Doctor of Philosophy

dissertationAltered mechanics are believed to initiate osteoarthritis in hips with acetabular dysplasia. Periacetabular osteotomy (PAO) is the preferred surgical treatment; however, it is unknown if the procedure normalizes joint anatomy and mechanics. Changes in three-dimensional (3D) morphology and chondrolabral mechanics were quantified after PAO. Finite element (FE) models demonstrated that PAO improved the distribution of coverage, reduced stress, increased congruity, and prevented cartilage thinning. However, changes in mechanics were not consistent. In fact, one patient exhibited increased stress after surgery, which was believed to be a result of over-correction. Therefore, methods to integrate morphologic and biomechanical analysis with clinical care could standardize outcomes of PAO. FE simulations are time-intensive and require significant computing resources. Therefore, the second aim was to implement an efficient method to estimate mechanics. An enhanced discrete element analysis (DEA) model of the hip that accurately incorporated cartilage geometry and efficiently calculated stress was developed and analyzed. Although DEA model estimates predicted elevated magnitudes of contact stress, the distribution corresponded well with FE models. As a computationally efficient platform, DEA could assist in diagnosis and surgical planning. Imaging is a precursor to analyzing morphology and biomechanics. Ideally, an imaging protocol would visualize bone and soft-tissue at high resolution without ionizing radiation. Magnetic resonance imaging (MRI) with 3D dual-echo-steady-state (DESS) is a promising sequence to image the hip noninvasively, but its accuracy has not been quantified. Therefore, the final aim was to implement and validate the use of 3D DESS MRI in the hip. Using direct measurements of cartilage thickness as the standard, 3D DESS MRI imaged cartilage to ~0.5 mm of the physical measurements with 95% confidence, which is comparable to the most accurate hip imaging protocol presented to date. In summary, this dissertation provided unique insights into the morphologic and biomechanical features following PAO. In the future, DEA could be combined with 3D DESS MRI to efficiently analyze contact stress distributions. These methods could be incorporated into preoperative planning software, where the algorithm would predict the optimal relocation of the acetabulum to maximize femoral head coverage while minimizing contact stress, and thereby improve long-term outcomes of PAO

Modeling and Simulation in Engineering

This book provides an open platform to establish and share knowledge developed by scholars, scientists, and engineers from all over the world, about various applications of the modeling and simulation in the design process of products, in various engineering fields. The book consists of 12 chapters arranged in two sections (3D Modeling and Virtual Prototyping), reflecting the multidimensionality of applications related to modeling and simulation. Some of the most recent modeling and simulation techniques, as well as some of the most accurate and sophisticated software in treating complex systems, are applied. All the original contributions in this book are jointed by the basic principle of a successful modeling and simulation process: as complex as necessary, and as simple as possible. The idea is to manipulate the simplifying assumptions in a way that reduces the complexity of the model (in order to make a real-time simulation), but without altering the precision of the results

Investigation of Subchondral Bone Abnormalities associated with Osteoarthritis using Image-Based Biomechanics

Osteoarthritis (OA) is degenerative disease caused by a mechanical failure of bone and cartilage. Common risk factors for developing OA include: being over-weight, female, having joint malalignment, or a history of prior joint injury. Post-traumatic OA is extremely common in the knee as individuals frequently suffer injuries to structures that provide stability to the joint. To enhance our understanding about OA, animal models are employed where the injury can be and monitored in a controlled environment. When used in conjunction with pre-clinical imaging techniques the longitudinal degradation of bone and cartilage can be quantitatively monitored in vivo. Recent evidence has identified cystic lesions within the subchondral bone as the possible source of painful symptoms and accelerated disease progression, but little is known about their etiology. The purpose of this thesis was to improve knowledge regarding the mechanism that causes subchondral cysts. OA was induced in the rodent knee via surgery, and the pathological changes were quantified with micro-CT and MRI. The composition of the cysts was correlated with end-stage histology. Thus, an accurate definition of OA bone cysts was achieved. To assess the effect of cysts in human bone, a study was conducted using a patient data set restrospectively. Using finite element (FE) analysis, higher stress values were found within bone surrounding cysts. Therefore, the probable mechanism of cyst expansion, stress induced resorption, was identified. Finally, the FE models of the bones were combined with soft tissue structures – from a co-registered MRI – to produce comprehensive patient-specific models of the knee

Developing a cationic contrast agent for computed tomographic imaging of articular cartilage and synthetic biolubricants for early diagnosis and treatment of osteoarthritis

Osteoarthritis (OA) causes debilitating pain for millions of people, yet OA is typically diagnosed late in the disease process after severe damage to the articular cartilage has occurred and few treatment options exist. Furthermore, destructive techniques are required to measure cartilage biochemical and mechanical properties for studying cartilage function and changes during OA. Hence, research and clinical needs exist for non-destructive measures of cartilage properties. Various arthroscopic (e.g., ultrasound probes) and imaging (e.g., MRI or CT) techniques are available for assessing cartilage less destructively. However, arthroscopic methods are limited by patient anesthesia/infection risks and cost, and MRI is hindered by high cost, long image acquisition times and low resolution. Contrast-enhanced CT (CECT) is a promising diagnostic tool for early-stage OA, yet most of its development work utilizes simplified and ideal cartilage models, and rarely intact, pre-clinical animal or human models. To advance CECT imaging for articular cartilage, this dissertation describes further development of a new cationic contrast agent (CA4+) for minimally-invasive assessment of cartilage biochemical and mechanical properties, including glycosaminoglycan content, compressive modulus, and coefficient of friction. Specifically, CA4+ enhanced CT is compared to these three cartilage properties initially using an ideal bovine osteochondral plug model, then the technique is expanded to examine human finger joints and both euthanized and live mouse knees. Furthermore, CECT attenuations with CA4+ map bovine meniscal GAG content and distribution, signifying CECT can evaluate multiple tissues involved in OA. CECT's sensitivity to critical cartilage and meniscal properties demonstrates its applicability as both a non-destructive research tool as well as a method for diagnosing and monitoring early-stage OA. Additionally, CECT enables evaluation of efficacy for a new biolubricant (2M TEG) for early-stage OA treatment. In particular, CECT can detect the reduced wear on cartilage surfaces for samples tested in 2M TEG compared to samples tested in saline (negative control). With its sensitivity to cartilage GAG content, surface roughness, and mechanical properties, CA4+ enhanced CT will serve as a valuable tool for subsequent in vivo animal and clinical use

Magnetic Resonance Imaging for the Functional Analysis of Tissues and Biomaterials

Articular cartilage provides mechanical load dissipation and lubrication between joints, and additionally provides protects from abrasion. At present, there are no treatments to cure or attenuate the degradation of cartilage. Early detection and the ability to monitor the progression of osteoarthritis is important for developing effective therapies. However, few reliable imaging biomarkers exist to detect cartilage disease before advanced degeneration in the tissue. One specialized MRI technique, termed displacements under applied loading by MRI (dualMRI), was developed to measure displacements and strain in musculoskeletal tissues, hydrogels and engineered constructs. However, deformation information does not directly describe spatial distributions of tissue properties (e.g. stiffness), which is critical to the understanding of disease progression. To achieve the stiffness measurement, we developed and validated an inverse modeling workflow that combined dualMRI, to directly measure intratissue deformation, with topology optimization in the application of heterogeneous (layered) materials representative of the complex gradient architecture of articular cartilage. We successfully reconstructed bi-layer stiffness from ideal displacements calculated from forward simulation as well as from experimental data measured from dualMRI. To monitor the progression of osteoarthritis, we measured and analyzed biomechanical changes of sheep stifle cartilage after meniscectomy. We found that 2nd principal strain and max shear strain in the femur contact region are sensitive to cartilage degeneration at different stages and compared to more conventional methods like quantitative MRI. To investigate the biomechanical changes in articular cartilage with defect and repair, we implanted decellularized cartilage implant into sheep cartilage defect and evaluate the repair results using quantitative MRI and dualMRI. We found that implants placed in joints demonstrated lower strains compared to joints with untreated defects

Three-dimensional Ultrasound Imaging For Quantifying Knee Cartilage Volume

Arthritis is the most common chronic health condition in Canada, with the most common form being osteoarthritis (OA). There is a great clinical need for an objective imaging-based point-of-care tool to assess OA status, progression, and response to treatment. This thesis aims to validate a handheld mechanical three-dimensional (3D) ultrasound (US) device against the current clinical standard of magnetic resonance imaging (MRI) for quantifying femoral articular cartilage (FAC) volume. Knee images of 25 healthy volunteers were acquired using 3D US and 3.0 Tesla MRI scans. Two raters manually segmented the trochlear FAC during separate sessions to assess intra- and inter-rater reliabilities. The results demonstrated that 3D US has excellent reliability and strong concurrent validity with MRI for measuring healthy FAC volume. 3D US is a promising, inexpensive, and widely accessible imaging modality that will enable clinicians and researchers to obtain additional information without added complexity or discomfort to patients

Book of Abstracts 15th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering and 3rd Conference on Imaging and Visualization

In this edition, the two events will run together as a single conference, highlighting the strong connection with the Taylor & Francis journals: Computer Methods in Biomechanics and Biomedical Engineering (John Middleton and Christopher Jacobs, Eds.) and Computer Methods in Biomechanics and Biomedical Engineering: Imaging and Visualization (JoãoManuel R.S. Tavares, Ed.). The conference has become a major international meeting on computational biomechanics, imaging andvisualization. In this edition, the main program includes 212 presentations. In addition, sixteen renowned researchers will give plenary keynotes, addressing current challenges in computational biomechanics and biomedical imaging. In Lisbon, for the first time, a session dedicated to award the winner of the Best Paper in CMBBE Journal will take place. We believe that CMBBE2018 will have a strong impact on the development of computational biomechanics and biomedical imaging and visualization, identifying emerging areas of research and promoting the collaboration and networking between participants. This impact is evidenced through the well-known research groups, commercial companies and scientific organizations, who continue to support and sponsor the CMBBE meeting series. In fact, the conference is enriched with five workshops on specific scientific topics and commercial software.info:eu-repo/semantics/draf

A diagnostic imaging technique and therapeutic strategy for early osteoarthritis

Thesis (Ph.D.)--Boston UniversityOsteoarthritis (OA) is a chronic, progressive disease of diarthrodial joints arising from the breakdown of articular cartilage. As one of the leading causes of disability and lifestyle limitations in the United States, osteoarthritis is estimated to affect 27 million people in the U.S. and cost the economy $128 billion annually. Current diagnostic techniques detect OA only in its later stages, when irreversible cartilage damage has already occurred. A reliable, non-invasive method for diagnosing OA in its early stages would provide an opportunity to intervene and potentially to stay disease progression. Likewise, the field of OA research would benefit from a technique that allows tissue engineering and small molecule therapies to be evaluated longitudinally. Contrast-enhanced computed tomography (CECT) of cartilage is a developing medical imaging technique for evaluating cartilage biochemical and biomechanical properties. CECT has been shown to accurately quantify measures of cartilage integrity such as glycosaminoglycan (GAG) content, equilibrium compressive modulus, and coefficients of friction. In the studies presented herein, cationic iodinated contrast agents are developed for quantitative cartilage CECT, a technique predicated on the diffusion and partitioning of a charged contrast agent into the cartilage. The experiments show that cationic contrast agents lack specific interactions with anionic GAGs and are highly taken up in cartilage due, instead, to their electrostatic attraction. At diffusion equilibrium, both anionic and cationic agents indicate GAG content and biomechanical properties as measured by microcomputed tomography, though cationic contrast agents were found to diffuse through cartilage more slowly than anionic ones. Translating CECT to intact joints with clinically available helical CT scanners bears promising results, but concerns remain regarding in vivo applicability. Anionic contrast agents enable GAG content quantification following brief contrast agent exposure, whereas cationic agents require full equilibration within the tissue. To explore treatment modalities for early OA, a novel interpenetrating hydrogel method was developed to reconstitute the mechanical properties of cartilage models for early OA. Preliminary results show that the interpenetrating network strengthened cartilage with respect to compressive loading suggesting that the treatment could potentially serve as a functional replacement for GAG lost in the early stages of OA

Impact of Homeostasis Disruption on the Structure and Function of Murine Articular Cartilage

Articular cartilage plays a vital role in facilitating pain-free movement and load distribution in synovial joints, such as the knee. Owing to its complex structure-functional requirements and limited regenerative capacity, articular cartilage is particularly vulnerable to deterioration triggered by intrinsic and extrinsic insults. For instance, abnormal loading, trauma and aging can disrupt cellular, anatomical, and functional homeostasis within the knee joint and/or articular cartilage microenvironment, contributing to the pathogenesis of tissue degradation and degenerative joint diseases, particularly osteoarthritis (OA). In this context, it is essential to understand how cartilage and the joint microenvironment respond to differential levels of tissue homeostatic disruption and the resulting implication on remodeling and repair outcomes. In this multifaceted study, I employed several transgenic mouse models in conjunction with histological, imaging, and mechanical testing modalities to deepen our understanding of structural and functional changes associated with degeneration and regeneration of murine articular cartilage