Angiogenesis in bone regeneration

Hankenson, Kurt D.; Dishowitz, Michael I.; Gray, Chancellor F.; Schenker, Mara L.

doi:10.1016/j.injury.2011.03.035

Cited by 410 publications

(326 citation statements)

References 95 publications

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“…Sufficient blood supply is critical for bone regeneration in fracture healing and for musculoskeletal tissue engineering (Hankenson et al 2011). Two main mechanisms are responsible for the formation of new blood vessels, also known as neovascularization.…”

Section: Epo and Bonementioning

confidence: 99%

The effect of erythropoietin on bone

Rölfing¹

2014

Acta Orthopaedica

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Section: Epo and Bonementioning

confidence: 99%

The effect of erythropoietin on bone

Rölfing¹

2014

Acta Orthopaedica

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“…We have previously used such computational models to provide support for the hypothesis that stem cell fate during fracture healing is governed by the local oxygen concentration and stiffness of the surrounding substrate (Burke and Kelly, 2012;Burke et al, 2013Burke et al, , 2014. This algorithm was developed based on in-vitro observations which demonstrate the fundamental role played by substrate stiffness in regulating MSC lineage commitment (Engler et al, 2006;Huebsch et al, 2010;Young et al, 2013;Park et al, 2011), and by experiments demonstrating that hypoxia inhibits osteogenesis and adipogenesis while promoting chondrogenesis (Kanichai et al, 2008;Cao, 2007;Hankenson et al, 2011;Peiffer et al, 2011;Hirao et al, 2006;Street et al, 2002;Gomillion and Burg, 2006;Hausman and Richardson, 2004). This computational model did not however propose a specific hypothesis for how environmental factors regulate the initiation and progression of chondrocyte hypertrophy and endochondral ossification, which is central to successful secondary fracture healing.…”

Section: Introductionmentioning

confidence: 99%

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

O'Reilly

Hankenson

Kelly

2016

Biomech Model Mechanobiol

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While it is well established that an adequate blood supply is critical to successful bone regeneration, it remains poorly understood how progenitor cell fate is affected by the altered conditions present in fractures with disrupted vasculature. In this study, computational models were used to explore how angiogenic impairment impacts oxygen availability within a fracture callus and hence regulates mesenchymal stem cell (MSC) differentiation and bone regeneration. Tissue differentiation was predicted using a previously developed algorithm which assumed that MSC fate is governed by the local oxygen tension and substrate stiffness. This was updated to include conditions for oxygen regu- lated cell death and endochondral ossification. The updated algorithm was validated by using it within a model of normal fracture healing where it predicted the experimentally observed quantity and spatial distribution of bone and cartilage at 10 and 20 days post fracture (dpf). Furthermore, it also predicted the ratio of cartilage which had become hypertrophic at 10 dpf. Following this, three models of fracture healing with increasing levels of angiogenic impairment were developed. Under mild impairment the model predicted the experimentally observed reduction in hypertrophic cartilage at 10 dpf as well as the persistence of cartilage at 20 dpf. Models of more severe angiogenic impairment predicted the development of fibrous and necrotic tissue within the callus. These results provide insight into how environmental factors specific to an ischemic callus regulate tissue regeneration and provide support for the hypothesis that endochondral ossification during fracture healing is governed by the local oxygen tension.

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“…10 Increased understanding of the role of angiogenesis in bone repair is also crucial for designing new therapies, including the use of bone scaffold, for promoting bone fracture healing. [11][12][13] In this context, it is desirable to develop a quantitative imaging technique for structure analysis of neomicrovessels that proliferate through newly formed bone. High-resolution X-ray micro-computed tomography (mCT) combined with a vascular casting technique has been used for three-dimensional (3D) imaging of bone microvasculature in rodents.…”

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Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

Matsumoto

Goto

Sato

2013

Laboratory Investigation

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Quantitative three-dimensional (3D) imaging of angiogenesis during bone repair remains an experimental challenge. We developed a novel contrast agent containing 0.07-to 0.1-mm particles of zirconium dioxide (ZrCA) and established subtraction mCT using synchrotron radiation (sSRCT) for quantitative imaging of angiogenesis and bone repair. This method was applied to a rat model of tibial bone repair 3 days (DAY3; n ¼ 2), 5 days (DAY5; n ¼ 8), or 10 days (DAY10; n ¼ 8) after drill-hole injury. Using the same drill-hole defect model, its potential use was illustrated by comparison of bone repair between hindlimbs subjected to mechanical unloading (n ¼ 6) and normal weight bearing (n ¼ 6) for 10 days. Following vascular casting with ZrCA, the defect site was scanned with 17.9-and 18.1-keV X-rays. In the latter, image contrast between ZrCA-filled vasculature and bone was enhanced owing to the sharp absorption jump of zirconium dioxide at 18.0 keV (k-edge). The two scan data sets were reconstructed with 2.74-mm voxel resolution, registered by mutual information, and digitally subtracted to extract the contrast-enhanced vascular image. K 2 HPO 4 phantom solutions were scanned at 17.9 keV for quantitative evaluation of bone mineral. Angiogenesis had already started, but new bone formation was not found on DAY3. New bone emerged near the defect boundary on DAY5 and took the form of trabecular-like structure invaded by microvessels on DAY10. Vascular and bone volume fractions, blood vessel and bone thicknesses, and mineralization were higher on DAY10 than on DAY5. All these parameters were found to be decreased after 10 days of hindlimb unloading, indicating the possible involvement of angiogenesis in bone repair impairment caused by reduced mechanical stimuli. In conclusion, the combined technique of sSRCT and ZrCA vascular casting is suitable for quantitative 3D imaging of angiogenesis and its surrounding bone regeneration. This method will be useful for better understanding the linkage between angiogenesis and bone repair.

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Angiogenesis in bone regeneration

Cited by 410 publications

References 95 publications

The effect of erythropoietin on bone

The effect of erythropoietin on bone

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

Subtraction micro-computed tomography of angiogenesis and osteogenesis during bone repair using synchrotron radiation with a novel contrast agent

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