A 3D Computational Simulation of Fracture Callus Formation: Influence of the Stiffness of the External Fixator

2005 ◽  
Vol 128 (3) ◽  
pp. 290-299 ◽  
Author(s):  
M. J. Gómez-Benito ◽  
J. M. García-Aznar ◽  
J. H. Kuiper ◽  
M. Doblaré
Keyword(s):  
Fracture Healing ◽  
External Fixator ◽  
Callus Formation ◽  
Computational Simulation ◽  
Element Model ◽  
Regenerative Process ◽  
Fracture Site ◽  
Three Dimensions ◽  
Fracture Callus ◽  
Clinical Observations

The stiffness of the external fixation highly influences the fracture healing pattern. In this work we study this aspect by means of a finite element model of a simple transverse mid-diaphyseal fracture of an ovine metatarsus fixed with a bilateral external fixator. In order to simulate the regenerative process, a previously developed mechanobiological model of bone fracture healing was implemented in three dimensions. This model is able to simulate tissue differentiation, bone regeneration, and callus growth. A physiological load of 500N was applied and three different stiffnesses of the external fixator were simulated (2300, 1725, and 1150N∕mm). The interfragmentary strain and load sharing mechanism between bone and the external fixator were compared to those recorded in previous experimental works. The effects of the stiffness on the callus shape and tissue distributions in the fracture site were also analyzed. We predicted that a lower stiffness of the fixator delays fracture healing and causes a larger callus, in correspondence to well-documented clinical observations.

scholarly journals Heterogeneity of murine periosteum osteochondroprogenitors involved in fracture healing

2020 ◽  
Author(s):  
Brya G Matthews ◽  
Francesca V Sbrana ◽  
Sanja Novak ◽  
Jessica L. Funnell ◽  
Ye Cao ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Callus Formation ◽  
Lineage Tracing ◽  
Fracture Callus ◽  
Stem And Progenitor Cells ◽  
Periosteal Cells ◽  
Osteoblast Lineage

AbstractThe periosteum is the major source of cells involved in fracture healing. We sought to characterize differences in progenitor cell populations between periosteum and other bone compartments, and identify periosteal cells involved in fracture healing. The periosteum is highly enriched for progenitor cells, including Sca1+ cells, CFU-F and label-retaining cells. Lineage tracing with αSMACreER identifies periosteal cells that contribute to >80% of osteoblasts and ~40% of chondrocytes following fracture. A subset of αSMA+ cells are quiescent long-term injury-responsive progenitors. Ablation of αSMA+ cells impairs fracture callus formation. In addition, committed osteoblast-lineage cells contributed around 10% of osteoblasts, but no chondrocytes in fracture calluses. Most periosteal progenitors, particularly those that form osteoblasts, can be targeted by αSMACreER. We have demonstrated that the periosteum is highly enriched for skeletal stem and progenitor cells and there is heterogeneity in the populations of cells that contribute to mature lineages during periosteal fracture healing.

scholarly journals Short Wave Enhances Mesenchymal Stem Cell Recruitment through Hypoxia-Inducible Factor-1 Signaling in Fracture Healing

2020 ◽  
Author(s):  
Dongmei Ye ◽  
Chen Chen ◽  
Qiwen Wang ◽  
Qi Zhang ◽  
Sha Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Fracture Healing ◽  
Callus Formation ◽  
Healing Process ◽  
Short Wave ◽  
Fracture Site ◽  
Related Factors ◽  
Femur Fractures

Abstract Background: As a type of high-frequency electrotherapy, a short wave can promote the fracture healing process; yet, its underlying therapeutic mechanisms still remain unclear.Purpose: To observe the effect of short wave on mesenchymal stem cell (MSC) homing and its mechanisms associated with fracture healing.Materials and Methods: The effect of short wave on a fracture healing was examined in 40 rats. Stabilized femur fractures were established by intramedullary fixation; radiography was used to analyze the morphology and micro-architecture of the callus. Additionally, fluorescence assays were used to analyze the MSC migration after treatment in 20 nude mice with a femoral fracture. For in vitro study, osteoblast simulated fracture site was first irradiated by the short wave; siRNA targeting HIF-1 was used to investigate the role of HIF-1. Osteoblast cultured supernatant was then collected as chemotaxis content of MSC, and the migration of MSC was evaluated using wound healing assay and trans-well chamber test. The expression of HIF-1 and its related factors were quantified by qRT-PCR, ELISA, and Western blot.Results: Our in vivo experiment indicated that short wave could promote MSC migration, increase local and serum HIF-1 levels, induce changes in callus formation, and improve callus microarchitecture and mechanical properties, thus speeding up the healing process of the fracture site. Moreover, the in vitro results further indicated that short waves upregulated HIF-1 expression in osteoblast and increased HIF-1, SDF-1 protein levels in the supernatant, as well as the expression of CXCR-4, β-catenin, F-actin and phosphorylation levels of FAK in MSC. On the other hand, the inhibition of HIF-1α was significantly restrained by the inhibition of HIF-1α in osteoblast and it partially inhibited the migration of MSC.Conclusions: These results suggested that short wave could increase HIF-1 in callus, which is one of the crucial mechanisms of chemotaxis MSC homing in fracture healing.

scholarly journals Differences in fracture healing between female and male C57BL/6J mice

2020 ◽  
Author(s):  
Melanie Haffner-Luntzer ◽  
Verena Fischer ◽  
Anita Ignatius
Keyword(s):  
Fracture Healing ◽  
Callus Formation ◽  
Fibrous Tissue ◽  
Biomechanical Testing ◽  
Transgenic Animals ◽  
Male Mice ◽  
Mineral Density ◽  
Fracture Callus ◽  
Female Mice ◽  
Tissue Mineral Density

Abstract Background: Mice are increasingly used in fracture healing research because of the opportunity to use transgenic animals. While both, male and female mice are employed, there is no consensus in the literature whether fracture healing differs between both sexes. Therefore, the aim of the present study was to analyse diaphyseal fracture healing in female and male C57BL/6J mice, a commonly used mouse strain in bone research. Methods: For that purpose, 12-week-old female (17–20 g) and male mice (22–26 g) received a standardised femur midshaft osteotomy stabilised by an external fixator. Mice were euthanized 10 and 21 days after fracture and bone healing was analysed by biomechanical testing, µCT, histology, immunohistochemistry and qPCR. Results: Ten days after fracture, male mice displayed significantly more cartilage but less fibrous tissue in the fracture callus compared to female mice, whereas the amount of bone did not differ. At day 21, male mice showed a significantly larger fracture callus compared to female mice. The relative amount of bone in the fracture callus did not significantly differ between both sexes, whereas its tissue mineral density was significantly higher in male mice on day 21, indicating more mature bone and slightly more rapid fracture healing. These results were confirmed by a significantly greater absolute bending stiffness of the fractured femurs of male mice on day 21. On the molecular level, male mice displayed increased active β-catenin expression in the fracture callus, whereas oestrogen receptor α (ERα) expression was lower. Conclusions: These results suggest that male mice display more rapid fracture healing with more prominent cartilaginous callus formation. This might be due to the higher weight of male mice, resulting in increased mechanical loading of the fracture. Furthermore, male mice displayed significantly greater activation of osteoanabolic Wnt/β-catenin signalling, which might also contribute to more rapid bone regeneration.

scholarly journals Modulation of fracture healing by the transient accumulation of senescent cells

2021 ◽  
Author(s):  
Sundeep Khosla ◽  
Dominik Saul ◽  
David Monroe ◽  
Jennifer L Rowsey ◽  
Robyn Laura Kosinsky ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Time Course ◽  
Callus Formation ◽  
In Silico Analysis ◽  
Skin Wound ◽  
Luciferase Reporter ◽  
Skin Wound Healing ◽  
Fracture Callus ◽  
Beneficial Effects

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified a subset of cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage. Then, using a genetic mouse model (p16LUC) containing a p16Ink4a55-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ("senolytics", Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather may improve fracture healing.

scholarly journals Age-related changes to macrophages are detrimental to fracture healing

2019 ◽  
Author(s):  
Daniel Clark ◽  
Sloane Brazina ◽  
Frank Yang ◽  
Diane Hu ◽  
Erene Niemi ◽  
...  
Keyword(s):  
Fracture Healing ◽  
The Elderly ◽  
Fracture Site ◽  
Rna Seq ◽  
Fracture Callus ◽  
Age Related ◽  
The Impact ◽  
Old Mice ◽  
Age Related Changes ◽  
Young Mice

AbstractThe elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age-related diseases. Therefore, we investigated age-related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA-seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an upregulation of M1/pro-inflammatory genes in macrophages from old mice as well as dysregulation of other immune-related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age-matched controls. After preventing infiltration by macrophages, the macrophages within the fracture callus were collected and examined via RNA-seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age-related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.

scholarly journals Site-Specific Fracture Healing: Comparison between Diaphysis and Metaphysis in the Mouse Long Bone

2021 ◽  
Vol 22 (17) ◽  
pp. 9299
Author(s):  
Satoshi Inoue ◽  
Jiro Takito ◽  
Masanori Nakamura
Keyword(s):  
Fracture Healing ◽  
Hox Genes ◽  
Callus Formation ◽  
Fracture Site ◽  
Long Bone ◽  
Site Specific ◽  
Ovariectomized Mice ◽  
Internal And External Factors ◽  
Specific Fracture

The process of fracture healing varies depending upon internal and external factors, such as the fracture site, mode of injury, and mechanical environment. This review focuses on site-specific fracture healing, particularly diaphyseal and metaphyseal healing in mouse long bones. Diaphyseal fractures heal by forming the periosteal and medullary callus, whereas metaphyseal fractures heal by forming the medullary callus. Bone healing in ovariectomized mice is accompanied by a decrease in the medullary callus formation both in the diaphysis and metaphysis. Administration of estrogen after fracture significantly recovers the decrease in diaphyseal healing but fails to recover the metaphyseal healing. Thus, the two bones show different osteogenic potentials after fracture in ovariectomized mice. This difference may be attributed to the heterogeneity of the skeletal stem cells (SSCs)/osteoblast progenitors of the two bones. The Hox genes that specify the patterning of the mammalian skeleton during embryogenesis are upregulated during the diaphyseal healing. Hox genes positively regulate the differentiation of osteoblasts from SSCs in vitro. During bone grafting, the SSCs in the donor’s bone express Hox with adaptability in the heterologous bone. These novel functions of the Hox genes are discussed herein with reference to the site-specificity of fracture healing.

scholarly journals Short-wave enhances mesenchymal stem cell recruitment in fracture healing by increasing HIF-1 in callus

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Dongmei Ye ◽  
Chen Chen ◽  
Qiwen Wang ◽  
Qi Zhang ◽  
Sha Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Fracture Healing ◽  
Callus Formation ◽  
Healing Process ◽  
Short Wave ◽  
Fracture Site ◽  
Related Factors

Abstract Background As a type of high-frequency electrotherapy, a short-wave can promote the fracture healing process; yet, its underlying therapeutic mechanisms remain unclear. Purpose To observe the effect of Short-Wave therapy on mesenchymal stem cell (MSC) homing and relative mechanisms associated with fracture healing. Materials and methods For in vivo study, the effect of Short-Wave therapy to fracture healing was examined in a stabilized femur fracture model of 40 SD rats. Radiography was used to analyze the morphology and microarchitecture of the callus. Additionally, fluorescence assays were used to analyze the GFP-labeled MSC homing after treatment in 20 nude mice with a femoral fracture. For in vitro study, osteoblast from newborn rats simulated fracture site was first irradiated by the Short-Wave; siRNA targeting HIF-1 was used to investigate the role of HIF-1. Osteoblast culture medium was then collected as chemotaxis content of MSC, and the migration of MSC from rats was evaluated using wound healing assay and trans-well chamber test. The expression of HIF-1 and its related factors were quantified by q RT-PCR, ELISA, and Western blot. Results Our in vivo experiment indicated that Short-Wave therapy could promote MSC migration, increase local and serum HIF-1 and SDF-1 levels, induce changes in callus formation, and improve callus microarchitecture and mechanical properties, thus speeding up the healing process of the fracture site. Moreover, the in vitro results further indicated that Short-Wave therapy upregulated HIF-1 and SDF-1 expression in osteoblast and its cultured medium, as well as the expression of CXCR-4, β-catenin, F-actin, and phosphorylation levels of FAK in MSC. On the other hand, the inhibition of HIF-1α was significantly restrained by the inhibition of HIF-1α in osteoblast, and it partially inhibited the migration of MSC. Conclusions These results suggested that Short-Wave therapy could increase HIF-1 in callus, which is one of the crucial mechanisms of chemotaxis MSC homing in fracture healing.

scholarly journals Strategies to Improve Bone Healing: Innovative Surgical Implants Meet Nano-/Micro-Topography of Bone Scaffolds

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 746
Author(s):  
Dirk Wähnert ◽  
Johannes Greiner ◽  
Stefano Brianza ◽  
Christian Kaltschmidt ◽  
Thomas Vordemvenne ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Callus Formation ◽  
Fracture Site ◽  
Self Healing ◽  
Non Union ◽  
Bone Scaffolds ◽  
Surgical Implants ◽  
And Migration ◽  
Biological Environment ◽  
Micro Topography

Successful fracture healing is dependent on an optimal mechanical and biological environment at the fracture site. Disturbances in fracture healing (non-union) or even critical size bone defects, where void volume is larger than the self-healing capacity of bone tissue, are great challenges for orthopedic surgeons. To address these challenges, new surgical implant concepts have been recently developed to optimize mechanical conditions. First, this review article discusses the mechanical environment on bone and fracture healing. In this context, a new implant concept, variable fixation technology, is introduced. This implant has the unique ability to change its mechanical properties from “rigid” to “dynamic” over the time of fracture healing. This leads to increased callus formation, a more homogeneous callus distribution and thus improved fracture healing. Second, recent advances in the nano- and micro-topography of bone scaffolds for guiding osteoinduction will be reviewed, particularly emphasizing the mimicry of natural bone. We summarize that an optimal scaffold should comprise micropores of 50–150 µm diameter allowing vascularization and migration of stem cells as well as nanotopographical osteoinductive cues, preferably pores of 30 nm diameter. Next to osteoinduction, such nano- and micro-topographical cues may also reduce inflammation and possess an antibacterial activity to further promote bone regeneration.

scholarly journals Short-Wave Enhances Mesenchymal Stem Cells Recruitment in Fracture Healing by Increasing HIF-1 in Callus

2020 ◽  
Author(s):  
Dongmei Ye ◽  
Chen Chen ◽  
Qiwen Wang ◽  
Qi Zhang ◽  
Sha Li ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Callus Formation ◽  
Healing Process ◽  
Short Wave ◽  
Fracture Site ◽  
Related Factors ◽  
Femur Fractures ◽  
Osteoblast Culture

Abstract Background: As a type of high-frequency electrotherapy, a Short-Wave can promote the fracture healing process; yet, its underlying therapeutic mechanisms remain unclear.Purpose: To observe the effect of Short-Wave therapy on mesenchymal stem cell (MSC) homing and relative mechanisms associated with fracture healing. Materials and Methods: For in vivo study, the effect of Short-Wave therapy to fracture healing was examined in stabilized femur fractures model of 40 SD rats. Radiography was used to analyze the morphology and microarchitecture of the callus. Additionally, fluorescence assays were used to analyze the GFP-labeled MSC homing after treatment in 20 nude mice with a femoral fracture. For in vitro study, osteoblast from newborn rats simulated fracture site was first irradiated by the Short-Wave; siRNA targeting HIF-1 was used to investigate the role of HIF-1. Osteoblast culture medium was then collected as chemotaxis content of MSC, and the migration of MSC from rats was evaluated using wound healing assay and trans-well chamber test. The expression of HIF-1 and its related factors were quantified by q RT-PCR, ELISA, and Western blot.Results: Our in vivo experiment indicated that Short-Wave therapy could promote MSC migration, increase local and serum HIF-1 and SDF-1 levels, induce changes in callus formation, and improve callus microarchitecture and mechanical properties, thus speeding up the healing process of the fracture site. Moreover, the in vitro results further indicated that Short-Waves therapy upregulated HIF-1 and SDF-1 expression in osteoblast and its cultured medium, as well as the expression of CXCR-4, β-catenin, F-actin and phosphorylation levels of FAK in MSC. On the other hand, the inhibition of HIF-1α was significantly restrained by the inhibition of HIF-1α in osteoblast, and it partially inhibited the migration of MSC.Conclusions: These results suggested that Short-Wave therapy could increase HIF-1 in callus, which is one of the crucial mechanisms of chemotaxis MSC homing in fracture healing.

scholarly journals Short-Wave Enhances MSC Recruitment in Fracture Healing from Increasing HIF-1 in Callus

2020 ◽  
Author(s):  
Dongmei Ye ◽  
Chen Chen ◽  
Qiwen Wang ◽  
Qi Zhang ◽  
Sha Li ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Callus Formation ◽  
Healing Process ◽  
Short Wave ◽  
Fracture Site ◽  
Related Factors ◽  
Femur Fractures ◽  
Osteoblast Culture

Abstract Background: As a type of high-frequency electrotherapy, a Short-Wave can promote the fracture healing process; yet, its underlying therapeutic mechanisms still remain unclear.Purpose: To observe the effect of Short-Wave therapy on mesenchymal stem cell (MSC) homing and relative mechanisms associated with fracture healing. Materials and Methods: For in vivo study, the effect of Short-Wave therapy in relation to fracture healing was examined in stabilized femur fractures model of 40 SD rats. Radiography was used to analyze the morphology and micro-architecture of the callus. Additionally, fluorescence assays were used to analyze the GFP-labeled MSC homing after treatment in 20 nude mice with a femoral fracture. For in vitro study, osteoblast from newborn rats simulated fracture site was first irradiated by the Short-Wave; siRNA targeting HIF-1 was used to investigate the role of HIF-1. Osteoblast culture medium was then collected as chemotaxis content of MSC, and the migration of MSC from rats was evaluated using wound healing assay and trans-well chamber test. The expression of HIF-1 and its related factors were quantified by q RT-PCR, ELISA, and Western blot.Results: Our in vivo experiment indicated that Short-Wave therapy could promote MSC migration, increase local and serum HIF-1 and SDF-1 levels, induce changes in callus formation, and improve callus microarchitecture and mechanical properties, thus speeding up the healing process of the fracture site. Moreover, the in vitro results further indicated that Short-Waves therapy upregulated HIF-1 and SDF-1 expression in osteoblast and in the medium, as well as the expression of CXCR-4, β-catenin, F-actin and phosphorylation levels of FAK in MSC. On the other hand, the inhibition of HIF-1α was significantly restrained by the inhibition of HIF-1α in osteoblast, and it partially inhibited the migration of MSC.Conclusions: These results suggested that Short-Wave therapy could increase HIF-1 in callus, which is one of the crucial mechanisms of chemotaxis MSC homing in fracture healing.

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