Heterotopic Ossification After Extremity Blast Amputation in a Sprague-Dawley Rat Animal Model

Tannous, Oliver; Griffith, Cullen; O’Toole, Robert V.; Pellegrini, Vincent D.

doi:10.1097/bot.0b013e31821f6265

Cited by 32 publications

(26 citation statements)

References 27 publications

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“…By Day 28, qualitative analysis of ectopic bone formation using 3-D high-resolution lCT showed a peak in the size of radiographically detectable bone in the soft tissue, which was supported by clear histological evidence of woven bone. This is similar to the results observed in another animal model of posttraumatic HO [30].…”

Section: Discussionsupporting

confidence: 91%

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Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

Qureshi

Crump

Pavey

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Heterotopic ossification (HO) affects the majority of combat-related lower extremity wounds involving severe fracture and amputation. Defining the timing of early osteogenic-related genes may help identify candidate prophylactic agents and guide the timing of prophylactic therapy after blast and other combat-related extremity injuries. Questions/purposes Using a recently developed animal model of combat-related HO, we sought to determine (1) the timing of early chondrogenesis, cartilage formation, and radiographic ectopic bone development; and (2) the early cartilage and bone-related gene and protein patterns in traumatized soft tissue. Methods We used an established rat HO model consisting of blast exposure, controlled femur fracture, crush injury, and transfemoral amputation through the zone of injury. Postoperatively, rats were euthanized on Days 3 to 28. We assessed evidence of early ectopic bone formation by micro-CT and histology and performed proteomic and gene expression analysis. Results All rats showed radiographic evidence of HO within 28 days. Key chondrogenic (collagen type I alpha 1 [COL1a1], p = 0.016) and osteogenic-related genes (RuntThis work was supported by CDMRP (W81XWH-14-2-0010; PI-JAF) and BUMED (602115HP.3720.001.A1014; PI-JAF). Some of the authors are employees of the US Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that ''Copyright protection under this title is not available for any work of the United States Government.'' Title 17 U.S.C. §101 defined a US Government work as a work prepared by a military service member or employees of the US Government as part of that person's official duties. The opinions or assertions contained in this paper are the private views of the authors and are not to be construed as reflecting the views, policy or positions of the Department of the Navy, Department of Defense nor the US Government. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research 1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA-approval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research. This work performed at the Naval Medical Research Center, Silver Spring, MD, USA. Conclusions We found that genes that regulate early chondrogenic and osteogenic signaling and bone development (COL1a1, RUNX-2, OCN, PHEX, and POU5F1) are induced early during the tissue reparative/healing phase in a rat model simulating a combat-related extremity injury. Clinical Relevance The ability to correlate molecular events with histologic and morphologic changes will assist re...

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Section: Discussionsupporting

confidence: 91%

“…First, clinically relevant animal models have only recently been developed [21,30]. Second, clinical diagnostic methods are unable to accurately predict the site of HO development [5,20].…”

Section: Introductionmentioning

confidence: 99%

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

Qureshi

Crump

Pavey

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…To further explore the phenomenon of ectopic bone formation occurring after blast amputation, we developed an animal model to replicate the process without addition of exogenous osteogenic agents. A previous study showed high survivability after controlled blast amputation of a single extremity in a Sprague-Dawley rat model [23]. In the current study, the model showed that the blasted medium had no effect on either the severity or type of heterotopic bone that developed, disproving our hypothesis that sand blasting would result in intensified ectopic bone growth.…”

Section: Discussioncontrasting

confidence: 67%

“…A previously conducted pilot study established a survivable, reproducible model for development of heterotopic bone in a blast-injured rat without the use of exogenous growth factors [23]. This original pilot model created clean amputations via a jet of blasted water.…”

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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“…23 It has been difficult to induce HO with trauma alone, although a recently developed model using blast amputation holds promise. 24 In the studies reported here we set out to develop a new murine model of traumatic HO that more closely mimics the formation of heterotopic bone associated with blunt physical muscle trauma such as occurs in accidents or injuries in a military setting. The model involves a one-time impaction injury of the quadriceps muscle combined with a sub-symptomatic dose of BMP-2.…”

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confidence: 99%

A novel mouse model of trauma induced heterotopic ossification

Liu

Kang

Shahnazari

et al. 2013

Journal Orthopaedic Research

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Severe soft tissue trauma is associated with heterotopic ossification (HO), the abnormal deposition of bone at extraskeletal sites. The pathophysiology of the development of trauma-induced HO remains largely unknown due in part to the lack of appropriate animal models. In this study, we sought to develop a new trauma-induced HO mouse model using muscle impact injury combined with low dose BMP-2. BMP-2 at doses ranging from 0 to 2 mg was injected into quadriceps muscles of adult male C57/BL6 mice. Animals then received a one-time quadriceps impaction injury to mimic the trauma associated with severe injuries. HO was monitored using in vivo microCT scanning at 1, 2, 4, and 8 weeks after treatment. After trauma, the expression of BMP-2, -4, BMP receptor 1, SOX9 and RUNX2 were increased in muscle. Although little or no HO was observed in mice receiving 1 mg BMP-2, combining this dose with muscle trauma produced an abundance of HO. At higher doses of BMP-2, trauma did not augment mineral deposition. These results suggest that BMP-2 signaling can sensitize muscle to trauma-induced HO. They also provide the basis for a new model to study the pathogenesis of trauma-induced HO. ß

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Heterotopic Ossification After Extremity Blast Amputation in a Sprague-Dawley Rat Animal Model

Abstract: We have developed a reproducible model for HO in the residual limbs of blast-amputated rats without addition of exogenous osteogenic stimulus. Hind limb amputation demonstrated a predilection for HO formation in comparison with forelimb amputation (P < 0.05).

Cited by 32 publications

References 27 publications

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

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

A novel mouse model of trauma induced heterotopic ossification

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