Dataset Information

Application of a mechanobiological algorithm to investigate mechanical mediation of heterotopic bone in trans-femoral amputees.

ABSTRACT: Heterotopic ossification (HO) is the process of bone formation in tissues that are not usually osseous. It occurs in 60% of those with blast-related amputations. HO can result in reduced range of motion, pain, nerve impingement and can affect prosthesis fitting and is caused by a combination of mechanical, biological, local and systemic factors. As with normal bone formation and remodelling, it is expected that heterotopic bone responds to mechanical stimuli and understanding this relationship can give insight into the pathology. The objective of this research was to investigate whether a physiological 2D computational model that considers both mechanical and biological factors can be used to simulate HO in the residual limb of a trans-femoral amputee. The study found that characteristic morphologies of HO were reproduced by adjusting the loading environment. Significant effects were produced by changing the loading direction on the femur; this is potentially associated with different initial surgical interventions such as muscle myodesis. Also, initial treatment such as negative pressure through a dressing was found to change the shape of heterotopic bone.

SUBMITTER: Rosenberg NM

PROVIDER: S-EPMC6155077 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Application of a mechanobiological algorithm to investigate mechanical mediation of heterotopic bone in trans-femoral amputees.

Rosenberg Naomi M NM Bull Anthony M J AMJ

Scientific reports 20180921 1

Heterotopic ossification (HO) is the process of bone formation in tissues that are not usually osseous. It occurs in 60% of those with blast-related amputations. HO can result in reduced range of motion, pain, nerve impingement and can affect prosthesis fitting and is caused by a combination of mechanical, biological, local and systemic factors. As with normal bone formation and remodelling, it is expected that heterotopic bone responds to mechanical stimuli and understanding this relationship c ...[more]

PMID: 30242273

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Project description:ObjectiveTo demonstrate the pro-osteogenic effect of burn injury on heterotopic bone formation using a novel burn ossicle in vivo model.BackgroundHeterotopic 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.MethodsMouse 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.ResultsSubcutaneously 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.ConclusionsBurn 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.

Project description:BackgroundMapping expression quantitative trait loci (eQTLs) has provided insight into gene regulation. Compared to cis-eQTLs, the regulatory mechanisms of trans-eQTLs are less known. Previous studies suggest that trans-eQTLs may regulate expression of remote genes by altering the expression of nearby genes. Trans-association has been studied in the mediation analysis with a single mediator. However, prior applications with one mediator are prone to model misspecification due to correlations between genes. Motivated from the observation that trans-eQTLs are more likely to associate with more than one cis-gene than randomly selected SNPs in the GTEx dataset, we developed a computational method to identify trans-eQTLs that are mediated by multiple mediators.ResultsWe proposed two hypothesis tests for testing the total mediation effect (TME) and the component-wise mediation effects (CME), respectively. We demonstrated in simulation studies that the type I error rates were controlled in both tests despite model misspecification. The TME test was more powerful than the CME test when the two mediation effects are in the same direction, while the CME test was more powerful than the TME test when the two mediation effects are in opposite direction. Multiple mediator analysis had increased power to detect mediated trans-eQTLs, especially in large samples. In the HapMap3 data, we identified 11 mediated trans-eQTLs that were not detected by the single mediator analysis in the combined samples of African populations. Moreover, the mediated trans-eQTLs in the HapMap3 samples are more likely to be trait-associated SNPs. In terms of computation, although there is no limit in the number of mediators in our model, analysis takes more time when adding additional mediators. In the analysis of the HapMap3 samples, we included at most 5 cis-gene mediators. Majority of the trios we considered have one or two mediators.ConclusionsTrans-eQTLs are more likely to associate with multiple cis-genes than randomly selected SNPs. Mediation analysis with multiple mediators improves power of identification of mediated trans-eQTLs, especially in large samples.

Dataset Information

Application of a mechanobiological algorithm to investigate mechanical mediation of heterotopic bone in trans-femoral amputees.

Publications

Application of a mechanobiological algorithm to investigate mechanical mediation of heterotopic bone in trans-femoral amputees.

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