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Indiana University-Purdue University Indianapolis (IUPUI) / Glaucoma is a multifactorial ocular disease progressively leading to irreversible blindness. There is clear evidence of correlations between alterations in ocular hemodynamics and glaucoma; however, the mechanisms giving rise to these correlations are still elusive. The objective of this thesis is to develop mathematical models and methods to help elucidate these mechanisms. First, we develop a mathematical model that describes the deformation of ocular structures and ocular blood flow using a reduced-order fluid-structure interaction model. This model is used to investigate the relevance of mechanical and vascular factors in glaucoma. As a first step in expanding this model to higher dimensions, we propose a novel energy-based technique for coupling partial and ordinary differential equations in blood flow, using operator splitting. Next, we combine clinical data and model predictions to propose possible explanations for the increase in venous oxygen saturation in advanced glaucoma patients. We develop a computer-aided manipulation process of color Doppler images to extract novel waveform parameters to distinguish between healthy and glaucomatous individuals. The results obtained in this work suggest that: 1) the increase in resistance of the retinal microcirculation contributes to the influence of intraocular pressure on retinal hemodynamics; 2) the influence of cerebrospinal fluid pressure on retinal hemodynamics is mediated by associated changes in blood pressure; 3) the increase in venous oxygen saturation levels observed among advanced glaucoma patients depends on the value of the patients’ intraocular pressure; 4) the normalized distance between the ascending and descending limb of the ophthalmic artery velocity profile is significantly higher in glaucoma patients than in healthy individuals.

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第24542号 / 人健博第113号 / 新制||人健||8(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 中尾 恵, 教授 杉本 直三, 教授 黒田 知宏 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Femoroacetabular impingement (FAI) is recognized as a pathomechanical process that leads to hip osteoarthritis (OA). It is hypothesized that mechanical stimuli are prominent at higher range of motions in hips with cam FAI (aspherical femoral head-neck deformity). Adverse loading conditions can impose elevated mechanical stimuli levels at the articulating surfaces and underlying subchondral bone, which plays a predominant mechanical role in early OA. The aim of this research was to determine the levels of mechanical stimuli within the hip, examining the effects of severe cam impingement on the onset of OA, using patient-specific biomechanics data, CT data, and finite element analysis (FEA). Patient-specific hip joint reaction forces were applied to two symptomatic patient models and two control-matched models, segmented from patient-specific CT data. The finite element models were simulated to compare the locations and magnitudes of mechanical stimuli during two quasi-static positions from standing to squatting. Maximum-shear stress (MSS) was analyzed to determine the adverse loading conditions within the joint and strain energy density (SED) was determined to examine its effect on the initiation of bone remodelling. The results revealed that peak mechanical stimuli concentrations were found on the antero-superior acetabulum during the squatting position, underlying to the cartilage. The MSS magnitudes were significantly higher and concentrated for the FAI patients (15.145 ± 1.715 MPa) in comparison with the MSS magnitudes for the control subjects (4.445 ± 0.085 MPa). The FAI group demonstrated a slight increase in peak SED values on the acetabulum from standing (1.005 ± 0.076 kPa) to squatting (1.018 ± 0.082 kPa). Insignificant changes in SED values were noticed for the control subjects. Squatting orients the femoral head into the antero-superior acetabulum, increasing the contact area with the cartilage and labral regions, thus resulting in higher peaks behind the cartilage on the acetabulum. The resultant location of the peak MSS and SED concentrations correspond well with the region of initial cartilage degradation and early OA observed during open surgical dislocation. Due to the relatively low elastic modulus of the articular cartilage, loads are transferred and amplified to the subchondral bone. This further suggests that elevated stimuli levels can provoke stiffening of the underlying subchondral plate, through bone remodelling, and consequently accelerating the onset of cartilage degradation. Since mechanical stimuli results are unique to their patient-specific loading parameters and conditions, it would be difficult to determine a patient-specific threshold to provoke bone remodeling at this stage.

Objective: Patient-specific musculoskeletal models have emerged as a reliable method to study how tibiofemoral joint (TFJ) morphology influences anterior cruciate ligament (ACL) injuries. However, there are no such models for adolescent populations that can be scaled to accommodate growth. To serve as the foundation for such models, the objective of this thesis was therefore to i) build a patient-specific model of natural knee motion in an ACL-injured (ACLi) adolescent sample using joint congruency and ii) to attempt to reconstruct patient-specific simplified articular contacts using principal component analysis (PCA). Design: Twelve magnetic resonance images (MRI) of ACi adolescents were segmented and used to generate spheres of simplified TFJ articulations. A congruence-based optimization algorithm was used to determine the envelope of tibiofemoral configurations that optimize joint congruency. Descriptive statistics were used to compare model outputs to existing literature. Combinations of marker trajectories and anthropometrics were used to determine the feasibility of reconstructing articular sphere simplifications using PCA. Root-mean squared error (RMSE) was used to compare predicted sphere contacts to MRI-extracted contacts. Results: Average knee joint anglesof the femur with respect to the tibia was slightly abducted and externally rotated, with a range of motion (ROM) of 1.60º ± 0.66 and 7.64 º ± 2.34 across 102° of flexion respectively. The percent elongation of the posterior cruciate ligament (PCL) varied the most across participants (8.65 ± 6.2%) compared to the ACL (2.34 ± 2.1%), MCL (1.41 ± 0.5%) and LCL (1.75 ± 1.6%) respectively. The combination of femur markers and anthropometrics was able to reconstruct simplified tibiofemoral articulations the best, but not within 5 mm of RMSE. Conclusion: Inter-subject variability in passive kinematic motion derived from patient-specific morphology highlights the need for personalized and accessible musculoskeletal models in growing populations. Furthermore, simplified distal femur morphology can be reconstructed from anthropometrics and marker positions, but proximal tibia morphology requires more information.

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Yes / Despite the abundant use of polyethylene oxides (PEOs) and their integration as an excipient in numerous pharmaceutical products, there have been no previous reports of applying this important thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. In this work, we have investigated the manufacture of oral doses via FDM 3D printing by employing PEOs as a backbone polymer in combination with polyethylene glycol (PEG). Blends of PEO (molecular weight 100 K, 200 K, 300 K, 600 K or 900 K) with PEG 6 K (plasticiser) and a model drug (theophylline) were hot-melt extruded. The resultant filaments were used as a feed for FDM 3D printer to fabricate oral dosage forms (ODFs) with innovative designs. ODFs were designed in a radiator-like geometry with connected paralleled plates and inter-plate spacing of either 0.5, 1, 1.5 or 2 mm. X-ray diffraction patterns of the filaments revealed the presence of two distinctive peaks at 2θ = 7° and 12°, which can be correlated to the diffraction pattern of theophylline crystals. Blends of PEO and PEG yielded filaments of variable mechanically resistance (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with PEO 100 K, 200 K, 300 K, 600 K or 900 K, respectively). Filaments of PEO at a molecular weight of 200–600 K were compatible with FDM 3D printing process. Further increase in PEO molecular weight resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing process. A minimal spacing (1 mm) between parallel plates of the radiator-like design deemed essential to boost drug release from the structure. This is the first report of utilising this widely used biodegradable polymer species (PEOs and PEG) in FDM 3D printing.

Presented work deals with Biomechanical study of the facial skeleton. This work is focused on the fixation of the mandible after removal of a tumor from affected bone tissue. The aim of the work is to perform biomechanical study of the facial skeleton with subsequent detailed stress strain analysis of two mandible implants designed and manufactured for specific patients. The geometry model of mandible used for design of mandible implants and used for computational modelling has been obtained on the basis of CT data of two patients. A Theoretical-Clinical sub-study that deals with the comparison the CT data processing which is necessary for creating the model of geometry is a part of the thesis. Two models of mandible with applied mandible implant have been created for two specific patients with tumorous mandible bone tissue. Stress strain analysis has been performed for these two models. Results of the stress strain analysis of two models of mandibles with mandible implants are presented in the final chapters of the thesis. Findings of the biomechanical study have been published and applied in clinical practice.