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Relationship between heterotopic ossification and traumatic brain injury: Why severe traumatic brain injury increases the risk of heterotopic ossification.

ABSTRACT: Heterotopic ossification (HO) is a pathological phenomenon in which ectopic lamellar bone forms in soft tissues. HO involves many predisposing factors, including congenital and postnatal factors. Postnatal HO is usually induced by fracture, burn, neurological damage (brain injury and spinal cord injury) and joint replacement. Recent studies have found that patients who suffered from bone fracture combined with severe traumatic brain injury (S-TBI) are at a significantly increased risk for HO occurrence. Thus, considerable research focused on the influence of S-TBI on fracture healing and bone formation, as well as on the changes in various osteogenic factors with S-TBI occurrence. Brain damage promotes bone formation, but the exact mechanisms underlying bone formation and HO after S-TBI remain to be clarified. Hence, this article summarises the findings of previous studies on the relationship between S-TBI and HO and discusses the probable causes and mechanisms of HO caused by S-TBI. The translational potential of this article: A better understanding of the probable causes of traumatic brain injury-induced HO can provide new perspectives and ideas in preventing HO and may support to design more targeted therapies to reduce HO or enhance the bone formation.

SUBMITTER: Huang H

PROVIDER: S-EPMC5866497 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Relationship between heterotopic ossification and traumatic brain injury: Why severe traumatic brain injury increases the risk of heterotopic ossification.

Huang Huan H Cheng Wen-Xiang WX Hu Yi-Ping YP Chen Jian-Hai JH Zheng Zheng-Tan ZT Zhang Peng P

Journal of orthopaedic translation 20171114

Heterotopic ossification (HO) is a pathological phenomenon in which ectopic lamellar bone forms in soft tissues. HO involves many predisposing factors, including congenital and postnatal factors. Postnatal HO is usually induced by fracture, burn, neurological damage (brain injury and spinal cord injury) and joint replacement. Recent studies have found that patients who suffered from bone fracture combined with severe traumatic brain injury (S-TBI) are at a significantly increased risk for HO occ ...[more]

PMID: 29662775

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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:ObjectivesThis study seeks to evaluate the incidence rate of heterotopic ossification (HO) formation in patients afflicted by an isolated limb fracture (ILF) and a concomitant mild traumatic brain injury (mTBI).MethodsThe current study is an observational study including ILF patients with or without a concomitant mTBI recruited from an orthopedic clinic of a Level 1 Trauma Hospital. Patients were diagnosed with a mTBI according to the American Congress of Rehabilitation Medicine (ACRM) criteria. Radiographs taken on average 3 months post-trauma were analyzed separately by two distinct specialists for the presence of HO proximally to the fracture site (joints or extra joints). Both raters referred to Brooker's and Della's Valle's classification to establish signs of HO. First, analyses were conducted for the full sample. Secondly, a matched cohort was used in order to control for specific factors, namely age, sex, type of injury, and time elapsed between the accident and the analyzed radiograph.ResultsThe full sample included a total of 183 patients with an ILF (94 females; 47.5 years old), of which 50 had a concomitant mTBI and 133 without. Radiographic evidence of HO was significantly higher in patients with an ILF and a mTBI compared to ILF patients (X2 = 6.50; p = 0.01). The matched cohort consisted of 94 participants (i.e.; 47 patients from the ILF + mTBI group and 47 patients from the ILF group). Again, ILF + mTBI patients presented significantly higher rates of HO signs in comparison to ILF patients (X2 = 3.69; p = 0.04). Presence of HO was associated with prolonged delays to return to work (RTW) only in ILF + mTBI patients (F = 4.055; p = 0.05) but not in ILF patients (F = 0.823; p = 0.37).ConclusionsStudy findings suggest that rates of HO are significantly higher proximally to fracture sites when ILF patients sustain a concomitant mTBI, even after controlling for factors known to influence HO. Moreover, results show that HO is associated with a prolonged RTW only in ILF patients with a concomitant mTBI but not in ILF-only patients. The impact of mTBI on HO formation warrants further attention to detect early signs of HO, to identify shared physiopathological mechanisms and, ultimately, to design targeted therapies.

Project description:ImportanceTraumatic brain injuries (TBIs) can have serious long-term consequences, including psychiatric disorders. However, few studies have assessed the association between TBI and risk of suicide.ObjectiveTo examine the association between TBI and subsequent suicide.Design, setting, and participantsRetrospective cohort study using nationwide registers covering 7 418 391 individuals (≥10 years) living in Denmark (1980-2014) with 164 265 624 person-years' follow-up; 567 823 (7.6%) had a medical contact for TBI. Data were analyzed using Poisson regression adjusted for relevant covariates, including fractures not involving the skull, psychiatric diagnoses, and deliberate self-harm.ExposureMedical contacts for TBI recorded in the National Patient Register (1977-2014) as mild TBI (concussion), skull fracture without documented TBI, and severe TBI (head injuries with evidence of structural brain injury).Main outcomes and measuresSuicide recorded in the Danish Cause of Death register until December 31, 2014.ResultsOf 34 529 individuals who died by suicide (mean age, 52 years [SD, 18 years]; 32.7% women; absolute rate 21 per 100 000 person-years [95% CI, 20.8-21.2]), 3536 (10.2%) had medical contact: 2701 with mild TBI, 174 with skull fracture without documented TBI, and 661 with severe TBI. The absolute suicide rate was 41 per 100 000 person-years (95% CI, 39.2-41.9) among those with TBI vs 20 per 100 000 person-years (95% CI, 19.7-20.1) among those with no diagnosis of TBI. The adjusted incidence rate ratio (IRR) was 1.90 (95% CI, 1.83-1.97). Compared with those without TBI, severe TBI (absolute rate, 50.8 per 100 000 person-years; 95% CI, 46.9-54.6) was associated with an IRR of 2.38 (95% CI, 2.20-2.58), whereas mild TBI (absolute rate, 38.6 per 100 000 person-years; 95% CI, 37.1-40.0), and skull fracture without documented TBI (absolute rate, 42.4 per 100 000 person-years; 95% CI, 36.1-48.7) had an IRR of 1.81 (95% CI, 1.74-1.88) and an IRR of 2.01 (95% CI, 1.73-2.34), respectively. Suicide risk was associated with number of medical contacts for TBI compared with those with no TBI contacts: 1 TBI contact, absolute rate, 34.3 per 100 000 person-years (95% CI, 33.0-35.7; IRR, 1.75; 95% CI, 1.68-1.83); 2 TBI contacts, absolute rate, 59.8 per 100 000 person-years (95% CI, 55.1-64.6; IRR, 2.31; 95% CI, 2.13-2.51); and 3 or more TBI contacts, absolute rate, 90.6 per 100 000 person-years (95% CI, 82.3-98.9; IRR, 2.59; 95% CI, 2.35-2.85; all P < .001 for the IRR's). Compared with the general population, temporal proximity since the last medical contact for TBI was associated with risk of suicide (P<.001), with an IRR of 3.67 (95% CI, 3.33-4.04) within the first 6 months and an incidence IRR of 1.76 (95% CI, 1.67-1.86) after 7 years.Conclusions and relevanceIn this nationwide registry-based retrospective cohort study individuals with medical contact for TBI, compared with the general population without TBI, had increased suicide risk.

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Relationship between heterotopic ossification and traumatic brain injury: Why severe traumatic brain injury increases the risk of heterotopic ossification.

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Relationship between heterotopic ossification and traumatic brain injury: Why severe traumatic brain injury increases the risk of heterotopic ossification.

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