Gastroschisis, a congenital abdominal wall defect located to the right of the intact umbilical cord (UC), results in the herniation of fetal abdominal organs into the amniotic cavity without a protective membrane covering these structures. Complex gastroschisis (CG), comprising approximately 10% of cases, is associated with significantly higher morbidity and mortality rates compared to simple gastroschisis. Fetoscopic repair of CG offers the potential to improve gastrointestinal health at birth, but thus far, no procedure has been successfully demonstrated as safe and feasible. Therefore, the goal of this graduation project was to provide a proof of principle for a novel dedicated method that enables the swift closure of the abdominal wall defect during a fetoscopic repair procedure for CG.

The development of this method began with an analysis of the clinical context, including the characteristics of the abdominal wall defect, the adjacent umbilical cord and vessels, and the fetoscopic surgical setup, which provided a clear design direction. After generating various concept solutions, the key concept — a silicone ring with membrane — was selected using the Harris Profile methodology. This concept was designed for insertion into the fetal abdominal cavity, with the membrane effectively covering the opening of the defect.

Eight configurations of the silicone ring with a membrane were then prototyped through injection molding of liquid silicone rubber in a 3D-printed mold. The rings varied in shape (round or rusk), diam- eter (20 mm and 30 mm), and stiffness (shore hardness A25 and A40). Additionally, a validation model simulating a 24-week-old fetus with CG was developed with input from medical experts.

The validation experiments demonstrated that the silicone ring with a membrane securely remained in place, effectively closing the abdominal wall defect under intra-abdominal pressure conditions ranging from 0 to 40 mmHg. These experiments, conducted using the validation model, simulated conditions during and immediately after fetal intervention in a 24-week-old fetus with CG following intestinal repositioning. These experiments provided proof of principle for the silicone ring with membrane as a novel method that enables the swift closure of the abdominal wall defect in CG during a fetoscopic repair procedure. Notably, round-shaped rings were favored, and larger diameters allowed for coverage of larger defects. However, it’s noteworthy that the 20 mm round ring effectively covered an oval-shaped defect measuring 13.5 × 12.7 mm, aligning with the reported mean defect size in CG. Furthermore, the experiments demonstrated the feasibility of introducing the rings through a 12 Fr (20 mm rings) or 14 Fr (30 mm rings) surgical port, aligning with the preferred surgical setup.

Future research is required to clinically investigate the defect diameter in CG and optimize the silicone ring with membrane’s design. Additionally, enhancing the validation model to serve dual purposes as both a validation and training model will facilitate user tests. Moreover, developing an instrument for introducing the ring into the uterus and refining the surgical technique for precise ring positioning will be essential steps toward the clinical application of this innovative approach.

Stroke, currently ranked as the second leading cause of mortality and the most prevalent source of enduring disability, imposes significant societal and economic consequences. These consequences encompass the necessity for extended care, rehabilitation, and the economic burdens associated with lost productivity. In the diagnostic process, physicians typically employ imaging techniques to assess cerebral blood vessels, ruling out alternative conditions when stroke is suspected. Subsequent to di agnosis, treatments like Intravenous Thrombolysis (IVT) and Endovascular Thrombectomy (EVT) are administered to either dissolve or retrieve thrombi. However, with EVT emerging as the new standard of stroke care and an increasing body of evidence indicating the substantial impact of thrombus me chanical properties on thrombectomy success, the use of clot analogues is gaining prominence as a means of facilitating efficient mechanical testing, both in terms of time and finances. By establishing a link between mechanical properties and image characteristic parameters, medical practitioners gain a better understanding of intracranial thrombi before embarking on surgical procedures. This knowledge can serve as a theoretical foundation for optimizing surgical instruments and devising effective surgical protocols in the future. In pursuit of these objectives, this study involved 29 patients and entailed several key steps: firstly, the extraction of imaging parameters from pre-EVT CT images; secondly, the creation of thrombus analogues from the patient’s blood; thirdly, the execution of five distinct mechanical tests to derive me chanical properties, encompassing cyclic compression, compression relaxation, tensile test to failure, tensile relaxation, and fracture testing. Additionally, the hyperelastic Yeoh model was utilized to simu late the behavior observed from cyclic compression and tensile to failure test. Prony series (n=2) was fitted to stress relaxation curves. In summary, this investigation revealed noteworthy observations pertaining to mechanical proper ties. Notably, hysteresis areas demonstrated robust and statistically significant correlations with com pression high-strain stiffness, low-strain stiffness, and tensile stiffness along with the ultimate tensile stress, implying that the thrombus analogue exhibits both hyperelastic and viscoelastic characteristics. In the domain of imaging parameters, the evident interdependence among the densities of the three regions of interest within both CTA and NCCT is apparent, respectively. However, it is essential to un derscore that the relationship between CTA and NCCT was not deemed statistically significant. Lastly, a noteworthy revelation was the strong negative monotonic correlation (ρ=-0.82, P=0.011) observed between the analogue contraction ratio of the thrombus analogue and the density of the middle part of NCCT in actual thrombi. This insight suggests that, in addition to thrombus composition, microstructure plays a pivotal role as well in determining their properties.

Critically ill patients in the Intensive Care Unit (ICU) are often comatose and thoroughly monitored. Neurological complications occur in up to 20% of these patients. Therefore, monitoring of the brain, which can be performed using electroencephalography (EEG), has the potential to significantly impact the outcomes of patients at the ICU. Despite the potential of EEG as a noninvasive method for monitoring the neurological status of critically ill patients, the labor-intensive and complex nature of its application and assessment has hindered widespread implementation. Therefore, the aim of this thesis was to identify the logistical and technical prerequisites for efficient and effective neuromonitoring using EEG in the ICU.

Chapter 1 provides an overview of neuromonitoring techniques in the critically ill patient. It delves into the neurophysiological background of the EEG, the techniques used for applying the EEG electrodes, and the EEG assessment.

In Chapter 2 we present a qualitative study on the optimal conditions for EEG monitoring in the ICU. Through 12 individual and 2 focus group interviews with employees from different departments within and outside of the hospital, the current workflow regarding neuromonitoring in the ICU is identified. Additionally, we evaluate the barriers and facilitators for change in this monitoring process through the Consolidated Framework for Implementation Research (CFIR). Factors such as motivation and willingness to change serve as facilitators, while a lack of interdepartmental communication and the high workload for various healthcare professionals involved can be significant barriers.

The qualitative research reveals that the largest group monitored using EEG in the ICU consists of patients suffering from postanoxic encephalopathy, which can be a complication of a cardiac arrest. Therefore, in Chapter 3, we examine the technical requirements for optimal EEG monitoring. Specifically, we focus on the necessary number of EEG electrodes for reliable automatic classification of the EEG background pattern in postanoxic encephalopathy. By training an Random Forest (RF) classifier with input from 12, 10, 8, 6, and 4 EEG electrodes, we develop a model with a micro-averaged One-vs-Rest (OvR) Area Under the Curve - Receiver Operating Characteristics (AUC-ROC) value of 0.923, 0.924, 0.924, 0.925, and 0.923 (p-value: 0.279) for the different numbers of electrodes respectively. The constant performance of the model suggests that a reduced number of electrodes may be sufficient for monitoring this patient group, potentially reducing the workload for EEG technicians. Automatic assessment of the EEG can also contribute to a decreased workload for clinical neurophysiologists.

In Chapter 4 we provide the conclusions and future perspectives of this thesis. We have demonstrated the potential for change in the EEG monitoring workflow at the ICU of the Erasmus MC, indicating that there is an opportunity to work towards more effective and efficient neuromonitoring. Future research should focus on a broader range of logistical and technical prerequisites - including effective interdepartmental collaboration and which EEG equipment to use - thereby creating opportunities to improve treatment and outcomes of critically ill patients.

Stroke, caused by large vessel occlusions, is the second leading cause of death worldwide. Large vessel occlusions are the result of thrombosis, the undesired coagulation of blood within the vasculature. Due to this coagulation, a vessel can get blocked, prohibiting blood flow to areas distal from the occlusion, with all the serious consequences that may ensue. Since 2015, mechanical thrombectomy procedures have been widely accepted as a successful treatment technique to remove thrombi from the vasculature. However, complete reperfusion is only reached in 50% of acute ischemic stroke cases.

To successfully remove a thrombus from the vasculature, it is necessary to apply a specific retrieval force. This force must exceed the opposing forces, including the impaction force generated by the blood pressure gradient across the thrombus and the interaction forces between the thrombus and the vessel wall. Multiple studies have focused on tensile and compressive properties of thrombi. However, little is known about shear loading of the thrombus and about the interaction properties of the thrombus-vessel wall interface. Therefore, the aim of this study is to gain a better comprehension of thrombus biomechanics by studying the shear behavior of thrombi and the interaction of the thrombus-vessel wall interface in vitro.

In order to perform these in vitro studies, two custom-made test setups have been designed and developed. The friction test setup contains a plate of which the angle can be inclined slowly. By placing a thrombus-vessel wall sample on top of this plate, it is aimed to determine the static and kinetic coefficient of friction of the thrombus-vessel wall interface. Furthermore, it is aimed to determine the effect of time on this interaction. The thrombus-vessel wall interface was created by obtaining a piece of vein and blood from pigs. To study the shear behavior of thrombi a shear test setup has been developed. Two thrombi types have been utilized for this study, red blood cell- and fibrin-rich. Within the shear test setup it is possible to perform shear experiments under different normal loading conditions. A comprehensive analysis of the data acquired from experiments performed with both test setups has been conducted. Furthermore, a computational model has been developed to fit towards the experimental data obtained from the shear experiments.

The friction experiments suggest that time positively influences the bonds formed between a thrombus and the vessel wall as the coefficients of friction increase with an increased waiting time. Furthermore, a strong positive correlation was found between the static and kinetic coefficient of friction. This result was also found when doing an extensive analysis of the data obtained from the shear experiments. Additionally, the shear experiment showed that the thrombus composition influences its mechanical properties. Higher shear moduli and kinetic coefficients of friction were found for the fibrin samples, compared to the red blood cell samples.

The results obtained from the friction and shear experiments provide valuable insights into thrombus biomechanics. By extending the performed studies a better comprehension on thrombus mechanics and the thrombus-vessel wall interaction can be achieved.

Mechanical thrombectomy (MT) treatment of acute ischemic stroke (AIS) patients typically involves use of stent retrievers or aspiration catheters alone or in combination. For in silico trials of AIS patients, it is crucial to incorporate the possibility of thrombus fragmentation during the intervention. This study focuses on two aspects of the thrombectomy simulation: i) Thrombus fragmentation on the basis of a failure model calibrated with experimental tests on clot analogs; ii) the combined stent-retriever and aspiration catheter MT procedure is modeled by adding both the proximal balloon guide catheter and the distal access catheter. The adopted failure criterion is based on maximum principal stress threshold value. If elements of the thrombus exceed this criterion during the retrieval simulation, then they are deleted from the calculation. Comparison with in-vitro tests indicates that the simulation correctly reproduces the procedures predicting thrombus fragmentation in the case of red blood cells rich thrombi, whereas non-fragmentation is predicted for fibrin-rich thrombi. Modeling of balloon guide catheter prevents clot fragments' embolization to further distal territories during MT procedure.

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Atherosclerotic plaque rupture is the underlying cause of 50% of deaths in western society. Although screening methodologies exist, plaques are highly complex, and the parameters used to measure plaque vulnerability are often insufficient for correct medical screening. Since plaque rupture occurs when the vascular forces exceed the plaque strength, the mechanical analysis of plaque stability could offer a new window into predicting rupture. By interpreting the mechanical behaviour of plaques, so-called mechanical markers could be derived, which could highlight vulnerable plaques before thrombosis. Unfortunately, the extensively modelled local stresses and energy functions are immeasurable in vivo. Therefore we turned to strains, a measure of material deformation that can be obtained clinically. This study investigates the predictive value of strain distributions in the early detection of fibrous caps rupture.
Simplistic plaque cap mimics were engineered to model atherosclerotic plaque rupture. Made from a fibrinous matrix and a soft lipidic inclusion (SI), the constructs were tailored to have mechanical properties similar to in vivo plaque caps. Tissue engineered caps offer a wide range of advantages over endarterectomy samples, including unlimited sample availability, robust geometry, high reproducibility and precise control over biological constituents. These constructs were uniaxially strained and subjected to 2D digital image correlation (DIC) to obtain their strain fields. Two-dimensional DIC is an algorithm that derives the material deformation by tracking surface features of its target sample. Therefore, it can very accurately calculate local strains for a material. This report analyses the patterns and maxima of the strain maps of five samples to evaluate unique features distinct at the rupture location that could serve as potential markers of plaque vulnerability. Besides inspecting the individual strain maps, their collective contribution through two strain-based failure criteria was analysed. These failure criteria approximate the strain energy in the samples.
The mechanical failure of the constructs was not instantaneous. All samples underwent failure in phases, starting with a small crack in the SI and concluding with the rupture of the fibrous tissue. Likewise, the strain and failure criteria patterns were consistent within all samples. Even though their strain values differ, the accumulations of low and high strains lie at nearly identical positions. These patterns emerged early in the tensile experiment, as the frames at a physiological (10%) and final (ultimate state before rupture) global strain measured a strong resemblance. In a more localised analysis, the fields were radially divided into ‘slices’ of data to produce distinct segment-based patterns. The rupture location consistently lies at a unique feature in the pattern, such as a peak or a valley. As was observed before, aside from the difference in their magnitude, the strain patterns showed no change between the frames. Finally, the local maxima of the strain and failure criteria maps were inspected. Their distances to the rupture site were comparable for all maps, indicating they performed similarly at estimating the rupture location. Moreover, the distances measured for the final frame showed no significant difference to those measured for the physiological frame.
The mechanical response of the five samples is similar. Aside from undergoing mechanical rupture in stages, the analysis of the tissue construct shows that a relationship exists between the local strains and rupture location. First, the rupture location always sits at the edge of a high valued region in the SI. Second, the tissue segmentation produces a highly reproducible pattern with a distinct colocalisation between segment patterns and the rupture location. Third, the maxima of the strain and failure criteria maps lie close to the rupture site, although they do not overlap. Accordingly, there is a clear relationship between the rupture location and the
local strain patterns.

Purpose: Atherosclerotic plaque development and progression signifies a complex inflammatory disease mediated by a multitude of proinflammatory leukocyte subsets. Using single photon emission computed tomography (SPECT) coupled with computed tomography (CT), this study tested a new dual-isotope acquisition protocol to assess each radiotracer’s capability to identify plaque phenotype and inflammation levels pertaining to leukocytes expressing leukocyte function-associated antigen-1 (LFA-1) and the leukocyte subset of proinflammatory macrophages expressing somatostatin receptor subtype-2 (SST₂). Individual radiotracer uptake was quantified and the presence of corresponding immunohistological cell markers was assessed. Methods: Human symptomatic carotid plaque segments were obtained from endarterectomy. Segments were incubated in dual-isotope radiotracers [¹¹¹In]In-DOTA-butylamino-NorBIRT ([¹¹¹In]In-Danbirt) and [^99mTc]Tc-[N^0–1 ₄,Asp⁰,Tyr³]-octreotate ([^99mTc]Tc-Demotate 2) before scanning with SPECT/CT. Plaque phenotype was classified as pathological intimal thickening, fibrous cap atheroma or fibrocalcific using histology sections based on distinct morphological characteristics. Plaque segments were subsequently immuno-stained with LFA-1 and SST₂ and quantified in terms of positive area fraction and compared against the corresponding SPECT images. Results: Focal uptake of co-localising dual-radiotracers identified the heterogeneous distribution of inflamed regions in the plaques which co-localised with positive immuno-stained regions of LFA-1 and SST₂. [¹¹¹In]In-Danbirt and [^99mTc]Tc-Demotate 2 uptake demonstrated a significant positive correlation (r = 0.651; p = 0.001). Fibrous cap atheroma plaque phenotype correlated with the highest [¹¹¹In]In-Danbirt and [^99mTc]Tc-Demotate 2 uptake compared with fibrocalcific plaques and pathological intimal thickening phenotypes, in line with the immunohistological analyses. Conclusion: A dual-isotope acquisition protocol permits the imaging of multiple leukocyte subsets and the pro-inflammatory macrophages simultaneously in atherosclerotic plaque tissue. [¹¹¹In]In-Danbirt may have added value for assessing the total inflammation levels in atherosclerotic plaques in addition to classifying plaque phenotype.

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Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term 'vulnerable plaque' was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of 'vulnerability' of a specific lesion to the more comprehensive goal of identifying patient 'cardiovascular vulnerability'. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and 'local' diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of 'high-risk' plaques occurring in 'vulnerable' patients.

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Left ventricular flow is intrinsically complex, three-dimensional and unsteady. Its features are susceptible to cardiovascular pathology and treatment, in particular to surgical interventions involving the valves (mitral valve replacement). To improve our understanding of intraventricular fluid mechanics and the impact of various types of prosthetic valves thereon, we have developed a custom-designed versatile left ventricular phantom with anatomically realistic moving left ventricular membrane. A biological, a tilting disc and a bileaflet valve (in two different orientations) were mounted in the mitral position and tested under the same settings. To investigate 3D flow within the phantom, a four-view tomographic particle image velocimetry setup has been implemented. The results compare side-by-side the evolution of the 3D flow topology, vortical structures and kinetic energy in the left ventricle domain during the cardiac cycle. Except for the tilting disc valve, all tested prosthetic valves induced a crossed flow path, where the outflow crosses the inflow path, passing under the mitral valve. The biological valve shows a strong jet with a peak velocity about twice as high compared to all mechanical heart valves, which makes it easier to penetrate deeply into the cavity. Accordingly, the peak kinetic energy in the left ventricle in case of the biological valve is about four times higher than the mechanical heart valves. We conclude that the tomographic particle imaging velocimetry setup provides a useful ground truth measurement of flow features and allows a comparison of the effects of different valve types on left ventricular flow patterns.

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Purpose: Quantitative and automatic analysis of intracoronary optical coherence tomography images is useful and time-saving to assess cardiovascular risk in the clinical arena. Methods: First, the interfaces of the intima, media, and adventitia layers are segmented, by means of an original front propagation scheme, running in a 4D multi-parametric space, to simultaneously extract three non-crossing contours in the initial cross-sectional image. Second, information resulting from the tentative contours is exploited by a machine learning approach to identify healthy and diseased regions of the arterial wall. The framework is fully automatic. Results: The method was applied to 40 patients from two different medical centers. The framework was trained on 140 images and validated on 260 other images. For the contour segmentation method, the average segmentation errors were 29±46μm for the intima–media interface, 30±50μm for the media–adventitia interface, and 50±64μm for the adventitia–periadventitia interface. The classification method demonstrated a good accuracy, with a median Dice coefficient equal to 0.93 and an interquartile range of (0.78–0.98). Conclusion: The proposed framework demonstrated promising offline performances and could potentially be translated into a reliable tool for various clinical applications, such as quantification of tissue layer thickness and global summarization of healthy regions in entire pullbacks.

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Purpose: Identification of rupture-prone plaques in coronary arteries is a major clinical challenge. Fibrous cap thickness and wall shear stress are two relevant image-based risk factors, but these two parameters are generally computed and analyzed separately. Accordingly, combining these two parameters can potentially improve the identification of at-risk regions. Therefore, the purpose of this study is to investigate the feasibility of the fusion of wall shear stress and fibrous cap thickness of coronary arteries in patient data. Methods: Fourteen patients were included in this pilot study. Imaging of the coronary arteries was performed with optical coherence tomography and with angiography. Fibrous cap thickness was automatically quantified from optical coherence tomography pullbacks using a contour segmentation approach based on fast marching. Wall shear stress was computed by applying computational fluid dynamics on the 3D volume reconstructed from two angiograms. The two parameters then were co-registered using anatomical landmarks such as side branches. Results: The two image modalities were successfully co-registered, with a mean (±SD) error corresponding to 8.6±6.7% of the length of the analyzed region. For all the analyzed participants, the average thinnest portion of each fibrous cap was 129±69μm, and the average WSS value at the location of the fibrous cap was 1.46±1.16Pa. A unique index was finally generated for each patient via the fusion of fibrous cap thickness and wall shear stress measurements, to translate all the measured parameters into a single risk map. Conclusion: The introduced risk map integrates two complementary parameters and has potential to provide valuable information about plaque vulnerability.@en