Macroscopic Anisotropic Bone Material Properties in Children with Severe \u3cem\u3eOsteogenesis imperfecta\u3c/em\u3e

Children with severe osteogenesis imperfecta(OI) typically experience numerous fractures and progressive skeletal deformities over their lifetime. Recent studies proposed finite element models to assess fracture risk and guide clinicians in determining appropriate intervention in children with OI, but lack of appropriate material property inputs remains a challenge. This study aimed to characterize macroscopic anisotropic cortical bone material properties and investigate relationships with bone density measures in children with severe OI. Specimens were obtained from tibial or femoral shafts of nine children with severe OI and five controls. The specimens were cut into beams, characterized in bending, and imaged by synchrotron radiation X-ray micro-computed tomography. Longitudinal modulus of elasticity, yield strength, and bending strength were 32–65% lower in the OI group (p \u3c 0.001). Yield strain did not differ between groups (p ≥ 0.197). In both groups, modulus and strength were lower in the transverse direction (p ≤ 0.009), but anisotropy was less pronounced in the OI group. Intracortical vascular porosity was almost six times higher in the OI group (p \u3c 0.001), but no differences were observed in osteocyte lacunar porosity between the groups (p = 0.086). Volumetric bone mineral density was lower in the OI group (p \u3c 0.001), but volumetric tissue mineral density was not (p = 0.770). Longitudinal OI bone modulus and strength were correlated with volumetric bone mineral density (p ≤ 0.024) but not volumetric tissue mineral density (p ≥ 0.099). Results indicate that cortical bone in children with severe OI yields at the same strain as normal bone, and that their decreased bone material strength is associated with reduced volumetric bone mineral density. These results will enable the advancement of fracture risk assessment capability in children with severe OI

Injury Risk Assessment of the Femur in Children with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility and decreased bone mass, which leads to high rates of bone fracture. OI has a prevalence of 1/5,000 to 1/10,000 in the United States. About 90% of persons with OI have a genetic mutation in the coding for collagen type I, which is the major protein of connective tissues, including bone. While its prevalence classifies it as a rare disease, it is the most common disorder of bone etiology. Until recently, little was known about the mechanics and materials of OI bone or their impact on fracture risk. Fracture risk is typically characterized by clinical type and radiographs. Finite element (FE) models have recently been developed to examine fracture risk during ambulation and various daily activities of the femur and tibia in children and adolescents with OI. This research aims to provide further information about the impact of OI in children and adolescents during loading conditions. FE models of the femur with normal bone, OI type I (mild) bone and OI type III (severe) bone material properties were developed and analyzed. These models showed the effects of lateral bowing versus increased gluteus medius and gluteus maximus force production on bone injury risk. Lateral bowing and muscle force increase permutations to the standard model of no bowing and normal muscle forces during ambulation showed significant changes to stress levels. Along with FE models, quantitative gait analyses were performed on 10 children with mild OI and ten age- and gender-matched controls to analyze the firing patterns of the gluteus medius and gluteus maximus muscles during normal ambulation. The OI population exhibited a delay in gluteus maximus activation. Additional FE models examined the impact of creating the model directly from a CT scan of a child with severe OI versus scaling a standard model to match the size and shape of and OI femur based on x-ray images alone. Comparison of these two model geometry development techniques resulted in a significant difference in femoral stresses and strains

Reconstruction of Cortical and Cancellous Bone in Tibia with Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is the bone fragility disorder that leads to long bone bowing. Finite Element Analysis (FEA) has become the tool of choice to assess behaviour structural within bones. Currently, the FEA performed on the tibia is based on the bone constructed without considering different components of the bone, where the bone was created as a single material. In an attempt to further investigate the bone with OI, the present study was conducted to investigate the mechanical stress distribution using finite element model of the OI affected tibia. The model was reconstructed from the CT images composed of cortical and cancellous bones obtained from Osirix database. The segmentation of the cortical and cancellous of the tibia was performed on 346 images using two different methods which are global thresholding and the selection of the binary object. The segmented images were used to develop a three-dimensional model of the tibia using VOXELCON software. The boundary conditions were set to the meshed model in preparation for the finite element analysis using the same software. Displacements ranging from 5 mm to 35 mm were assigned to a point in between the proximal and distal of the tibia model. In the coronal plane, the highest stress levels were recorded on the medial side of the cortical bone, whereas in the sagittal plane, the highest stress levels were recorded on the anterior side of the cortical bone when the model was subjected to 35 mm displacement. The cancellous bone, however, showed lower stress levels on both planes when subjected to similar displacement. With each increment of displacement, the model experienced more stress and caused the higher percentage volume of individual cortical and cancellous that exceed critical stress of 115 MPa. There were no significant differences in the percentage volume of voxels affected between the cortical and cancellous bones for both coronal and sagittal planes with the pvalue of 0.29 and 0.32 respectively (p > 0.05). There was no significant difference obtained for the percentage volume of voxels affected between the coronal and sagittal planes with the p-value is 0.13 (p > 0.05)

Characterization of Bone Material Properties and Microstructure in Osteogenesis Imperfecta/Brittle Bone Disease

Osteogenesis imperfecta (OI) is a genetic disorder primarily associated with mutations to type I collagen and resulting in mild to severe bone fragility. To date, there is very little data quantifying OI cortical bone mechanics. The purpose of this dissertation was to investigate bone microstructure, mineralization, and mechanical properties in adolescents with OI. Characterization studies were performed on small osteotomy specimens obtained from the extremities during routine corrective surgeries. Nanoindentation was used to examine the longitudinal elastic modulus and hardness at the material level for mild OI type I vs. severe OI type III. Both modulus and hardness were significantly higher (by 7% and 8%, respectively) in mild OI cortical bone compared to the more severe phenotype. Lamellar microstructure also affected these properties, as the younger bone material immediately surrounding osteons showed decreased modulus (13%) and hardness (11%) compared to the older interstitial material. A high resolution micro-computed tomography system utilizing synchrotron radiation (SRµCT) was described and used to analyze the microscale vascular porosity, osteocyte lacunar morphometry, and bone mineral density in OI vs. healthy individuals. Vascular porosity, canal diameter, and osteocyte lacunar density were all two to six times higher in OI cortical bone. Osteocytes were also more spherical in shape. Finally, three-point bending techniques were used to evaluate the microscale mechanical properties of OI cortical bone in two different orientations. Elastic modulus, flexural yield strength, ultimate strength, and crack-growth toughness were three to six times higher in specimens whose pore structure was primarily oriented parallel vs. perpendicular to the long bone axis. There was also a strong negative correlation between the elevated vascular porosity of OI cortical bone and its elastic modulus, flexural yield strength, and ultimate strength. This relationship was independent of osteocyte lacunar density and tissue mineral density. In summary, these findings highlight new material and microstructural changes within OI cortical bone that help contribute to its fragility. They also underscore a deep connection between bone structure and mechanical integrity at multiple length scales

Modelling of patient-specific femur with osteogenesis imperfecta to determine the fracture risk under various loads

Osteogenesis imperfecta (OI) is a fragile bone disease characterized by easy fractures. The femur consists of cortical and cancellous bone, each with different mechanical properties. Bone fractures often occur throughout patients’ lifetime. However, doctors still have no quantitative method to predict fractures. Therefore, this project’s purpose is to investigate the OI femoral fracture risk to help prevent fractures. The project consists of three sections; cortical and cancellous segmentation, reconstruction of 3D OI femoral model and finite element analysis (FEA) of the OI femur to obtain fracture risk. The fracture risk in daily activities and the fracture load were examined. All the stress values were judged by the fracture criteria, assumed as 115 MPa. The exercises that exerted force more than 6 times of body weight can cause fractures. In addition, the optimal compressive force and tensile force were 919.7 N and 912.1 N, respectively, while medial and lateral impact were 230.8 N. Cancellous bone was not affected even a fracture happen. Based on these findings, we can conclude that when the OI femur is subjected to lateral or medial forces, the femur breaks easily. The bone can be reconstructed into a solid body without having to separate bone into cortical and cancellous

Current concepts in osteogenesis imperfecta:bone structure, biomechanics and medical management

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity. Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is - considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult. Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation. This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society

Pediatric Fractures

This reprint contains original research and review chapters concerning the latest advancements in various topics related to pediatric fractures. Topics include fractures of the face, clavicle, shoulder, elbow, forearm, wrist, pelvis, femur, and tibia; special considerations focus on osteogenesis imperfecta patients; and consideration is also given to general pediatric fracture topics, such as the influence of the COVID-19 pandemic, mortality after pediatric trauma, the effects of NSAID and electronic cigarette use, and chapters on epidemiology and physical activity

Biomechanics

Biomechanics is a vast discipline within the field of Biomedical Engineering. It explores the underlying mechanics of how biological and physiological systems move. It encompasses important clinical applications to address questions related to medicine using engineering mechanics principles. Biomechanics includes interdisciplinary concepts from engineers, physicians, therapists, biologists, physicists, and mathematicians. Through their collaborative efforts, biomechanics research is ever changing and expanding, explaining new mechanisms and principles for dynamic human systems. Biomechanics is used to describe how the human body moves, walks, and breathes, in addition to how it responds to injury and rehabilitation. Advanced biomechanical modeling methods, such as inverse dynamics, finite element analysis, and musculoskeletal modeling are used to simulate and investigate human situations in regard to movement and injury. Biomechanical technologies are progressing to answer contemporary medical questions. The future of biomechanics is dependent on interdisciplinary research efforts and the education of tomorrow’s scientists

Novel Models to Image and Quantify Bone Drug Efficacy and Disease Progression In Vivo: Addressing the Fragility Phenotype

Bone is a composite biomaterial of mineral crystals, organic matrix, and water. Each contributes to bone quality and strength and may change independently, or together, with disease progression and treatment. Even so, there is a near ubiquitous reliance on ionizing x-ray-based approaches to characterize bone mineral density (BMD) which only accounts for ~60% of bone strength and may not adequately predict fracture risk. In a rare and severe bone disease such as osteogenesis imperfecta (OI), the hallmark genotypic and phenotypic variability makes clinical management particularly challenging. Treatment strategies rely on anti-resorptive bisphosphonates which address osteoclastic, but not osteoblastic deficiencies. Radiographic characterization of efficacy identifies structural, but not biomaterial-level alterations. Together, there is an unmet need for improved treatment strategies and means to longitudinally monitor treatment outcomes at the biomaterial-level to improve clinical management of bone disease. This thesis will describe a novel model to understand and predict individual patient treatment response to an emerging therapeutic, sclerostin antibody (SclAb) prior to clinical exposure. We then challenge the current bone imaging gold-standard with the characterization of a novel zero echo time (ZTE) magnetic resonance imaging (MRI) technique that may hold promise in identifying matrix-level and biochemical changes characteristic of OI and other diseases. SclAb has gained interest as a promising bone-forming therapeutic suggesting a novel treatment strategy through inhibition of endogenous sclerostin but effects in human pediatric OI bone remains unknown. We treated bone samples retrieved from pediatric OI patients during surgery with SclAb in vitro and quantified transcriptional response of Wnt-related genes. Results demonstrated a bone-forming response in a manner paralleling pre-clinical experience. Factors inherent to the unique phenotypic/genotypic patient profile such as the patient’s baseline cellular phenotype appear to govern response magnitude; OI patients with low untreated expression of osteoblast-related genes demonstrated the greatest magnitude of upregulation during treatment. To expand findings in vivo, we developed a novel OI xenograft model where bone was implanted into a host-derived microenvironment. The model was efficacious; bone was bioaccessible by the host and retained patient-derived bone cells throughout implantation. Treatment increased bone density and volume with a variable outcome between cortical and trabecular bone. Patients with low baseline osterix demonstrated robust human-derived osterix-expression with treatment supporting in vitro findings. The validated xenograft model can be used to establish patient-specific factors influencing treatment response suggesting a personalized medicine approach to managing OI. Characterization of treatment efficacy for OI, as well as other metabolic bone diseases, is complicated by the lack of imaging modality able to safely monitor material-level and biochemical changes in vivo. To improve upon BMD, we tested the efficacy of a 3D ZTE-MRI approach in an estrogen-deficient (OVX) model of osteoporosis during growth. ZTE-MRI-derived BMD correlated significantly with BMD measured using the gold standard, µCT, which significantly increased longitudinally over the duration of the study. Growth appeared to overcome estrogen-deficient changes in bone mass yet ZTE-MRI detected significant changes consistent with estrogen deficiency by ten weeks in cortical water, cortical matrix organization (T1) and marrow fat. Findings point to ZTE-MRI’s ability to quantify BMD in good agreement with the gold standard and detect biochemical alterations consistent with disease independent of the mineral phase suggesting its value for bone imaging. Together, results from this thesis indicate a new treatment design and non-ionizing imaging strategy to improve management of bone diseases such as OI.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149889/1/rachelks_1.pd

Development of procedures to perform nanoindentation tests on different bone structures

Negli ultimi anni, la nanoindentazione è emersa come potente tecnica per indagare le proprietà micromeccaniche dell'osso. L'indentazione consiste nel premere una punta rigida con una forza nota in un semispazio semi-infinito e nel misurare direttamente o indirettamente l'area di contatto. L'obiettivo principale di questo lavoro è stato quello di sviluppare una procedura per eseguire test di nanoindentazione al fine di studiare le proprietà elastiche e inelastiche di diverse strutture ossee. Dalle misure di nanoindentazione sono stati ricavati i valori di reduced modulus, hardness, indentation modulus ed elastic modulus. L'idea era di eseguire test di nanoindentazione sia per applicazioni precliniche che cliniche e per questo motivo, i tests sono stati effettuati sia su ossa di topo che su ossa umane affette da una particolare condizione patologica, chiamata Osteogenesi Imperfetta. È la prima volta che questi tests vengono eseguiti su tibie di topo, nello specifico su fette di quattro tibie di due ceppi (C57B1/6 e Balb/C), sia su osso corticale che trabecolare. Abbiamo trovato che il modulo elastico varia tra 16.50 ± 7.10 GPa (C57B1/6, osso trabecolare) e 25.08 ± 5.21 GPa (Balb/C, osso corticale). L’hardness varia tra 0.62 ± 0.27 GPa (C57B1/6, osso trabecolare) e 0.96 ± 0.20 GPa (Balb/C, osso corticale). Le nanoindentazioni sul campione di OI (proveniente dall’arto superiore) sono state condotte su diverse fette, per analizzare le potenziali differenze tra le due regioni e le quattro sezioni. Abbiamo trovato un modulo elastico di 12.14 ± 5.79 GPa e l’hardness di 0.49 ± 0.21 GPa. In conclusione, abbiamo sviluppato questo nuovo protocollo che può essere applicato a diversi lavori futuri. Ad esempio, per le applicazioni precliniche aumentando il numero di topi diversi o per applicazioni cliniche aumentando il numero dei campioni di OI, raccogliendo campioni con diversi tipi di OI, indagando l'effetto dei trattamenti o confrontando le ossa di OI con osso sano