Do Inflammatory Markers Portend Heterotopic Ossification and Wound Failure in Combat Wounds?

Abstract

Background After a decade of war in Iraq and Afghanistan, we have observed an increase in combat-related injury survival and a paradoxical increase in injury severity, mainly because of the effects of blasts. These severe injuries have a devastating effect on each patient's immune system resulting in massive upregulation of the systemic inflammatory response. By examining inflammatory mediators, preliminary data suggest that it may be possible to correlate complications such as wound failure and heterotopic ossification (HO) with distinct systemic and local inflammatory profiles, but this is a relatively new topic. Questions/purposes We asked whether systemic or local markers of inflammation could be used as an objective means, independent of demographic and subjective factors, to estimate the likelihood of (1) HO and/or (2) wound failure (defined as wounds requiring surgical débridement after definitive closure, or wounds that were not closed or covered within 21 days of injury) in patients sustaining combat wounds. Methods Two hundred combat wounded active-duty service members who sustained high-energy extremity The institution of one or more of the authors (JAF) has received, during the study period, funding from a grant from the Orthopaedic Trauma Research Program (OTRP) and the US Navy Bureau of Medicine and Surgery Advance Medical Development Program. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This work was performed at the Naval Medical Research Center, Silver Spring, MD, USA, and the National Military Medical Center, Bethesda, MD, USA. The views expressed this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. This study protocol was approved by the Institutional Review Boards at both the National Military Medical Center and Naval Medical Research Center in compliance with all applicable Federal regulations governing the protection of human subjects. One or more of the authors is a military service member (or employee of the U.S. Government). This work was prepared as part of his or her 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 defines a U.S. Government work as a work prepared by a military service ...

Bioburden Increases Heterotopic Ossification Formation in an Established Rat Model

“…In the neurogenic form, neurotransmitters such as glutamate, substance P, and catecholamines act to induce osteoblasts to form ectopic bone within a permissive local environment [5,18,27]. Therefore, the induction of progenitor cells with varying osteoinductive factors is common in both traumatic and neurogenic; however, the difference lies in the elevated levels of systemic and local inflammatory cytokines in the former and neurotransmitters in the latter [14]. That having been said, the expression and/or production of inflammatory mediators in this current study was not assessed; therefore, inferences regarding the role of local infection on HO development are based only on histopathological changes noted at study termination.…”

“…However, the cellular and early signaling mechanism(s) for combat injury-induced HO formation remain unclear. Recent findings suggest that the heightened and prolonged expression of inflammatory and other reparative mediators may be contribute to HO formation [11,14]. Moreover, the combat wound appears to provide a unique microenvironment conducive to osteogenesis that promotes the skewed differentiation of endogenous tissue-derived progenitor cells toward ectopic bone development within injured and healing soft tissue [10].…”

Pathogenesis of wound healing disorders in the elderly

“…On the other hand, wound fl uid markers have also been identifi ed, including increased expression of metalloproteinases (e. g. MMP-1, 2, 3, 7, 8, 9, 10, 11, 13), decreased expression of their inhibitors (e. g. TIMP-1) [61][62][63] , increased IL-1 and IL-6 [ 64 ] levels, as well as decreased levels of albumin and total protein [ 65 ] . Systemic biomarkers associated with a high risk of developing chronic wounds have also been reported, with chronic ulcer patients showing high serum levels of procalcitonin [ 66 ] as well as MMP3 and 2 [ 67 ] , and a reduced number of CD34+/CD45-dim circulating cells [ 68 ] and micro RNAs such as miRNA-200b and miRNA-191 [ 69 ] .…”

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

“…At least 41% of those patients who develop HO require additional excision procedures. Moreover, delayed healing and wound dehiscence are major problems in severely injured patients recovering from survivable severe battlefield blast-related extremity injuries [12]. Studies from our group have established that acute wound failures and subsequent HO formation are related to multiple complex interrelated systemic and local inflammatory responses to traumatic injury [8,12].…”

“…In this report, we use our model to address (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 subsequent to calcium deposition, tissue mineralization, and ectopic bone formation. It is important to confirm the timing and upregulation of bone-related genes and proteins in our model because some observational clinical studies with soft tissue injury (without fracture or amputation) have shown elevated levels of such genes in a minority of cases [6,9,12].…”