Introduction: Deep brain stimulation (DBS) is an important therapeutic option for various neurological diseases. For certain indications the optimal target cannot be identified on structural magnetic resonance imaging (MRI), but can be visualized with tractography. A recent improvement for clinical practice is the probabilistic tractography algorithm, providing superior results to the deterministic counterpart. However, it is suggested that clinical users are unfamiliar with the complex technology of this new approach, which might lead to missed potential of tractography in DBS-care. The overall aims of this thesis were threefold: to create an overview of the national landscape on the application of tractography, to narrow the gap between medicine and advanced technology in the application of tractography in DBS surgery planning, and to report potentialities and pitfalls of the implementation of tractography in a general hospital. Methods: In the first part, a survey was conducted among Dutch DBS clinicians on the deployment of tractography. The survey consisted of 25 questions about the provision of DBS care, the use of tractography, the expert’s opinion and the respondent’s demographic characteristics. A comprehensive literature study is conducted in the second part. In the third part, an economic evaluation is performed by analyzing the costs and benefits of tractography. Guidelines are suggested based on literature and expert experience. Results: Tractography is considered valuable for essential tremor (p<0.001) and not valuable for epilepsy (p=0.002) and chronic cluster headache (p=0.016). The majority uses deterministic approaches like DTI. Probabilistic users consider tractography more valuable than deterministic users (p=0.036). There is a heterogeneity in used image acquisition parameters and a lack of knowledge exist on technical background of tractography. The key elements of the technical principles of tractography are summarized, including diffusion weighted MRI, the concept of estimating the diffusion tensors, image acquisition parameters and tract reconstruction with the deterministic and probabilistic approach and quantitative measures. Conclusion: Tractography is used by DBS clinicians with limited knowledge on the technical aspects. Generally the inferior deterministic approach is used without an (inter)nationally standardized protocol for image acquisition and tract reconstruction. A comprehensive explanation of the technical concepts and suggested practical guidelines should contribute to better application of this promising technology in DBS-care.

Duchenne Muscular Dystrophy (DMD) patients suffer from a severe form of progressive muscular weakness. Consequently, as the disease progresses these patients become more and more dependent on assistive devices for their daily activities. For instance lifting their arms against gravity already becomes challenging. So far, a considerable amount of effort has been put in the development of assistive devices. However, compensating the weight of the hand remains challenging as the required balancing torques are dependent on the position of the hand and the orientation of the forearm. In this research a solution is proposed to passively compensate the weight of the hand by making use of a simplified torque profile (a constant torque). The effectiveness of this profile was assessed experimentally in a group of healthy subjects. For this the wrist muscle activity required to lift the hand against gravity was measured through surface electromyography, for several types of compensation. From this experiment the conclusion can be drawn that a constant torque profile performs similar to the theoretically ideal type of balancing, showing a similar reduction in the anti-gravity muscle activity. Based on these findings, a mechanism has been developed capable of providing an adjustable constant force, by making use of a combination of positive and negative stiffness springs, for implementation in a wrist support for DMD patients.

Introduction: Amputees may be eligible to use a socket or osseointegrated (OI) prosthesis after losing a limb. A lot is known about the stump-socket interface in transtibial (TT) amputees. However, there are hardly any articles that explain the load transfers between the tibia and an OI prosthesis. For this reason, this study will focus on the load pattern at the bone-implant interface. The aim is to investigate how the osseointegrated loading for TT amputees is compared to able-bodied subjects. Method: Two generic musculoskeletal models were created in OpenSim: a transtibial osseointegrated (TTO) model and an able-bodied model. The able-bodied model includes all muscles in the lower limb, where the TTO model had no muscles around the tibia. Two datasets, consisting of five able-bodied participants (healthy control (HC)) and five transtibial amputees (TTA) with a socket prosthesis, were used. The internal reaction forces and moments were analysed for the affected side during the stance phase of the gait cycle. These normalized forces and moments were expressed in bodyweight (BW) and bodyweight x height (BWH), respectively. Results: The largest forces at the bone-implant interface were measured in the longitudinal direction (-6.92 BW) for the able-bodied model, the lowest in the mediolateral direction (-0.09 BW) for the TTO model. The loading differences were the highest between the able-bodied model and the TTO model with TTA data. Around the antero-posterior axis, the largest moments were found. The able-bodied model measured 0.027 BWH, where the TTO model with HC data found 0.023 BWH and 0.017 BWH for the TTA data. Conclusion: Transtibial amputees have decreased loading at the bone-implant interface compared to able-bodied subjects. The muscles play the most prominent role in comparison with the gait pattern.

Introduction Atrial fibrillation (AF) is the most common age-related, progressive tachyarrhythmia in the USA and in European countries. AF is associated with an increased risk of stroke, heart failure, impaired cognitive function, and increased mortality. An obstacle for optimal diagnosis and treatment is the relatively unknown (electro-)pathophysiology of AF. In combination with intra-operative cardiac mapping, accurate analysis of the AF burden using post-operative continuous rhythm registrations might provide great insight into the underlying mechanisms of AF development. However, manual analysis of these continuous rhythm registrations is both time-consuming and subject to interpretation. Therefore, the aim of this study is to develop an automated AF detection algorithm for use in the research setting. Methods Using 6,400 manually annotated 30-seconds electrograms (ECGs) derived from the post-operative continuous rhythm registrations in the Erasmus Medical Center (Rotterdam), and 192 annotated records from standard MIT-BIH ECG databases, a classifier was developed with three output classes: AF, No AF, and Unusable (due to noise/artefacts). QRS-complexes were detected using a method based on the Pan-Tompkins algorithm. Subsequently, P- and T-waves were detected and features were extracted, which can be grouped into eight groups: RR-interval characteristics, peak-interval characteristics, amplitude characteristics, P-wave characteristics, T-wave characteristics, QRS-morphology characteristics, autocorrelation characteristics, and noise. Multiple classifiers were trained using a training set containing 4,800 post-operative ECGs and a hidden test set containing the remaining 1,600 post-operative ECGs. The optimal classifier in terms of accuracy was further optimized. Results Optimal classification was achieved using boosted decision trees. For the hidden test set, this resulted in an accuracy of 96.44% (95% CI: 95.41% - 97.24%) for detection of AF with a false negative rate of 2.8% (95% CI: 1.5% - 4.9%) and a false positive rate of 3.8% (95% CI: 2.9% - 5.1%). Of all 74 misclassifications, 36 (49%) were made in the group with irregular rhythms without AF. Classification was mainly based on the RR-interval characteristics. Conclusion An automated AF classifier based on post-operative continuous rhythm registrations for use in the research setting was proposed. Careful use of the classifier in combination with manual validation of detected AF segments makes the classifier suitable for supervised research purposes.

The incidence of osteoporotic vertebral compression fractures (VCFs) is rapidly increasing, necessitating the identification of the most appropriate treatment method. The well-established first and second generation surgical procedures are not capable of giving optimal outcomes. Moreover, my literature study has shown little to no improvements for four of the most prevailing third generation procedures. As a consequence, the med-tech company Amber Implants B.V. developed a new 3D-printed porous titanium implant that has the potential to resolve difficulties and drawbacks that were identified for all former procedures. Nonetheless, the performance of this implant has never been tested before. Thus, the aim of this study was to pre-clinically evaluate the biomechanical properties regarding the spinal deformities for this implant. For the quantification, the prevention of spinal deformities was subdivided into the anterior height restoration and the kyphotic angle correction. The pre-clinical evaluation was conducted on isolated vertebrae originating from three human cadaver specimens. First, the most abundant type of all osteoporotic VCFs, a wedge fracture, was generated on the vertebrae with 40% anterior height decrease. Thereafter, vertebral restoration was performed with the implants. Besides, vertebral restoration with the second generation surgical procedure, the Balloon Kyphoplasty procedure (BKP), was performed likewise to serve as a comparative. After vertebral restoration, half of the implant group and the total BKP group were tested in a cyclic loading test that mimicked the activity during the first week after surgical VCF repair, i.e. 10.000 cycles with loads ranging from 100N to 600N. The other half of the implant group was tested under higher loading conditions, i.e. 10.000 cycles with loads ranging from 100N to 1000N. At each test stage the spinal deformities, which were subdivided into the anterior height and the kyphotic angle, were evaluated from micro-CT (μCT) data. Eventually, the μCT scans were compared in order to quantify the implant's performance. The anterior height restoration after vertebral restoration with the implant was outstanding compared to the BKP procedure. Thereby, a statistical significance difference (p<0.05) was not only observed for the anterior height restoration, but also for the central and posterior height restorations, between the two surgical procedures. Additionally, the kyphotic angle correction of the implant procedure outperformed the outcomes observed for the BKP. Nonetheless, after cyclic loading various drawbacks for the implants were observed, resulting in substantial decreases in outcomes for the height restoration and the kyphotic angle correction. Regarding the height decrease, most was found in the trabecular bone inferior to the implant. Presumably, the plastic deformation was induced by high local stresses as a result of the minimal contact area between the implant and the trabecular bone. Complementary, the rotation of the implant was observed to effect the implant's performance. Ultimately, it was concluded that the implant in its current design could not compete with the BKP procedure, neither with the third generation surgical repair procedures for an osteoporotic VCF such as Vertebral Body Stenting (VBS) and SpineJack. Nevertheless, the outcomes after vertebral restoration were promising. Therefore, it was assumed that the implant has a decent chance of succeeding after implementing some adjustments on the implant's geometry and the corresponding surgical tools.

Due to neuromuscular capacity decline, sit-to-stand, an essential daily life activity, is increasingly difficult to perform for elderly. In practice, elderly frequently use compensatory arm-strategies in sit-to-stand. However, the specific advantages of these compensatory strategies are unclear. The focus of this research is to study the influence of thigh push-off, a common compensatory strategy, on the stability of sit-to-stand for both the young and elderly. Motion data was retrieved from 50 young and elderly participants who performed sit-to-stand with and without thigh push-off. To mimic realistic daily-life strategies, participants were not restricted in sit-to-stand style in any way but arm-use. The experimental sit-to-stand data was fitted to a pendulum model with feedforward and feedback control to simulate the stability limits of the observed sit-to-stand strategies. The model allows us to explore stability limits without the need of perturbation. For each arm-strategy and participant a stability basin, i.e. all potential trajectories of motion, was formed. We compared the stability basins between arm-strategies and between age-groups. The size of the computed stability basin for thigh push-off was larger than for no arm push-off implicating thigh push-off is a more stable sit-to-stand strategy. The difference between arm strategies was larger for the elderly than for the young participants. Overall, the stability basins of the elderly were larger compared to those of the young participants, for both arm strategies. The resulting stability basins suggest that thigh push-off increases the stability of sit-to-stand and thus could indeed be an effective compensatory strategy. Stability basin shape differences indicate that without thigh push-off elderly compensate for possible early sit-down and a step halfway sit-to-stand, and with the thigh push-off strategy only for early sit-down. The age-groups differences confirm stability basins quantify the stability of the observed movement strategy rather than the stability of the participants. We observed that elderly use more precautious sit-tot-stand movements.

Goal: Build and evaluate the first prototype of the Cloud Walker, a passive assistive gait orthosis. Method: The Cloud Walker uses muscles of the upper body to store energy in the springs at the back of the Cloud Walker. This energy can than be used to swing the legs forward. The Cloud Walker was evaluated by 9 healthy participants walking on a treadmill. The participants walked at different speeds with and without the Cloud Walker. Finishing speed, EMG, heart rate, stride length and questionnaires are used to obtain insight on the performance of the Cloud Walker. Results: 3 out of 9 participants finished the test at the maximum speed of 4 km/h. The muscle activity of the measured upper leg muscles was higher with the Cloud Walker than without it. The heart rate increased more when walking with the Cloud Walker than walking without the Cloud Walker. The stride length at a slower pace was larger with the Cloud Walker. The stride length was smaller at a higher pace with the Cloud Walker than without it. The questionnaires showed that the Cloud Walker is a little uncomfortable and that walking with it takes a lot of effort. Discussion: It is expected that SCI patients are able to walk in the Cloud Walker since the device is comparable to other orthotic devices such as the ARGO. The Cloud Walker can obtain a higher speed and costs less effort than comparable devices.

Pompe disease is a progressive muscular disorder that will affect the respiratory muscles, in particular the diaphragm, thereby seriously limiting the respiratory function. Respiratory function is typically assessed using spirometry. However early stages of diaphragm impairment may not be detected by conventional spirometry measurements due to compensatory efforts of other inspiratory muscles. In this study we aimed to use 3D MRI as a sensitive method to assess diaphragm function and identify diaphragm impairment. Static breath-hold 3D MRI scans at maximal inspiration and maximal expiration were obtained from a previously used dataset in 18 healthy controls and 35 Pompe patients with varying degrees of diaphragm weakness. Images were segmented using an automatic script. The segmentations were used to create an anatomically accurate 3D mesh model of the lungs. The surface of the mesh was divided into topographical segments based on the anatomical surfaces of the lungs. Vital capacity (VC) measurements were retrieved from the mesh model (VCmesh) and compared against spirometry VC measurements made during the MRI acquisition (VCspiro) in order to validate the mesh model. Segmental volumes, derived from the topographical segments identified on the surface of the mesh model, were reallocated based on changes in lung dimensions to provide a more accurate functional topographical representation of the underlying diaphragm and intercostal muscle functions. The relative contributions of the diaphragm and intercostal muscles to the total increase in lung volume during inspiration were assesses for differences between healthy controls and Pompe patients and compared against common spirometry and 2D analysis outcomes. A large and significant correlation was established between VCmesh and VCspiro, rs = 0.971, p < 0.001. Median VCspiro was significantly larger than median VCmesh across all population groups (p < 0.001), by an average amount of 0.31 L. This represented a mean difference between the two measurement methods of 9.3% of the mean VC measurements. It has also been demonstrated that median changes in diaphragm volume (p < 0.001) and the median relative contribution of the diaphragm to the total increase in lung volume during inspiration (p = 0.009) were lower in Pompe patients with decreased spirometry results when compared against healthy controls. Changes in diaphragm volumes correlated well with conventional VC and FVC measurements (rs = 0.997, p < 0.001) as well as with changes in superoinferior lung sizes (rs = 0.936, p < 0.001). In some Pompe patients with decreased spirometry results no indication for diaphragm impairment was found when assessing the relative contribution of the diaphragm to the total increase in lung volume during inspiration. A mesh model based on 3D MRI segmentations provides an accurate method of assessing diaphragm function. Changes in diaphragm volume and the contribution of the diaphragm to the increase in lung volume during inspiration allow for the assessment of diaphragm impairment in Pompe patients. These biomarkers of diaphragm function may prove to be highly useful in determining a personalized treatment plan for Pompe patients as well as a sensitive outcome in trials to test future treatment modalities.

Neuropathic pain (NP) affects approximately seven to ten percent of the general population. Seventeen percent of NP patients scored their life as “worse than death”. A myriad of causes may underlie NP, such as stroke or spinal cord injury. Also, damage or disease of the peripheral nervous system (PNS) may result in NP. One of the main issues of NP caused by a peripheral nerve injury (PNI) is the development of a neuroma, which is a tumor-like mass at the proximal end of a severed nerve that can become very painful. Neuromas show unique neurophysiological characteristics. Cell membrane alternations lead to different ion channel distributions, which in turn result in subthreshold oscillations (SO) and ectopic discharges (ED). It is assumed that this behavior could lead to NP generation. Electrical neurostimulation (ENS) is used to treat patients, thereby applying pre-programmed stimulation patterns to the affected nerves. However, the pain-provoking signals which run through the nerves are not detected and analyzed before ENS is provided. Furthermore, it is questionable whether (the currently applied) pre-programmed ENS defuses these signals anyway. In addition, pre-programmed ENS is not effective at all moments of the pain experience caused by fluctuations in signal intensity. As the clinical results are discouraging, and in view of the high costs, the popularity of this technology is currently waning. Optimization of this potentially powerful technique is needed to improve the outcome and make this technology useful to implement in the treatment strategy of patients with intractable otherwise difficult to treat pain syndromes. Theoretically, optimization of stimulation technology is possible by actually neutralizing SO and ED, which should lead to mitigating the generation of NP. We propose an approach to neutralize SO and ED consisting of several steps. Firstly, the nerve activity is real-time monitored. Secondly, a decision mechanism (called a ‘controller’) is developed that constructs electrical neurostimulation (ENS) patterns to neutralize SO and ED. Finally, these patterns are actually applied to the nerve by an electrical stimulator...

INTRODUCTIOND istal radius fractures are traditionally treated with plaster casts. Although this has been the gold standard for treatment for years, it also comes with disadvantages. These are the weight, not being water-resistant and a lack of ventilation, leading to skin problems, itching and compromised hygiene. Furthermore, plaster has no possibility for visual inspection of the skin, while up to 30% of all treatments with plaster casting lead to, mainly skin related, problems. With 3D printing, a lightweight, waterproof, open latticed and personalized cast can be created to overcome the issues with plaster casting. Multiple start-ups, researchers and other individuals already created these 3D printed casts, however, there is no consensus about the materials and design that should be used. Also, implementation of these 3D printed wrist casts into clinical practice stays out. The main research goal is to investigate the feasibility of in-house design, production and implementation of 3D printed wrist casts for the treatment of distal radius fractures. METHODS To answer the main research question, multiple sub studies were performed. First, design requirements were formulated in consultation with clinicians. Then, material tests were performed, followed by creating a design workflow. Subsequently, the optimal design pattern and validation of the stabilization requirements were investigated during a mechanical phantom study. Also, to affirm adequate ease of use and comfort, a comfort study was carried out. The final step was a pilot study, in which the necessary alterations in the workflow were investigated, as well as clinical outcomes and patient experiences. RESULTS The material tests showed that color resin, printed with an SLA printer is most suitable for the production of 3D printed wrist casts. A semi-automated design workflow was created in which a 3D printed wrist cast can be produced within 24 hours. A 3D printed cast with a Voronoi design pattern is most successful for adequate wrist immobilization, achieving similar stabilization abilities as a plaster cast. Furthermore, the comfort study showed that the 3D printed wrist casts ensure adequate comfort, with a mean score of 8.1 out of 10.0 and sufficient ease of use. During the pilot study, two children with greenstick or buckle/torus fractures were successfully treated with the wrist casts. To implement the treatment of distal radius fractures with 3D printed wrist casts into the current workflow, a workflow as used for traditional treatment during the evenings and weekends is required. CONCLUSIONA customized, lightweight, water-resistant and ventilated wrist cast can successfully be designed, with adequate stabilization abilities. This cast can be produced within 24 hours, with the use of a semi-automated design algorithm that creates a wrist cast with ventilation holes based on a Voronoi pattern. The 3D printing should be performed with an SLA printer, with the use of color resin. The produced wrist casts ensure adequate comfort and ease of use and can be implemented clinically for successful treatment of children with greenstick and buckle/torus fractures. Only small alterations are necessary in the current workflow to allow for the production of the 3D printed wrist casts. No extra hospital visits are required and the new workflow is comparable to the weekend workflow. Further research is necessary to tackle the unfavorable cost-effectiveness and the adaption of the casts to swelling. For the future, treatment with 3D printed casts should be extrapolated to unstable fractures, other body parts and the field of orthotics.

BACKGROUND: Knee problems are the most common complaints of the lower extremity in the Netherlands. Osteoarthritis has the highest prevalence of all knee complaints. Knee osteoarthritis is likely to start at the patellofemoral joint and is associated with the aggravation of pain. Mechanical overloading is hypothesized to contribute to the development and progression of patellofemoral osteoarthritis (PFOA). Several studies have explored the mechanical loading pattern of the patellofemoral joint. Because different biomechanical models were used, vastly different estimations of the patellofemoral joint contact force (PFJCF) were concluded. This diversity prevents a clear understanding of the role of mechanical overloading in PFOA, since it is unknown how different biomechanical models affect the PFJCF estimation. OBJECTIVES: This study will explore how different biomechanical models of the patellofemoral joint affect the estimated PFJCF for common weight-bearing activities. METHODS: Ten healthy participants were included in this study. Common weight-bearing activities (walking, stair ascending, stair descending, sit-to-stand and stand-to-sit) were performed in the motion lab. Marker trajectory data and force plate data were collected. The data were input to biomechanical models used to estimate the quadriceps muscle force and subsequently the PFJCF. The quadriceps muscle force was estimated using the inverse dynamics and static optimization method. From there on, the PFJCF was estimated using three PFJCF to quadriceps muscle force ratios (P2QFRs), each based on a different patellofemoral joint model (i.e. van Eijden’s model, Yamaguchi’s model and Gill’s model). For each weight-bearing activity, the peak PFJCF was obtained and the magnitude of the difference among the biomechanical models was explored. RESULTS: The static optimization method resulted in a significantly higher peak PFJCF compared to the inverse dynamics method in walking (largest effect size was 0.10 BW). However, for stair descending, sit-to-stand and stand-to-sit, the inverse dynamics method resulted in a significantly higher peak PFJCF compared to the static optimization method (largest effect size was 0.45 BW, 1.17 BW, 1.25 BW, respectively). No significantly difference was found for stair ascending. For walking, Yamaguchi’s model resulted in a significantly higher peak PFJCF compared to van Eijden’s model and Gill’s model, and van Eijden’s model resulted in a significantly higher peak PFJCF compared to Gill’s model (largest effect size was 0.06 BW). For stair ascending, stair descending, sit-to-stand and stand-to-sit, Gill’s model resulted in a significantly higher peak PFJCF compared to van Eijden’s model and Yamaguchi’s model. For stair descending the van Eijden’s model resulted in a significantly higher peak PFJCF compared to Yamaguchi’s model. The largest effect size was 0.15 BW, 0.32 BW, 0.72 BW and 0.72 BW, for respectively stair ascending, stair descending, sit-to-stand and stand-to-sit. CONCLUSION: The choice of a biomechanical model has a critical effect on the estimation of the magnitude of the PFJCF. Its differences might reach half the clinical size effects when comparing control to symptomatic PF pain patients.

Admission to the intensive care unit often has long lasting effects on patients’ further life. Not only can the reason for their admission leave several problems, but also mechanical ventilation, physical inactivity, sedation and delirium are only some of the factors that contribute to the problems left after ICU stay. Over 80,000 people are annually admitted to the intensive care units of the Dutch hospitals alone and, due to technical advancements, a rising number of patients survives critical illness. Post intensive care syndrome is the overarching name that combines all the physical and mental problems related to intensive care unit stay. It has been well established that rehabilitation and early mobilisation are effective counter measures against post intensive care syndrome. It has also been shown that interactive video gaming can play a useful role in rehabilitation as an addition to conventional therapy. Evidence has shown that the use of visual feedback improves performance and adherence to the therapy in comparison to regular of physical therapy. This design study is meant to create a new interactive video gaming device that allows ICU patients that are at least semi mobile and semi cooperative, to play video games with the aim to help them leave the ICU in the best physical and cognitive state as possible. To come up with the right design, a literature study on the relevant subjects has been done. Also, expert interviews with intensive care unit care-giving staff have been conducted and experience has been gained on the intensive care unit of the Erasmus medical center Rotterdam to make sure the design is done in the right context. Based on the outcomes of this research the decision was made to aim the design to help in activities of daily living. From this aim a specific goal was formulated: The goal is to create an interactive video game controlling system that allows ICU patients, that are at least semi mobile and semi cooperative, to play video games that simultaneously helps in increasing muscle strength, delivers distraction from the daily routine in the ICU and stimulates patients cognitively. Together with physiotherapists and intensivists from the Erasmus medical center Rotterdam a list of requirements for the final designs was created. As during activities of daily living hand grip is one of the most important aspects, the decision was made to use sub-maximal grip force control as the desired training form. Because of this two different versions of grip strength trainers were proposed. The first concept uses the medium wrap grasp as input movement and the second concept uses the power-sphere grasps. These are two of the most frequently used grasp types in daily life. The concepts are designed in a way that the force exerted on the device can be used to control a video game. Internal force sensing resistors, connected to an Arduino, translate the force to a useful signal to control the game. Ten prototypes were created to get to the final designs, which were then tested with patients on the ICU. As result of testing and iterating the concepts, two final designs were delivered, fulfilling the list of requirements. Feasibility tests of these designs were done on the ICU of the Erasmus medical center Rotterdam and were promising. ICU patients participating in the tests understood the game well, were capable of performing the required movements to play the game and delivered feedback on the design and the gaming experience. This paper has lead up to a final prototype that has gone through basic testing to check for feasibility and has proven to work. Further scientific research on a larger scale should be the next step to review the clinical effects of the device.

To better understand and predict osteoarthritis, researchers are developing so-called coupled modelling workflows. Coupled workflows convert data from gait analysis studies to subject-specific tissue mechanical response estimations through the use of musculoskeletal and finite element models. The tissue mechanical response inside the joint is thought to play an integral role in the onset and progression of osteoarthritis. To study this, the design of coupled workflow was proposed. This design contained subject-specific gait data which was processed by a musculoskeletal model with a single degree of freedom knee joint. Musculoskeletal output was transferred through an adjusted generic finite element model of the knee to calculate maximum principal stress and shear strain values in the tibial cartilage of the knee. Proper marker placement is crucial for making an accurate assessment of the patient’s function in gait analysis studies. It has been claimed that marker misplacement is the main cause of measurement variability in gait analysis studies. It however remains unclear how potential marker misplacement propagates to the coupled modelling workflow results. To investigate this, in addition to the design of a coupled workflow, a sensitivity analysis was performed. With this sensitivity analysis we tried to answer the following question: How does marker placement of knee joint markers in gait analysis influence the tissue mechanical response calculated by a coupled workflow? For the sensitivity analysis, knee joint marker placements were virtually perturbed along anterior-posterior, proximal-distal and medial-lateral direction, to mimic marker misplacement. Corresponding knee biomechanics were estimated from the perturbed input data in the coupled workflow. Peak maximum principal stress values varied by up to 0.60MPa and peak shear strain varied by up to 0.08% as a result of perturbed knee marker placement. For cumulative stress levels, broader relative ranges were found. Moreover, the results showed that marker placement along the anterior-posterior direction had the greatest influence on corresponding tissue mechanical response estimations. In future studies a standard error of measurement margin is proposed in the assessment of coupled modelling worfklow results. In conclusion, the proposed workfow was relatively easy to build and provided similar tissue mechanical response result to those as reported by more complex models which were more computationally intensive. This implies that in the future, coupled modelling processes may very well be incorporated into the clinical decision-making process for musculoskeletal disorders like osteoarthritis.

Objectives: In double outlet right ventricle (DORV) both the pulmonary artery and the aorta originate predominantly from the right ventricle (RV) and a ventricular septum defect (VSD) is present. Each DORV patient requires an individual surgical approach. In complex cases the optimal surgical approach may be difficult to assess based on conventional 2D imaging. The aim of this study is to assess the added value of 3D printed and 3D Virtual Reality (VR) models used for surgical planning in DORV patients, supplementary to the gold standard 2D imaging modalities, in a retrospective clinical setting. Methods: Five patients with different DORV-subtypes were selected, of which 3D prints and good quality cardiac CT scans were available. Participants were twelve congenital cardiac surgeons and paediatric cardiologists, from 3 different hospitals. Participants were shown the 2D images first, after which they assessed the VR and 3D model in random order. After each imaging method, a questionnaire was filled in on the visibility of essential structures, feasibility of four-chamber repair, and the surgical plan. Results: Spatial relationships were generally best visible using 3D methods. The feasibility of VSD patch closure was accessible best on the VR 3D reconstructions (good visible: VR 92%, 3D print 66%, and US/CT 46%, P<.01). Moreover, based on the three different visualisation modalities, surgical plans were proposed. The proportion of proposed surgical plans similar to the performed surgical approach was 72% for plans based on conventional imaging, 85% for plans based on 3D printing, and 87% for plans based on VR visualisation.Conclusions: In this study, we determined that the use of both 3D modalities is very useful and participants could visualize spatial relationships better compared with conventional 2D imaging. Moreover, based on the 3D visualisations, the proposed surgical plans were corresponding more to the actual performed surgery. However, still some research is needed to fully implement 3D visualisation in clinical practise.

Vertebral fractures are the most common osteoporotic fractures, with a prevalence of 12-20% in Europe, making them a major health problem because of the associated morbidity, mortality and costs. Without adequate treatment, vertebral fractures are often followed by subsequent fractures, leading to further invalidation and deterioration of health. Therefore, early detection of vertebral fractures is important so preventative treatment can be initiated. Vertebral fracture assessment (VFA) using Dual-Energy X-ray Absorptiometry (DXA) equipment is an imaging technique in which a lateral image of the spine is made. With vertebral morphometry, vertebral heights are measured and fractures are identified when vertebral height is lower than expected. However, vertebral morphometry is time and labor-intensive, and is subject to inter-operator variability. Automating VFA using Artificial Intelligence (AI) could help to overcome these limitations. We employed a co-development approach, aiming to create an AI-based tool to automatically perform vertebral morphometry on VFA images to identify vertebral fractures. Firstly, we conducted a literature review to investigate the current use of AI in quantitative DXA imaging in a broad sense (Chapter 2). Besides VFA, other quantitative parameters describing bone macrogeometry and microgeometry can be extracted from DXA images. Incorporating these risk factors into multivariate prediction models could improve the identification of those at risk of fracture and help in clinical decision making. Although still in development, AI has been successfully applied in aid of fracture risk assessment, showing promising results. In Chapter 3, the results of our reader study are described, evaluating VFA with manual vertebral morphometry as it is currently performed. This study served as a baseline measurement to quantify the effort needed to perform manual VFA and assess the potential value of automating VFA. The average annotation time per VFA image was 259 seconds. Although the intraclass correlation for vertebral height measurements between different readers was high, inter-observer agreement for fracture classification was only poor to moderate. Together with our industry partner, we developed an AI-based software tool to perform vertebral morphometry. This tool is still in development, and we evaluated its current performance and potential impact in the study described in Chapter 4. Although its current standalone performance is suboptimal and shows room for improvement, this initial investigation showed that automated VFA has the potential to significantly reduce the required reader time. Finally, in Chapter 5 we reflect on our user-centered co-development process and the next steps to bring our AI tool to market. We believe that collaboration between academic healthcare institutions and industry are essential for successful development of AI products. Validation of these products throughout the development process and actively involving intended users should be done. In the near future, vertebral fracture assessment can be supported by our AI-based application, potentially leading to lower annotation times and improving clinical workflow. However, further improvements have to be made and independent validation is required before market access.

Various neuromuscular disorders such as spinal cord injury, Charcot-Marie-Tooth disease and poliomyelitis lead to calf muscle weakness, which limits the patient's ability to propel their body forward during gait. Their abnormal gait pattern is characterized by increased ankle dorsiflexion, excessive knee flexion during stance and reduced ankle push-off power which leads to decreased walking speed and increased energy cost of gait. To improve walking ability, dorsal leaf spring (DLS) ankle-foot orthoses (AFOs) are often worn that provide stiffness around the ankle joint which is its most important characteristic. Selecting optimal AFO stiffness is important because it can substantially reduce the net metabolic cost of gait, while improper AFO stiffness can lead to discomfort, fatigue and overall reduced activity. Experimental data shows that the effect of AFOs is dependent on the individual characteristics of the patients, such as level of muscle weakness, spasticity and body mass. Despite the importance of AFO stiffness, empirically determining the stiffness of the applied AFO remains time-consuming and ad hoc. This master thesis aims to uncover the mechanism relating AFO stiffness to the metabolic cost of transport (CoT) as observed in experimental trends from individuals with calf muscle weakness. We used predictive forward musculoskeletal simulations to reproduce the experimental trends and analyzed our simulations to explain the relationship between AFO stiffness and metabolic CoT. The predicted optimal AFO stiffness was within 1 Nm/deg of the patient's experimentally measured one. From the experimentally observed effects, all kinematic and kinetic trends were predicted within 0.5-2.5 SD from the mean of the experimental slopes of all patients' results. Moreover, the differences between the slopes of the simulation results were mostly lower compared to the modelled patient's individual experimental slopes than compared to the experimental slope of the group average results. We identified a reduction in the vasti muscle metabolic cost due to larger external knee extension moments with increasing AFO stiffness as the main mechanism resulting in the net metabolic CoT trend. Limitations on translating our findings to patient behavior include: modelled calf muscle strength, where the model may be significantly stronger or weaker than the patient, and the relative importance of metabolic cost minimization to other goals during walking, such as minimizing the loading rate at heel strike.