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This proposal addresses the treatment of segmental bone defects and methods that can be used to manipulate the Masquelet induced membrane (IM) to create a graft bed that optimizes bone regeneration. The Chronic Caprine Tibial Defect (CCTD) model is used 1) to improve surgical technique and 2) to optimize spacer design; these are likely to advance bone regeneration strategies and translate into clinical practice, The original document contains color images.

This study will recruit wounded warriors with severe extremity trauma, which places them at high risk for heterotopic ossification (HO); bone formation at abnormal sites, which causes pain, limits motion and/or limits the use of a prosthetic device. There are three goals: 1) to understand the mechanisms involved in HO; 2) to define accurate and practical methods to predict where HO will develop; and 3) to define potential therapies for prevention or mitigation of HO., The original document contains color images.

This study will recruit wounded warriors with severe extremity trauma, which places them at high risk for heterotopic ossification (HO); bone formation at abnormal sites, which causes pain, limits motion and/or limits the use of a prosthetic device. There are three goals: 1) to understand the mechanisms involved in HO; 2) to define accurate and practical methods to predict where HO will develop; and 3) to define potential therapies for prevention or mitigation of HO.

In this project we study Heterotopic Ossification (HO) and are a potential novel therapy to cure it. HO consists of formation of extra bone within the muscles, near tendons and ligaments, inside the blood vessels and other places in the body. HO is triggered by trauma, burns, nerve damage, immobilization and other condition and can also occur in patients undergoing large surgeries such as hip or knee replacement. Because trauma, burns and other severe wounds are regrettably common in our soldiers in the current war theaters and conflicts, HO often affects and afflicts many of them.

Background: The prevalence of penetrating wartime trauma to the extremities has increased in recent military conflicts. Substantial controversy remains in the orthopaedic and prosthetic literature regarding which surgical technique should be performed to obtain the most functional transtibial amputation. We compared self-reported functional outcomes associated with two surgical techniques for transtibial amputation: bridge synostosis (modified Ertl) and non-bone-bridging (modified Burgess). Methods: A review of the prospective military amputee database was performed to identify patients who had undergone transtibial amputation between June 2003 and December 2010 at three military institutions receiving the majority of casualties from the most recent military conflicts; two of those institutions, Walter Reed Army Medical Center and National Naval Medical Center, have since been consolidated. Short Form-36, Prosthesis Evaluation Questionnaire, and functional data questions were completed by twenty-seven modified Ertl and thirty-eight modified Burgess isolated transtibial amputees. Results: The average duration of follow-up after amputation (and standard deviation) was 32 22.7 months, which was similar between groups. Residual limb length was significantly longer in the modified Ertl cohort by 2.5 cm (p 0.005), and significantly more modified Ertl patients had delayed amputations (p 0.005). There were no significant differences between groups with regard to any of the Short Form-36 domains or Prosthesis Evaluation Questionnaire subsections. Conclusions: The modified Ertl and Burgess techniques offer similar functional outcomes in the young, active-duty military population managed with transtibial amputation., Published in the Journal of Bone and Joint Surgery of America, v95A n10 p888-893, 15 May 2013. Sponsored in part by the Military Amputee Intramural Research Program (MAIRP) via the Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD.

This study will recruit wounded warriors with severe extremity trauma, which places them at high risk for heterotopic ossification (HO); bone formation at abnormal sites, which causes pain, limits motion and/or limits the use of a prosthetic device. There are three goals: 1) to understand the mechanisms involved in HO; 2) to define accurate and practical methods to predict where HO will develop; and 3) to define potential therapies for prevention or mitigation of HO., The original document contains color images.

This study will recruit wounded warriors with severe extremity trauma, which places them at high risk for heterotopic ossification (HO); bone formation at abnormal sites, which causes pain, limits motion and/or limits the use of a prosthetic device. There are three goals: 1) to understand the mechanisms involved in HO; 2) to define accurate and practical methods to predict where HO will develop; and 3) to define potential therapies for prevention or mitigation of HO., The original document contains color images.

Background The ability to forecast whether a wound will heal after closure without further debridement(s), would provide substantial benefits to patients with severe extremity trauma. Methods Wound effluent is a readily available material which can be collected without disturbing healthy tissue. For analysis of potential host response biomarkers, forty four serial combat wound effluent samples from 19 patients with either healing or failing traumatic- and other combat-related wounds were examined by 2-D DIGE. Spot map patterns were correlated to eventual wound outcome (healed or wound failure) and analyzed using DeCyder 7.0 and differential proteins identified via LC-MS/MS. Results This approach identified 52 protein spots that were differentially expressed and thus represent candidate biomarkers for this clinical application. Many of these proteins are intimately involved in inflammatory and immune responses. Furthermore, discriminate analysis further refined the 52 differential protein spots to a smaller subset of which successfully differentiate between wounds that will heal and those that will fail and require further surgical intervention with greater than 83% accuracy. Conclusion These results suggest candidates for a panel of protein biomarkers that may aid traumatic wound care prognosis and treatment. We recommend that this strategy be refined, and then externally validated, in future studies of traumatic wounds.

Successful treatment of pathologic femur fractures can preserve a patient's independence and quality of life. The choice of implant depends on several disease and patient-specific variables; however, its durability must generally match the patient's estimated life expectancy. Failures do occur, however, it is unclear which implants are associated with greater risk of failure. We evaluated patients with femoral metastases in whom implants failed to determine (1) the rate of reoperation; (2) the timing of and most common causes for failure; and (3) incidence of perioperative complications and death., SYMPOSIUM: PAPERS PRESENTED AT THE 2011 ISOLS MEETING IN BEIJING, CHINA, Sept 15-18, 2011, Published in Clinical Orthopaedics and Related Research, Sept. 5, 2012, Government or Federal Purpose Rights License. The original document contains color images.

The objective of this retrospective study was to determine the incidence of pulmonary embolism (PE) in casualties of wartime extremity wounds and specifically in casualties with a trauma-associated amputation., Pub. in the Journal of Trauma Injury, Infection, and Critical Care, v71 n3, p607-613, Sep 2011. Sponsored in part by Office of Naval Research

Background: Predictive models permitting individualized prognostication for patients with fracture nonunion are lacking. The objective of this study was to train, test, and cross-validate a native Bayesian classifier for predicting fracture-nonunion healing in a population treated with extracorporeal shock wave therapy. Methods: Prospectively collected data from 349 patients with delayed fracture union or a nonunion were utilized to develop a naive Bayesian belief network model to estimate site-specific fracture-nonunion healing in patients treated with extracorporeal shock wave therapy. Receiver operating characteristic curve analysis and tenfold cross-validation of the model were used to determine the clinical utility of the approach. Results: Predictors of fracture-healing at six months following shock wave treatment were the time between the fracture and the first shock wave treatment, the time between the fracture and the surgery, intramedullary stabilization, the number of bone-grafting procedures, the number of extracorporeal shock wave therapy treatments, work-related injury, and the bone involved (p < 0.05 for all comparisons). These variables were all included in the naive Bayesian belief network model. Conclusions: A clinically relevant Bayesian classifier was developed to predict the outcome after extracorporeal shock wave therapy for fracture nonunions. The time to treatment and the anatomic site of the fracture nonunion significantly impacted healing outcomes. Although this study population was restricted to patients treated with shock wave therapy, Bayesian-derived predictive models may be developed for application to other fracture populations at risk for nonunion., Investigation performed at the AUVA-Trauma Center, Meidling, Vienna, Austria; DecisionQ Corporation, Washington, DC; Walter Reed Army Medical Center, Washington, DC; and National Naval Medical Center, Bethesda, Maryland.. The original document contains color images. Published in Journal of Bone and Joint Surgery, v93 A p187-194, 19 Jan 2011.

Matrix metalloproteinases (MMPs) are crucial in the inflammatory and remodeling phases of wound healing. We previously reported the correla tion between pro-inflammatory cytokines and timing of successful combat-wound closure. We now extend our studies to investigate the correlation between wound-remodeling MMP expression and wound healing. Methods. Thirty-eight wounds in 25 patients with traumatic extremity combat wounds were prospectively studied. Surgical debridement with vacuum-assisted closure (VAC) device application was repeated every 48 to 72h until surgical wound closure. Wound effluent and patient serum were collected at each wound debridement and analyzed for five matrix metalloproteinases using the Luminex multiplex system; Millipore Corp, Billerica, MA. The primary outcome was wound healing within 30 d of definitive wound closure. Impairment was defined as delayed wound closure ( 21 d from injury) or wound dehiscence. MMP expression was com pared between impaired and normal healing wounds. Results. Elevated levels of serum MMP-2 and MMP-7 and reduced levels of effluent MMP3 were seen in im paired wounds (n = 9) compared with wounds that healed (n = 29;P 0.001). Receiver operating characteristic (ROC) curve analysis yielded area-under-the-curve (AUC) of0.744, 0.783, and 0.805, respectively. Conclusions. Impaired wound healing is characterized by pro-inflammatory MMP-2 and MMP-7. Serum and effluent concentrations of MMP-2, MMP-3, and MMP-7 can effectively predict the outcome of 1 To whom correspondence and reprint requests should be addressed at Naval Medical Research Center, Regenerative Medicine Department, 503 Robert Grant Ave, Silver Spring, MD 20910. E-mail: Trevor.Brown@med.navy.mil. traumatic war wounds and can potentially provide decision-supportive, objective evidence for the timing of wound closure., Pub. in Journal of Surgical research, v159, p633-639, 2010.

The term heterotopic ossification refers to the aberrant formation of mature, lamellar bone in nonosseous tissue. Translated from its Greek (heteros and topos) and Latin (ossificatio) etymologic origins, heterotopic ossification can be literally defined as bone formation in other location. The first written account of heterotopic ossification describes the treatment of symptomatic lesions. Al-Zahrawi (more commonly known in Western cultures as Albucasis ), widely considered the father of surgery, wrote in the year 1000 C. E., This callus often occurs after the healing of a fracture ... and sometimes there is limitation of the natural function of the limb ... if the callus is stony hard and its removal is urgent, incise the place and cut away the superfluous prominence, or pare it away with a scraper until it is gone; and dress the wound until it heals.' Currently, orthopaedic surgeons faced with treating mature, refractory, symptomatic heterotopic ossification are left with few options other than operative excision. Although it is remarkable that the treatment of heterotopic ossification has scarcely changed in the last millennium, it is generally accepted that prophylaxis against heterotopic ossification is far preferable than the later treatment of symptomatic lesions. As such, the focus of scientific effort in recent years has been directed toward prophylaxis, not treatment., Published in the Journal of Bone and Joint Surgery v92-A, Supplement 2 p74-89, 2010.

Heterotopic ossification (HO) refers to the formation of mature lamellar bone in nonosseous tissue. In the setting of high-energy wartime extremity wounds, HO is expected to complicate up to 64% of patients, has a predilection for the residual limbs of amputees, and remains a significant source of disability. Although the inciting events and the definitive cell(s) of origin continue to remain elusive, animal models and human histology samples suggest that HO formation follows a predictable sequence of events culminating in endochondral ossification. Primary prophylaxis is not medically or logistically practical in most cases because patients have generally sustained massive wounds and are undergoing serial debridements during an intercontinental aeromedical evacuation. Surgical excision of symptomatic lesions is warranted only after an appropriate trial of conservative measures and is associated with low recurrence rates in appropriately selected patients. Future research regarding prognostication and defining the early molecular biology of ectopic bone may permit individualized prophylaxis and development of novel targeted therapies., Published in Journal of Surgical Orthopaedic Advances, v19 n1 p54-61, Spring 2010.

Objectives: Delayed and nonunion of the tibia are not uncommon in orthopaedic practice. Multiple methods of treatment have been developed with variable results. The objective of this study was to define disease-specific and treatment-related factors of prognostic significance in patients undergoing shock wave therapy for tibia nonunion. Design: Retrospective analysis. Patients: One hundred ninety-two patients treated with extracorporeal shock wave therapy (ESWT) at a single referral trauma center, AUVA-Trauma Center Meidling, a large single-referral trauma center located in Vienna, Austria, in an attempt to determine the feasibility and factors associated with the use of ESWT in the treatment for tibia nonunion. Intervention: ESWT coupled with posttreatment immobilization, external fixation, or ESWT alone. Main Outcome Measures: Fracture healing, overall healing percent, and factors associated with ESWT success or failure. Results: At the time of last follow up, 138 of 172 ( 80.2%) patients have demonstrated complete fracture healing. Mean time from first shock wave therapy to complete healing of the tibia nonunion was 4.8 + or - 4.0 months. Number of orthopaedic operations (P = 0.003). shock wave treatments (P = 0.002), and pulses delivered (P = 0.04) were significantly associated with complete bone healing. Patients requiring multiple (more than one) shock wave treatments versus a single treatment had a significantly lower likelihood of fracture healing (P = 0.003). This may be attributable to the finding that a significantly greater proportion of patients with multiple rather than single ESWT treatments had three or more prior orthopaedic procedures (more than one ESWT, 63.9% versus one ESWT. 23.5%; p 0.001). Conclusions: ESWT is a feasible treatment modality for tibia nonunion., Published in Journal of Orthopaedic Trauma, v24 n3 p133-141, Mar 2010.

Graphical probabilistic models have the ability to provide insights as to how clinical factors are conditionally related. These models can be used to help us understand factors influencing health care outcomes and resource utilization, and to estimate morbidity and clinical outcomes in trauma patient populations., Published in Journal of Multidisciplinary Healthcare, v3 p125-135, 13 Aug 2010.

Alexander Stojadinovic1, John Eberhardt2, Trevor S Brown3, Jason S Hawksworth4, Frederick Gage3, Douglas K Tadaki3, Jonathan A Forsberg5, Thomas A Davis3, Benjamin K Potter5, James R Dunne6, E A Elster31Combat Wound Initiative Program, 4Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA; 2DecisionQ Corporation, Washington, DC, USA; 3Regenerative Medicine Department, Combat Casualty Care, Naval Medical Research Center, Silver Spring, MD, USA; 5Integrated Department of Orthopaedics and Rehabilitation, 6Department of Surgery, National Naval Medical Center, Bethesda, MD, USABackground: Graphical probabilistic models have the ability to provide insights as to how clinical factors are conditionally related. These models can be used to help us understand factors influencing health care outcomes and resource utilization, and to estimate morbidity and clinical outcomes in trauma patient populations.Study design: Thirty-two combat casualties with severe extremity injuries enrolled in a prospective observational study were analyzed using step-wise machine-learned Bayesian belief network (BBN) and step-wise logistic regression (LR). Models were evaluated using 10-fold cross-validation to calculate area-under-the-curve (AUC) from receiver operating characteristics (ROC) curves.Results: Our BBN showed important associations between various factors in our data set that could not be developed using standard regression methods. Cross-validated ROC curve analysis showed that our BBN model was a robust representation of our data domain and that LR models trained on these findings were also robust: hospital-acquired infection (AUC: LR, 0.81; BBN, 0.79), intensive care unit length of stay (AUC: LR, 0.97; BBN, 0.81), and wound healing (AUC: LR, 0.91; BBN, 0.72) showed strong AUC.Conclusions: A BBN model can effectively represent clinical outcomes and biomarkers in patients hospitalized after severe wounding, and is confirmed by 10-fold ­cross-validation a