Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model.

Objectives: The main goal of this work was to analyse how treatment intervention with tofacitinib prevents the early disturbances of bone structure and mechanics in the rat model of adjuvant-induced arthritis. This is the first study to access the impact of tofacitinib on the skeletal bone effects of inflammation. Methods: Fifty Wistar rats with adjuvant-induced arthritis were randomly housed in experimental groups, as follows: non-arthritic healthy group (n = 20); arthritic non-treated group (n = 20); and 10 animals undergoing tofacitinib treatment. Rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight. Healthy non-arthritic rats were used as controls for comparison. After 22 days of disease progression, rats were killed and bone samples collected for histology, micro-CT, three-point bending and nanoindentation analysis. Blood samples were also collected for quantification of bone turnover markers and systemic cytokines. Results: At the tissue level, measured by nanoindentation, tofacitinib increased bone cortical and trabecular hardness. However, micro-CT and three-point bending tests revealed that tofacitinib did not reverse the effects of arthritis on the cortical and trabecular bone structure and on mechanical properties. Conclusion: Possible reasons for these observations might be related to the mechanism of action of tofacitinib, which leads to direct interactions with bone metabolism, and/or to the kinetics of its bone effects, which might need longer exposure.

Predicting the Fracture Toughness of Human Cancellous Bone in Fractured Neck of Femur Patients Using Bone Volume and Micro-Architecture.

The current protocol used to determine if an individual is osteoporotic relies on assessment of the individual's bone mineral density (BMD), which allows clinicians to judge the condition of a patient with respect to their peers. This, in essence, evaluates a person's fracture risk, because BMD is a good surrogate measure for strength and stiffness. In recent studies, the authors were the first to produce fracture toughness (FT) data from osteoporotic (OP) and osteoarthritic (OA) patients, by using a testing technique which basically analyzes the prerequisite stress conditions for the onset of growth of a major crack through cancellous bone tissue. FT depends mainly on bone quantity (BV/TV, bone volume/tissue volume), but also on bone micro-architecture (mArch), the inner trabecular design of the bone. The working research hypothesis of the present study is that mArch offers added prediction power to BV/TV in determining FT parameters. Consequently, our aim was to investigate the use of predictive models for fracture toughness and also to investigate if there are any significant differences between the models produced from samples loaded across (AC, transverse to) the main trabecular orientation and along (AL, in parallel) the trabeculae. In multilinear regression analysis, we found that the strength of the relationships varied for a crack growing in these two orthogonal directions. Adding mArch variables in the Ac direction helped to increase the R2 to 0.798. However, in the AL direction, adding the mArch parameters did not add any predictive power to using BV/TV alone; BV/TV on its own could produce R2 = 0.730. The present results also imply that the anisotropic layout of the trabeculae makes it more difficult for a major crack to grow transversely across them. Cancellous bone models and remodels itself in a certain way to resist fracture in a specific direction, and thus, we should be mindful that architectural quality as well as bone quantity are needed to understand the resistance to fracture.

Parametrization of the Calcaneus and Medial Cuneiform to Aid Potential Advancements in Flatfoot Surgery.

INTRODUCTION: Flatfoot is a condition commonly seen in children; however, there is general disagreement over its incidence, characterization and correction. Painful flatfoot accompanied with musculoskeletal and soft tissue problems requires surgery to avoid arthritis in adulthood, the most common surgical approach being two osteotomies to the calcaneus and medial cuneiform bones of the foot. OBJECTIVES: This study focuses on the parametrization of these two bones to understand their bone morphology differences in a population sample among 23 normal subjects. Population differences could help in understanding whether bone shape may be an important factor in aiding surgical planning and outcomes. METHODS: A total of 45 sets of CT scans of these subjects were used to generate surface meshes of the two bones and converted to be iso-topological meshes, simplifying the application of Generalized Procrustes Analysis and Principal Component Analysis, allowing the main sources of variation between the subjects to be quantified. RESULTS: For the calcaneus, 16 Principal Components (PCs) and, for the medial cuneiform, 12 PCs were sufficient to describe 90% of the dataset variability. The quantitative and qualitative analyses confirm that for the calcaneus PC1 describes the Achilles attachment location and PC2 largely describes the anterior part of the bone. For the medial cuneiform, PC1 describes the medial part of the bone, while PC2 mainly describes the superior part. CONCLUSION: Most importantly, the PCs did not seem to describe the osteotomy sites for both bones, suggesting low population variability at the bone cutting points. Further studies are needed to evaluate how shape variability impacts surgical outcomes. Future implications could include better surgical planning and may pave the way for complex robotic surgeries to become a reality.

New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties.

Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr(-/-)) and wild-type (Ahr(+/+)) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200µg/kgbw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr(+/+) mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr(-/-) mice displayed a slightly modified bone phenotype as compared with untreated Ahr(+/+) mice, while TCDD exposure caused only a few changes in bones of Ahr(-/-) mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr(+/+) mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations.

Quantifying microcracks on fractured bone surfaces - Potential use in forensic anthropology.

Bone fracture surface morphology (FSM) can provide valuable information on the cause of failure in forensic and archaeological applications and it depends primarily on three factors, the loading conditions (like strain rate), the ambient conditions (wet or dry bone material) and the quality of bone material itself. The quality of bone material evidently changes in taphonomy as a result of the decomposition process and that in turn is expected to affect FSM. Porcine bones were fractured by a standardised impact during the course of soft tissue decomposition, at 28-day intervals, over 140 days (equivalent to 638 cooling degree days). Measurements of the associated microcracks on the fractured cortical bone surfaces indicated a progressive increase in mean length during decomposition from around 180 µm-375 µm. The morphology of these microcracks also altered, from multiple intersecting microcracks emanating from a central point at 0-28 cumulative cooling degree days, to longer linear cracks appearing to track lamellae as soft tissue decomposition progressed. The implications of these findings are that taphonomic changes of bone may offer the real possibility of distinguishing perimortem and taphonomic damage and also provide a new surrogate parameter for estimation of post-mortem interval (PMI) in forensics.

Association between nanoscale strains and tissue level nanoindentation properties in age-related hip-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.

Assessing bone maturity: Compositional and mechanical properties of rib cortical bone at different ages.

Understanding what maturity entails for bone, when it arrives, and its pre- and post-maturity traits and properties are very important for understanding its evolution and physiology. There is a clear but fine distinction between the chronological age of bone (the age of its donor) and the tissue age of the bone packets it comprises at the microscopic level. Whole bone fragility changes with age due to mass and architecture effects, but so do the properties of bone at the tissue level. Tissue age and tissue-level properties are therefore increasingly attracting a great deal of attention recently. The present study investigated compositional and material changes in the hydroxyapatite crystals, the collagenous phase, changes in bone matrix composition and its nanoindentation properties and their decline with chronological age in later life. The aim was to track the age threshold at which cortical bone arrives at maturity and what happens following that threshold. To do so FTIR, DSC/TGA, XRD, nanoindentation and microindentation were used to investigate rib cortical bone material across a cohort of 86 individuals from one ethnic group with age spanning between 17 and 82 years. Results of this cross-sectional study showed a clear increase in mineral content relative to the organic and water contents across all ages. Furthermore, an increase in crystal size and consequent decrease in strain (coherence length) was detected associated with secondary mineralisation and an increase in carbonate substitution. Overall, we observe a number of modifications which contribute to a typical functional behaviour of bone showing an increase in both indentation modulus and hardness until the age of about 35 after which both of these properties decline gradually and concomitantly to other physicochemical changes and seemingly until the end of one's life.

The interplay between BMU activity linked to mechanical stress, specific surface and inhibitory theory dictate bone mass distribution: Predictions from a 3D computational model.

Bone mechanical and biological properties are closely linked to its internal tissue composition and mass distribution, which are in turn governed by the purposeful action of the basic multicellular units (BMUs). The orchestrated action of osteoclasts and osteoblasts, the resorbing and forming tissue cells respectively, in BMUs is responsible for tissue maintenance, repair and adaptation to changing load demands through the phenomenon known as remodelling. In this work, a computational mechano-biological model of bone remodelling based on the inhibitory theory and a new scheme of bone resorption introduced previously in a 2D model, is extended to a 3D model of the real external geometry of a femur under normal walking loads. Starting from a uniform apparent density (ratio of tissue local mass to total local volume) distribution, the BMU action can be shown to lead naturally to an internal density distribution similar to that of a real bone, provided that the initial density value is high enough to avoid unrealistic final mass deposition in zones of high energy density and excessive damage. Physiological internal density values are reached throughout the whole 3D geometry, and at the same time a 'boomerang'-like relationship between apparent and material density (ratio of tissue mass to tissue volume) emerges naturally under the proposed remodelling scheme. It is also shown here that bone-specific surface is a key parameter that determines the intensity of BMU action linked to the mechanical and biological requirements. Finally, by engaging in simulations of bone in disuse, we were able to confirm the appropriate selection of the model parameters. As an example, our results show good agreement with experimental measurements of bone mass on astronauts a fact that strengthens our belief in the insightful nature of our novel 3D computational model.

Age related changes of rib cortical bone matrix and the application to forensic age-at-death estimation.

Forensic anthropology includes, amongst other applications, the positive identification of unknown human skeletal remains. The first step in this process is an assessment of the biological profile, that is: sex, age, stature and ancestry. In forensic contexts, age estimation is one of the main challenges in the process of identification. Recently established admissibility criteria are driving researchers towards standardisation of methodological procedures. Despite these changes, experience still plays a central role in anthropological examinations. In order to avoid this issue, age estimation procedures (i) must be presented to the scientific community and published in peer reviewed journals, (ii) accurately explained in terms of procedure and (iii) present clear information about the accuracy of the estimation and possible error rates. In order to fulfil all these requirements, a number of methods based on physiological processes which result in biochemical changes in various tissue structures at the molecular level, such as modifications in DNA-methylation and telomere shortening, racemization of proteins and stable isotopes analysis, have been developed. The current work proposes a new systematic approach in age estimation based on tracing physicochemical and mechanical degeneration of the rib cortical bone matrix. This study used autopsy material from 113 rib specimens. A set of 33 parameters were measured by standard bio-mechanical (nanoindentation and microindentation), physical (TGA/DSC, XRD and FTIR) and histomorphometry (porosity-ImageJ) methods. Stepwise regressions were used to create equations that would produce the best 'estimates of age at death' vs real age of the cadavers. Five equations were produced; in the best of cases an equation counting 7 parameters had an R2 = 0.863 and mean absolute error of 4.64 years. The present method meets all the admissibility criteria previously described. Furthermore, the method is experience-independent and as such can be performed without previous expert knowledge of forensic anthropology and human anatomy.

Evaluation of bone excision effects on a human skull model-II: Finite element analysis.

Patient-specific computational models are powerful tools which may assist in predicting the outcome of invasive surgery on the musculoskeletal system, and consequently help to improve therapeutic decision-making and post-operative care. Unfortunately, at present the use of personalized models that predict the effect of biopsies and full excisions is so specialized that tends to be restricted to prominent individuals, such as high-profile athletes. We have developed a finite element analysis model to determine the influence of the location of an ellipsoidal excision (14.2 mm × 11.8 mm) on the structural integrity of a human skull when exposed to impact loading, representing a free fall of an adult male from standing height. The finite element analysis model was compared to empirical data based on the drop-tower testing of three-dimensional-printed physical skull models where deformations were recorded by digital image correlation. In this bespoke example, we found that the excision site did not have a major effect on the calculated stress and strain magnitudes unless the excision was in the temporal region, where the reduction in stiffness around the excision caused failure within the neighboring area. The finite element analysis model allowed meaningful conclusions to be drawn for the implications of using such a technique based on what we know about such conditions indicating that the approach could be both clinically beneficial and also cost-effective for wider use.

Ageing bone fractures: The case of a ductile to brittle transition that shifts with age.

Human bone becomes increasingly brittle with ageing. Bones also fracture differently under slow and fast loadings, being ductile and brittle, respectively. The effects of a combination of these two factors have never been examined before. Here we show that cortical bone is most fracture-resistant at the physiologically prevalent intermediate strain rates of 10-3 s-1 to 10-2 s-1 such as they occur in walking or running, slightly weaker at slower quasistatic and much weaker at fast impact loading rates. In young cortical bone (15 years of age) the ductile-to-brittle transition (DBT) occurs at strain rates of 10-2 s-1, in old cortical bone (85 yrs) at speeds lower by a factor of 10 to 40. Other research has shown that the energy required to break bone (per unit of fracture surface) drops as much as 60% between these two ages. Therefore, DBT seems to compound the well-known phenomenon of 'brittle old bones'. Old bones can only cope with slow movement, young ones with both slow and fast movement. These observed material characteristics of (i) a shift of the DBT and (ii) a reduced energy absorption capacity appear to contribute at least as much to the loss of bone quality as the various quantity based (lowered bone density and mineral content) explanations of the past. They also provide a new powerful paradigm, which allows us to demonstrate mechanically, and uniquely, how human bone becomes increasingly brittle with age.

Evaluation of bone excision effects on a human skull model - I: Mechanical testing and digital image correlation.

The mechanisms of skull impact loading may change following surgical interventions such as the removal of bone lesions, but little is known about the consequences in the event of subsequent head trauma. We, therefore, prepared acrylonitrile butadiene styrene human skull models based on clinical computed tomography skull data using a three-dimensional printer. Six replicate physical skull models were tested, three with bone excisions and three without. A drop tower was used to simulate the impact sustained by falling backwards onto the occipital lobe region. The impacts were recorded with a high-speed camera, and the occipital strain response was determined by digital image correlation. Although the hole affected neither the magnitude nor the sequence of the fracture pattern, the digital image correlation analysis highlighted an increase in strain around the excised area (0.45%-16.4% of the principal strain). Our approach provides a novel method that could improve the quality of life for patients on many fronts, including protection against trauma, surgical advice, post-operative care, advice in litigation cases, as well as facilitating general biomechanical research in the area of trauma injuries.

Age-Related Trends in the Trabecular Micro-Architecture of the Medial Clavicle: Is It of Use in Forensic Science?

The mechanical and structural properties of bone are known to change significantly with age. Within forensic and archaeological investigations, the medial end of the clavicle is typically used for estimating the age-at-death of an unknown individual. Although, this region of the skeleton is of interest to forensic and clinical domains, alterations beyond the macro-scale have not been fully explored. For this study, non-destructive micro-computed tomography (µ-CT) was employed to characterize structural alterations to the cancellous bone of the medial clavicle. Fresh human cadaveric specimens (12-59 years) obtained at autopsy were utilized for this study, and were scanned with a voxel size of ~83 µm. Morphometric properties were quantified and indicated that the bone volume, connectivity density, mineral density, and number of trabeculae decreased with age, while the spacing between the trabeculae increased with age. In contrast to other sub-regions of the skeleton, trabecular thickness, and degree of anisotropy did not correlate with age. Collectively, this could suggest that the network is becoming increasingly perforated with age rather than exhibiting trabecular thinning. These results are used in the context of deriving a potential protocol for forensic investigations by using this particular and largely unexplored region of the skeleton, and provide inspiration for future experiments concerning micro-architectural and small scale changes in other regions of the human skeleton.

Microcracking damage and the fracture process in relation to strain rate in human cortical bone tensile failure.

It is difficult to define the 'physiological' mechanical properties of bone. Traumatic failures in-vivo are more likely to be orders of magnitude faster than the quasistatic tests usually employed in-vitro. We have reported recently [Hansen, U., Zioupos, P., Simpson, R., Currey, J.D., Hynd, D., 2008. The effect of strain rate on the mechanical properties of human cortical bone. Journal of Biomechanical Engineering/Transactions of the ASME 130, 011011-1-8] results from tests on specimens of human femoral cortical bone loaded in tension at strain rates (epsilon ) ranging from low (0.08s(-1)) to high (18s(-1)). Across this strain rate range the modulus of elasticity generally increased, stress at yield and failure and strain at failure decreased for rates higher than 1s(-1), while strain at yield was invariant for most strain rates and only decreased at rates higher than 10s(-1). The results showed that strain rate has a stronger effect on post-yield deformation than on initiation of macroscopic yielding. In general, specimens loaded at high strain rates were brittle, while those loaded at low strain rates were much tougher. Here, a post-test examination of the microcracking damage reveals that microcracking was inversely related to the strain rate. Specimens loaded at low strain rates showed considerable post-yield strain and also much more microcracking. Partial correlation and regression analysis suggested that the development of post-yield strain was a function of the amount of microcracking incurred (the cause), rather than being a direct result of the strain rate (the excitation). Presumably low strain rates allow time for microcracking to develop, which increases the compliance of the specimen, making them tougher. This behaviour confirms a more general rule that the degree to which bone is brittle or tough depends on the amount of microcracking damage it is able to sustain. More importantly, the key to bone toughness is its ability to avoid a ductile-to-brittle transition for as long as possible during the deformation. The key to bone's brittleness, on the other hand, is the strain and damage localisation early on in the process, which leads to low post-yield strains and low-energy absorption to failure.

Some basic relationships between density values in cancellous and cortical bone.

Density is a salient property of bone and plays a crucial role in determining the mechanical properties of both its cancellous and cortical structural forms. Density is defined in a number of ways at either the bone tissue (D(app), apparent) or the bone material level (D(mat), material). The concept of density is relatively simple, but measuring it in the context of bone is a complex issue. The third dimension of the problem is the concept of porosity, or BV/TV (ratio of bone material volume over tissue volume). Recent investigations from our laboratory have revealed an interdependence of D(app) and D(mat) in the cancellous bone of at least four different cohorts of human patients. To clarify the underlying causes of this behaviour, we produced here equivalent relationships from specimens originating from cortical and cancellous areas of the same bone. Plots of D(app) vs. D(mat) showed that D(mat) was not a monotonic function of increasing D(app), but instead showed a 'boomerang'-like pattern. By empirically dissecting the data in two regions for D(app) above and below a value equal to 1.3gcm(-3), we were able to objectively isolate the bone in trabecular and compact forms. Our findings may have implications not only for the segregation of bone in these two structural forms, but also for the mechanobiological and physiological processes that govern the regulation of compact and trabecular bone areas.

Using risk factors and quantitative ultrasound to identify postmenopausal caucasian women at risk of osteoporosis.

There is a need to prescreen large numbers of individuals for osteoporosis due to current demands on clinical resources. Some previous attempts to predict individuals at risk have used simple indices based on patient information, or Quantitative Ultrasound (QUS) and have shown good sensitivity but also demonstrated low specificity, which means that many individuals with good bone mineral density were also selected. The aim of this study was to determine if a tool based on a combination of risk factors and QUS measurements could also be made to provide improved specificity. A risk factors measurement questionnaire was created and completed for a sample of Caucasian postmenopausal women (n=235) who had undergone Dual-energy X-ray absorptiometry scanning. QUS measurements were also taken at various skeletal sites. Assessment tools were generated using stepwise regression to predict osteoporosis, evaluated by receiver operating characteristic curves, and assessed using area under the curve values. Specificity values were determined at a sensitivity of 0.90 to establish the comparative utility of each assessment tool. Using only a risk factors model the specificities were 0.28 at the lumbar spine, 0.45 for the femoral neck and 0.68 for the total hip. In a risk factors+QUS data model the specificities measured were 0.44 for the lumbar spine, 0.78 for the femoral neck, and 0.84 for the total hip. These novel assessment tools can identify those with low bone mineral density at a number of skeletal sites and help towards avoiding many unnecessary investigations in the future.

Age-Related Changes in Femoral Head Trabecular Microarchitecture.

Osteoporosis is a prevalent bone condition, characterised by low bone mineral density and increased fracture risk. Currently, the gold standard for identifying osteoporosis and increased fracture risk is through quantification of bone mineral density using dual energy X-ray absorption. However, many studies have shown that bone strength, and consequently the probability of fracture, is a combination of both bone mass and bone 'quality' (architecture and material chemistry). Although the microarchitecture of both non-fracture and osteoporotic bone has been previously investigated, many of the osteoporotic studies are constrained by factors such as limited sample number, use of ovariectomised animal models, and lack of male and female discrimination. This study reports significant differences in bone quality with respect to the microarchitecture between fractured and non-fractured human femur specimens. Micro-computed tomography was utilised to investigate the microarchitecture of femoral head trabecular bone from a relatively large cohort of non-fracture and fracture human donors. Various microarchitectural parameters have been determined for both groups, providing an understanding of the differences between fracture and non -fracture material. The microarchitecture of non-fracture and fracture bone tissue is shown to be significantly different for many parameters. Differences between sexes also exist, suggesting differences in remodelling between males and females in the fracture group. The results from this study will, in the future, be applied to develop a fracture model which encompasses bone density, architecture and material chemical properties for both female and male tissues.

Early arthritis induces disturbances at bone nanostructural level reflected in decreased tissue hardness in an animal model of arthritis.

INTRODUCTION: Arthritis induces joint erosions and skeletal bone fragility. OBJECTIVES: The main goal of this work was to analyze the early arthritis induced events at bone architecture and mechanical properties at tissue level. METHODS: Eighty-eight Wistar rats were randomly housed in experimental groups, as follows: adjuvant induced arthritis (AIA) (N = 47) and a control healthy group (N = 41). Rats were monitored during 22 days for the inflammatory score, ankle perimeter and body weight and sacrificed at different time points (11 and 22 days post disease induction). Bone samples were collected for histology, micro computed tomography (micro-CT), 3-point bending and nanoindentation. Blood samples were also collected for bone turnover markers and systemic cytokine quantification. RESULTS: At bone tissue level, measured by nanoindentation, there was a reduction of hardness in the arthritic group, associated with an increase of the ratio of bone concentric to parallel lamellae and of the area of the osteocyte lacuna. In addition, increased bone turnover and changes in the microstructure and mechanical properties were observed in arthritic animals, since the early phase of arthritis, when compared with healthy controls. CONCLUSION: We have shown in an AIA rat model that arthritis induces very early changes at bone turnover, structural degradation and mechanical weakness. Bone tissue level is also affected since the early phase of arthritis, characterized by decreased tissue hardness associated with changes in bone lamella organization and osteocyte lacuna surface. These observations highlight the pertinence of immediate control of inflammation in the initial stages of arthritis.

'Phoenix polymers': fire induced nanohardness in fibril-forming aromatic cyanate esters.

For the first time we present nanoindentation analysis of charred, cured aromatic cyanate esters, which exhibit outstanding mechanical properties when analysed under applied loads of 0.1-300 mN. Following charring (900 °C for 10 minutes to achieve graphitised structures), the samples display a remarkable combination of a modulus of elasticity of around 25 GPa and nanohardness of 300 kgf mm-2, making them some 30-40% stiffer than bone and practically as hard as tooth enamel. At the same time we find that under the same conditions the chars are highly resilient, displaying complete elastic recovery with very little plastic deformation. When cured in the presence of copper(ii) acetylacetonate (200 ppm) in dodecylphenol (1% w/v active copper suspension) to form a polycyanurate, compound (2) forms a dense, consolidated structure compared with compound (1) under the same conditions. At high magnification, the presence of a nanoscale, fibrillar structure is observed, accounting for the high resilience.