A Cross-Sectional Study of Bone Nanomechanics in Hip Fracture and Aging.

Bone mechanics is well understood at every length scale except the nano-level. We aimed to investigate the relationship between bone nanoscale and tissue-level mechanics experimentally. We tested two hypotheses: (1) nanoscale strains were lower in hip fracture patients versus controls, and (2) nanoscale mineral and fibril strains were inversely correlated with aging and fracture. A cross-sectional sample of trabecular bone sections was prepared from the proximal femora of two human donor groups (aged 44-94 years): an aging non-fracture control group (n = 17) and a hip-fracture group (n = 20). Tissue, fibril, and mineral strain were measured simultaneously using synchrotron X-ray diffraction during tensile load to failure, then compared between groups using unpaired t-tests and correlated with age using Pearson's correlation. Controls exhibited significantly greater peak tissue, mineral, and fibril strains than the hip fracture (all p < 0.05). Age was associated with a decrease in peak tissue (p = 0.099) and mineral (p = 0.004) strain, but not fibril strain (p = 0.260). Overall, hip fracture and aging were associated with changes in the nanoscale strain that are reflected at the tissue level. Data must be interpreted within the limitations of the observational cross-sectional study design, so we propose two new hypotheses on the importance of nanomechanics. (1) Hip fracture risk is increased by low tissue strain, which can be caused by low collagen or mineral strain. (2) Age-related loss of tissue strain is dependent on the loss of mineral but not fibril strain. Novel insights into bone nano- and tissue-level mechanics could provide a platform for the development of bone health diagnostics and interventions based on failure mechanisms from the nanoscale up.

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.

Can guided wave ultrasound predict bone mechanical properties at the femoral neck in patients undergoing hip arthroplasty?

The bone quality of patients undergoing hip replacement surgery is poorly predicted by radiographs alone. With better bone quality information available to a surgeon, the operation can be performed more safely. The aim of this study was to investigate whether ultrasound signals of cortical bone at peripheral sites such as the tibia and radius can be used to predict the compressive mechanical properties of cortical bone at the femoral neck. We recruited 19 patients undergoing elective hip arthroplasty and assessed the radius and tibia of these patients with the Azalée guided wave ultrasound to estimate the porosity and thickness of the cortex. Excess bone tissues were collected from the femoral neck and the compressive mechanical properties of the cortex were characterised under a mechanical loading rig to determine stiffness, ultimate strength, and density. The correlations between the ultrasound measurements and mechanical properties were analysed using linear regression, Pearson correlation statistics, and multiple regression analysis. Cortical mechanical properties were weakly to moderately correlated with the ultrasound measurements at various sites (R2 = 0.00-0.36). The significant correlations found were not consistent across all 4 peripheral measurement sites. Additionally, weak to moderate ability of the ultrasound to predict mechanical properties at the neck of femur with multiple regression analysis was found (R2 = 0.00-0.48). Again, this was inconsistent across the different anatomical sites. Overall, the results demonstrate the need for ultrasound scans to be collected directly from clinically relevant sites such as the femoral neck due to the inconsistency of mechanical properties across various sites.

Digital health interventions for osteoporosis and post-fragility fracture care.

The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.

Opportunistic diagnosis of osteoporosis, fragile bone strength and vertebral fractures from routine CT scans; a review of approved technology systems and pathways to implementation.

Osteoporosis causes bones to become weak, porous and fracture more easily. While a vertebral fracture is the archetypal fracture of osteoporosis, it is also the most difficult to diagnose clinically. Patients often suffer further spine or other fractures, deformity, height loss and pain before diagnosis. There were an estimated 520,000 fragility fractures in the United Kingdom (UK) in 2017 (costing £4.5 billion), a figure set to increase 30% by 2030. One way to improve both vertebral fracture identification and the diagnosis of osteoporosis is to assess a patient's spine or hips during routine computed tomography (CT) scans. Patients attend routine CT for diagnosis and monitoring of various medical conditions, but the skeleton can be overlooked as radiologists concentrate on the primary reason for scanning. More than half a million CT scans done each year in the National Health Service (NHS) could potentially be screened for osteoporosis (increasing 5% annually). If CT-based screening became embedded in practice, then the technique could have a positive clinical impact in the identification of fragility fracture and/or low bone density. Several companies have developed software methods to diagnose osteoporosis/fragile bone strength and/or identify vertebral fractures in CT datasets, using various methods that include image processing, computational modelling, artificial intelligence and biomechanical engineering concepts. Technology to evaluate Hounsfield units is used to calculate bone density, but not necessarily bone strength. In this rapid evidence review, we summarise the current literature underpinning approved technologies for opportunistic screening of routine CT images to identify fractures, bone density or strength information. We highlight how other new software technologies have become embedded in NHS clinical practice (having overcome barriers to implementation) and highlight how the novel osteoporosis technologies could follow suit. We define the key unanswered questions where further research is needed to enable the adoption of these technologies for maximal patient benefit.

Clinical Importance of Bone Matrix Damage Mechanisms for Fracture Prevention.

PURPOSE OF REVIEW: Bone matrix exhibits great complexity in its composition, structure and mechanics. Here, we provide a review of recent research articles and appraise the evidence that bone matrix quality is clinically important and possibly targetable for fracture prevention. RECENT FINDINGS: Deformation of mineralised collagen fibrils determines bone fracture mechanics. Slipping and separation at the mineral-fibril and fibril-fibril interfaces, respectively, are the structural mechanisms for plastic deformation and microcrack nucleation. Existing technologies for assessing bone tissue in vivo cannot measure matrix structure or fracture mechanics but have shown limited use in clinical settings for identifying fragility or following treatment outcomes based on composition. Matrix is biomechanically and clinically important, but the knowledge has not translated into clinical practice. The structural mechanisms by which a load is transferred from mineralised collagen fibrils to the whole bone via microcracking have been proven too complex to measure in vivo. The mineral-fibril or fibril-fibril interfaces might be suitable targets for diagnosing fragility or delivering molecules that reduce fracture risk by strengthening the mineral bonds while maintaining flexibility in the fibrils.

Nanoscale mechanisms in age-related hip-fractures.

Nanoscale mineralized collagen fibrils may be important determinants of whole-bone mechanical properties and contribute to the risk of age-related fractures. In a cross-sectional study nano- and tissue-level mechanics were compared across trabecular sections from the proximal femora of three groups (n = 10 each): ageing non-fractured donors (Controls); untreated fracture patients (Fx-Untreated); bisphosphonate-treated fracture patients (Fx-BisTreated). Collagen fibril, mineral and tissue mechanics were measured using synchrotron X-Ray diffraction of bone sections under load. Mechanical data were compared across groups, and tissue-level data were regressed against nano. Compared to controls fracture patients exhibited significantly lower critical tissue strain, max strain and normalized strength, with lower peak fibril and mineral strain. Bisphosphonate-treated exhibited the lowest properties. In all three groups, peak mineral strain coincided with maximum tissue strength (i.e. ultimate stress), whilst peak fibril strain occurred afterwards (i.e. higher tissue strain). Tissue strain and strength were positively and strongly correlated with peak fibril and mineral strains. Age-related fractures were associated with lower peak fibril and mineral strain irrespective of treatment. Indicating earlier mineral disengagement and the subsequent onset of fibril sliding is one of the key mechanisms leading to fracture. Treatments for fragility should target collagen-mineral interactions to restore nano-scale strain to that of healthy bone.

A method for fracture toughness measurement in trabecular bone using computed tomography, image correlation and finite element methods.

The fracture resistance of load-bearing trabecular bone is adversely affected by diseases such as osteoporosis. However, there are few published measurements of trabecular bone fracture toughness due to the difficulty of conducting reliable tests in small specimens of this highly porous material. A new approach is demonstrated that uses digital volume correlation of X-ray computed tomographs to measure 3D displacement fields in which the crack shape and size can be objectively identified using a phase congruency analysis. The criteria for crack propagation, i.e. fracture toughness, can then be derived by finite element simulation, with knowledge of the elastic properties.

Hemiarthroplasties: the choice of prosthetic material causes different levels of damage in the articular cartilage.

BACKGROUND: Hemiarthroplasty has clear advantages over alternative procedures and is used in 20% of all shoulder joint replacements. Because of cartilage wear, the clinical outcome of hemiarthroplasty is unreliable and controversial. This paper suggests that the optimal choice of prosthetic material may reduce cartilage degeneration and improve the reliability of the procedure. The specific objectives were to assess 3 materials and assess how the severity of arthritis might affect the choice of prosthetic material. METHODS: A CoCr alloy, an AL2O3 ceramic, and a polycarbonate urethane polymer (PCU) were mechanically tested against 5 levels of human osteoarthritic cartilage (from intact to severely arthritic, n = 45). A high friction coefficient, a decrease in Young's modulus, an increase in permeability, a decrease in relaxation time, an increase in surface roughness, and a disrupted appearance of the cartilage after testing were used as measures of cartilage damage. The biomaterial that caused minimal cartilage damage was defined as superior. RESULTS: The CoCr caused the most damage. This was followed by the AL2O3 ceramic, whereas the PCU caused the least amount of damage. Although the degree of arthritis had an effect on the results, it did not change the trend that CoCr performed worst and PCU the best. DISCUSSION AND CONCLUSION: This study indicates that ceramic implants may be a better choice than metals, and the articulating surface should be as smooth as possible. Although our results indicate that the degree of arthritis should not affect the choice of prosthetic material, this suggestion needs to be further investigated.

Computed tomography porosity and spherical indentation for determining cortical bone millimetre-scale mechanical properties.

The cortex of the femoral neck is a key structural element of the human body, yet there is not a reliable metric for predicting the mechanical properties of the bone in this critical region. This study explored the use of a range of non-destructive metrics to measure femoral neck cortical bone stiffness at the millimetre length scale. A range of testing methods and imaging techniques were assessed for their ability to measure or predict the mechanical properties of cortical bone samples obtained from the femoral neck of hip replacement patients. Techniques that can potentially be applied in vivo to measure bone stiffness, including computed tomography (CT), bulk wave ultrasound (BWUS) and indentation, were compared against in vitro techniques, including compression testing, density measurements and resonant ultrasound spectroscopy. Porosity, as measured by micro-CT, correlated with femoral neck cortical bone's elastic modulus and ultimate compressive strength at the millimetre length scale. Large-tip spherical indentation also correlated with bone mechanical properties at this length scale but to a lesser extent. As the elastic mechanical properties of cortical bone correlated with porosity, we would recommend further development of technologies that can safely measure cortical porosity in vivo.

Measuring bone stiffness using spherical indentation.

OBJECTIVES: Bone material properties are a major determinant of bone health in older age, both in terms of fracture risk and implant fixation, in orthopaedics and dentistry. Bone is an anisotropic and hierarchical material so its measured material properties depend upon the scale of metric used. The scale used should reflect the clinical problem, whether it is fracture risk, a whole bone problem, or implant stability, at the millimetre-scale. Indentation, an engineering technique involving pressing a hard-tipped material into another material with a known force, may be able to assess bone stiffness at the millimetre-scale (the apparent elastic modulus). We aimed to investigate whether spherical-tip indentation could reliably measure the apparent elastic modulus of human cortical bone. MATERIALS AND METHODS: Cortical bone samples were retrieved from the femoral necks of nineteen patients undergoing total hip replacement surgery (10 females, 9 males, mean age: 69 years). The samples underwent indentation using a 1.5 mm diameter, ruby, spherical indenter tip, with sixty indentations per patient sample, across six locations on the bone surfaces, with ten repeated indentations at each of the six locations. The samples then underwent mechanical compression testing. The repeatability of indentation measurements of elastic modulus was assessed using the co-efficient of repeatability and the correlation between the bone elastic modulus measured by indentation and compression testing was analysed by least-squares regression. RESULTS: In total, 1140 indentations in total were performed. Indentation was found to be repeatable for indentations performed at the same locations on the bone samples with a mean co-efficient of repeatability of 0.4 GigaPascals (GPa), confidence interval (C.I): 0.33-0.42 GPa. There was variation in the indentation modulus results between different locations on the bone samples (mean co-efficient of repeatability: 3.1 GPa, C.I: 2.2-3.90 GPa). No clear correlation was observed between indentation and compression values of bone elastic modulus (r = 0.33, p = 0.17). The mean apparent elastic modulus obtained by spherical indentation was 9.9 GPa, the standard deviation for each indent cycle was 0.11 GPa, and the standard deviation between locations on the same sample was 1.01 GPa. The mean compression apparent elastic modulus was 4.42 GPa, standard deviation 1.02 GPa. DISCUSSION: Spherical-tip indentation was found to be a repeatable test for measuring the elastic modulus of human cortical bone, demonstrated by a low co-efficient of repeatability in this study. It could not, however, reliably predict cortical bone elastic modulus determined by platens compression testing in this study. This may be due to indentation only probing mechanical properties at the micro-scale while platens compression testing assesses millimetre length-scale properties. Improvements to the testing technique, including the use of a larger diameter spherical indenter tip, may improve the measurement of bone stiffness at the millimetre scale and should be investigated further.

Femoral fracture type can be predicted from femoral structure: A finite element study validated by digital volume correlation experiments.

Proximal femoral fractures can be categorized into two main types: Neck and intertrochanteric fractures accounting for 53% and 43% of all proximal femoral fractures, respectively. The possibility to predict the type of fracture a specific patient is predisposed to would allow drug and exercise therapies, hip protector design, and prophylactic surgery to be better targeted for this patient rendering fracture preventing strategies more effective. This study hypothesized that the type of fracture is closely related to the patient-specific femoral structure and predictable by finite element (FE) methods. Fourteen femora were DXA scanned, CT scanned, and mechanically tested to fracture. FE-predicted fracture patterns were compared to experimentally observed fracture patterns. Measurements of strain patterns to explain neck and intertrochanteric fracture patterns were performed using a digital volume correlation (DVC) technique and compared to FE-predicted strains and experimentally observed fracture patterns. Although loaded identically, the femora exhibited different fracture types (six neck and eight intertrochanteric fractures). CT-based FE models matched the experimental observations well (86%) demonstrating that the fracture type can be predicted. DVC-measured and FE-predicted strains showed obvious consistency. Neither DXA-based BMD nor any morphologic characteristics such as neck diameter, femoral neck length, or neck shaft angle were associated with fracture type. In conclusion, patient-specific femoral structure correlates with fracture type and FE analyses were able to predict these fracture types. Also, the demonstration of FE and DVC as metrics of the strains in bones may be of substantial clinical value, informing treatment strategies and device selection and design. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:993-1001, 2018.

Deformation of the Lamina Cribrosa and Optic Nerve Due to Changes in Cerebrospinal Fluid Pressure.

Purpose: Cerebrospinal fluid pressure (CSFp) changes are involved or implicated in various ocular conditions including glaucoma, idiopathic intracranial hypertension, and visual impairment and intracranial pressure syndrome. However, little is known about the effects of CSFp on lamina cribrosa and retrolaminar neural tissue (RLNT) biomechanics, potentially important in these conditions. Our goal was to use an experimental approach to visualize and quantify the deformation of these tissues as CSFp increased. Methods: The posterior eye and RLNT of porcine eyes (n = 3) were imaged using synchrotron radiation phase-contrast micro-computed tomography (PC µCT) at an intraocular pressure of 15 mm Hg and CSFps of 4, 10, 20, and 30 mm Hg. Scans of each tissue region were acquired at each CSFp step and analyzed using digital volume correlation to determine 3-dimensional tissue deformations. Results: Elevating CSFp increased the strain in the lamina cribrosa and RLNT of all three specimens, with the largest strains occurring in the RLNT. Relative to the baseline CSFp of 4 mm Hg, at 30 mm Hg, the lamina cribrosa experienced a mean first and third principal strain of 4.4% and -3.5%, respectively. The corresponding values for the RLNT were 9.5% and -9.1%. Conclusions: CSFp has a significant impact on the strain distributions within the lamina cribrosa and, more prominently, within the RLNT. Elevations in CSFp were positively correlated with increasing deformations in each region and may play a role in ocular pathologies linked to changes in CSFp.

Long-term effects of bisphosphonate therapy: perforations, microcracks and mechanical properties.

Osteoporosis is characterised by trabecular bone loss resulting from increased osteoclast activation and unbalanced coupling between resorption and formation, which induces a thinning of trabeculae and trabecular perforations. Bisphosphonates are the frontline therapy for osteoporosis, which act by reducing bone remodelling, and are thought to prevent perforations and maintain microstructure. However, bisphosphonates may oversuppress remodelling resulting in accumulation of microcracks. This paper aims to investigate the effect of bisphosphonate treatment on microstructure and mechanical strength. Assessment of microdamage within the trabecular bone core was performed using synchrotron X-ray micro-CT linked to image analysis software. Bone from bisphosphonate-treated fracture patients exhibited fewer perforations but more numerous and larger microcracks than both fracture and non-fracture controls. Furthermore, bisphosphonate-treated bone demonstrated reduced tensile strength and Young's Modulus. These findings suggest that bisphosphonate therapy is effective at reducing perforations but may also cause microcrack accumulation, leading to a loss of microstructural integrity and consequently, reduced mechanical strength.

Synchrotron Imaging Assessment of Bone Quality.

Bone is a complex hierarchical structure, and its principal function is to resist mechanical forces and fracture. Bone strength depends not only on the quantity of bone tissue but also on the shape and hierarchical structure. The hierarchical levels are interrelated, especially the micro-architecture, collagen and mineral components; hence, analysis of their specific roles in bone strength and stiffness is difficult. Synchrotron imaging technologies including micro-CT and small/wide angle X-ray scattering/diffraction are becoming increasingly popular for studying bone because the images can resolve deformations in the micro-architecture and collagen-mineral matrix under in situ mechanical loading. Synchrotron cannot be directly applied in vivo due to the high radiation dose but will allow researchers to carry out systematic multifaceted studies of bone ex vivo. Identifying characteristics of aging and disease will underpin future efforts to generate novel devices and interventional therapies for assessing and promoting healthy aging. With our own research work as examples, this paper introduces how synchrotron imaging technology can be used with in situ testing in bone research.

Motion-driven flow in an unusual piscine nasal region.

Fishes have several means of moving water to effect odorant transport to their olfactory epithelium ('olfactory flow'). Here we show that olfactory flow in the adult garpike Belone belone (Belonidae, Teleostei), a fish with an unusual nasal region, can be generated by its motion relative to water (swimming, or an external current, or both). We also show how the unusual features of the garpike's nasal region influence olfactory flow. These features comprise a triangular nasal cavity in which the olfactory epithelium is exposed to the external environment, a papilla situated within the nasal cavity, and an elongated ventral apex. To perform our investigation we first generated life-like plastic models of garpike heads from X-ray scans of preserved specimens. We then suspended these models in a flume and flowed water over them to simulate swimming. By directing filaments of dye at the static models, we were able to visualise flow in the nasal regions at physiologically relevant Reynolds numbers (700-2,000). We found that flow of water over the heads did cause circulation in the nasal cavity. Vortices may assist in this circulation. The pattern of olfactory flow was influenced by morphological variations and the asymmetry of the nasal region. The unusual features of the nasal region may improve odorant sampling in the garpike, by dispersing flow over the olfactory epithelium and by creating favourable conditions for odorant transport (e.g. steep velocity gradients). Unexpectedly, we found that the mouth and the base of the garpike's jaws may assist the sampling process. Thus, despite its apparent simplicity, the garpike's nasal region is likely to act as an effective trap for odorant molecules.

Effects of Peripapillary Scleral Stiffening on the Deformation of the Lamina Cribrosa.

PURPOSE: Scleral stiffening has been proposed as a treatment for glaucoma to protect the lamina cribrosa (LC) from excessive intraocular pressure-induced deformation. Here we experimentally evaluated the effects of moderate stiffening of the peripapillary sclera on the deformation of the LC. METHODS: An annular sponge, saturated with 1.25% glutaraldehyde, was applied to the external surface of the peripapillary sclera for 5 minutes to stiffen the sclera. Tissue deformation was quantified in two groups of porcine eyes, using digital image correlation (DIC) or computed tomography imaging and digital volume correlation (DVC). In group A (n = 14), eyes were subjected to inflation testing before and after scleral stiffening. Digital image correlation was used to measure scleral deformation and quantify the magnitude of scleral stiffening. In group B (n = 5), the optic nerve head region was imaged using synchrotron radiation phase-contrast microcomputed tomography (PC µCT) at an isotropic spatial resolution of 3.2 µm. Digital volume correlation was used to compute the full-field three-dimensional deformation within the LC and evaluate the effects of peripapillary scleral cross-linking on LC biomechanics. RESULTS: On average, scleral treatment with glutaraldehyde caused a 34 ± 14% stiffening of the peripapillary sclera measured at 17 mm Hg and a 47 ± 12% decrease in the maximum tensile strain in the LC measured at 15 mm Hg. The reduction in LC strains was not due to cross-linking of the LC. CONCLUSIONS: Peripapillary scleral stiffening is effective at reducing the magnitude of biomechanical strains within the LC. Its potential and future utilization in glaucoma axonal neuroprotection requires further investigation.

Exploring miniature insect brains using micro-CT scanning techniques.

The capacity to explore soft tissue structures in detail is important in understanding animal physiology and how this determines features such as movement, behaviour and the impact of trauma on regular function. Here we use advances in micro-computed tomography (micro-CT) technology to explore the brain of an important insect pollinator and model organism, the bumblebee (Bombus terrestris). Here we present a method for accurate imaging and exploration of insect brains that keeps brain tissue free from trauma and in its natural stereo-geometry, and showcase our 3D reconstructions and analyses of 19 individual brains at high resolution. Development of this protocol allows relatively rapid and cost effective brain reconstructions, making it an accessible methodology to the wider scientific community. The protocol describes the necessary steps for sample preparation, tissue staining, micro-CT scanning and 3D reconstruction, followed by a method for image analysis using the freeware SPIERS. These image analysis methods describe how to virtually extract key composite structures from the insect brain, and we demonstrate the application and precision of this method by calculating structural volumes and investigating the allometric relationships between bumblebee brain structures.

Phase-Contrast Micro-Computed Tomography Measurements of the Intraocular Pressure-Induced Deformation of the Porcine Lamina Cribrosa.

The lamina cribrosa (LC) is a complex mesh-like tissue in the posterior eye. Its biomechanical environment is thought to play a major role in glaucoma, the second most common cause of blindness. Due to its small size and relative inaccessibility, high-resolution measurements of LC deformation, important in characterizing LC biomechanics, are challenging. Here we present a novel noninvasive imaging method, which enables measurement of the three-dimensional deformation of the LC caused by acute elevation of intraocular pressure (IOP). Posterior segments of porcine eyes were imaged using synchrotron radiation phase contrast micro-computed tomography (PC µCT) at IOPs between 6 and 37 mmHg. The complex trabecular architecture of the LC was reconstructed with an isotropic spatial resolution of 3.2 µm. Scans acquired at different IOPs were analyzed with digital volume correlation (DVC) to compute full-field deformation within the LC. IOP elevation caused substantial tensile, shearing and compressive devformation within the LC, with maximum tensile strains at 30 mmHg averaging 5.5%, and compressive strains reaching 20%. We conclude that PC µCT provides a novel high-resolution method for imaging the LC, and when combined with DVC, allows for full-field 3D measurement of ex vivo LC biomechanics at high spatial resolution.

A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol.

BACKGROUND: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. OBJECTIVE: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). DESIGN, SETTING, AND PARTICIPANTS: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. INTERVENTIONS: LHRHa as per local practice, OP (FemSeven 100µg/24h patches). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. RESULTS AND LIMITATIONS: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001). CONCLUSIONS: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. PATIENT SUMMARY: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. TRIAL REGISTRATION: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).