Characterization of Heterotopic Ossification Using Radiographic Imaging: Evidence for a Paradigm Shift

Brownley, R. Cameron; Agarwal, Shailesh; Loder, Shawn; Oluwatobi, Eboda; Li, John; Peterson, Joshua; Hwang, Charles; Breuler, Christopher; Kaartinen, Vesa; Zhou, Bin; Mishina, Yuji; Lévi, Benjamin

doi:10.1371/journal.pone.0141432

Cited by 13 publications

(10 citation statements)

References 29 publications

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“…36,37 Although the sensitivity of micro-CT, rather than conventional CT scans, has been shown to be significantly higher in detecting early HO lesions, this may have questionable clinical utility. 38,39 An emerging, high-resolution imaging technique, nano-computed tomography, is an advancement of micro-CT. Using special target transmission tubes and specific detectors, a very high spatial resolution (400 nm) can be achieved, thereby increasing its sensitivity several-fold as compared with micro-CT.…”

Section: Diagnostics: Ct Raman Nir Ultrasoundmentioning

confidence: 99%

The traumatic bone: trauma-induced heterotopic ossification

Dey

Wheatley

Cholok

et al. 2017

Translational Research

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Heterotopic ossification (HO) is a common occurrence after multiple forms of extensive trauma. These include arthroplasties, traumatic brain and spinal cord injuries, extensive burns in the civilian setting, and combat-related extremity injuries in the battlefield. Irrespective of the form of trauma, heterotopic bone is typically endochondral in structure and is laid down via a cartilaginous matrix. Once formed, the heterotopic bone typically needs to be excised surgically, which may result in wound healing complications, in addition to a risk of recurrence. Refinements of existing diagnostic modalities, like micro- and nano-CT are being adapted toward early intervention. Trauma-induced HO is a consequence of aberrant wound healing, systemic and local immune system activation, infections, extensive vascularization, and innervation. This intricate molecular crosstalk culminates in activation of stem cells that initiate heterotopic endochondral ossification. Development of animal models recapitulating the unique traumatic injuries has greatly facilitated the mechanistic understanding of trauma-induced HO. These same models also serve as powerful tools to test the efficacy of small molecules which specifically target the molecular pathways underlying ectopic ossification. This review summarizes the recent advances in the molecular understanding, diagnostic and treatment modalities in the field of trauma-induced HO.

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Section: Diagnostics: Ct Raman Nir Ultrasoundmentioning

confidence: 99%

The traumatic bone: trauma-induced heterotopic ossification

Dey

Wheatley

Cholok

et al. 2017

Translational Research

Self Cite

109

108

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“…In vivo μCT has been used to quantify heterotopic ossification over time in a murine burn/Achilles tenotomy model[ 8 ]. The advantage of in vivo μCT over radiographic imaging in this setting is the increased spatial resolution.…”

Section: Introductionmentioning

confidence: 99%

Validation of a Radiography-Based Quantification Designed to Longitudinally Monitor Soft Tissue Calcification in Skeletal Muscle

et al. 2016

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IntroductionSoft tissue calcification, including both dystrophic calcification and heterotopic ossification, may occur following injury. These lesions have variable fates as they are either resorbed or persist. Persistent soft tissue calcification may result in chronic inflammation and/or loss of function of that soft tissue. The molecular mechanisms that result in the development and maturation of calcifications are uncertain. As a result, directed therapies that prevent or resorb soft tissue calcifications remain largely unsuccessful. Animal models of post-traumatic soft tissue calcification that allow for cost-effective, serial analysis of an individual animal over time are necessary to derive and test novel therapies. We have determined that a cardiotoxin-induced injury of the muscles in the posterior compartment of the lower extremity represents a useful model in which soft tissue calcification develops remote from adjacent bones, thereby allowing for serial analysis by plain radiography. The purpose of the study was to design and validate a method for quantifying soft tissue calcifications in mice longitudinally using plain radiographic techniques and an ordinal scoring system.MethodsMuscle injury was induced by injecting cardiotoxin into the posterior compartment of the lower extremity in mice susceptible to developing soft tissue calcification. Seven days following injury, radiographs were obtained under anesthesia. Multiple researchers applied methods designed to standardize post-image processing of digital radiographs (N = 4) and quantify soft tissue calcification (N = 6) in these images using an ordinal scoring system. Inter- and intra-observer agreement for both post-image processing and the scoring system used was assessed using weighted kappa statistics. Soft tissue calcification quantifications by the ordinal scale were compared to mineral volume measurements (threshold 450.7mgHA/cm3) determined by μCT. Finally, sample-size calculations necessary to discriminate between a 25%, 50%, 75%, and 100% difference in STiCSS score 7 days following burn/CTX induced muscle injury were determined.ResultsPrecision analysis demonstrated substantial to good agreement for both post-image processing (κ = 0.73 to 0.90) and scoring (κ = 0.88 to 0.93), with low inter- and intra-observer variability. Additionally, there was a strong correlation in quantification of soft tissue calcification between the ordinal system and by mineral volume quantification by μCT (Spearman r = 0.83 to 0.89). The ordinal scoring system reliably quantified soft tissue calcification in a burn/CTX-induced soft tissue calcification model compared to non-injured controls (Mann-Whitney rank test: P = 0.0002, ***). Sample size calculations revealed that 6 mice per group would be required to detect a 50% difference in STiCSS score with a power of 0.8. Finally, the STiCSS was demonstrated to reliably quantify soft tissue calcification [dystrophic calcification and heterotopic ossification] by radiographic analysis, independent of the histopathologi...

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“…Skeletal and HO bone was differentiated from “non-bone” by an upper threshold of 1000 Hounsfield units and a lower threshold of 150 Hounsfield units. A recent study demonstrated the usefulness of using micro-CT as an imaging tool for the evaluation of HO in animal models [15]. …”

Section: Methodsmentioning

confidence: 99%

Analog Method for Radiographic Assessment of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva

et al. 2017

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Rationale and Objectives Severe progressive multi-focal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate due to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in FOP patients. Materials and Methods IRB approval was obtained from the University of Pennsylvania and all data comply with HIPAA regulations. The University of Pennsylvania Institutional Animal Care and Use Committee (IACUC) approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semi-quantitative analogue scale for estimating relative heterotopic bone volume. Second, we used this validated scale to estimate the relative amount of HO from a retrospective analysis of plain radiographs from 63 patients with classic FOP. Finally, the scale was applied to a retrospective analysis of CT images from three FOP patients. Results In the FOP-mouse model, the observed rating on the analogue scale is highly correlated to heterotopic bone volumes measured by micro-computed tomography (R2 = 0.89). The scoring system that was applied to radiographs of FOP patients captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of CT scans of FOP patients found that observed radiograph ratings were highly correlated with HO volume (R2 = 0.80). Conclusion The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. Clinical Relevance The development of the six-point analogue scale described here provides and validates a much-needed, reproducible and quantifiable method for describing and assessing heterotopic ossification in FOP patients. This scale has the potential to be a key descriptor that can inform FOP patients and clinicians about disease progression and response of heterotopic ossification lesions to interventions and treatments.

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Characterization of Heterotopic Ossification Using Radiographic Imaging: Evidence for a Paradigm Shift

Cited by 13 publications

References 29 publications

The traumatic bone: trauma-induced heterotopic ossification

The traumatic bone: trauma-induced heterotopic ossification

Validation of a Radiography-Based Quantification Designed to Longitudinally Monitor Soft Tissue Calcification in Skeletal Muscle

Analog Method for Radiographic Assessment of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva

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