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Bullet fragments have been previously observed in the remains and edible portions of big game animals that were harvested using rifles. The fragmentation issue has attracted attention because traditional hunting bullets are more than 70% lead, which is toxic to humans and scavengers in the ecosystem. We prepared gunshot wounds in ballistic gelatin blocks, and then applied synchrotron X-ray imaging technology to the bullet fragmentation process for the first time. The K edge subtraction (KES) imaging method allowed a clear separation of lead in an image from false positives, including the other major bullet component, copper, and non-lead objects such as bone fragments. The superior brightness of synchrotron radiation was also harnessed to resolve thousands of embedded sub-10 μm fragments, a size range not previously observed using commonly applied X-ray imaging modalities. The results challenge the current understanding of the maximum extent that fragments may be distributed, and the effectiveness of imaging methods used to screen wild game donations at food banks for lead bullet fragments. [ABSTRACT FROM AUTHOR]

Bone acts as a reservoir for many trace elements. Understanding the extent and pattern of elemental accumulation in the skeleton is important from diagnostic, therapeutic, and toxicological perspectives. Some elements are simply adsorbed to bone surfaces by electric force and are buried under bone mineral, while others can replace calcium atoms in the hydroxyapatite structure. In this article, we investigated the extent and pattern of skeletal uptake of barium and strontium in two different age groups, growing, and skeletally mature, in healthy rats. Animals were dosed orally for 4 weeks with either strontium chloride or barium chloride or combined. The distribution of trace elements was imaged in 3D using synchrotron K-edge subtraction micro-CT at 13.5 µm resolution and 2D electron probe microanalysis (EPMA). Bulk concentration of the elements in serum and bone (tibiae) was also measured by mass spectrometry to study the extent of uptake. Toxicological evaluation did not show any cardiotoxicity or nephrotoxicity. Both elements were primarily deposited in the areas of active bone turnover such as growth plates and trabecular bone. Barium and strontium concentration in the bones of juvenile rats was 2.3 times higher, while serum levels were 1.4 and 1.5 times lower than adults. In all treatment and age groups, strontium was preferred to barium even though equal molar concentrations were dosed. This study displayed spatial co-localization of barium and strontium in bone for the first time. Barium and strontium can be used as surrogates for calcium to study the pathological changes in animal models of bone disease and to study the effects of pharmaceutical compounds on bone micro-architecture and bone remodeling in high spatial sensitivity and precision. [ABSTRACT FROM AUTHOR]

ABSTRACT The study objective was to visualize regions of bone that undergo pathological mineralization and/or remodeling during pathogenesis of osteoarthritis, by employing non-radioactive strontium as a dynamic tracer of bone turnover. Post traumatic osteoarthritis was surgically induced in skeletally mature rats, followed by in vivo micro-CT imaging for 12 weeks to assess bone micro-structural changes. Rats either received strontium ranelate daily for the entire course of study or only last 10 days before euthanization. Distribution of strontium in bone was assessed in two and three dimensions, using electron probe micro-analysis (EPMA) and synchrotron dual energy K-edge subtraction micro-CT (SRμCT), respectively. Considerable early formation of osteophytes around the collateral ligament attachments and margins of articulating surfaces were observed, followed by subchondral sclerosis at the later stages. Accordingly, strontium was heavily incorporated by mineralizing osteophytes at 4, 8, and 12 weeks post-surgery, whereas subchondral bone only incorporated strontium between weeks 8-12.This study showed low dose stable strontium can effectively serve as a dynamic tracer of bone turnover to study pathological bone micro-structural changes, at resolution higher than nuclear medicine. Co-administration of strontium during therapeutic drug intervention may show enormous utility in assessing the efficacy of those compounds upon adaptive bone physiology. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1655-1662, 2015. [ABSTRACT FROM AUTHOR]

Abstract: Superparamagnetic Iron Oxide Nanoparticles (SPIONs) were synthesized and coated with pseudopolyrotaxanes (PPRs) and proposed as a novel hybrid nanostructure for medical imaging and drug delivery. PPRs were prepared by addition of α-cyclodextrin rings to functionalized polyethylene glycol (PEG) chain with hydrophobic triazine end-groups. Non-covalent interactions between SPIONs and PPRs led to the assembly of SPIONs@PRs hybrid nanomaterials. Measurements of the 1H Nuclear Magnetic Resonance (NMR) relaxation times T 1 and T 2 allowed us to determine the NMR dispersion profiles. Comparison between our SPIONs@PRs hybrid nano-compound and the commercial SPION compound, Endorem®, showed a higher transverse relaxivity for SPIONs@PRs. In vitro MRI experiments showed that our SPIONs@PRs produces better negative contrast compared to Endorem® and can be considered as a novel MRI contrast agent. [Copyright &y& Elsevier]

Purpose: Multiple-image radiography (MIR) is an analyzer-based synchrotron X-ray imaging approach capable of dissociating absorption, refraction, and scattering components of X-ray interaction with the material. It generates additional image contrast mechanisms (besides absorption), especially in the case of soft tissues, while minimizing absorbed radiation dose. Our goal is to develop a contrast agent for MIR using ultrasound microbubbles by carrying out a systematic assessment of size, shell material, and concentration. Procedures: Microbubbles were synthesized with two different shell materials: phospholipid and polyvinyl-alcohol. Polydisperse perfluorobutane-filled lipid microbubbles were divided into five size groups using centrifugation. Two distributions of air-filled polymer microbubbles were generated: 2–3 µm and 3–4 µm. A subset of polymer microbubbles 3–4 µm had iron oxide nanoparticles incorporated into their shell or coated on their surface. Microbubbles were immobilized in agar with different concentrations: 5 × 107, 5 × 106, and 5 × 105 MBs/ml. MIR was conducted on the BioMedical Imaging and Therapy beamline at the Canadian Light Source. Three images were generated: Gaussian amplitude, refraction, and ultra-small-angle X-ray scattering (USAXS). The contrast signal was quantified by measuring mean pixel values and comparing them with agar. Results: No difference was detected in absorption or refraction images of all tested microbubbles. Using USAXS, a significant signal increase was observed with lipid microbubbles 6–10 µm at the highest concentration (p = 0.02), but no signal was observed at lower concentrations. Conclusions: These data indicate that lipid microbubbles 6–10 µm are candidates as contrast agents for MIR, specifically for USAXS. A minimum concentration of 5 × 107 microbubbles (lipid-shell 6–10 µm) per milliliter was needed to generate a detectable signal. [ABSTRACT FROM AUTHOR]

Objective: X-ray phase contrast imaging generates contrast from refraction of X-rays, enhancing soft tissue contrast compared to conventional absorption-based imaging. Our goal is to develop a contrast agent for X-ray in-line phase contrast imaging (PCI) based on ultrasound microbubbles (MBs), by assessing size, shell material, and concentration. Methods: Polydisperse perfluorobutane-core lipid-shelled MBs were synthesized and size separated into five groups between 1 and 10 μm. We generated two size populations of polyvinyl-alcohol (PVA)-MBs, 2-3 μm and 3-4 μm, whose shells were either coated or integrated with iron oxide nanoparticles (SPIONs). Microbubbles were then embedded in agar at three concentrations: 5 × 107, 5 × 106 and 5 × 105 MBs/ml. In-line phase contrast imaging was performed at the Canadian Light Source with filtered white beam micro-computed tomography. Phase contrast intensity was measured by both counting detectable MBs, and comparing mean pixel values (MPV) in minimum and maximum intensity projections of the overall samples. Results: Individual lipid-MBs 6-10 μm, lipid-MBs 4-6 μm and PVA-MBs coated with SPIONs were detectable at each concentration. At the highest concentration, lipid-MBs 6-10 μm and 4-6 μm showed an overall increase in positive contrast, whereas at a moderate concentration, only lipid-MBs 6-10 μm displayed an increase. Negative contrast was also observed from two largest lipid-MBs at high concentration. Conclusion: These data indicate that lipid-MBs larger than 4 μm are candidates for PCI, and 5 × 106 MBs/ml may be the lowest concentration suitable for generating visible phase contrast in vivo. Significance: Identifying a suitable MB for PCI may facilitate future clinical translation. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to prepare a bisphosphonate (BP) mediated bone targeting di-PEGylated salmon calcitonin analogue sCT-2(PEG-BP) as a novel bone targeting pharmaceutical. Methods: HPLC was used for isolation of sCT-2(PEG-BP) from the reaction mixture, followed by determination of possible PEGylation sites by trypsin digestion. Stability of the compound over time, bone mineral affinity using hydroxyapatite, and biodistribution in normal rats after radiolabeling of sCT-2(PEG-BP) or control sCT with I was evaluated. Results: PEGylated sCT analogues were synthesized, and sCT-2(PEG-BP) was isolated by HPLC and confirmed by MALDI-TOF and ICP-MS. MALDI-TOF analysis of trypsinized fragments suggested Cys (or Lys) and Lys to be the two PEGylation sites. Bone mineral affinity test showed sCT-2(PEG-BP) or I-sCT-2(PEG-BP) exhibited significantly increased bone mineral affinity over sCT or I-sCT, respectively. sCT-2(PEG-BP) remained stable for at least 1 month. In vivo biodistribution study showed significantly increased bone retention and prolonged plasma circulation time for sCT-2(PEG-BP) compared to the control sCT. Conclusion: Those results support sCT-2(PEG-BP) as a promising new drug candidate for the treatment of resorptive and/or maladaptive bone conditions, such as Osteoporosis, Osteoarthritis, Rheumatoid Arthritis, Paget's disease and bone cancers. [ABSTRACT FROM AUTHOR]

Basic Multicellular Units (BMUs) conduct bone remodeling, a critical process of tissue turnover which, if imbalanced, can lead to disease, including osteoporosis. Parathyroid hormone (PTH 1–34; Teriparatide) is an osteoanabolic treatment for osteoporosis; however, it elevates the rate of intra-cortical remodeling (activation frequency) leading, at least transiently, to increased porosity. The purpose of this study was to test the hypothesis that PTH not only increases the rate at which cortical BMUs are initiated but also increases their progression (Longitudinal Erosion Rate; LER). Two groups (n = 7 each) of six-month old female New Zealand white rabbits were both administered 30 μg/kg of PTH once daily for a period of two weeks to induce remodeling. Their distal right tibiae were then imaged in vivo by in-line phase contrast micro-CT at the Canadian Light Source synchrotron. Over the following two weeks the first group (PTH) received continued daily PTH while the second withdrawal group (PTHW) was administrated 0.9 % saline. At four weeks all animals were euthanized, their distal tibiae were imaged by conventional micro-CT ex vivo and histomorphometry was performed. Matching micro-CT datasets (in vivo and ex vivo) were co-registered in 3D and LER was measured from 612 BMUs. Counter to our hypothesis, mean LER was lower (p < 0.001) in the PTH group (30.19 ± 3.01 μm/day) versus the PTHW group (37.20 ± 2.77 μm/day). Despite the difference in LER, osteonal mineral apposition rate (On.MAR) did not differ between groups indicating the anabolic effect of PTH was sustained after withdrawal. The slowing of BMU progression by PTH warrants further investigation; slowed resorption combined with elevated bone formation rate, may play an important role in how PTH enhances coupling between resorption and formation within the BMU. Finally, the prolonged anabolic response following withdrawal may have utility in terms of optimizing clinical dosing regimens. • In-line phase contrast Micro-CT tracks rabbit cortical bone remodeling events in 4D. • PTH 1–34 slows Basic Multicellular Units (BMU) advancement in rabbit cortical bone. • Osteonal mineral apposition remains elevated 2 weeks after PTH withdrawal in rabbits. [ABSTRACT FROM AUTHOR]

Strontium‐based medications, such as strontium ranelate, have been suggested to have therapeutic effects in patients with osteoporosis. Strontium salts available off‐shelf in stores across North America are assumed to provide similar effects as strontium ranelate and thus should lead to similar distributions of elemental strontium incorporated in bone. The objective of this study was to compare the spatial distribution of strontium in animal bones following the administration of strontium ranelate and strontium citrate. Seventeen‐week‐old Sprague–Dawley rats were split into three groups over 10 weeks and given 625 mg/kg/day of strontium ranelate and 676 mg/kg/day of strontium citrate; the control group received no additional supplementary strontium. The humeri were collected from all animals, and strontium distribution was mapped using 2D micro‐XRF and 3D dual energy K‐edge subtraction (KES) imaging. 2D and 3D elemental mapping methods demonstrated that strontium delivered during treatment by both salts had the same spatial distribution. 3D elemental strontium maps of treated animal bones showed that strontium was largely observed in the trabecular regions under the epiphyseal (growth) plate. The thickness of the strontium layers in both the strontium ranelate and strontium citrate sample was not significantly different (p =.9201). 2D micro‐XRF and 3D dual‐energy KES images effectively elucidated the spatial distribution of elemental strontium in calcified tissue. These methods provide a novel approach to evaluating the potential efficacy of strontium supplements in the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

The Biomedical Imaging and Therapy (BMIT) beamlines at the Canadian Light Source (CLS) comprise a multi-modality synchrotron imaging facility capable of imaging objects with 2–200 μm resolution with beam sizes up to ~200 mm wide and ~10 mm high in the experimental hutches [1–3]. BMIT hosts two beamlines, a bend magnet 05B1-1 and an insertion device 05ID-2, with capabilities to apply absorption imaging, in-line phase contrast imaging (PCI), analyzer-based imaging (ABI) or diffraction-enhanced imaging (DEI), and K-Edge Subtraction (KES) imaging. Talbot or grating interferometry is under development. [ABSTRACT FROM PUBLISHER]