Heterotopic Ossification in the Residual Limbs of Traumatic and Combat-Related Amputees

Potter, Benjamin K.; Burns, Travis C.; Lacap, Anton P.; Granville, Robert; Gajewski, D. A.

doi:10.5435/00124635-200600001-00042

Cited by 86 publications

(77 citation statements)

References 56 publications

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“…The development of acquired HO is predominantly associated with severe trauma, particularly to muscle or neuronal tissues, such as traumatic brain injury, spinal cord injury, joint arthroplasty, severe burns or combat blast wounds and amputations [4,5]. In fact, of the 80% of war victims who suffer major extremity trauma during combat injury, approximately 64% of these patients go on to develop some degree of HO [6,7]. Aside from physical trauma, HO is also associated with the hereditary condition fibrodysplasia ossificans progressiva (FOP).…”

Section: Heterotopic Ossificationmentioning

confidence: 99%

“…Both hereditary and acquired HO are debilitating conditions that can lead to the atrophy of skin and soft tissue breakdown throughout the residual limb, severe pain, nerve entrapment and impaired joint movement. Current treatments are invasive (surgical removal) or non-specific (radiation therapy or non-steroidal anti-inflammatory drugs), with the likelihood of HO recurrence potentially reaching levels of 25% [6,8]. Therefore, the need to understand the complex pathological mechanisms underlying HO is of great importance if effective therapies are to be devised.…”

Section: Heterotopic Ossificationmentioning

confidence: 99%

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Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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Section: Heterotopic Ossificationmentioning

confidence: 99%

Section: Heterotopic Ossificationmentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

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“…The incidence rate for HO varies from 15% to 90%, depending on the source of trauma and the grading criteria used [1,7,39,43,51]. Current treatments for patients with HO emphasize reducing inflammation and/or inactivating tissue-resident stem cells at the trauma site to minimize pathological bone formation.…”

Section: Introductionmentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) may occur after musculoskeletal trauma, traumatic brain injury, and total joint arthroplasty. As such, HO is a compelling clinical concern in both military and civilian medicine. A possible etiology of HO involves dysregulated signals in the bone morphogenetic protein osteogenic cascade. Contemporary treatment options for HO (ie, nonsteroidal antiinflammatory drugs and radiation therapy) have adverse effects associated with their use and are not biologically engineered to abrogate the molecular mechanisms that govern osteogenic differentiation. Questions/purposes We hypothesized that (1) nanogelmediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (Runx2) and osterix (Osx) genes will decrease messenger RNA expression; (2) inhibit activity of the osteogenic marker alkaline phosphatase (ALP); and (3) inhibit hydroxyapatite (HA) deposition in osteoblast cell cultures. Methods Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators, Runx2 and Osx, in murine calvarial preosteoblasts (MC3T3-E1.4) stimulated for osteogenic differentiation by recombinant human bone morphogenetic protein (rhBMP-2). The efficacy of RNA interference (RNAi) therapeutics was determined by quantitation of messenger RNA knockdown (by quantitative reverse transcription-polymerase chain reaction), downstream protein knockdown (determined ALP enzymatic activity assay), and HA deposition (determined by OsteoImage TM assay). Results Gene expression assays demonstrated that nanogelbased RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced Runx2 expression by 48.59% ± 19.53% (p \ 0.001) and 43.22% ± 18.01% (both p \ 0.001). The same 1:1 and 5:1 treatments against both Runx2 and Osx reduced expression of Osx by 51.65% ± 10.85% and 47.65% ± 9.80% (both p \ 0.001). Moreover, repeated 48-hour RNAi treatment cycles against Runx2 and Osx rhBMP-2 administration reduced ALP activity after 4 and 7 days. ALP reductions after 4 days in culture by nanogel 5:1 and 10:1 RNAi treatments were 32.4% ± 12.0% and 33.6% ± 13.8% (both p \ 0.001). After 7 days in culture, nanogel 1:1 and 5:1 RNAi treatments produced 35.9% ± 14.0% and 47.7% ± 3.2% reductions in ALP activity. Osteoblast mineralization data after 21 days suggested that Two of the authors (ARS, EH) contributed equally.

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“…Abnormal growth results from a disturbance in regulation of normal skeletogenesis and frequently is encountered in other orthopaedic settings, including THA and elbow fracture [1, 3, 11, 20-22, 24, 25] and traumatic brain injury and spinal cord injury [4,8]. Despite being documented as far back as the Civil War, few comprehensive reports on HO frequency in combat-related injuries exist [7,18,19]. Potter et al [18,19] examined rates of ectopic bone formation in cases of battlefield amputations and found a prevalence approaching nearly 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Despite being documented as far back as the Civil War, few comprehensive reports on HO frequency in combat-related injuries exist [7,18,19]. Potter et al [18,19] examined rates of ectopic bone formation in cases of battlefield amputations and found a prevalence approaching nearly 2 .…”

Section: Introductionmentioning

confidence: 99%

Does Blast Medium Affect Heterotopic Ossification in a Blast-amputation Model?

Yoo

Blevins

Gasbarro

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) develops after nearly 2 .3 of traumatic blast amputations in the contemporary battlefield. This phenomenon has potentially devastating consequences for servicemen and women and its pathophysiology warrants further investigation using a previously developed animal blast model. Questions/purposesWe asked, what is the (1) severity (quantity) and (2) type (location) of HO bone formation after a hindlimb blast amputation with two distinct blast media. We hypothesized that a more ''war-relevant'' blast medium could be a more accurate model and potentially intensify the development of HO. Methods Using a Sprague-Dawley rat model, the pathophysiology of ectopic bone formation in a traumatic hindlimb blast amputation was evaluated. Twenty-four animals underwent blast amputations and closure based on a previously established experimental model. Half the amputations were subjected to blasted sand and the other 1/2 to blasted water. Serial orthogonal radiography was performed on each animal until euthanasia at 24 weeks to track the development of HO. Heterotopic bone severity and type were assessed by three independent graders at each time using a novel grading scale to assess quantity and quality of HO. Results All animals had radiographic evidence of HO develop. No differences were observed in ectopic bone development between sand and water blasting regarding severity or type at any time. Animals that received water and sand blasting had moderate HO develop at 24 weeks (median, 2.0 and 2.5 weeks, respectively; range, 1-3 weeks; difference of medians, 0.5; p = 0.67). At the time of euthanasia, 10 animals that were water blasted had Type 3 HO compared with 11 in the sand-blasted group (p = 1.00).The institution of one or more of the authors (DEJ, VDP) has received, during the study period, funding from the United States Department of Defense Congressionally Directed Medical Research Program (Washington, DC, USA). One of the authors certifies that he (VDP), or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount of USD 100,000-USD 1,000,000, from the United States Department of Defense Congressionally Directed Medical Research Program (Washington, DC, USA), an amount of USD 100,000-USD 1,000,000 from DePuy Orthopaedics (Warsaw, IN, USA), and USD 100,000-USD 1,000,000 from the Agency for Healthcare Research and Quality (Rockville, MD, USA). Conclusions Our study showed a clear development of HO after hindlimb blast amputation in a Sprague-Dawley rat model; however, no difference was observed in HO development based on the type of blast media. This suggests it is the blast mechanism that induces ectopic bone development, regardless of the blasted medium. The grading scale we developed for our animal-model study provided a reliable means of assessing HO severity and type. Clinical Relevance We anticipate that future investigations will elucidate similarities between service members' wartime extremity injuries and the animal...

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Heterotopic Ossification in the Residual Limbs of Traumatic and Combat-Related Amputees

Cited by 86 publications

References 56 publications

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Does Blast Medium Affect Heterotopic Ossification in a Blast-amputation Model?

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