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All sources NASA NTRS DOE OSTI

DOE OSTI2020

Improving radiograph analysis throughput through transfer learning and object detection

SIGN Fracture Care International partners with surgeons in low-resource hospitals worldwide to provide access to effective orthopedic care by donating educational materials and innovatively designed surgical implants. Over two decades, SIGN’s Online Surgical Database (SOSD) has grown to contain over 500,000 medical images, with radiographs holding the majority share. One challenge in working with hospitals worldwide is that both the radiographs uploaded to the SOSD and the data entry accompanying the uploads vary in quality. To improve the accuracy of data in the SOSD, we trained a model to detect surgical implants in radiographs. We first developed a tool to automatically detect radiographs, then trained an object detection model to determine the number and placement of surgical implants visible in the radiograph. Active learning was used to generate a training set containing 2,510 radiographs with screws, nails, and plates labeled by bounding boxes. Training a model to simultaneously recognize all three classes of implants gave a low average precision (AP) for the plate class, likely due to the low number of plate instances in our training set and the large variety of surgical plates used by SIGN-partnered surgeons. Applying standard image augmentation techniques to increase the plate count in our training set did not appreciably increase the AP of plate detection. To improve plate detection, we redrew the bounding boxes to account for correlations between the screw and plate classes. Training one model to detect nails and screws and a separate model to detect plates increased the AP of plate detection by 78.8 percentage points. The AP of each class was 80.7% for screws, 93.6% for nails, and 92.6% for plates; meanwhile, the sensitivity was 92% for screws, 86% for nails, and 81% for plates. We show that object detection methods can be used to detect surgical implants in radiographs of varying quality; however, the detection ability is dependent on the type of implant, and some implants, in our case plates, must be treated differently than others. Such tools can improve the throughput of radiograph analysis, assisting physicians and surgeons with the treatment of bone fractures.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Optimization of a Lethal, Combat-Relevant Model of Sterile Inflammation in Mice for Drug Candidate Screening

ABSTRACT Introduction Extensive trauma, commonly seen in wounded military Service Members, often leads to a severe sterile inflammation termed systemic inflammatory response syndrome (SIRS), which can progress to multiple organ dysfunction syndrome (MODS) and death. MODS is a serious threat to wounded Service Members, historically causing 10% of all deaths in trauma admissions at a forward deployed combat hospital. The importance of this problem will be exacerbated in large-scale combat operations, in which evacuation will be delayed and care of complex injuries at lower echelons of care may be prolonged. The main goal of this study was to optimize an existing mouse model of lethal SIRS/MODS as a therapeutic screening platform for the evaluation of immunomodulatory drugs. Materials and Methods Male C57BL/6 mice were euthanized, and the bones and muscles were collected and blended into a paste termed tissue–bone matrix (TBX). The TBX at 12.5%–20% relative to body weight of each recipient mouse was implanted into subcutaneous pouches created on the dorsum of anesthetized animals. Mice were observed for clinical scores for up to 48 hours postimplantation and euthanized at the preset point of moribundity. To test effects of anesthetics on TBX-induced mortality, animals received isoflurane or ketamine/xylazine (K/X). In a separate set of studies, mice received TBX followed by intraperitoneal injection with 20 mg/kg or 40 mg/kg Eritoran or a placebo carrier. All Eritoran studies were performed in a blinded fashion. Results We observed that K/X anesthesia significantly increased the lethality of the implanted TBX in comparison to inhaled anesthetics. Although all the mice anesthetized with isoflurane and implanted with 12.5% TBX survived for 24 hours, 60% of mice anesthetized with K/X were moribund by 24 hours postimplantation. To mimic more closely the timing of lethal SIRS/MODS following polytrauma in human patients, we extended observation to 48 hours. We performed TBX dose–response studies and found that as low as 15%, 17.5%, and 20% TBX caused moribundity/mortality in 50%, 80%, and 100% mice, respectively, over a 48-hour time period. With 17.5% TBX, we tested if moribundity/mortality could be rescued by anti-inflammatory drug Eritoran, a toll-like receptor 4 antagonist. Neither 20 mg/kg nor 40 mg/kg doses of Eritoran were found to be effective in this model. Conclusions We optimized a TBX mouse model of SIRS/MODS for the purpose of evaluating novel therapeutic interventions to prevent trauma-related pathophysiologies in wounded Service Members. Negative effects of K/X on lethality of TBX should be further evaluated, particularly in the light of widespread use of ketamine in treatment of pain. By mimicking muscle crush, bone fracture, and necrosis, the TBX model has pleiotropic effects on physiology and immunology that make it uniquely valuable as a screening tool for the evaluation of novel therapeutics against trauma-induced SIRS/MODS.

General & Internal Medicine↗

DOE OSTI2019

Mortality and injury assessment for three species of fish exposed to simulated turbine blade strike

Injury and mortality of fish during downstream passage through hydropower turbines is among the leading direct impacts of hydropower. Understanding the relationships among various strike variables and injury and mortality rates are necessary for improvements in turbine design. We subjected three species of fish to simulated blade strike in laboratory studies with different blade thicknesses, impact velocities, and body orientations to develop relationships between these variables and probability of injury and mortality. Midbody strikes resulted in higher mortality than head strikes, and tail strikes produced the least mortality. Lateral strikes caused more mortality than dorsal and ventral strikes, and higher strike velocities and thinner blades contributed to increased mortality. Several injury types were significantly associated with increased mortality, including injuries to the operculum, gills, viscera, heart, liver, swim bladder, muscle, and bone fractures. Here, the results from this study will be used to define biologically based design criteria that can be used by turbine designers to improve designs (e.g., increased leading-edge thickness and slower turbine speeds) to minimize the probability and impact of blade strike.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

In Vitro Calcite Crystal Morphology Is Modulated by Otoconial Proteins Otolin-1 and Otoconin-90

Otoconia are formed embryonically and are instrumental in detecting linear acceleration and gravity. Degeneration and fragmentation of otoconia in elderly patients leads to imbalance resulting in higher frequency of falls that are positively correlated with the incidence of bone fractures and death. In this work we investigate the roles otoconial proteins Otolin-1 and Otoconin 90 (OC90) perform in the formation of otoconia. We demonstrate by rotary shadowing and atomic force microscopy (AFM) experiments that Otolin-1 forms homomeric protein complexes and self-assembled networks supporting the hypothesis that Otolin-1 serves as a scaffold protein of otoconia. Our calcium carbonate crystal growth data demonstrate that Otolin-1 and OC90 modulate in vitro calcite crystal morphology but neither protein is sufficient to produce the shape of otoconia. Coadministration of these proteins produces synergistic effects on crystal morphology that contribute to morphology resembling otoconia.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1993

Fibers and materials of medical application

Efferent sorption methods of organism detoxication (by medical trend) are presented. Recently, specialists have shown their keen interest in the problem of treating exogenous and endogenous intoxications. This was stipulated by the growing production and accumulation of chemical products for industrial, agricultural, and domestic needs. To solve this problem the industrial production of carbon fibrous adsorbents was developed and implemented at NII Chimvolokno in St. Petersburg. A description of the carbon fibers is given. Also, application of modern composite materials for manufacturing compression-distraction apparatus used for setting fractured bones is described.

Fridman, L. I.↗

NASA NTRS1996

The Physiology of Bed Rest

Prolonged rest in bed has been utilized by physicians and other health-care workers to immobilize and confine patients for rehabilitation and restoration of health since time immemorial. The sitting or horizontal position is sought by the body to relieve the strain of the upright or vertical postures, for example during syncopal situations, bone fractures, muscle injuries, fatigue, and probably also to reduce energy expenditure. Most health-care personnel are aware that adaptive responses occurring during bed rest proceed concomitantly with the healing process; signs and symptoms associated with the former should be differentiated from those of the latter. Not all illnesses and infirmities benefit from prolonged bed rest. Considerations in prescribing bed rest for patients-including duration, body position, mode and duration of exercise, light-dark cycles, temperature, and humidity-have not been investigated adequately. More recently, adaptive physiological responses have been measured in normal, healthy subjects in the horizontal or slightly head-down postures during prolonged bed rest as analogs for the adaptive responses of astronauts exposed to the microgravity environment of outer and bed-rest research.

Fortney, Suzanne M.↗

NASA NTRS2003

Evaluation of Critical Care Monitor Technology During the US Navy Strong Angel Exercise

The NASA critical path road map identifies "trauma and acute medical problems" as a clinical capability risk category (http://criticalDath.isc.nasa.gov). Specific risks include major trauma, organ laceration or contusion, hemoperitoneum, pulmonary failure, pneumo- and hemothorax, burn, open bone fracture, blunt head trauma, and penetrating injury. Mitigation of these risks includes the capability for critical care monitoring. Currently, the International Space Station (ISS) Crew Health Care System (CHeCS) does not provide such a capability. The Clinical Space Medicine Strategic Planning Forum (4/8/97), sponsored by NASA Medical Operations, identified the development of trauma care capabilities as one of the top priorities for space medicine. The Clinical Care Capability Development Project (CCCDP) subsequently undertook the task to address this need.

Johannesen, John↗

NASA NTRS2010

Smart Ultrasound Remote Guidance Experiment (SURGE)- Concept of Operations Evaluation for Using Remote Guidance Ultrasound for Planetary Space Flight

Introduction Use of remote guidance (RG) techniques aboard the International Space Station (ISS) has enabled astronauts to collect diagnostic-level ultrasound images. Exploration class missions will require this cohort of (typically) non-formally trained sonographers to operate with greater autonomy given the longer communication delays (2 seconds for ISS vs. >6 seconds for missions beyond the Moon) and communication blackouts. To determine the feasibility and training requirements for autonomous ultrasound image collection by non-expert ultrasound operators, ultrasound images were collected from a similar cohort using three different image collection protocols: RG only, RG with a computer-based learning tool (LT), and autonomous image collection with LT. The groups were assessed for both image quality and time to collect the images. Methods Subjects were randomized into three groups: RG only, RG with LT, and autonomous with LT. Each subject received 10 minutes of standardized training before the experiment. The subjects were tasked with making the following ultrasound assessments: 1) bone fracture and 2) focused assessment with sonography in trauma (FAST) to assess a patient s abdomen. Human factors-related questionnaire data were collected immediately after the assessments. Results The autonomous group did not out-perform the two groups that received RG. The mean time for the autonomous group to collect images was less than the RG groups, however the mean image quality for the autonomous group was less compared to both RG groups. Discussion Remote guidance continues to produce higher quality ultrasound images than autonomous ultrasound operation. This is likely due to near-instant feedback on image quality from the remote guider. Expansion in communication time delays, however, diminishes the capability to provide this feedback, thus requiring more autonomous ultrasound operation. The LT has the potential to be an excellent training and coaching component for autonomous ultrasound image collection during exploration missions.

Hurst, Victor, IV↗

NASA NTRS2006

NASA Tech Briefs, September 2006

Topics covered include: Improving Thermomechanical Properties of SiC/SiC Composites; Aerogel/Particle Composites for Thermoelectric Devices; Patches for Repairing Ceramics and Ceramic- Matrix Composites; Lower-Conductivity Ceramic Materials for Thermal-Barrier Coatings; An Alternative for Emergency Preemption of Traffic Lights; Vehicle Transponder for Preemption of Traffic Lights; Automated Announcements of Approaching Emergency Vehicles; Intersection Monitor for Traffic-Light-Preemption System; Full-Duplex Digital Communication on a Single Laser Beam; Stabilizing Microwave Frequency of a Photonic Oscillator; Microwave Oscillators Based on Nonlinear WGM Resonators; Pointing Reference Scheme for Free-Space Optical Communications Systems; High-Level Performance Modeling of SAR Systems; Spectral Analysis Tool 6.2 for Windows; Multi-Platform Avionics Simulator; Silicon-Based Optical Modulator with Ferroelectric Layer; Multiplexing Transducers Based on Tunnel-Diode Oscillators; Scheduling with Automated Resolution of Conflicts; Symbolic Constraint Maintenance Grid; Discerning Trends in Performance Across Multiple Events; Magnetic Field Solver; Computing for Aiming a Spaceborne Bistatic- Radar Transmitter; 4-Vinyl-1,3-Dioxolane-2-One as an Additive for Li-Ion Cells; Probabilistic Prediction of Lifetimes of Ceramic Parts; STRANAL-PMC Version 2.0; Micromechanics and Piezo Enhancements of HyperSizer; Single-Phase Rare-Earth Oxide/Aluminum Oxide Glasses; Tilt/Tip/Piston Manipulator with Base-Mounted Actuators; Measurement of Model Noise in a Hard-Wall Wind Tunnel; Loci-STREAM Version 0.9; The Synergistic Engineering Environment; Reconfigurable Software for Controlling Formation Flying; More About the Tetrahedral Unstructured Software System; Computing Flows Using Chimera and Unstructured Grids; Avoiding Obstructions in Aiming a High-Gain Antenna; Analyzing Aeroelastic Stability of a Tilt-Rotor Aircraft; Tracking Positions and Attitudes of Mars Rovers; Stochastic Evolutionary Algorithms for Planning Robot Paths; Compressible Flow Toolbox; Rapid Aeroelastic Analysis of Blade Flutter in Turbomachines; General Flow-Solver Code for Turbomachinery Applications; Code for Multiblock CFD and Heat-Transfer Computations; Rotating-Pump Design Code; Covering a Crucible with Metal Containing Channels; Repairing Fractured Bones by Use of Bioabsorbable Composites; Kalman Filter for Calibrating a Telescope Focal Plane; Electronic Absolute Cartesian Autocollimator; Fiber-Optic Gratings for Lidar Measurements of Water Vapor; Simulating Responses of Gravitational-Wave Instrumentation; SOFTC: A Software Correlator for VLBI; Progress in Computational Simulation of Earthquakes; Database of Properties of Meteors; Computing Spacecraft Solar-Cell Damage by Charged Particles; Thermal Model of a Current-Carrying Wire in a Vacuum; Program for Analyzing Flows in a Complex Network; Program Predicts Performance of Optical Parametric Oscillators; Processing TES Level-1B Data; Automated Camera Calibration; Tracking the Martian CO2 Polar Ice Caps in Infrared Images; Processing TES Level-2 Data; SmaggIce Version 1.8; Solving the Swath Segment Selection Problem; The Spatial Standard Observer; Less-Complex Method of Classifying MPSK; Improvement in Recursive Hierarchical Segmentation of Data; Using Heaps in Recursive Hierarchical Segmentation of Data; Tool for Statistical Analysis and Display of Landing Sites; Automated Assignment of Proposals to Reviewers; Array-Pattern-Match Compiler for Opportunistic Data Analysis; Pre-Processor for Compression of Multispectral Image Data; Compressing Image Data While Limiting the Effects of Data Losses; Flight Operations Analysis Tool; Improvement in Visual Target Tracking for a Mobile Robot; Software for Simulating Air Traffic; Automated Vectorization of Decision-Based Algorithms; Grayscale Optical Correlator Workbench; "One-Stop Shopping" for Ocean Remote-Sensing and Model Data; State Analysis Database Tool; Generating CAHV and CAHVOmages with Shadows in ROAMS; Improving UDP/IP Transmission Without Increasing Congestion; FORTRAN Versions of Reformulated HFGMC Codes; Program for Editing Spacecraft Command Sequences; Flight-Tested Prototype of BEAM Software; Mission Scenario Development Workbench; Marsviewer; Tool for Analysis and Reduction of Scientific Data; ASPEN Version 3.0; Secure Display of Space-Exploration Images; Digital Front End for Wide-Band VLBI Science Receiver; Multifunctional Tanks for Spacecraft; Lightweight, Segmented, Mostly Silicon Telescope Mirror; Assistant for Analyzing Tropical-Rain-Mapping Radar Data; and Anion-Intercalating Cathodes for High-Energy- Density Cells.

Source record↗

NASA NTRS2011

Biomechanical Analysis of Treadmill Locomotion on the International Space Station

Treadmill locomotion exercise is an important aspect of ISS exercise countermeasures. It is widely believed that an optimized treadmill exercise protocol could offer benefits to cardiovascular and bone health. If training heart rate is high enough, treadmill exercise is expected to lead to improvements in aerobic fitness. If impact or bone loading forces are high enough, treadmill exercise may be expected to contribute to improved bone outcomes. Ground-based research suggests that joint loads increase with increased running speed. However, it is unknown if increases in locomotion speed results in similar increases in joint loads in microgravity. Although data exist regarding the biomechanics of running and walking in microgravity, a majority were collected during parabolic flight or during investigations utilizing a microgravity analog. The Second Generation Treadmill (T2) has been in use on the International Space Station (ISS) and records the ground reaction forces (GRF) produced by crewmembers during exercise. Biomechanical analyses will aid in understanding potential differences in typical gait motion and allow for modeling of the human body to determine joint and muscle forces during exercise. By understanding these mechanisms, more appropriate exercise prescriptions can be developed that address deficiencies. The objective of this evaluation is to collect biomechanical data from crewmembers during treadmill exercise prior to and during flight. The goal is to determine if locomotive biomechanics differ between normal and microgravity environments and to determine how combinations of subject load and speed influence joint loading during in-flight treadmill exercise. Further, the data will be used to characterize any differences in specific bone and muscle loading during locomotion in these two gravitational conditions. This project maps to the HRP Integrated Research Plan risks including Risk of Bone Fracture (Gap B15), Risk of Early Onset Osteoporosis Due to Spaceflight (Gap B15), Risk of Impaired Performance Due to Reduced Muscle Mass, Strength, and Endurance (Gaps M3, M4, M6, Ml, M8, M9) and Risk of reduced Physical Performance Capabilities Due to Reduce Aerobic Capacity (Gaps M7, M8, M9).

De Witt, J. K.↗

NASA NTRS2016

Novel Musculoskeletal Loading System for Small Exercise Devices

Long duration spaceflight places astronauts at increased risk for muscle strain and bone fracture upon return to a 1-g or partial gravity environment. Functionally limiting decrements in musculoskeletal health are likely during Mars proving-ground and Earth-independent missions given extended transit times and the vehicle limitations for exercise devices (low-mass, small volume, little to no power). This is particularly alarming for exploration missions because astronauts will be required to perform novel and physically demanding tasks (i.e. vehicle egress, exploration, and habitat building activities) on unfamiliar terrain. Accordingly, NASA's exploration roadmap identifies the need for development of small exercise equipment that can prevent musculoskeletal atrophy and has the ability to assess musculoskeletal health at multiple time points during long-duration missions.

Downs, Meghan↗

NASA NTRS2020

Development and Comparison of an Artificial Gravity Concept for Human Spaceflight

This Internship served as a resource to find specific research about the many facets of artificial gravity. With three main areas to be addressed in detail: the negative health effects of microgravity and how current mitigation methods fall short, the knowns and unknowns of artificial gravity as a countermeasure, and past artificial gravity habitat concepts. This report primarily focuses on the negative health effects of microgravity and how current mitigation methods fall short. Through NASA resources such as the NTRS, and external sources such as the AIAA, research papers were gathered that were pertinent to the topic. Each paper was uploaded to a NASA SharePoint and abstracts were drafted to highlight the important information. The expected results were to build a library of easily accessible information that would allow for Ryan Joyce and Gabe Merrill to easily get up to speed on relevant information. This process should allow for a faster period of understanding with high relevancy material. The ability to quickly reference data will help to build an informed and detailed case for any future proposals on artificial gravity. This also prevents the need to spend many hours searching for relevant documentation, allowing for more time to be dedicated to the creation process. The project has successfully met expectations and is continuing to add pertinent documentation. Current research shows great potential for artificial gravity as a countermeasure on long duration missions. The gravity like forces created in an artificial gravity ship could help to prevent serious problems such as muscle loss, bone fractures, vision loss due to increased intracranial pressure, and would allow for transition to other gravity environments with little to no recovery period. These conditions are highly favorable for long duration missions as current mitigation methods have yet to be proven beyond one year in space and often only slow symptoms instead of preventing them.

Alice Elberfeld↗

NASA NTRSDate not supplied

Human System Risk Changes in 2021

The Human System Risk Board (HSRB) has the overall responsibility for tracking the evolution of the top ~30 human system risks that it has identified to be associated with human spaceflight. As part of this process, the Board is charged with maintaining a consistent, integrated process to mitigate those risks, and developing evidence-based risk posture recommendations. Risks are re-evaluated in a Continuous Risk Management (CRM) process. This session will summarize the risk posture changes that have occurred in the last year and what high level research, performance, and epidemiologic data have informed those changes. Human System Risks updated in 2021 include: Dynamic Loads, Sensorimotor, EVA, Crew Egress, Behavioral Medicine, Electrical Shock, Human System Integration Architecture (HSIA), Toxic Exposure, Bone Fracture, Cardiovascular, Medical Conditions, Renal Stone, CO2 Exposure, and Pharmacology.

Mary Van Baalen↗

NASA NTRS1994

Irreversibility of advanced osteoporosis: Limited role for pharmacologic intervention

Osteoporosis is of medical interest only because it increases bone fragility and risk of fracture, and except for relief of symptoms, preventing fracture is the only purpose of intervention. To prevent the first fracture, adequate bone density must be accumulated and conserved, but to prevent subsequent fracture, bone density must be augmented so that the supportive function of the skeleton can be restored. Almost 50 years after the recognition of post menopausal osteoporosis as a clinical entity, not one of the many treatments that have been used has been demonstrated to be efficacious in reducing subsequent fracture risk. My purpose is not to recite this chronicle of disappointment, but to account for it in terms of bone biology, to consider some possible exceptions, and to reiterate the importance of preventing damage to the skeleton rather than belatedly attempting its repair.

Parfitt, A. M.↗

NASA NTRS1985

An Elastic Analysis of a Plated Bone to Determine Fracture Gap Motion

An elastic analysis to determine fracture gap motions occurring in the osteotomized and plated canine femur was performed using the finite element program NASTRAN. The femur was idealized as a hollow right cylinder, and transverse anisotropy was assumed for the elastic properties of the bone. A 3-D 360 degree model consisting of 224 isoparametric quadrilateral hexahedral and 11 beam elements was created. A range of plate stiffnesses was tested by varying the modulus of elasticity of the plate from 207 GPa to 1 GPA. Moments were applied in the plane of the plate, about the axis of the plate, and in the plane of the screws. Results showed that, for plates of typical geometry and elastic modulus under 10 GPa, the contribution to fracture gap motion occurring due to deformation in the bone was negligible compared to that contribution from deformation in the plate.

Cooke, F. W.↗

DOE OSTI2019

Laboratory Monitoring of Bone Tissue Remodeling after Augmentation of Impression Intraarticular Fracture with Different Types of Bone Graft

The effects of bone graft materials on the inflammatory response and biochemical markers of bone remodeling were studied on a rabbit model of fracture augmentation with the following grafts: β-tricalcium phosphate, demineralized bone matrix, nanostructured carbon implant, and porous titanium implant made by additive 3D printing. The markers of bone remodeling and the blood system response in the postoperative period were studied. It was found that porous titanium implant and β-tricalcium phosphate induced osteogenesis and minimized osteoclastic resorption. Augmentation with nanostructured carbon implant and demineralized bone matrix stimulated the processes of osteoclastic resorption.

3D PRINTING↗

NASA NTRS2009

A Biomechanical Approach to Assessing Hip Fracture Risk

Bone loss in microgravity is well documented, but it is difficult to quantify how declines in bone mineral density (BMD) contribute to an astronaut's overall risk of fracture upon return. This study uses a biomechanical approach to assessing hip fracture risk, or Factor of Risk (Phi), which is defined as the ratio of applied load to bone strength. All long-duration NASA astronauts from Expeditions 1-18 were included in this study (n=25), while crewmembers who flew twice (n=2) were treated as separate subjects. Bone strength was estimated based on an empirical relationship between areal BMD at the hip, as measured by DXA, and failure load, as determined by mechanical testing of cadaver femora. Fall load during a sideways fall was calculated from a previously developed biomechanical model, which takes into account body weight, height, gender, and soft tissue thickness overlying the lateral aspect of the hip that serves to attenuate the impact force. While no statistical analyses have been performed yet, preliminary results show that males in this population have a higher FOR than females, with a post- flight Phi of 0.87 and 0.36, respectively. FOR increases 5.1% from preflight to postflight, while only one subject crossed the fracture "threshold" of Phi = 1, for a total of 2 subjects with a postflight Phi > 1. These results suggest that men may be at greater risk for hip fracture due largely in part to their relatively thin soft tissue padding as compared to women, since soft tissue thickness has the highest correlation (R(exp 2)= .53) with FOR of all subject-specific parameters. Future work will investigate changes in FOR during recovery to see if baseline risk levels are restored upon return to 1-g activity. While dual x-ray absorptiometry (DXA) is the most commonly used clinical measure of bone health, it fails to provide compartment-specific information that is useful in assessing changes to bone quality as a result of microgravity exposure. Peripheral quantitative computed tomography (pQCT) accomplishes this by imaging transverse "slices" of the long bones. This project was a re-analysis of a 90 day bed rest study to determine if changes to cortical and trabecular compartments could be detected in the distal tibia with statistical significance using a new pQCT image analysis method. Nearly all changes in bone mineral density (BMD) and cross sectional area (CSA) measures were seen with statistical significance, with the exception of a change in cortical BMD. Total bone CSA increased by 1.1 % (p =0.01), cortical CSA decreased by - 5.6% (p<0.001) and trabecular CSA increased by 1.76% (p=0.007); the combination of which suggests bone resorption occurred at the endocortical surface in response to mechanical unloading by bed rest. Furthermore, total BMD and trabecular BMD decreased (-3.8%, p=0.001 and -2.8%, p =0.007, respectively), while decreases in cortical BMD failed to reach significance (-1.2%, p=0.07). Given that compartment-specific changes are seen with significance and are likely to influence bone strength, it is recommended that pQCT remain a standard measure used in bed rest because it provides a unique measure by which to better evaluate the efficacy of countermeasures to microgravity-induced bone loss.

Ellman, Rachel↗

DOE OSTI2017

Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic β-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/β-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice. - Graphical abstract: Schematic shows RAR ligand regulation of osteoblast differentiation in vitro. RARγ antagonists±RARα antagonists promote osteoblast differentiation. RARγ and RARα agonists alone or in combination block osteoblast differentiation, which correlates with upregulation of Sfrp4, and downregulation of nuclear and cytosolic β-catenin and reduced expression of the Wnt target gene Axin2. Red arrows indicate effects of RAR agonists on mediators of Wnt signalling.

60 APPLIED LIFE SCIENCES↗