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Advances in nanoscopic mechanobiological structure-property relationship in human bones for tailored fragility prevention
... The concurrent modelling approach integrates the multiple scales into a unified numerical framework, providing a simultaneous analysis across these scales. The approach is particularly useful for structures such as cellular designs, which experience large deformation, as the strategy has the capacity to capture real-time responses, and inter-scale interactions [126][127][128][129][130]. Even though it is computationally demanding, concurrent modelling provides valuable insights into the possible occurring deformation mechanisms and failure modes across various scales, improving the accuracy of structural behaviour predictions. ...
Natural cellular structures inspire numerous engineering applications due to their lightweight and good load-bearing capabilities. Variations in their structural configurations result in diverse mechanical properties, rendering them ideal for bioinspired designs. This review explores the occurrence, properties, and applications of cellular structures in nature and their engineering counterparts built via additive manufacturing (AM). Additive manufacturing technologies enable replication of natural cellular structures with enhanced geometrical complexity. However, they face challenges associated with scale-based geometrical constraints and minimum printable size of various features. Current constraints and techniques for overcoming these challenges, including advancements in nanotechnology, multiscale modelling, novel biomimetic designs, and improved mechanical testing methods are discussed in this paper. It is noted in the paper that it becomes increasingly possible with these advancements to optimise bioinspired engineering parts for complicated applications.
Purpose
The aim of this work is to develop a 3D finite elements model to study the nanomechanical behavior of mineralized collagen microfibrils, which consists of three phases, (i) collagen phase formed by five tropocollagen (TC) molecules linked together with cross-links, (ii) a mineral phase (Hydroxyapatite), and (iii) impure mineral phase, and to investigate the important role of individual properties of every constituent.
Methods
The mechanical and geometric properties (TC molecule diameter) of both tropocollagen and mineral were taken into consideration as well as cross-links, which was represented by spring elements with adjusted properties based on experimental data. In this paper an equivalent homogenized model was developed to assess the whole microfibril mechanical properties (Young's modulus and Poisson's ratio) under varying mechanical properties of each phase.
Results
In this study, both equivalent Young's modulus and Poisson's ratio, which were expressed as functions of Young's modulus of each phase, were obtained under tensile load with symmetric and periodic boundary conditions.
Current clinical methods of bone health assessment depend to a great extent on bone mineral density (BMD) measurements. However, these methods only act as a proxy for bone strength and are often only carried out after the fracture occurs. Besides BMD, composition and tissue-level mechanical properties are expected to affect the whole bone’s strength and toughness. While the elastic properties of the bone extracellular matrix (ECM) have been extensively investigated over the past two decades, there is still limited knowledge of the yield properties and their relationship to composition and architecture. In the present study, morphological, compositional and micropillar compression bone data was collected from patients who underwent hip arthroplasty. Femoral neck samples from 42 patients were collected together with anonymous clinical information about age, sex and primary diagnosis (coxarthrosis or hip fracture). The femoral neck cortex from the inferomedial region was analyzed in a site-matched manner using a combination of micromechanical testing (nanoindentation, micropillar compression) together with micro-CT and quantitative polarized Raman spectroscopy for both morphological and compositional characterization. Mechanical properties, as well as the sample-level mineral density, were constant over age. Only compositional properties demonstrate weak dependence on patient age: decreasing mineral to matrix ratio (p=0.02, R2=0.13, 2.6% per decade) and increasing amide I sub-peak ratio I~1660/ I~1683 (p=0.04, R2=0.11, 1.5% per decade). The patient’s sex and diagnosis did not seem to influence investigated bone properties. A clear zonal dependence between interstitial and osteonal cortical zones was observed for compositional and elastic bone properties (p<0.0001). Site-matched microscale analysis confirmed that all investigated mechanical properties except yield strain demonstrate a positive correlation with the mineral fraction of bone. The output database is the first to integrate the experimentally assessed microscale yield properties, local tissue composition and morphology with the available patient clinical information. The final dataset was used for bone fracture risk prediction in-silico through the principal component analysis and the Naïve Bayes classification algorithm. The analysis showed that the mineral to matrix ratio, indentation hardness and micropillar yield stress are the most relevant parameters for bone fracture risk prediction at 70% model accuracy (0.71 AUC). Due to the low sample number, further studies to build a universal fracture prediction algorithm are anticipated with the higher number of patients (N>200). The proposed classification algorithm together with the output database of bone tissue properties can be used for the future comparison of existing methods to evaluate bone quality as well as to form a better understanding of the mechanisms through which bone tissue is affected by aging or disease.
Bone is a highly hierarchical complex structure that consists of organic and mineral components represented by collagen molecules (CM) and hydroxyapatite crystals (HAC), respectively. The nanostructure of bone can significantly affect its mechanical properties. There is a lack of understanding how collagen fibrils (CF) in different orientations may affect the mechanical properties of the bone. The objective of this study is to investigate the effect of interaction, orientation, and hydration on atomic models of the bone composed of collagen helix (CH) and HAC, using molecular dynamics simulations and therefrom bone-related disease origins. The results demonstrate that the mechanical properties of the bone are affected significantly by the orientation of the CF attributed to contact areas at 0° and 90° models. The molecular dynamics simulation illustrated that there is significant difference (p < 0.005) in the ultimate tensile strength and toughness with respect to the orientation of the hydrated and un-hydrated CF. Additionally, the results indicated that having the force in a longitudinal direction (0°) provides more strength compared with the CF in the perpendicular direction (90°). Furthermore, the results show that substituting glycine (GLY) with any other amino acid affects the mechanical properties and strength of the CH, collagen–hydroxyapatite interface, and eventually affects the HAC. Generally, hydration dramatically influences bone tissue elastic properties, and any change in the orientation or any abnormality in the atomic structure of either the CM or the HAC would be the main reason of the fragility in the bone, affecting bone pathology.
Preclinical studies often require animal models for in vivo experiments. Particularly in dental research, pig species are extensively used due to their anatomical similarity to humans. However, there is a considerable knowledge gap on the multiscale morphological and mechanical properties of the miniature pigs' jawbones, which is crucial for implant studies and a direct comparison to human tissue. In the present work, we demonstrate a multimodal framework to assess the jawbone quantity and quality for a minipig animal model that could be further extended to humans.
Three minipig genotypes, commonly used in dental research, were examined: Yucatan, Göttingen, and Sinclair. Three animals per genotype were tested. Cortical bone samples were extracted from the premolar region of the mandible, opposite to the teeth growth. Global morphological, compositional, and mechanical properties were assessed using micro-computed tomography (micro-CT) together with Raman spectroscopy and nanoindentation measurements, averaged over the sample area. Local mineral-mechanical relationships were investigated with the site-matched Raman spectroscopy and micropillar compression tests. For this, a novel femtosecond laser ablation protocol was developed, allowing high-throughput micropillar fabrication and testing.
At the global averaged sample level, bone relative mineralization demonstrated a significant difference between the genotypes, which was not observed from the complementary micro-CT measurements. Moreover, bone hardness measured by nanoindentation showed a positive trend with the relative mineralization. For all genotypes, significant differences between the relative mineralization and elastic properties were more pronounced within the osteonal regions of cortical bone. Site-matched micropillar compression and Raman spectroscopy highlighted the differences between the genotypes' yield stress and mineral to matrix ratios.
The methods used at the global level (averaged over sample area) could be potentially correlated to the medical tools used to assess jawbone toughness and morphology in clinics. On the other hand, the local analysis methods can be applied to quantify compressive bone mechanical properties and their relationship to bone mineralization.
Background
SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper—Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells—DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts—OBs and osteoclasts—OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002–2004 revealed the long-term negative impact (decreased bone mineral density—BMDs) of these infections on bone health.
Methodology
We used the keywords “immunopathogenesis of SARS-CoV-2,” “SARS-CoV-2 and bone cells,” “factors influencing bone health and COVID-19,” “GUT microbiota,” and “COVID-19 and Bone health” to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus.
Conclusion
Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota—GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.
Introduction
The WHO definition of osteoporosis, and published BMD (Bone Mineral Density) references ranges, do not consider differences in bone size. Because it is a two-dimensional technique, and cannot measure bone depth, aBMD (areal BMD) measured using DXA (Dual-energy X-Ray Absorptiometry) is affected by bone size variability. Mathematical models have been devised to correct aBMD for bone size, but these are confounded by variations in soft tissue surrounding bone. Confirmation of the actual quantitative effect on clinical results for patients requires precise changes in bone size and mineral density, but studies of humans and animals are limited by the inability to precisely control these in natural bones.
Purpose
The objectives of this experiment were to obtain precise, repeatable, quantitative data from sets of artificial vertebrae to confirm the dependence of aBMD on bone size in clinical practice, and to test the effect of applying corrections based on assumptions that the vertebrae were simple geometric shapes to produce corrected BMAD (Bone Mineral Apparent Density).
Methods and materials
Four sets of artificial bones, each set containing four cylinders of different diameters but identical in height, were constructed by casting a mixture of epoxy resin and calcium carbonate powder into a mould. The cylinders were considered to be artificial vertebrae L1 to L4 so that all four in a set may be tested in a single scan. The X-Ray attenuation of the material used was varied between the sets, to represent differences in BMD. Each set of vertebrae was inserted into a soft-tissue analogue and DXA scanned, in the anteroposterior position, with the GE Lunar Prodigy and the Hologic Discovery.
Results
The results verify the theoretical direct proportionality between aBMD and diameter, confirming that aBMD is significantly affected by bone size. Applying a BMAD correction, by assuming the vertebrae to be cylinders, reduced the effect of change in bone diameter by approximately two orders of magnitude to an insignificant level.
Conclusion
This experiment has confirmed that BMD measured using DXA, accepted in clinical practice as the “gold standard” means of diagnosing osteoporosis, could lead to misdiagnosis because it is significantly affected by differences in bone size.
Extrapulmonary complications of different organ systems have been increasingly recognized in patients with severe or chronic Coronavirus Disease 2019 (COVID-19). However, limited information on the skeletal complications of COVID-19 is known, even though inflammatory diseases of the respiratory tract have been known to perturb bone metabolism and cause pathological bone loss. In this study, we characterize the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on bone metabolism in an established golden Syrian hamster model for COVID-19. SARS-CoV-2 causes significant multifocal loss of bone trabeculae in the long bones and lumbar vertebrae of all infected hamsters. Moreover, we show that the bone loss is associated with SARS-CoV-2-induced cytokine dysregulation, as the circulating pro-inflammatory cytokines not only upregulate osteoclastic differentiation in bone tissues, but also trigger an amplified pro-inflammatory cascade in the skeletal tissues to augment their pro-osteoclastogenesis effect. Our findings suggest that pathological bone loss may be a neglected complication which warrants more extensive investigations during the long-term follow-up of COVID-19 patients. The benefits of potential prophylactic and therapeutic interventions against pathological bone loss should be further evaluated. Although extrapulmonary complications of different organ systems are recognized in patients with severe COVID19 effects are less well studied. Here, Qiao et al. characterize the pathogenesis of SARS-CoV-2 on bone metabolism in Syrian hamster and find that bone loss is associated with virus-mediated cytokine dysregulation.
Atomic Force Microscopy nanoindentation method is a powerful technique that can be used for the nano-mechanical characterization of bio-samples. Significant scientific efforts have been performed during the last two decades to accurately determine the Young’s modulus of collagen fibrils at the nanoscale, as it has been proven that mechanical alterations of collagen are related to various pathological conditions. Different contact mechanics models have been proposed for processing the force–indentation data based on assumptions regarding the shape of the indenter and collagen fibrils and on the elastic or elastic–plastic contact assumption. However, the results reported in the literature do not always agree; for example, the Young’s modulus values for dry collagen fibrils expand from 0.9 to 11.5 GPa. The most significant parameters for the broad range of values are related to the heterogeneous structure of the fibrils, the water content within the fibrils, the data processing errors, and the uncertainties in the calibration of the probe. An extensive discussion regarding the models arising from contact mechanics and the results provided in the literature is presented, while new approaches with respect to future research are proposed.
Understanding the properties of bone is of both fundamental and clinical relevance. The basis of bone’s quality and mechanical resilience lies in its nanoscale building blocks (i.e., mineral, collagen, non-collagenous proteins, and water) and their complex interactions across length scales. Although the structure–mechanical property relationship in healthy bone tissue is relatively well characterized, not much is known about the molecular-level origin of impaired mechanics and higher fracture risks in skeletal disorders such as osteoporosis or Paget’s disease. Alterations in the ultrastructure, chemistry, and nano-/micromechanics of bone tissue in such a diverse group of diseased states have only been briefly explored. Recent research is uncovering the effects of several non-collagenous bone matrix proteins, whose deficiencies or mutations are, to some extent, implicated in bone diseases, on bone matrix quality and mechanics. Herein, we review existing studies on ultrastructural imaging—with a focus on electron microscopy—and chemical, mechanical analysis of pathological bone tissues. The nanometric details offered by these reports, from studying knockout mice models to characterizing exact disease phenotypes, can provide key insights into various bone pathologies and facilitate the development of new treatments.
Given the progressive ageing of Western populations, the fragility fractures market has a growing socioeconomic impact. Fragility fractures are common in the elderly, negatively impacting their quality of life, limiting autonomy, increasing disability, and decreasing life expectancy. Different causes contribute to the development of a fractures in frail individuals. Among all, targeting fragile patients before the development of a fracture may represent the greatest challenge, and current diagnostic tools suffer from limitations. This study summarizes the current evidence on the management of fragility fractures, discussing risk factors, prevention, diagnosis, and actual limitations of the clinical therapeutic options, putting forward new ideas for further scientific investigation.
Bone is a complex natural material with a complex hierarchical multiscale organization, crucial to perform its functions. Ultrastructural analysis of bone is crucial for our understanding of cell to cell communication, the healthy or pathological composition of bone tissue, and its three‐dimensional (3D) organization. A variety of techniques has been used to analyze bone tissue. This article describes a combined approach of optical, scanning electron, and transmission electron microscopy for the ultrastructural analysis of bone from the nanoscale to the macroscale, as illustrated by two pathological bone tissues. By following a top‐down approach to investigate the multiscale organization of pathological bones, quantitative estimates were made in terms of calcium content, nearest neighbor distances of osteocytes, canaliculi diameter, ordering, and D‐spacing of the collagen fibrils, and the orientation of intrafibrillar minerals which enable us to observe the fine structural details. We identify and discuss a series of two‐dimensional (2D) and 3D imaging techniques that can be used to characterize bone tissue. By doing so we demonstrate that, while 2D imaging techniques provide comparable information from pathological bone tissues, significantly different structural details are observed upon analyzing the pathological bone tissues in 3D. Finally, particular attention is paid to sample preparation for and quantitative processing of data from electron microscopic analysis.
The comprehension of trabecular bone damage processes could be a crucial hint for understanding how bone damage starts and propagates. Currently, different approaches to bone damage identification could be followed. Clinical approaches start from dual X-ray absorptiometry (DXA) technique that can evaluate bone mineral density (BMD), an indirect indicator of fracture risk. DXA is, in fact, a two-dimensional technology, and BMD alone is not able to predict the effective risk of fractures. First attempts in overcoming this issue have been performed with finite element (FE) methods, combined with the use of three-dimensional high-resolution micro-computed tomographic images. The purpose of this work is to evaluate damage initiation and propagation in trabecular vertebral porcine samples using 2D linear-elastic FE models from DXA images and 3D linear FE models from micro-CT images. Results show that computed values of strains with 2D and 3D approaches (e.g., the minimum principal strain) are of the same order of magnitude. 2D DXA-based models still remain a powerful tool for a preliminary screening of trabecular regions that are prone to fracture, while from 3D micro-CT-based models, it is possible to reach details that permit the localization of the most strained trabecula.
Graphical abstract
Severe coronavirus disease 2019 (COVID-19) is often indicated by lymphopenia and increased myelopoiesis; however, the underlying mechanism is still unclear, especially the alteration of hematopoiesis. It is important to explore to what extent and how hematopoietic stem cells contribute to the impairment of peripheral lymphoid and myeloid compartments in COVID-19 patients. In this study, we used single-cell RNA sequencing to assess bone marrow mononuclear cells from COVID-19 patients with peripheral blood mononuclear cells as control. The results showed that the hematopoietic stem cells in these patients were mainly in the G1 phase and prone to apoptosis, with immune activation and anti-viral responses. Importantly, a significant accumulation of immature myeloid progenitors and a dramatic reduction of lymphoid progenitors in severe cases were identified, along with the up-regulation of transcription factors (such as SPI1, LMO4, ETS2, FLI1 , and GATA2 ) that are important for the hematopoietic stem cell or multipotent progenitor to differentiate into downstream progenitors. Our results indicate a dysregulated hematopoiesis in patients with severe COVID-19.
The increased risk of fracture in the elderly associated with metabolic conditions like osteoporosis poses a significant strain on health care systems worldwide. Due to bone's hierarchical nature, it is necessary to study its mechanical properties and failure mechanisms at several length scales. We conducted micropillar compression experiments on cortical ovine bone to assess the anisotropic mechanical response at the lamellar scale over a wide range of strain rates (10⁻⁴ to 8•10² s⁻¹). At the microscale, lamellar bone exhibits a strain rate sensitivity similar to what is reported at the macroscale suggesting that it is an intrinsic property of the extracellular matrix. Significant shear band thickening was observed at high strain rates by HRSEM and STEM imaging. This is likely caused by the material's inability to accommodate the imposed deformation by propagation of thin kink bands and shear cracks at high strain rates, leading to shear band thickening and nucleation. The post-yield behavior is strain rate and direction dependent: hardening was observed for transverse oriented micropillars and hardening modulus increases with strain rate by a factor of almost 2, while axially oriented micropillars showed strain softening and an increase of the softening peak width and work to ultimate stress as a function of strain rate. This suggests that for compression at the micrometer scale, energy absorption increases in bone with strain rate. This study highlights the importance of investigating bone strength and post-yield behavior at lower length scales, under hydrated conditions and at clinically relevant strain rates.
Engineering biomaterials that mimic the extracellular matrix (ECM) of bone is of significant importance since most of the outstanding properties of the bone are due to matrix constitution. Bone ECM is composed of a mineral part comprising hydroxyapatite and of an organic part of primarily collagen with the rest consisting on non-collagenous proteins. Collagen has already been described as critical for bone tissue regeneration; however, little is known about the potential effect of non-collagenous proteins on osteogenic differentiation, even though these proteins were identified some decades ago. Aiming to engineer new bone tissue, peptide-incorporated biomimetic materials have been developed, presenting improved biomaterial performance. These promising results led to ongoing research focused on incorporating non-collagenous proteins from bone matrix to enhance the properties of the scaffolds namely in what concerns cell migration, proliferation, and differentiation, with the ultimate goal of designing novel strategies that mimic the native bone ECM for bone tissue engineering applications. Overall, this review will provide an overview of the several non-collagenous proteins present in bone ECM, their functionality and their recent applications in the bone tissue (including dental) engineering field.
The investigation of bone damage processes is a crucial point to understand the mechanisms of age-related bone fractures. In order to reduce their impact, early diagnosis is key. The intricate architecture of bone and the complexity of multiscale damage processes make fracture prediction an ambitious goal. This review, supported by a detailed analysis of bone damage physical principles, aims at presenting a critical overview of how multiscale imaging techniques could be used to implement reliable and validated numerical tools for the study and prediction of bone fractures. While macro- and meso-scale imaging find applications in clinical practice, micro- and nano-scale imaging are commonly used only for research purposes, with the objective to extract fragility indexes. Those images are used as a source for multiscale computational damage models. As an example, micro-computed tomography (micro-CT) images in combination with micro-finite element models could shed some light on the comprehension of the interaction between micro-cracks and micro-scale bone features. As future insights, the actual state of technology suggests that these models could be a potential substitute for invasive clinical practice for the prediction of age-related bone fractures. However, the translation to clinical practice requires experimental validation, which is still in progress.
Bone is a natural composite possessing outstanding mechanical properties combined with a lightweight design. The key feature contributing to this unusual combination of properties is the bone hierarchical organization ranging from the nano- to the macro-scale. Bone anisotropic mechanical properties from two orthogonal planes (along and perpendicular to the main bone axis) have already been widely studied. In this work, we demonstrate the dependence of the microscale compressive mechanical properties on the angle between loading direction and the mineralized collagen fibril orientation in the range between 0° and 82°. For this, we calibrated polarized Raman spectroscopy for quantitative collagen fibril orientation determination and validated the method using widely used techniques (small angle X-ray scattering, micro-computed tomography). We then performed compression tests on bovine cortical bone micropillars with known mineralized collagen fibril angles. A strong dependence of the compressive micromechanical properties of bone on the fibril orientation was found with a high degree of anisotropy for both the elastic modulus (Ea/Et=3.80) and the yield stress (σay/σty=2.54). Moreover, the post-yield behavior was found to depend on the MCF orientation with a transition between softening to hardening behavior at approximately 50°. The combination of methods described in this work allows to reliably determine structure-property relationships of bone at the microscale, which may be used as a measure of bone quality.
Bone features a remarkable combination of toughness and strength which originates from its complex hierarchical structure and motivates its investigation on multiple length scales. Here, in situ microtensile experiments were performed on dry ovine osteonal bone for the first time at the length scale of a single lamella. The micromechanical response was brittle and revealed larger ultimate tensile strength compared to the macroscale (factor of 2.3). Ultimate tensile strength for axial and transverse specimens was 0.35 ± 0.05 GPa and 0.13 ± 0.02 GPa, respectively. A significantly greater strength anisotropy relative to compression was observed (axial to transverse strength ratio of 2.7:1 for tension, 1.3:1 for compression). Fracture surface and transmission electron microscopic analysis suggested that this may be rationalized by a change in failure mode from fibril-matrix interfacial shearing for axial specimens to fibril-matrix debonding in the transverse direction. An improved version of the classic Hashin's composite failure model was applied to describe lamellar bone strength as a function of fibril orientation. Together with our experimental observations, the model suggests that cortical bone strength at the lamellar level is remarkably tolerant to variations of fibrils orientation of about ±30°. This study highlights the importance of investigating bone's hierarchical organization at several length scales for gaining a deeper understanding of its macroscopic fracture behavior.
Statement of Significance
Understanding bone deformation and failure behavior at different length scales of its hierarchical structure is fundamental for the improvement of bone fracture prevention, as well as for the development of multifunctional bio-inspired materials combining toughness and strength. The experiments reported in this study shed light on the microtensile properties of dry primary osteonal bone and establish a baseline from which to start further investigations in more physiological conditions. Microtensile specimens were stronger than their macroscopic counterparts by a factor of 2.3. Lamellar bone strength seems remarkably tolerant to variations of the sub-lamellar fibril orientation with respect to the loading direction (±30°). This study underlines the importance of studying bone on all length scales for improving our understanding of bone's macroscopic mechanical response.
Understanding how bones are innately designed, robustly developed and delicately maintained through intricate anatomical features and physiological processes across the lifespan is vital to inform our assessment of normal bone health, and essential to aid our interpretation of adverse clinical outcomes affecting bone through primary or secondary causes. Accordingly this review serves to introduce new researchers and clinicians engaging with bone and mineral metabolism, and provide a contemporary update for established researchers or clinicians. Specifically, we describe the mechanical and non-mechanical functions of the skeleton; its multidimensional and hierarchical anatomy (macroscopic, microscopic, organic, inorganic, woven and lamellar features); its cellular and hormonal physiology (deterministic and homeostatic processes that govern and regulate bone); and processes of mechanotransduction, modelling, remodeling and degradation that underpin bone adaptation or maladaptation. In addition, we also explore commonly used methods for measuring bone metabolic activity or material features (imaging or biochemical markers) together with their limitations.
This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five countries of the European Union plus Sweden (EU6). In 2017, new fragility fractures in the EU6 are estimated at 2.7 million with an associated annual cost of €37.5 billion and a loss of 1.0 million quality-adjusted life years.
Introduction:
Osteoporosis is characterized by reduced bone mass and strength, which increases the risk of fragility fractures, which in turn, represent the main consequence of the disease. This report provides an overview and a comparison of the burden and management of fragility fractures in the largest five EU countries and Sweden (designated the EU6).
Methods:
A series of metrics describing the burden and management of fragility fractures were defined by a scientific steering committee. A working group performed the data collection and analysis. Data were collected from current literature, available retrospective data and public sources. Different methods were applied (e.g. standard statistics and health economic modelling), where appropriate, to perform the analysis for each metric.
Results:
Total fragility fractures in the EU6 are estimated to increase from 2.7 million in 2017 to 3.3 million in 2030; a 23% increase. The resulting annual fracture-related costs (€37.5 billion in 2017) are expected to increase by 27%. An estimated 1.0 million quality-adjusted life years (QALYs) were lost in 2017 due to fragility fractures. The current disability-adjusted life years (DALYs) per 1000 individuals age 50 years or more were estimated at 21 years, which is higher than the estimates for stroke or chronic obstructive pulmonary disease. The treatment gap (percentage of eligible individuals not receiving treatment with osteoporosis drugs) in the EU6 is estimated to be 73% for women and 63% for men; an increase of 17% since 2010. If all patients who fracture in the EU6 were enrolled into fracture liaison services, at least 19,000 fractures every year might be avoided.
Conclusions:
Fracture-related burden is expected to increase over the coming decades. Given the substantial treatment gap and proven cost-effectiveness of fracture prevention schemes such as fracture liaison services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are appropriately assessed and treated.
The data processing regarding AFM nanoindentation experiments on biological samples relies on the basic contact mechanics models like the Hertz model and the Oliver & Pharr analysis. Despite the fact that the two aforementioned techniques are assumed to provide equivalent results since they are based on the same underlying theory of contact mechanics, significant differences regarding the Young's modulus calculation even on the same tested sample have been presented in the literature. The differences can be even greater than 30 % depending on the used model. In addition, when the Oliver & Pharr analysis is used, a systematic greater Young's modulus value is always calculated compared to the Hertzian analysis. In this paper, the two techniques are briefly described and two possible reasons that accurately explain the observed differences in the calculated value of the Young's modulus are presented.
Abstract Background This study aimed to determine the influence of ageing on the incidence and site of femoral fractures in trauma patients, by taking the sex, body weight, and trauma mechanisms into account. Methods This retrospective study reviewed data from adult trauma patients aged ≥20 years who were admitted into a Level I trauma center, between January 1, 2009 and December 31, 2016. According to the femoral fracture locations, 3859 adult patients with 4011 fracture sites were grouped into five subgroups: proximal type A (n = 1359), proximal type B (n = 1487), proximal type C (n = 59), femoral shaft (n = 640), and distal femur (n = 466) groups. A multivariate logistic regression analysis was applied to identify independent effects of the univariate predictive variables on the occurrence of fracture at a specific site. A two-dimensional plot was presented visually with age and the propensity score accounts for the risk of a fracture at a specific femoral site. Results This analysis revealed that older age was an independent variable that could positively predict the occurrence of proximal type A (OR [95%CI]: 1.03 [1.03–1.04], p
A novel microtensile setup was developed to overcome typical issues encountered in small-scale testing, particularly sample fabrication, sample handling, and misalignment. The system features a silicon (Si) gripper, which is able to self-align with the specimen main axis. Finite element simulations were employed to optimize the microtensile specimen geometry and to mechanically characterize the system. Specimens were prepared using focused ion beam milling, while reactive ion etching was employed to produce the grippers. The system was calibrated using single-crystal (100) Si specimens. The strength asymmetry of brittle crystals was investigated on the example of gallium arsenide (GaAs). Microtensile GaAs specimens and square micropillars sharing lowest dimensions of 1.70 ± 0.19 lm were tested along the [001] crystallographic orientation. Micropillars underwent plastic deformation via twinning in {111} planes and exhibited yield stress of 2.60 ± 0.14 GPa. The tensile experiment showed brittle failure at 1.86 ± 0.17 GPa associated with complex fracture surfaces and no measurable dislocation activity.
The discipline of fracture mechanics was born almost a century ago through the pioneering work of A.A. Griffith, and saw particularly rapid growth in the second half of 20th century when it became an indispensable tool in the development of advanced transportation, civil construction, and energy systems. Forty years ago, Materials & Design published a series of papers devoted to the state-of-the-art in the field of Fracture Mechanics. The present review reflects the lasting legacy and surviving importance of this theme: it is associated with the Virtual Special Issue on nanoscale materials testing and characterisation, and focuses on the modern experimental approaches to fine scale fracture toughness evaluation, with particular emphasis on micro-cantilever bending and micro-pillar splitting. The fundamental aspects of these approaches are overviewed, and their application to a range of systems is described. Implications for further development of these methods are discussed.
The skeleton is one of the largest organs in the human body. In addition to its conventional functions such as support, movement and protection, the skeleton also contributes to whole body homeostasis and maintenance of multiple important non-bone organs/systems (extraskeletal functions). Both conventional and extraskeletal functions of the skeleton are defined as bone function. Bone-derived factors (BDFs) are key players regulating bone function. In some pathophysiological situations, including diseases affecting bone and/or other organs/systems, the disorders of bone itself and the subsequently impaired functions of extraskeletal organs/systems caused by abnormal bone (impaired extraskeletal functions of bone) are defined as bone dysfunction. In critical illness, which is a health status characterized by the dysfunction or severe damage of one or multiple important organs or systems, the skeleton shows rapid bone loss resulting from bone hyper-resorption and impaired osteoblast function. In addition, the dysfunctions of the skeleton itself are also closely related to the severity and prognosis of critical illness. Therefore, we propose that there is bone dysfunction in critical illness. Some methods to inhibit osteoclast activity or promote osteoblast function by the treatment of bisphosphonates or PTH1-34 benefit the outcome of critical illness, which indicates that enhancing bone function may be a potential novel strategy to improve prognosis of diseases including critical illness.
Osteogenesis imperfecta (OI) is a monogenetic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. Mutations in at least 18 other genes can also lead to an OI phenotype. As genetic testing is more widely used, mutations in these genes are also more frequently discovered in individuals who have a propensity for fractures but who do not have other typical clinical characteristics of OI. Intravenous bisphosphonate therapy is still the most widely used drug treatment approach. Preclinical studies in OI mouse models have shown encouraging effects when the antiresorptive effect of a bisphosphonates was combined with bone anabolic therapy using a sclerostin antibody. Other novel experimental treatment approaches include inhibition of transforming growth factor beta signaling with a neutralizing antibody and the inhibition of myostatin and activin A by a soluble activin receptor 2B. This article is protected by copyright. All rights reserved
Bone ultrastructure at sub-lamellar length scale is a key structural unit in bone that bridges nano- and microscale hierarchies of the tissue. Despite its influence on bulk response of bone, the mechanical behavior of bone at ultrastructural level remains poorly understood. To fill this gap, in this study, a two-dimensional cohesive finite element model of bone at sub-lamellar level was proposed and analyzed under tensile and compressive loading conditions. In the model, ultrastructural bone was considered as a composite of mineralized collagen fibrils (MCFs) embedded in an extrafibrillar matrix (EFM) that is comprised of hydroxyapatite (HA) polycrystals bounded via thin organic interfaces of non-collagenous proteins (NCPs). The simulation results indicated that in compression, EFM dictated the pre-yield deformation of the model, then damage was initiated via relative sliding of HA polycrystals along the organic interfaces, and finally shear bands were formed followed by delamination between MCF and EFM and local buckling of MCF. In tension, EFM carried the most of load in pre-yield deformation, and then an array of opening-mode nano-cracks began to form within EFM after yielding, thus gradually transferring the load to MCF until failure, which acted as crack bridging filament. The failure modes, stress–strain curves, and in situ mineral strain of ultrastructural bone predicted by the model were in good agreement with the experimental observations reported in the literature, thus suggesting that this model can provide new insights into sub-microscale mechanical behavior of bone.
Objectives
The ability to determine human bone stiffness is of clinical relevance in many fields, including bone quality assessment and orthopaedic prosthesis design. Stiffness can be measured using compression testing, an experimental technique commonly used to test bone specimens in vitro. This systematic review aims to determine how best to perform compression testing of human bone.
Methods
A keyword search of all English language articles up until December 2017 of compression testing of bone was undertaken in Medline, Embase, PubMed, and Scopus databases. Studies using bulk tissue, animal tissue, whole bone, or testing techniques other than compression testing were excluded.
Results
A total of 4712 abstracts were retrieved, with 177 papers included in the analysis; 20 studies directly analyzed the compression testing technique to improve the accuracy of testing. Several influencing factors should be considered when testing bone samples in compression. These include the method of data analysis, specimen storage, specimen preparation, testing configuration, and loading protocol.
Conclusion
Compression testing is a widely used technique for measuring the stiffness of bone but there is a great deal of inter-study variation in experimental techniques across the literature. Based on best evidence from the literature, suggestions for bone compression testing are made in this review, although further studies are needed to establish standardized bone testing techniques in order to increase the comparability and reliability of bone stiffness studies.
Cite this article: S. Zhao, M. Arnold, S. Ma, R. L. Abel, J. P. Cobb, U. Hansen, O. Boughton. Standardizing compression testing for measuring the stiffness of human bone. Bone Joint Res 2018;7:524–538. DOI: 10.1302/2046-3758.78.BJR-2018-0025.R1.
Bone’s resistance to fracture depends on several factors, such as bone mass, microarchitecture, and tissue material properties. The clinical assessment of bone strength is generally performed by Dual-X Ray Photon Absorptiometry (DXA), measuring bone mineral density (BMD) and trabecular bone score (TBS). Although it is considered the major predictor of bone strength, BMD only accounts for about 70% of fragility fractures, while the remaining 30% could be described by bone “quality” impairment parameters, mainly related to tissue microarchitecture. The assessment of bone microarchitecture generally requires more invasive techniques, which are not applicable in routine clinical practice, or X-Ray based imaging techniques, requiring a longer post-processing. Another important aspect is the presence of local damage in the bony tissue that may also affect the prediction of bone strength and fracture risk. To provide a more comprehensive analysis of bone quality and quantity, and to assess the effect of damage, here we adopt a framework that includes clinical, morphological, and mechanical analyses, carried out by means of DXA, μCT and mechanical compressive testing, respectively. This study has been carried out on trabecular bones, taken from porcine trabecular vertebrae, for the similarity with human lumbar spine. This study confirms that no single method can provide a complete characterization of bone tissue, and the combination of complementary characterization techniques is required for an accurate and exhaustive description of bone status. BMD and TBS have shown to be complementary parameters to assess bone strength, the former assessing the bone quantity and resistance to damage, and the latter the bone quality and the presence of damage accumulation without being able to predict the risk of fracture.
While advanced imaging strategies have improved the diagnosis of bone-related pathologies, early signs of bone alterations remain difficult to detect. The Covid-19 pandemic has brought attention to the need for a better understanding of bone micro-scale toughening and weakening phenomena. This study used an artificial intelligence-based tool to automatically investigate and validate four clinical hypotheses by examining osteocyte lacunae on a large scale with synchrotron image-guided failure assessment. The findings indicate that trabecular bone features exhibit intrinsic variability related to external loading, micro-scale bone characteristics affect fracture initiation and propagation, osteoporosis signs can be detected at the micro-scale through changes in osteocyte lacunar features, and Covid-19 worsens micro-scale porosities in a statistically significant manner similar to the osteoporotic condition. Incorporating these findings with existing clinical and diagnostic tools could prevent micro-scale damages from progressing into critical fractures.
Measurement of the properties of bone as a material can happen in various length scales in its hierarchical and composite structure. The aim of this study was to test the tissue level properties of clinically-relevant human bone samples which were collected from donors belonging to three groups: ageing donors who suffered no fractures (Control); untreated fracture patients (Fx-Untreated) and patient who experienced hip fracture despite being treated with bisphosphonates (Fx-BisTreated). Tissue level properties were assessed by (a) nanoindentation and (b) synchrotron tensile tests (STT) where strains were measured at the ‘tissue’, ‘fibril’ and ‘mineral’ levels by using simultaneous Wide-angle - (WAXD) and Small angle- X-ray diffraction (SAXD). The composition was analysed by thermogravimetric analysis and material level endo- and exo-thermic reactions by differential scanning calorimetry (TGA/DSC3+). Irrespective of treatment fracture donors exhibited significantly lower tissue, fibril and mineral strain at the micro and nanoscale respectively and had a higher mineral content than controls. In nanoindentation only nanohardness was significantly greater for Controls and Fx-BisTreated versus Fx-Untreated. The other nanoindentation parameters did not vary significantly across the three groups. There was a highly significant positive correlation (p < 0.001) between organic content and tissue level strain behaviour. Overall hip-fractures were associated with lower STT nanostrains and it was behaviour measured by STT which proved to be a more effective approach for predicting fracture risk because evidently it was able to demonstrate the mechanical deficit for the bone tissue of the donors who had experienced fractures.
Mineralized collagen fibrils (MCFs) are the fundamental building blocks of bone tissue and contribute significantly to the mechanical behavior of bone. However, it is still largely unknown how the collagen network in bone responds to aging and the disuse normally accompanying it. Utilizing atomic force microscopy, nanoindentation and Raman spectroscopy, age-related alterations in the microstructure and mechanical properties of murine cortical tibia at multiple scales were investigated in this study. The potential difference in the responses of bone to disuse at different ages was studied. The results indicated that the age- and disuse-related alterations in bone initiate from MCFs in the bone matrix. The D-periodic spacing, radial elastic modulus of a single MCF and the mineral-to-matrix ratio on the cortical bone surface were larger in aged mice than in adult mice. Disuse, on the other hand, mainly has a major influence on aged mice, particularly on the morphology and mechanical properties of MCFs, but it only has modest effects on adult bone. These findings revealed insights into the morphological and mechanical adaptation of mineralized collagen fibrils in murine cortical bone to aging and disuse.
Statement of Significance
Bone is a complex structured composite material consisting of an interwoven framework of collagen fibrils reinforced by mineral particles and embedded in an extrafibrillar mineralized matrix. Utilizing atomic force microscopy, nanoindentation and Raman spectroscopy, this study suggests that the effects of aging, as well as the accompanying disuse, on the morphology and mechanical properties of bone initiate from the mineralized collagen fibril level. More interestingly, the MCF in the bone of aged mice seems to be more sensitive to disuse than that in adult mice. These findings significantly further the current understanding of the adaptation process of bone to aging at the mineralized collagen fibril level and provide direct insights into the physiological response of bone to aging and the abnormal mechanical environment.
The dramatic increase in fragility fractures and the related health and economic burden rise the urge of a cutting-edge perspective to anticipate catastrophic fracture propagation in human bones. Recent studies address the issue from a multi-scale perspective, elevating the micro-scale phenomena as the key for detecting early damage occurrence. However, several limitations arise specifically for defining a quantitative framework to assess the contribution of lacunar micro-pores to fracture initiation and propagation. Moreover, the need for high resolution imaging imposes time-demanding post-processing phases. Here, we exploit synchrotron scans in combination with micro-mechanical tests, to offer a fracture mechanics-based approach for quantifying the critical stress intensification in healthy and osteoporotic trabecular human bones. This is paired with a morphological and densitometric framework for capturing lacunar network differences in presence of pathological alterations. To address the current time-consuming and computationally expensive manual/semi-automatic segmenting steps, we implement convolutional neural network to detect the initiation and propagation of micro-scale damages. The results highlight the intimate cross talks between toughening and weakening phenomena at micro-scale as a fundamental aspect for fracture prevention.
Modeling of the multiscale dynamics of new bone formation in tissue scaffolds is still challenging due to the computational complexity in solving the mechanics–material–biology interactions. Recent work proposes a machine learning approach to address this challenge.
A mechanistic understanding of bone fracture is indispensable for developing improved fracture risk assessment in clinics. Since bone is a hierarchically structured material, gaining such knowledge requires analysis at multiple length scales. Here, the tensile response of cortical bone is characterized at the lamellar length scale under dry and hydrated conditions with the aim of investigating the influence of bone's microstructure and hydration on its microscale strength and toughness. For individual lamellae, bone strength strongly correlates with the underlying mineralized collagen fibrils orientation and shows a 2.3-fold increase compared to the macroscale. When specimen size is increased to a few lamellae, the influence of fibril orientation and the size effect on strength are significantly reduced. These findings highlight the critical influence of defects, such as canaliculi and interlamellar interfaces, when assessing larger volumes. Hydration leads up to a 3-fold strength decrease but activates several toughening mechanisms enabling post-yield deformation. In axial specimens, toughening is seen through fibril bridging and crack kinking. In transverse specimens, water presence leads to a progressive but stable crack growth parallel to the fibril orientation, suggesting crack-tip plasticity at the fibrillar interfaces. This work offers a better understanding of the role of interfaces, porosity, and hydration in crack initiation under tensile loading, which is a crucial step towards improved clinical management of disease-related bone fractures through multiscale modeling approaches.
Older adults spend more than 8 h/day in sedentary behaviours. Detrimental effects of sedentary behaviour (SB) on health are established, yet little is known about SB and bone health (bone mineral density; BMD) in older adults. The purpose of this review is to examine associations of SB with BMD in older adults. Five electronic databases were searched: Web of Science (Core Collection); PubMed; EMBASE; Sports Medicine and Education and PsycInfo. Inclusion criteria were healthy older adults mean age ≥ 65 years; measured SB and measured BMD using dual-energy X-ray absorptiometry. Quality was assessed using National Institute of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. After excluding duplicates 17813 papers were assessed; 17757 were excluded on title/abstract, 49 at full text, resulting in two prospective and five cross-sectional observational studies reviewed. Four were rated ‘good’ and three were rated ‘fair’ using the quality assessment criteria. Findings varied across the studies and differed by gender. In women, four studies reported significant positive associations of SB with BMD at different sites, and two found significant negative associations. Five studies which examined both men and women, men reported negative or no associations of SB with femoral neck, pelvic, whole body, spine or leg BMD. Whilst these findings suggest differences between men and women in the associations of SB with BMD, they may be due to the varying anatomical sections examined for BMD, the different methods used to measure SB, the varied quality of the studies included and the limited number of published findings.
Patient-specific approach is gaining a wide popularity in computational simulations of biomechanical systems. Simulations (most often based on the finite element method) are to date routinely created using data from imaging devices such as computed tomography which seemingly very complex and sophisticated. However, using a computed tomography in finite element calculations does not necessarily enhance the quality or even credibility of the models as these depend on the quality of the input images. Low-resolution (medical-)CT datasets do not always offer detailed representation of trabecular bone in FE models and thus might lead to incorrect calculation of mechanical response to external loading. The effect of image resolution on mechanical simulations of bone-implant interaction has not been thoroughly studied yet. In this study, the effect of image resolution on the modeling procedure and resulting mechanical strains in bone was analyzed on the example of cranial implant. For this purpose, several finite element models of bone interacting with fixation-screws were generated using seven computed tomography datasets of a bone specimen but with different image resolutions (ranging from micro-CT resolution of 25 μm to medical-CT resolution of 1250 μm). The comparative analysis revealed that FE models created from images of low resolution (obtained from medical computed tomography) can produce biased results. There are two main reasons: 1. Medical computed tomography images do not allow generating models with complex trabecular architecture which leads to substituting of the intertrabecular pores with a fictitious mass; 2. Image gray value distribution can be distorted resulting in incorrect mechanical properties of the bone and thus in unrealistic or even completely fictitious mechanical strains. The biased results of calculated mechanical strains can lead to incorrect conclusion, especially when bone-implant interaction is investigated. The image resolution was observed not to significantly affect stresses in the fixation screw itself; however, selection of bone material representation might result in significantly different stresses in the screw.
Osteogenesis imperfecta (OI), a brittle bone disease, is known to result in severe bone fragility. However, its ultrastructural origins are still poorly understood. In this study, we hypothesized that deficient intrafibrillar mineralization is a key contributor to the OI induced bone brittleness. To test this hypothesis, we explored the mechanical and ultrastructural changes in OI bone using the osteogenesis imperfecta murine (oim) model. Synchrotron X-ray scattering experiments indicated that oim bone had much less intrafibrillar mineralization than wild type bone, thus verifying that the loss of mineral crystals indeed primarily occurred in the intrafibrillar space of oim bone. It was also found that the mineral crystals were organized from preferentially in longitudinal axis in wild type bone to more randomly in oim bone. Moreover, it revealed that the deformation of mineral crystals was more coordinated with collagen fibrils in wild type than in oim bone, suggesting that the load transfer deteriorated between the two phases in oim bone. The micropillar test revealed that the compression work to fracture of oim bone (8.2 ± 0.9 MJ/m³) was significantly smaller (p < 0.05) than that of wild type bone (13.9 ± 2.7 MJ/m³), while the bone strength was not statistically different (p > 0.05) between the two genotype groups. In contrast, the uniaxial tensile test showed that the ultimate strength of wild type bone (50 ± 4.5 MPa) was significantly greater (p < 0.05) than that of oim bone (38 ± 5.3 MPa). Furthermore, the nanoscratch test showed that the toughness of oim bone was much less than that of wild type bone (6.6 ± 2.2 GJ/m³ vs. 12.6 ± 1.4 GJ/m³). Finally, in silico simulations using a finite element model of sub-lamellar bone confirmed the links between the reduced intrafibrillar mineralization and the observed changes in the mechanical behavior of OI bone. Taken together, these results provide important mechanistic insights into the underlying cause of poor mechanical quality of OI bone, thus pave the way toward future treatments of this brittle bone disease.
Objectives:
Studies performed in the medical area have shown that an indirect diagnosis of bone mineral density (BMD) is feasible by assessing the amount of bone marrow fat with non-ionizing magnetic resonance imaging (MRI). In dentistry, radiographic methods are still the most used for alveolar bone diagnosis. The present literature review aimed at addressing the role of MRI in assessing BMD in medicine and dentistry.
Methods:
MEDLINE and EMBASE databases were searched for articles published up to 2019.
Results:
A total of 428 potentially eligible papers were screened. Of these, 397 were excluded after title, abstract and keyword assessment, yielding 31 papers that potentially met the inclusion criteria. Eleven studies were then excluded because their full texts did not discuss the role of MRI in the indirect diagnosis of BMD. As a result, a total of 20 studies were finally identified as eligible for inclusion in this literature review. Most studies found satisfactory accuracy of MRI for indirectly assessing BMD by quantifying bone mineral fat (BMF). However, only one of these studies was on dentistry.
Conclusion:
Within the limitations of this study, the present findings suggest that MRI is accurate to indirectly estimate bone density by assessing BMF, and could be clinically relevant during dental treatment planning.
Collagen and elastin are the most abundant structural proteins in animals and play an integral biological and structural role in the extracellular matrix. The biosynthesis and maturation of collagen and elastin occurs via multi-step intracellular and extracellular processes including the formation of several covalent crosslinks to stabilise their structure, confer thermal stability and provide biochemical properties to tissues. There are two major groups of crosslinks based on their formation pathways, enzymatic and non-enzymatic. The biosynthesis of enzymatic crosslinks starts with the enzymatic oxidation of lysine or hydroxylysine residues into aldehydes. These aldehdyes undergo a series of spontaneous condensation reactions with lysine, hydroxylysine or other aldehdye residues to form immature covalent crosslinks which are further matured via poorly understood mechanisms into multivalent crosslinks. While enzymatic crosslinks make up the majority of protein-protein crosslinks, the non-enzymatic unselective glycation of lysine residues via the Maillard reaction results in the formation of Advanced Glycation Endproducts (AGEs). These latter biosynthesis pathways are not fully understood as they are produced by a series of oxidative reactions between carbohydrates and collagen via Amadori rearrangements. Both covalent crosslinks and AGEs appear to correlate with several diseases such as skin and bone disorders, cancer metastasis, diabetes, Alzheimer's and cardiovascular diseases. Although several crosslinks are isolated, purified and described in collagen and elastin, only a few of them are chemically synthesized. Chemical synthesis plays an essential and important role in research providing pure crosslinks as reference materials and enabling the discovery of compounds to understand the biosynthesis of crosslinks and their properties. Synthetic crosslinks are crucial to verify the structures of collagen and elastin crosslinks where only a handful of structures have been determined by NMR spectroscopy and many other structures have only been predicted using mass spectrometry. This makes crosslinks and AGEs an interesting target for organic synthesis to produce sufficient quantities of material to enable studies on their biological significance and determine their absolute stereochemistry. The biological and chemical synthesis of both enzy-matic and non-enzymatic crosslinks are extensively described in this review. Collagen Collagen is integral for the structure of the extracellular matrix (ECM) and therefore vital for living organisms like mammals. 1 Collagen is expressed throughout all organs and tissues making it the main component of connective tissues in the body. 2 In vertebrates, up to 28 different types of collagen are known, most of them interact with other ECM proteins to form supramolecular network architecture which play a vital part in cell adhesion, migration and proliferation as well as providing strength. 3 The most common type is the fibrillar type I collagen (Col-I) contributing about 90% of total collagen content in the body. Col-I has an average size of 3000 amino acid residues and is involved in the formation of the structural network of tissues including skin, tendons, bones, cornea and the vascular system. 4 There are significant differences between the amino acid number and sequence, structure, and the role of different col-lagen types, however all share a common feature of at least one triple helical domain. 5 This domain is formed by three helical polyproline type II (PP-II) chains tightly packed into a right-handed triple helix which consists of a characteristic repeating amino acid motif (X AA-Y AA-Gly)n. Glycine occupies every third position in the sequence which fit into the centre of the triple helix, therefore larger residues are not tolerated. Even minor
The COVID-19 pandemic has broad implications for the care of patients with bone fragility. A dramatic surge in fractures and related mortality is expected in the next few months. We pledge to intensify the current efforts to improve the management of bone health, and to prioritize fragility fracture care and prevention.
The assessment of bone mainly relies on standard radiographs, CT, MRI, and bone scintigraphy depending on the anatomic region complexity and clinical scenario. Ultrasound (US), due to different acoustic impedance between soft tissues and the bone cortex, only allows the evaluation of the bone surfaces. Nevertheless, US can be useful in the evaluation of several bone disorders affecting the limbs as a result of its tomographic capabilities and high definition. This pictorial review article summarises our clinical experience in adults and reviews the literature on US bone examination. We first present the US appearance of normal bone and the main congenital anatomic variations, after which we illustrate the US findings of a variety of bone disorders. Although US has limits in bone assessment, its analysis must be a part of every musculoskeletal US examination.
Bone tissue is a mineralized and viscous-elastic connective tissue, which exerts crucial functions in our body such as support and protection of other tissues and mineral storage. Bone can adapt itself through a remodeling process, which is controlled by its cells, various local and systemic factors. It is a very complicated process composed of both cellular reactions and its effects on the internal structure of the bone. An imbalance between bone resorption and formation due to disease may alter its structure and mechanics. Mechanical properties of bone tissue are affected by different loading grades. Collagen material found in the extracellular matrix gives bone its elasticity. Bone is, nevertheless, a fragile structure depending on the loading and mineral content that also strengthens the bone. In this chapter, the structure of the bone in micro and macro scale, its mechanical properties in physiological circumstances and adaptation to pathological conditions will be discussed.
This chapter describes definition, etiology, pathology, diagnosis, treatment and management of Paget disease of bone. This is the second most common bone disease after osteoporosis. Both genetic and environmental factors have been implicated in the pathogenesis of Paget disease. Paget disease occurs commonly in families and can be transmitted vertically in an autosomal dominant pattern. Pagetic bone contains more numerous osteoclasts than normal, and these osteoclasts contain substantially more nuclei than normal osteoclasts. When Paget disease is suspected, the diagnostic evaluation should include a careful medical history, including family history of the condition and symptom history, and a focused physical examination. Laboratory tests include measurement of serum total alkaline phosphatase (SAP), and serum calcium and 25‐hydroxyvitamin D if bisphosphonate treatment is considered. Current guidelines suggest treatment of most patients with active disease at risk for complications with high potency bisphosphonates, either intravenous zolendronic acid, or oral alendronate or risedronate.
The mechanical properties of bone are fundamental to the ability of our skeletons to support movement and to provide protection to our vital organs. As such, deterioration in mechanical behavior with aging and/or diseases such as osteoporosis and diabetes can have profound consequences for individuals’ quality of life. This article reviews current knowledge of the basic mechanical behavior of bone at length scales ranging from hundreds of nanometers to tens of centimeters. We present the basic tenets of bone mechanics and connect them to some of the arcs of research that have brought the field to recent advances. We also discuss cortical bone, trabecular bone, and whole bones, as well as multiple aspects of material behavior, including elasticity, yield, fracture, fatigue, and damage. We describe the roles of bone quantity (e.g., density, porosity) and bone quality (e.g., cross-linking, protein composition), along with several avenues of future research.