFD) models of PEG flow in microchannels are then developed and validated using the µPIV study. The validated computational model is applied to a realistic, microscopy-derived myocardial tissue model. From the realistic tissue reconstruction, it is evident that the myocardial flow region plays an important role in the distribution of PEG, and therefore, in the retention of material.

Systems Approach to Human Hair Fibers: Interdependence Between Physical, Mechanical, Biochemical and Geometric Properties of Natural Healthy Hair.

Contextual interpretation of hair fiber data is often blind to the effects of the dynamic complexity between different fiber properties. This intrinsic complexity requires systems thinking to decipher hair fiber accurately. Hair research, studied by various disciplines, follows a reductionist research approach, where elements of interest are studied from a local context with a certain amount of detachment from other elements or contexts. Following a systems approach, the authors are currently developing a cross-disciplinary taxonomy to provide a holistic view of fiber constituents and their interactions within large-scale dynamics. Based on the development process, this paper presents a review that explores the associated features, interrelationships and interactive complexities between physical, mechanical, biochemical and geometric features of natural, healthy hair fibers. Through the review, the importance of an appropriate taxonomy for interpreting hair fiber data across different disciplines is revealed. The review also demonstrates how seemingly unrelated fiber constituents are indeed interdependent and that these interdependencies may affect the behavior of the fiber. Finally, the review highlights how a non-integrative approach may have a negative impact on the reliability of hair data interpretation.

Thrombosis in Cerebral Aneurysms and the Computational Modeling Thereof: A Review.

Thrombosis is a condition closely related to cerebral aneurysms and controlled thrombosis is the main purpose of endovascular embolization treatment. The mechanisms governing thrombus initiation and evolution in cerebral aneurysms have not been fully elucidated and this presents challenges for interventional planning. Significant effort has been directed towards developing computational methods aimed at streamlining the interventional planning process for unruptured cerebral aneurysm treatment. Included in these methods are computational models of thrombus development following endovascular device placement. The main challenge with developing computational models for thrombosis in disease cases is that there exists a wide body of literature that addresses various aspects of the clotting process, but it may not be obvious what information is of direct consequence for what modeling purpose (e.g., for understanding the effect of endovascular therapies). The aim of this review is to present the information so it will be of benefit to the community attempting to model cerebral aneurysm thrombosis for interventional planning purposes, in a simplified yet appropriate manner. The paper begins by explaining current understanding of physiological coagulation and highlights the documented distinctions between the physiological process and cerebral aneurysm thrombosis. Clinical observations of thrombosis following endovascular device placement are then presented. This is followed by a section detailing the demands placed on computational models developed for interventional planning. Finally, existing computational models of thrombosis are presented. This last section begins with description and discussion of physiological computational clotting models, as they are of immense value in understanding how to construct a general computational model of clotting. This is then followed by a review of computational models of clotting in cerebral aneurysms, specifically. Even though some progress has been made towards computational predictions of thrombosis following device placement in cerebral aneurysms, many gaps still remain. Answering the key questions will require the combined efforts of the clinical, experimental and computational communities.