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.

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.

Organ-on-chips (OoCs) are micro-fabricated cell culture platforms that mimic the function and structure of human organs. Limitations arose in the use of OoCs when they lacked sensing abilities and real-time monitoring. Throughout this thesis, an attempt is being made to address these complications by developing an extit{in situ} glucose sensor for OoCs in collaboration with Bi/ond. The foundation of this proof-of-concept is an etalon, consisting of two reflective layers separated by a dielectric layer that allows light to enter and resonate between the reflective layers. The dielectric layer for this purpose will be microgels, with particular emphasis on the biomedical potential of the thermoresponsive polymer poly-(N-isopropylacrylamide) (pNIPAAm). This sensor was developed on silicon and PDMS substrate using evaporation of Cr/Au, spin-coating pNIPAAm-co-10%-AAc and pNIPAAm-co-10%, and mid or post process modification with APBA. Plasma treatment was employed to create a monolithic layer, resulting in a successfully completed fabrication process verified through SEM. Reflectance spectroscopy confirmed the functionality and response, along with an effective generation of a calibration curve for glucose for both substrates and modification processes. The post process approach emerged as more preferable while exhibiting resilience to sterilization procedures that even improved its response to glucose due to removal of unbound APBA during sterilization. Post process samples were used to detect changes in glucose levels in cell medium that had been in contact with C2C12 mouse myoblast cells over 1-, 3-, and 7-day periods. The results showed that the concentration of glucose declined approximately 16 mg/dL after day 1, 130 mg/dL after day 3 and 227 mg/dL after day 7, in comparison to the control measurement. Additionally, there was optical confirmation of the non-toxic effects of the microgel-beads on cell culturing. The investigation of this proof-of-concept of glucose responsive microgel-based etalons was successful, and the next stage would involve integrating this sensor into a chip of Bi/ond.

Congenital heart disease (CHD) affects almost 1% of newborns. Right ventricular outflow tract (RVOT) CHD affects 20% of newborns and includes anomalies such as tetralogy of Fallot (TOF) with or without pulmonary atresia, transposition of the great vessels, and truncus arteriosus. All these anomalies require RVOT reconstruction. Prosthetic heart valves are needed to improve the quality of life of patients suffering from CHD. One such prosthetic device is the pulmonary valved Conduit developed by XeltisTM. This study aimed to investigate the difference in the mechanical response of the XeltisTM pulmonary valved Conduit sizes 16, 18, and 20 (XPV16, XPV18, and XPV20) using mechanical experiments and a predictive finite element model. Experiments of two load cases, Leaflet opening behavior (LC1) and parallel compression (LC2) have been done where measurements were taken for input parameters used for uncertainty quantification (UQ) in the FE model. Furthermore, the reaction force and displacement were measured to calculate the force values and stiffness values of the device during each experiment. The experiments were replicated with a developed FE model. From the results of the FE model, a metamodel (MM) was developed and a Monte Carlo simulation was performed to retrieve a distribution of the force values and stiffness values obtained in the simulation. Furthermore, UQ was performed and the sensitivity of the input parameters on the force values and stiffness values were quantified. Finally, with an area metric the accuracy of computational finite element (FE) models in simulating the mechanical response observed in the experiments of the XeltisTM pulmonary valved Conduit size 16, 18, and 20 mm was quantified. For the Leaflet opening behavior, the reaction force increases when the device size increases while the stiffness doesn’t change with device size. As for the accuracy of the predictive FE model, the predictive FE model can simulate the mechanical response of the stiffness with an accuracy of at least 70.7% for the reaction force and at least 50.3% for the stiffness. For the parallel plate compression, the reaction force and the stiffness increase when the XPV size decreases from size 18 to size 16. Furthermore, the difference between the XPV18 and the XPV20 is smaller for both the reaction force and the stiffness. As for the accuracy of the predictive FE model, the predictive FE model can simulate the mechanical response of the stiffness with an accuracy of at least 37.3% for the reaction force and at least 38.1% for the stiffness. As for the important variables influencing the mechanical response, the reaction force and the stiffness are influenced mostly by the fiber stiffness of the component that is subjected to the load. Furthermore, the reaction force and stiffness are also influenced by the direction of the fibers. If the fibers are in the same direction as the load, the reaction force and stiffness increase. Although specifically for the Leaflet the amount of material has more influence on the reaction force and stiffness for larger XPV sizes with the Leaflet opening behavior load case. This indicates that for larger XPV sizes the material properties of the Leaflet have a smaller influence and the Leaflet geometry has a higher influence on the stiffness of the Leaflet opening. Improvements are possible for a better agreement between the simulation and the experiment. These include performing more experiments with different samples from different production batches, and better estimation of input parameters with a high sensitivity to the output parameters. This study provides a step in the direction of predictive computational device modeling that will help shorten the development time of new pulmonary heart valve devices. As the devices in this study are designed for pediatrics, this will help improve the quality of life of pediatrics suffering from congenital heart disease.

Brachytherapy (BT) is an essential component in the curative treatment of cervical cancer. With commercial BT implant devices, called applicators, the radioactive sources can only be positioned in fixed intracavitary channels or in a fixed array of interstitial needles. Patient-tailored BT applicators containing individualised needle channels have the potential to enhance the delivered dose to the tumour while minimising tissue damage of the organs-at-risk (OARs). During the optimisation process of the needle channels, several constraints must be considered. The needle paths in the applicator are curvature-constrained, and the needles should not collide with each other or potentially perforate OARs. Furthermore, clinicians can impose additional constraints based on their preferences. Existing approaches in literature for optimising needle placement in patient-tailored BT applicators for cervical cancer treatment have employed various algorithms. However, these approaches often rely on significant approximations. For instance, some assume that all needles are inserted in parallel or focus solely on optimising geometric coverage as opposed to optimising the dose distribution. Moreover, the few methods in literature incorporating needle path planning in the optimisation process require manually pre-specified dwell positions. To improve dose conformity and minimise the dependence on the clinician’s expertise and time, there is a need for the development of software that optimises the needle placement and paths without resorting to these severe assumptions. This work proposes and validates a novel three-stage approach to generate a patient-tailored applicator configuration without resorting to fully geometric optimisation. First, a high-potential set of dwell positions is obtained by running a modified version of the dwell time optimisation software BiCycle (Erasmus Medical Centre, Rotterdam, the Netherlands) on a grid of possible dwell positions. This results in a resolution optimal treatment plan when not considering geometry and applicator constraints. The positions with the highest dwell times according to the resolution optimal treatment plan are selected in the high-potential set. Next, a weighted set cover problem is used iteratively to find a combination of feasible needle segments to cover all dwell points in the high-potential set at a minimum distance. Lastly, needle channels to steer the needle to these segments are simultaneously optimised to be of minimum curvature and mutually collision-free. To evaluate our approach, a virtual configuration and planning study was performed in a cohort of 22 locally advanced cervical cancer patients previously treated with the Venezia (Elekta AB, Stockholm, Sweden). The resulting treatment plans of the clinically used configuration were compared with the resulting treatment plans of the proposed patient-tailored and grid configurations on clinically relevant dose-volume histogram parameters, dwell times, conformity index and number of interstitial needles. Statistical significance is assessed with Wilcoxon signed-rank tests. The proposed workflow was demonstrated to be feasible, and for every patient, a configuration could be generated in clinically acceptable time. All treatment plans generated for the grid configuration, the patient-tailored configuration and the clinical configuration were acceptable following the EMBRACE ll aims. Planning aims, however, were met more frequently with both the grid configurations (145/151 instances) and the patient-tailored configurations (137/151 instances) in comparison with the clinically used configurations (119/151 instances). The treatment plans generated with the grid configurations obtained significantly better (p < 0.01) median normalised CTVIR D98 dose with respect to the clinical configurations. Moreover, with the grid configurations, there was a significant improvement in median normalised D2cm3 dose for the bladder (p < 0.001), rectum (p < 0.001), sigmoid (p < 0.01) and bowel (p < 0.001) compared to treatment plans obtained with the clinical configurations. The treatment plans generated with the patient-tailored configurations obtained comparable target doses, but median normalised D2cm3 doses for the bladder (p < 0.001), rectum (p < 0.01) and bowel (p < 0.01) were significantly better for the patient-tailored configurations compared to the clinical configurations. The proposed automated patient-tailored BT source channel configuration planning method was demonstrated to be clinically feasible. The resulting treatment plans have dosimetric advantages over the treatment plans generated with the clinical applicator configuration. Improvements to the intracavitary dwell position placement are expected to further increase dose conformity.