Early local delivery of vancomycin suppresses ectopic bone formation in a rat model of trauma‐induced heterotopic ossification

Abstract

Heterotopic ossification (HO) is a debilitating sequela of high-energy injuries. It frequently requires surgical excision once symptomatic and there is no practical prophylaxis for combat-injured patients. In this study, we examined the effect of local vancomycin powder on HO formation in a small animal model of blast-related, post-traumatic HO. Male Sprague-Dawley rats were subjected to a polytraumatic extremity injury and amputation with or without methicillin-resistant Staphylococcus aureus infection. Animals were randomized to receive a single local application of vancomycin (20 mg/kg) at the time of injury (POD-0, n = 34) or on postoperative day-3 (POD-3, n = 11). Quantitative volumetric measurement of ectopic bone was calculated at 12-weeks post-injury by micro-CT. Bone marrow and muscle tissues were also collected to determine the bacterial burden. Blood for serum cytokine analysis was collected at baseline and post-injury. Vancomycin treatment on POD-0 suppressed HO formation by 86% and prevented bone marrow and soft tissue infections. We concurrently observed a marked reduction histologically in nonviable tissue, chronic inflammatory cell infiltrates, bone infection, fibrous tissue, and areas of bone necrosis within this same cohort. Delayed treatment was significantly less efficacious. Neither treatment had a marked effect on the production of pro-inflammatory cytokines. Our study demonstrates that local vancomycin treatment at the time of injury significantly reduces HO formation in both the presence and absence of infection, with decreased efficacy if not given early. These findings further support the concept that the therapeutic window for prophylaxis is narrow, highlighting the need to develop early treatment strategies for clinical management. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2397-2406, 2017.

Discovery of a bone‐like blood particle in the peripheral circulation of humans and rodents

“…In addition, vascular injury in the form of rupture may permit leakage of OSP from the vascular system, resulting in heterotopic bone formation. Heterotopic bone formation is characterized by the formation of lamellar bone in soft tissues, has been reported following several types of injury (eg, burn injuries, bone fractures, neurologic injury), and is prevalent in the majority of service personnel whom have experienced combat injuries related to blasts . As demonstrated in this investigation, OSP have the potential to serve as emboli in the circulatory system.…”

“…The elemental composition of the ossified particles was determined by EDS using the x-ray detector (Inca X-act, Oxford Instruments) attached to the Hitachi S-4700 SEM. For this analysis, the accelerating voltage of the SEM was set at 10 kV with a beam current of [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] μA. The x-ray spectra were collected with a 60-s acquisition time within several regions of interest of the sample, and spectral peaks were identified qualitatively.…”

“…Regardless, the absence of a lumen in the case of ossified bone marrow blood vessels is presumably linked to age-related declines in skeletal perfusion, 14,16 as well as to other bone and bone marrow pathologies (eg, marrow ischemia). 23 25 has been reported following several types of injury (eg, burn injuries, bone fractures, neurologic injury), 26 and is prevalent in the majority of service personnel whom have experienced combat injuries related to blasts. [27][28][29] As demonstrated in this investigation, OSP have the potential to serve as emboli in the circulatory system.…”

Post‐Traumatic Heterotopic Ossification: An Old Problem in Need of New Solutions

“…Further evidence of the potential of antibiotic drugs to prevent HO comes from recent work in a rodent high-energy extremity trauma model. 48 Early topical vancomycin reduced the burden of HO in this model, independent of whether or not the wound was infected. As with the work using echinomycin (above), this suggests that the relevant action of vancomycin is not mediated through its antibiotic activity.…”

“…Further evidence of the potential of antibiotic drugs to prevent HO comes from recent work in a rodent high‐energy extremity trauma model . Early topical vancomycin reduced the burden of HO in this model, independent of whether or not the wound was infected.…”