Browsing by Subject "Bone healing"

Now showing 1 - 8 of 8
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    Bone Density Changes Following Radiotherapy to Vertebral Metastases
    (Springer Nature, 2021-06-03) Jensen, Garrett L.; Gaddipati, Ravi; Hammonds, Kendall P.; Morrow, Andrew; Swanson, Gregory P.; Radiation Oncology, School of Medicine
    Introduction: Patients have increasing longevity and time for bone healing following radiotherapy (RT) for treatment of bone metastases (BM). Attempts to assess the treatment response of bone metastases have been either limited or heavily subjective. Our goal was to try to quantitate cancer-involved bone changes after RT using changes in bone mineral density (BMD) from computer tomographic (CT) imaging. Methods: Retrospectively, 117 spinal metastases were identified that received RT with follow-up CT scans >9 months following CT simulation. Contoured volumes included: the metastasis (gross tumor volume; GTV); the involved vertebra (gross bone volume; GBV); a total lytic volume (Lyt); a dominant lytic volume (Domlyt); a control volume, and the nearest uninvolved, unirradiated vertebra (control bone volume; CBV). The Hounsfield-density calibration curve was used to measure the density of these volumes before and after treatment. Results: Whether using raw or control-adjusted changes, the absolute and percent change in density of the GBV, GTV, Lyt, and Domlyt volumes all significantly increased (each p<0.0001). The increase in the density of Domlyt volumes was greater than that of Lyt volumes (p=0.0465), which were greater than GTV (p=0.0065), which were greater than GBV (p<0.0001). On multivariate analysis, only the biologically effective dose (BED) dose significantly correlated with GTV density change (p=0.0175). K means clustering created groups by initial lesion size, GTV, or GBV density. A significant difference in GTV density change was not detected between any groups. Conclusion: Increases in BMD are associated with healing regardless of lesion size or initial density. A prospective study to determine whether long-term control is related to early density measurements is needed.
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    Clinically relevant doses of tiludronate do not affect bone remodelling in pasture‐exercised horses
    (Wiley, 2025) Tippen, Samantha P.; Metzger, Corinne E.; Sacks, Spencer A.; Allen, Matthew R.; Mitchell, Colin F.; McNulty, Margaret A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Bisphosphonates are widely used in equine athletes to reduce lameness associated with skeletal disorders. Widespread off-label use has led to concern regarding potential negative effects on bone healing, but little evidence exists to support or refute this. Objectives: To investigate the influence of clinically relevant doses of tiludronate on bone remodelling and bone healing. Study design: Randomised, controlled in vivo experiments. Methods: Each horse had a single tuber coxae biopsied (Day 0), then were divided into a treatment (IV tiludronate) or control (IV saline) group. Treatments were administered 30 and 90 days following initial biopsy. Biopsy of the tuber coxae was repeated on Day 60 to evaluate bone healing following a single treatment. Oxytetracycline was administered on Days 137 and 147 to label bone formation. The contralateral tuber coxae was biopsied on Day 150 to evaluate effects of repeated treatment. Bone biopsies were evaluated with micro-computed tomography and/or dynamic histomorphometry using standard techniques. Results: Nineteen horses completed the study, with no complications following the biopsies and treatments. No significant differences in the trabecular bone parameters or bone formation rate were observed between treatment groups. Main limitations: The use of a first-generation bisphosphonate may mean some effects of these drugs are underrepresented using this model. The results pertain to the tuber coxae and may not reflect injury or the healing response that occurs in long bones in training or racing. Conclusions: In this model, tiludronate did not affect normal bone remodelling in the horse, despite repeat dosages.
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    A Comprehensive Review of Mouse Diaphyseal Femur Fracture Models
    (Elsevier, 2020-07) Gunderson, Zachary J.; Campbell, Zachery R.; McKinley, Todd O.; Natoli, Roman M.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Complications related to treatment of long bone fractures still stand as a major challenge for orthopaedic surgeons. Elucidation of the mechanisms of bone healing and development, and the subsequent alteration of these mechanisms to improve outcomes, typically requires animal models as an intermediary between in vitro and human clinical studies. Murine models are some of the most commonly used in translational research, and mouse fracture models are particularly diverse, offering a wide variety of customization with distinct benefits and limitations depending on the study. This review critically examines three common femur fracture models in the mouse, namely cortical hole, 3-point fracture (Einhorn), and segmental bone defect. We lay out the general procedure for execution of each model, evaluate the practical implications and important advantages/disadvantages of each and describe recent innovations. Furthermore, we explore the applications that each model is best adapted for in the context of the current state of murine orthopaedic research.
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    Editorial: Impaired bone healing due to bone disuse and osteometabolic disorders
    (Frontiers Media, 2024-03-28) Zamarioli, Ariane; Kacena, Melissa A.; Volpon, José B.; Orthopaedic Surgery, School of Medicine
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    The Glycogen Synthase Kinase-3β Inhibitor LSN 2105786 Promotes Zebrafish Fin Regeneration
    (MDPI, 2019-04-19) Sarmah, Swapnalee; Curtis, Courtney; Mahin, Jennifer; Farrell, Mark; Engler, Thomas A.; Sanchez-Felix, Manuel V.; Sato, Masahiko; Ma, Yanfai Linda; Chu, Shaoyou; Marrs, James A.; Biology, School of Science
    The Wnt pathway has been shown to regulate bone homeostasis and to influence some bone disease states. We utilized a zebrafish model system to study the effects of a synthetic, orally bioavailable glycogen synthase kinase-3β (GSK3β) inhibitor LSN 2105786, which activates Wnt signaling during bone healing and embryogenesis. GSK3β inhibitor treatment was used to phenocopy GSK3β morpholino oligonucleotide (MO) knockdown in zebrafish embryos. Human and zebrafish synthetic mRNA injection were similarly effective at rescue of GSK3β MO knockdown. During caudal fin regeneration, bony rays are the first structure to differentiate in zebrafish fins, providing a useful model to study bone healing. Caudal fin regeneration experiments were conducted using various concentrations of a GSK3β inhibitor, examining duration and concentration dependence on regenerative outgrowth. Experiments revealed continuous low concentration (4-5 nM) treatment to be more effective at increasing regeneration than intermittent dosing. Higher concentrations inhibited fin growth, perhaps by excessive stimulation of differentiation programs. Increased Wnt responsive gene expression and differentiation were observed in response to GSK3b inhibitor treatment. Activating Wnt signaling also increased cell proliferation and osteoblast differentiation in fin regenerates. Together, these data indicate that bone healing in zebrafish fin regeneration was improved by activating Wnt signaling using GSK3b inhibitor treatment. In addition, caudal fin regeneration is useful to evaluate dose-dependent pharmacological efficacy in bone healing, various dosing regimens and possible toxicological effects of compounds.
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    Systemic effects of BMP2 treatment of fractures on non-injured skeletal sites during spaceflight
    (Frontiers Media, 2022-08-15) Zamarioli, Ariane; Adam, Gremah; Maupin, Kevin A.; Childress, Paul J.; Brinker, Alexander; Ximenez, Joao P. B.; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Unloading associated with spaceflight results in bone loss and increased fracture risk. Bone morphogenetic protein 2 (BMP2) is known to enhance bone formation, in part, through molecular pathways associated with mechanical loading; however, the effects of BMP2 during spaceflight remain unclear. Here, we investigated the systemic effects of BMP2 on mice sustaining a femoral fracture followed by housing in spaceflight (International Space Station or ISS) or on Earth. We hypothesized that in spaceflight, the systemic effects of BMP2 on weight-bearing bones would be blunted compared to that observed on Earth. Nine-week-old male mice were divided into four groups: 1) Saline+Earth; 2) BMP+Earth; 3) Saline+ISS; and 4) BMP+ISS (n = 10 mice/group, but only n = 5 mice/group were reserved for micro-computed tomography analyses). All mice underwent femoral defect surgery and were followed for approximately 4 weeks. We found a significant reduction in trabecular separation within the lumbar vertebrae after administering BMP2 at the fracture site of mice housed on Earth. In contrast, BMP2 treatment led to a significant increase in trabecular separation concomitant with a reduction in trabecular number within spaceflown tibiae. Although these and other lines of evidence support our hypothesis, the small sample size associated with rodent spaceflight studies limits interpretations. That said, it appears that a locally applied single dose of BMP2 at the femoral fracture site can have a systemic impact on distant bones, affecting bone quantity in several skeletal sites. Moreover, our results suggest that BMP2 treatment works through a pathway involving mechanical loading in which the best outcomes during its treatment on Earth occurred in the weight-bearing bones and in spaceflight occurred in bones subjected to higher muscle contraction.
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    Thrombopoietic agents enhance bone healing in mice, rats, and pigs
    (Oxford University Press, 2024) Childress, Paul J.; Nielsen, Jeffery J.; Bemenderfer, Thomas B.; Dadwal, Ushashi C.; Chakraborty, Nabarun; Harris, Jonathan S.; Bethel, Monique; Alvarez, Marta B.; Tucker, Aamir; Wessel, Alexander R.; Millikan, Patrick D.; Wilhite, Jonathan H.; Engle, Andrew; Brinker, Alexander; Rytlewski, Jeffrey D.; Scofield, David C.; Griffin, Kaitlyn S.; Shelley, W. Christopher; Manikowski, Kelli J.; Jackson, Krista L.; Miller, Stacy-Ann; Cheng, Ying-Hua; Ghosh, Joydeep; Mulcrone, Patrick L.; Srour, Edward F.; Yoder, Mervin C.; Natoli, Roman M.; Shively, Karl D.; Gautam, Aarti; Hammamieh, Rasha; Low, Stewart A.; Low, Philip S.; McKinley, Todd O.; Anglen, Jeffrey O.; Lowery, Jonathan W.; Chu, Tien-Min G.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Achieving bone union remains a significant clinical dilemma. The use of osteoinductive agents, specifically bone morphogenetic proteins (BMPs), has gained wide attention. However, multiple side effects, including increased incidence of cancer, have renewed interest in investigating alternatives that provide safer, yet effective bone regeneration. Here we demonstrate the robust bone healing capabilities of the main megakaryocyte (MK) growth factor, thrombopoietin (TPO), and second-generation TPO agents using multiple animal models, including mice, rats, and pigs. This bone healing activity is shown in two fracture models (critical-sized defect [CSD] and closed fracture) and with local or systemic administration. Our transcriptomic analyses, cellular studies, and protein arrays demonstrate that TPO enhances multiple cellular processes important to fracture healing, particularly angiogenesis, which is required for bone union. Finally, the therapeutic potential of thrombopoietic agents is high since they are used in the clinic for other indications (eg, thrombocytopenia) with established safety profiles and act upon a narrowly defined population of cells.
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    Validation of the modified radiographic union score for tibia fractures (mRUST) in murine femoral fractures
    (Frontiers Media, 2022-08-03) Alentado, Vincent J.; Knox, Adam M.; Staut, Caio A.; McGuire, Anthony C.; Chitwood, Joseph R.; Mostardo, Sarah L.; Shaikh, Mustufa Z.; Blosser, Rachel J.; Dadwal, Usashi C.; Chu, Tien-Min Gabriel; Collier, Christopher D.; Li, Jiliang; Liu, Ziyue; Kacena, Melissa A.; Natoli, Roman M.; Neurological Surgery, School of Medicine
    Bony union is a primary predictor of outcome after surgical fixation of long bone fractures. Murine models offer many advantages in assessing bony healing due to their low costs and small size. However, current fracture recovery investigations in mice frequently rely on animal sacrifice and costly analyses. The modified Radiographic Union Score for Tibia fractures (mRUST) scoring system is a validated metric for evaluating bony healing in humans utilizing plain radiographs, which are relatively inexpensive and do not require animal sacrifice. However, its use has not been well established in murine models. The aim of this study was to characterize the longitudinal course of mRUST and compare mRUST to other conventional murine fracture analyses. 158 mice underwent surgically created midshaft femur fractures. Mice were evaluated after fracture creation and at 7, 10, 14, 17, 21, 24, 28, 35, and 42 days post-injury. mRUST scoring of plain radiographs was performed by three orthopaedic surgeons in a randomized, blinded fashion. Interrater correlations were calculated. Micro-computed tomography (μCT) was analyzed for tissue mineral density (TMD), total callus volume (TV), bone volume (BV), trabecular thickness, trabecular number, and trabecular separation. Histomorphometry measures of total callus area, cartilage area, fibrous tissue area, and bone area were performed in a blinded fashion. Ultimate torque, stiffness, toughness, and twist to failure were calculated from torque-twist curves. A sigmoidal log-logistic curve fit was generated for mRUST scores over time which shows mRUST scores of 4 to 6 at 7 days post-injury that improve to plateaus of 14 to 16 by 24 days post-injury. mRUST interrater correlations at each timepoint ranged from 0.51 to 0.86, indicating substantial agreement. mRUST scores correlated well with biomechanical, histomorphometry, and μCT parameters, such as ultimate torque (r=0.46, p<0.0001), manual stiffness (r=0.51, p<0.0001), bone percentage based on histomorphometry (r=0.86, p<0.0001), cartilage percentage (r=-0.87, p<0.0001), tissue mineral density (r=0.83, p<0.0001), BV/TV based on μCT (r=0.65, p<0.0001), and trabecular thickness (r=0.78, p<0.0001), among others. These data demonstrate that mRUST is reliable, trends temporally, and correlates to standard measures of murine fracture healing. Compared to other measures, mRUST is more cost-effective and non-terminal. The mRUST log-logistic curve could be used to characterize differences in fracture healing trajectory between experimental groups, enabling high-throughput analysis.