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Early detection of heterotopic ossification using near-infrared optical imaging reveals dynamic turnover and progression of mineralization following Achilles tenotomy and burn injury.

ABSTRACT: Heterotopic ossification (HO) is the abnormal formation of bone in soft tissue. Current diagnostics have low sensitivity or specificity to incremental progression of mineralization, especially at early time points. Without accurate and reliable early diagnosis and intervention, HO progression often results in incapacitating conditions of limited range of motion, nerve entrapment, and pain. We hypothesized that non-invasive near-infrared (NIR) optical imaging can detect HO at early time points and monitor heterotopic bone turnover longitudinally. C57BL6 mice received an Achilles tenotomy on their left hind limb in combination with a dorsal burn or sham procedure. A calcium-chelating tetracycline derivative (IRDye 680RD BoneTag) was injected bi-weekly and imaged via NIR to measure accumulative fluorescence for 11 wk and compared to in vivo microCT images. Percent retention of fluorescence was calculated longitudinally to assess temporal bone resorption. NIR detected HO as early as five days and revealed a temporal response in HO formation and turnover. MicroCT could not detect HO until 5 wk. Confocal microscopy confirmed fluorophore localization to areas of HO. These findings demonstrate the ability of a near-infrared optical imaging strategy to accurately and reliably detect and monitor HO in a murine model.

SUBMITTER: Perosky JE

PROVIDER: S-EPMC4408934 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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Project description:To demonstrate the pro-osteogenic effect of burn injury on heterotopic bone formation using a novel burn ossicle in vivo model.Heterotopic ossification (HO), or the abnormal formation of bone in soft tissue, is a troubling sequela of burn and trauma injuries. The exact mechanism by which burn injury influences bone formation is unknown. The aim of this study was to develop a mouse model to study the effect of burn injury on heterotopic bone formation. We hypothesized that burn injury would enhance early vascularization and subsequent bone formation of subcutaneously implanted mesenchymal stem cells.Mouse adipose-derived stem cells were harvested from C57/BL6 mice, transfected with a BMP-2 adenovirus, seeded on collagen scaffolds (ossicles), and implanted subcutaneously in the flank region of 8 adult mice. Burn and sham groups were created with exposure of 30% surface area on the dorsum to 60°C water or 30°C water for 18 seconds, respectively (n = 4/group). Heterotopic bone volume was analyzed in vivo by micro-computed tomography for 3 months. Histological analysis of vasculogenesis was performed with platelet endothelial cell adhesion molecule staining. Osteogenic histological analysis was performed by Safranin O, Picrosirius red, and aniline blue staining. Qualitative analysis of heterotopic bone composition was completed with ex vivo Raman spectroscopy.Subcutaneously implanted ossicles formed heterotopic bone. Ossicles from mice with burn injuries developed significantly more bone than sham control mice, analyzed by micro-computed tomography at 1, 2, and 3 months (P < 0.05), and had enhanced early and late endochondral ossification as demonstrated by Safranin O, Picrosirius red, and aniline blue staining. In addition, burn injury enhanced vascularization of the ossicles (P < 0.05). All ossicles demonstrated chemical composition characteristic of bone as demonstrated by Raman spectroscopy.Burn injury increases the predilection to osteogenic differentiation of ectopically implanted ossicles. Early differences in vascularity correlated with later bone development. Understanding the role of burn injury on heterotopic bone formation is an important first step toward the development of treatment strategies aimed to prevent unwanted and detrimental heterotopic bone formation.

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Early detection of heterotopic ossification using near-infrared optical imaging reveals dynamic turnover and progression of mineralization following Achilles tenotomy and burn injury.

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