Open Wedge High Tibial Osteotomy (OWHTO) is an extensively used, effective treatment option for medical conditions such as medial knee osteoarthritis and varus malalignment. The current developments in the 3D printing industry facilitated using 3D printed patient-specific guides (PSSGs), making OWHTO a desirable treatment option. Although the PSSG improves the outcomes (e.g., high accuracy, lower radiation) of the OWHTO, lateral hinge fractures and posterior soft tissue injuries of the tibia are two main risks still present. Therefore, this study aims to facilitate an optimal 3D printed PSSG design with a lateral hinge protecting K-wire and a soft tissue protecting sleeve for OWHTO that can prevent or reduce these two critical risks. For this purpose, first, 3D models were constructed from pre-operative CT images of the cadaver specimens. Afterward, a monopolar osteotomy cut was created at a location where the orthopedic surgeon Tom Piscaer decided on the 3D-constructed models to develop Finite Element (FE) analysis. Using the FE analysis and 3D constructed models, different intact lateral hinge lengths (5 mm, 6 mm, 7 mm, 8 mm, 9 mm, and 10 mm) without apical drill holes were analyzed for relative comparison between six different simulations. The intact hinge length was chosen between 10 mm and 5 mm according to the information in the literature. Von Mises stress was used as an outcome measure. The decrease in distribution and magnitude for the von Mises stress at the lateral side of the tibia and the lateral hinge was used to point out the overall impact of the hinge length reduction. As the intact hinge length decreased, the von Mises stress on the lateral hinge generally decreased. According to the results from FE analysis using a high-quality mesh, leaving a 6 mm intact hinge was determined to be the optimum case among other cases. It reduced the stress around the hinge, maintained sufficient cortical and cancellous bone, had a higher margin of error, and likely reduced the fraction risk. The results of this FE analysis were used to develop the hinge K-wire location on the PSSG. Several PSSG models with soft tissue-protecting sleeves were created. Among these designs, the second and third prototypes (3 prototypes in total) were tested on the cadaver specimens. After the tests, post-operative CT images of the cadavers were taken. From these images, 3D models of the tibia were constructed. Pre- and post-operative 3D models were registered onto each other for measuring the deviation between the planned and obtained osteotomy. This was used to analyze the accurate placement of the PSSG and its effect on the sleeve function. While the translation deviations ranged from 5.2 mm, 2.05 mm, and 7.81 mm, the rotational deviations ranged from 7.04°, 1.55°, and 9.16° for cases 1, 2, and 3, respectively. Two PSSG designs passed the acceptable region for translational malpositioning (lower than 5 mm). Although the malpositioning of the PSSG affected the sleeve position slightly, the cadaver test results showed that the sleeve still protected the tibia's posterior side from soft tissue injuries by stopping the cutting saw at the cutting trajectory due to its lengthy coverage at the posterior side of the tibia. Since the cadavers did not have the necessary soft tissues, it wasn't easy to give a concrete answer. Still, according to the results, the sleeve is expected to ensure soft tissue protection. Using the PSSG with a hinge-protecting K-wire and a soft tissue-protecting sleeve will likely provide lower radiation exposure, shorter operation time, fewer complication risks and lateral hinge fractures, less posterior soft tissue damage, and increased healing.

Introduction: A combined bone growth and remodeling model should be created, to investigate the effect of different femur shapes on the risk of developing cam type deformities. The different femur shapes needed for this study can be created using a statistical shape and appearance model (SSAM). The workflow of the combined bone growth and remodeling model has been (semi)-automated for increased efficiency and other future uses. Methods: An algorithm was created that leads the user through a (semi)-automated workflow, where the necessary features are added to the simulation. The model uses remodeling and growth simulations in sequence to estimate both the change in density distribution and in shape. The used loading conditions correspond to the 10% gait cycle phase. The remodeling is driven by strain energy density, and the growth by the osteogenic index. Results: The resulting density distributions are similar to those found in other studies, while the growth model predicts larger changes in the neck-axis angle than other studies. The growth was also predicted for two MRI pilot scans and the predicted growth was similar to the growth found in follow up scans of the same children. To investigate the influence of the bone shape on the development on cam-deformities, three different shape modes were varied and their influence on the osteogenic index in the growth plate was analyzed. The results from this study indicate that an increased femoral neck-axis angle increase the growth stimulation in the cam region of the growth plate. Discussion: The created bone adaptation model performs mostly as expected, only the included growth model occasionally performs unreliably. To improve its reliability, recommendations have been given to improve its behaviour. Because of the increased growth stimulation in the cam region of the growth plate, the results indicate that femurs with a large neck-axis angle have an increased risk of developing cam type deformities. The effect of other shape characteristics is unclear, and more research is recommended to investigate the effect of other characteristics, such as the femoral anteversion.

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.

That mechanical properties of the extracellular environment can influence cell behaviour has already been established. Recent studies indicate that human mesenchymal stem cells are affected by the surface curvature of the underlying substrate. However, how meso-scale substrate curvature affects cell behaviour is still not clear. This study utilised the finite element method to simulate a prestressed human mesenchymal stem cell conforming and attaching to a flat control substrate, concave hemispherical and concave cylindrical substrates with curvature radii from 300 µm to 75 µm. The cell model comprises the actin cortex, cytoskeleton, and nucleus modelled with a hyperelastic material definition and 30 linear elastic stress fibres prestressed with a force of 10 nN. The effects of surface curvature on cellular traction forces, cell height, nuclear aspect ratio and actin cortex was studied. The vertical traction forces were observed to be 70% and 40% lower for the hemispherical and cylindrical substrates of the highest curvatures compared to the flat control substrate, respectively. Cellular traction forces towards the cell periphery were roughly 10-20% higher than the more central cellular traction forces independent of substrate curvature. Stresses in the actin cortex were observed to increase by 290% and 220% from the flat control substrate to the hemispherical and cylindrical substrates of the highest curvatures, respectively. These results indicate that the cell is more sensitive to hemispherical substrates than cylindrical substrates. The results also support in vitro observations where hMSCs are seen to span hemispherical substrates and avoid continuous contact.

Osteoarthritis (OA) is a progressive joint degeneration disease resulting in joint pain, stiffness, and loss of mobility. Among patients with anterior cruciate ligament reconstruction (ACLR), OA incidence is increased. Articular cartilage (AC) degeneration is irreversible, therefore prevention and early detection are essential. Specifically, the possibility to predict the risk of AC degeneration would provide options for patient-specific early interventions. This thesis presents a Finite Element (FE) workflow for a patient-specific FE knee model of a patient with ACLR. A degeneration algorithm is implemented to predict AC degeneration. Uncertainties in the parameters of a FE workflow can affect the model's outcome. The sensitivity of the workflow to the AC and meniscal Young's moduli should be determined, as these influence the stress distribution in the joint but in-vivo measurement is not possible for patient-specific values. Therefore, the developed FE knee model is used to answer the main research question: how sensitive is the predicted AC degeneration of a patient-specific Finite Element ACL reconstructed knee model to changes in the AC and meniscal Young's moduli? The FE knee model was created based on patient-specific MRI and gait analysis data. For the sensitivity analysis, 24 models were simulated with AC and meniscal Young's moduli varying between 5 MPa and 35 MPa, and 59 MPa and 80 MPa, respectively. A degeneration algorithm was implemented for the calculation of AC degeneration, based on max principal stresses. Minimal AC degeneration was calculated for both the tibial AC and the femoral AC, ranging from no degeneration to a degeneration level of 0.9812, and 0.9694, respectively. The 5-year follow-up MRI showed no AC degeneration either. Statistical analysis was performed with the volume of degenerated AC. A multiple regression analysis showed an exponential relationship between the degenerated volume and the AC Young's modulus for the tibial AC (R2 = 0.995, p<0.05), and the femoral AC (R2 = 0.989, p<0.05). The meniscal Young's modulus did not affect the degenerated volume. The sensitivity analysis demonstrated that increasing AC Young's modulus resulted in an exponentially larger volume of degeneration. In conclusion, the established FE workflow showed promise for the calculation of AC degeneration following ACLR. A foundation was laid for future development of the model. The sensitivity of the workflow to the AC Young's modulus was determined, highlighting the need for patient-specific estimation of the AC Young's modulus for reliable patient-specific AC degeneration results.

Background Adolescent idiopathic scoliosis (AIS) with a Cobb angle larger than 45° is a spinal deformity that needs surgical treatment to stop progression and reduce pain. Spinal fusion is a surgical procedure where rods are attached to the spine through screws to diminish the Cobb angle. Objective The metal rods are pre-bent to correct the spinal deformity as much as possible. This rod shape is currently based on experience of the orthopedic surgeon. The aim of this thesis is to use Fi-nite element analysis (FEA) to predict a suitable rod shape for AIS patients that need to un-dergo surgery.  Method An FE model of an AIS spine was created based on high quality CT images. Rotation of ver-tebrae led to the optimal shape of the spine in the coronal plane. Vertebral bodies in this model were one by one rotated to a new position from top to bottom, to bring the spine to a new state and align it as much as possible to a normal physiological shape. However, alignment of the spine is an iterative process and rotation of every subsequent vertebra affects the shape of the entire spine. For each vertebral rotation, the reaction moments to maintain the new position is determined in the FE spine model. The acquired reaction moments are transferred to an FE rod model to provide the pre-bending of a rod that can bring the spine in its new state. Results The FE spine model was corrected to reduce the Cobb angle as much as possible. The highest stresses were found at the spinal apex. The reaction moments were transferred to a rod that became deformed in such a manner that straightened the spine model and corrected the Cobb angle to its pre-determined position with 33% reduction. Discussion This is an exploratory study that examines the possibility to predict ideal rod shapes pre-operatively to reduce surgical duration and improve the quality of the procedure. An accessory rod shape was accomplished but could not be validated due to lack of comparable studies. Improved FE spine models will lead to higher reliability of FE pre-bent rod models. This can be accomplished by, for example, inclusion of ligaments, muscles and other structures in the FE model and use of time-dependent material properties. The current model did not lead to a perfect aligned physiological spine and optimization algorithms should be developed in future models to further improve pre-bending of the rods. Conclusion Pre-operative prediction can improve the quality and reduce the time of spinal fusion. Im-provements to the FE spine- and rod model, such as automation, generalization, inclusion of more structures, and optimization algorithms will lead to optimal pre-bending of rods and bet-ter and quicker surgical outcome.

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.

Bone defects are a common problem in healthcare today. When the damage is too extensive, the human body is not able to heal itself. Different solutions are available, but they all have limitations. Therefore, the search for a solution to overcome these limitations is important. In this theses a way to create a scaffold out of seperate crumpled elements is explored. Mechanical and morphological properties are examined.