Modelling gait abnormalities and bone deformities in children with cerebel palsy

Cerebral palsy (CP) is a neuromuscular disorder that affects the motor control of muscles. CP children exhibit abnormal walking patterns and frequently develop lower limb, long bone deformities. To improve functionality and guide orthopaedic treatments effectively, it is critical to elucidate the relationship existing between bone morphology and movement of the lower limbs CP children. The hypothesis of this study is that gait abnormalities result in bone deformities. The investigation of this complex relationship represents the core of this thesis. The examination of magnetic resonance images and gait analysis of healthy and CP children showed different development in femoral and tibial morphology and varied gait characteristics between them. Similarly, different correlations between bone morphology and gait characteristics resulted in healthy and CP children. Gait characteristics also varied between CP children. An objective and quantitative graphical classification method of CP gait patterns was developed. This classified the CP children in overlapping clusters according to their gait patterns, confirming the presence of multiple gait abnormalities on the same lower limb for CP children. With the intention to define the effect of the walking characteristics on the bone structure, femoral muscle and hip contact forces in healthy and CP children with different walking strategies were estimated by using inverse dynamic analysis. The different gait styles resulted in different loadings on the developing femur bone. These constituted the loading conditions for bone growth analysis. A three-dimensional finite element model for femoral growth was developed and mechanobiological theories applied in order to predict femur changes over time in healthy and CP children. The models predicted higher femoral anteversion and neck3 shaft angle formation in children with CP, emphasizing how different gait characteristics can influence bone morphology. This information has potential to explain and eventually prevent or treat the development of bone deformities in CP children

Comfort-Centered Design of a Lightweight and Backdrivable Knee Exoskeleton

This paper presents design principles for comfort-centered wearable robots and their application in a lightweight and backdrivable knee exoskeleton. The mitigation of discomfort is treated as mechanical design and control issues and three solutions are proposed in this paper: 1) a new wearable structure optimizes the strap attachment configuration and suit layout to ameliorate excessive shear forces of conventional wearable structure design; 2) rolling knee joint and double-hinge mechanisms reduce the misalignment in the sagittal and frontal plane, without increasing the mechanical complexity and inertia, respectively; 3) a low impedance mechanical transmission reduces the reflected inertia and damping of the actuator to human, thus the exoskeleton is highly-backdrivable. Kinematic simulations demonstrate that misalignment between the robot joint and knee joint can be reduced by 74% at maximum knee flexion. In experiments, the exoskeleton in the unpowered mode exhibits 1.03 Nm root mean square (RMS) low resistive torque. The torque control experiments demonstrate 0.31 Nm RMS torque tracking error in three human subjects.Comment: 8 pages, 16figures, Journa

A systematic review and meta-analysis on the efficacy of stem cell therapy on bone brittleness in mouse models of osteogenesis imperfecta

There is no cure for osteogenesis imperfecta (OI), and current treatments can only partially correct the bone phenotype. Stem cell therapy holds potential to improve bone quality and quantity in OI. Here, we conduct a systematic review and meta-analysis of published studies to investigate the efficacy of stem cell therapy to rescue bone brittleness in mouse models of OI. Identified studies included bone marrow, mesenchymal stem cells, and human fetal stem cells. Effect size of fracture incidence, maximum load, stiffness, cortical thickness, bone volume fraction, and raw engraftment rates were pooled in a random-effects meta-analysis. Cell type, cell number, injection route, mouse age, irradiation, anatomical bone, and follow up time were considered as moderators. It was not possible to investigate further parameters due to the lack of standards of investigation between the studies. Despite the use of oim mice in the majority of the investigations considered and the lack of sham mice as control, this study demonstrates the promising potential of stem cell therapy to reduce fractures in OI. Although their low engraftment, cell therapy in mouse models of OI had a beneficial effect on maximum load, but not on stiffness, cortical thickness and bone volume. These parameters all depend on bone geometry and do not inform on its material properties. Being bone fractures the primary symptom of OI, there is a critical need to measure the fracture toughness of OI bone treated with stem cells to assess the actual efficacy of the treatment to rescue OI bone brittleness

Ex vivo determination of bone tissue strains for an in vivo mouse tibial loading model

AbstractPrevious studies introduced the digital image correlation (DIC) as a viable technique for measuring bone strain during loading. In this study, we investigated the sensitivity of a DIC system in determining surface strains in a mouse tibia while loaded in compression through the knee joint. Specifically, we examined the effect of speckle distribution, facet size and overlap, initial vertical alignment of the bone into the loading cups, rotation with respect to cameras, and ex vivo loading configurations on the strain contour maps measured with a DIC system.We loaded tibiae of C57BL/6 mice (12 and 18 weeks old male) up to 12N at 8N/min. Images of speckles on the bone surface were recorded at 1N intervals and DIC was used to compute strains. Results showed that speckles must have the correct size and density with respect to the facet size of choice for the strain distribution to be computed and reproducible. Initial alignment of the bone within the loading cups does not influence the strain distribution measured during peak loading, but bones must be placed in front of the camera with the same orientation in order for strains to be comparable. Finally, the ex vivo loading configurations with the tibia attached to the entire mouse, or to the femur and foot, or only to the foot, showed different strain contour maps.This work provides a better understanding of parameters affecting full field strain measurements from DIC in ex vivo murine tibial loading tests

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom's macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy

Spatial relationship between bone formation and mechanical stimulus within cortical bone: Combining 3D fluorochrome mapping and poroelastic finite element modelling

Bone is a dynamic tissue and adapts its architecture in response to biological and mechanical factors. Here we investigate how cortical bone formation is spatially controlled by the local mechanical environment in the murine tibia axial loading model (C57BL/6). We obtained 3D locations of new bone formation by performing ‘slice and view’3D fluorochrome mapping of the entire bone and compared these sites with the regions of high fluid velocity or strain energy density estimated using a finite element model, validated with ex-vivo bone surface strain map acquired ex-vivo using digital image correlation. For the comparison, 2D maps of the average bone formation and peak mechanical stimulus on the tibial endosteal and periosteal surface across the entire cortical surface were created. Results showed that bone formed on the periosteal and endosteal surface in regions of high fluid flow. Peak strain energy density predicted only the formation of bone periosteally. Understanding how the mechanical stimuli spatially relates with regions of cortical bone formation in response to loading will eventually guide loading regime therapies to maintain or restore bone mass in specific sites in skeletal pathologies

Age and Sex Differences in Load-Induced Tibial Cortical Bone Surface Strain Maps

Bone adapts its architecture to the applied load; however, it is still unclear how bone mechano-adaptation is coordinated and why potential for adaptation adjusts during the life course. Previous animal models have suggested strain as the mechanical stimulus for bone adaptation, but yet it is unknown how mouse cortical bone load-related strains vary with age and sex. In this study, full-field strain maps (at 1 N increments up to 12 N) on the bone surface were measured in young, adult, and old (aged 10, 22 weeks, and 20 months, respectively), male and female C57BL/6J mice with load applied using a noninvasive murine tibial model. Strain maps indicate a nonuniform strain field across the tibial surface, with axial compressive loads resulting in tension on the medial side of the tibia because of its curved shape. The load-induced surface strain patterns and magnitudes show sexually dimorphic changes with aging. A comparison of the average and peak tensile strains indicates that the magnitude of strain at a given load generally increases during maturation, with tibias in female mice having higher strains than in males. The data further reveal that postmaturation aging is linked to sexually dimorphic changes in average and maximum strains. The strain maps reported here allow for loading male and female C57BL/6J mouse legs in vivo at the observed ages to create similar increases in bone surface average or peak strain to more accurately explore bone mechano-adaptation differences with age and sex

Age and Sex Differences in Load-Induced Tibial Cortical Bone Surface Strain Maps

Bone adapts its architecture to the applied load; however, it is still unclear how bone mechano-adaptation is coordinated and why potential for adaptation adjusts during the life course. Previous animal models have suggested strain as the mechanical stimulus for bone adaptation, but yet it is unknown how mouse cortical bone load-related strains vary with age and sex. In this study, full-field strain maps (at 1 N increments up to 12 N) on the bone surface were measured in young, adult, and old (aged 10, 22 weeks, and 20 months, respectively), male and female C57BL/6J mice with load applied using a noninvasive murine tibial model. Strain maps indicate a nonuniform strain field across the tibial surface, with axial compressive loads resulting in tension on the medial side of the tibia because of its curved shape. The load-induced surface strain patterns and magnitudes show sexually dimorphic changes with aging. A comparison of the average and peak tensile strains indicates that the magnitude of strain at a given load generally increases during maturation, with tibias in female mice having higher strains than in males. The data further reveal that postmaturation aging is linked to sexually dimorphic changes in average and maximum strains. The strain maps reported here allow for loading male and female C57BL/6J mouse legs in vivo at the observed ages to create similar increases in bone surface average or peak strain to more accurately explore bone mechano-adaptation differences with age and sex