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Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

The musculoskeletal system is critical for movement and the protection of organs. In addition to abrupt injuries, daily physical demands inflict minor injuries, necessitating a coordinated process of repair referred to as the acute‐phase response (APR). Dysfunctional APRs caused by severe injuries or underlying chronic diseases are implicated in pathologic musculoskeletal repair, resulting in decreased mobility and chronic pain. The molecular mechanisms behind these phenomena are not well understood, hindering the development of clinical solutions. Recent studies indicate that, in addition to regulating intravascular clotting, the coagulation and fibrinolytic systems are also entrenched in tissue repair. Although plasmin and fibrin are considered antithetical to one another in the context of hemostasis, in a proper APR, they complement one another within a coordinated spatiotemporal framework. Once a wound is contained by fibrin, activation of plasmin promotes the removal of fibrin and stimulates angiogenesis, tissue remodeling, and tissue regeneration. Insufficient fibrin deposition or excessive plasmin‐mediated fibrinolysis in early convalescence prevents injury containment, causing bleeding. Alternatively, excess fibrin deposition and/or inefficient plasmin activity later in convalescence impairs musculoskeletal repair, resulting in tissue fibrosis and osteoporosis, while inappropriate fibrin or plasmin activity in a synovial joint can cause arthritis. Together, these pathologic conditions lead to chronic pain, poor mobility, and diminished quality of life. In this review, we discuss both fibrin‐dependent and ‐independent roles of plasminogen activation in the musculoskeletal APR, how dysregulation of these mechanisms promote musculoskeletal degeneration, and the possibility of therapeutically manipulating plasmin or fibrin to treat musculoskeletal disease.

BACKGROUND Displaced pediatric supracondylar humeral fractures (SCHFs) are stabilized after reduction by smooth pins. Although some SCHFs are biomechanically stable after lateral-only entry pinning (lateral pinning), an additional medial entry pin (cross-pinning) confers superior stabilization in some SCHFs. There is a recognized risk of iatrogenic ulnar nerve injury with medial entry pinning. The best existing evidence has estimated an iatrogenic ulnar nerve injury rate of approximately 3.4% in cross-pinning. In similar studies, the rate of iatrogenic nerve injury (all nerves) in lateral pinning is estimated at 1.9%. This study aimed to use a large, single-center, single-technique (mini-open) retrospective case series to determine the rate of iatrogenic ulnar nerve injury in cross-pinning. METHODS Patients undergoing percutaneous cross-pinning via the mini-open technique for SCHFs from 2007 to 2017 were retrospectively reviewed. Injury characteristics, operative variables, fixation technique, and complications, such as iatrogenic nerve injury, were recorded. Patients who underwent operative treatment at another hospital, had no postoperative follow-up, or died due to polytrauma were excluded. RESULTS In this study, 698 patients undergoing cross-pinning during the study period were identified. Patients treated with cross-pinning had severe fractures, including a total of 198 preoperative neurovascular injuries (28.4%), 32 patients (4.6%) with skin tenting, and 19 patients (2.7%) with open fractures. Iatrogenic nerve injury was reported in 3 cases (0.43%), all of which affected the ulnar nerve. In 2 of 3 cases of iatrogenic nerve injury, the ulnar nerve symptoms resolved at a mean follow-up of 15 weeks. CONCLUSIONS The mini-open approach for medial pin insertion is safer than previous estimates. Here, in the largest single-center study of cross-pinning for SCHFs, the iatrogenic ulnar nerve injury rate of 0.43% was nearly 10 times lower than estimated rates from recent meta-analyses. Considering all nerves, the iatrogenic injury rate for this cross-pinning cohort was also lower than the estimated iatrogenic nerve injury rate for lateral pinning. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Severely injured patients are beleaguered by complications during convalescence, such as dysregulated biomineralization. Paradoxically, severely injured patients experience the loss of bone (osteoporosis), resulting in diminished skeletal integrity and increased risk of fragility fractures; yet they also accrue mineralization in soft tissues, resulting in complications such as heterotopic ossification (HO). The pathophysiology leading to dysregulated biomineralization in severely injured patients is not well defined. It has been postulated that these pathologies are linked, such that mineralization is “transferred” from the bone to soft tissue compartments. The goal of this study was to determine if severe injury-induced osteoporosis and soft tissue calcification are temporally coincident following injury. Using a murine model of combined burn and skeletal muscle injury to model severe injury, it was determined that mice developed significant progressive bone loss, detectable as early as 3 days post injury, and marked soft tissue mineralization by 7 days after injury. The observed temporal concordance between the development of severe injury-induced osteoporosis and soft tissue mineralization indicates the plausibility that these complications share a common pathophysiology, though further experiments are required., Highlights • Severely injured patients can experience both the loss of bone or the accrual of mineralization in soft tissues following injury. • It has been postulated that these pathologies are linked, such that mineralization is “transferred” between compartments. • In a murine model, we observed a temporal concordance between severe injury-induced osteoporosis and soft tissue mineralization. • These results support the plausibility that these complications share a common pathophysiology.

Objectives: Spinal fusion is often complicated by high blood loss and the clinically observed phenomenon of increased bleeding times throughout the case. Although the pathophysiology of this phenomenon involves hyperfibrinolysis and occurs to a lesser extent in the presence of antifibrinolytics (e.g. TXA), we hypothesize that perioperative changes in platelet function also contribute to this continued observation. Methods: Blood samples were acquired from patients undergoing posterior spinal fusion for correcting scoliosis (5 neuromuscular, 3 idiopathic ). Samples were obtained immediately before the procedure, at 2, 4, and 6 hours post-incision, and the subsequent morning (POD1). Platelet activation in response to stimulation with an intravascular agonist, thrombin, and an extravascular agonist, convulxin, was measured by flow cytometry. Activation of the fibrin-binding integrin glycoprotein IIb/IIIa (GpIIb/IIIa) was reported by PAC-1 binding and expression of the alpha-granule component P-selectin was reported by CD62p binding. CBCs and Thromboelastography (TEG) were performed on samples in parallel. Estimated blood loss (EBL) was calculated using a hematocrit-based analysis of red cell mass. Results:All 5 neuromuscular patients exhibited a marked and progressive decline in platelet count and activity throughout surgery and early postoperative period. Reductions were most notable for thrombin-stimulated GpIIb/IIIa activation (Th PAC1) at 4 hrs (mean 41.7%, p=0.0056) and 6 hrs (50.9%, p=0.0096). Similar trends in mean reductions were observed for thrombin stimulated P- selectin expression (Th P-Selectin) at 6 hrs (22.5%, p=0.0112) and on POD1 (39.2%, p=0.0274). Patients with idiopathic scoliosis demonstrated significant reductions in convulxin-stimulated GpIIb/IIIa activation (32.8%, p=0.0087) and P-selectin expression (35.1%, p=0.0147) at 2 hrs, which recovered to or increased beyond baseline thereafter. These trends also manifested on TEG for all neuromuscular patients as the average time to maximum clot strength increased by 48.8% at 6 hrs (p=0.0058). Furthermore, platelet activity correlated with the calculated EBL for all 8 patients (Th PAC1 at 4 hrs R= -0.673, p=0.146 and 6 hrs: R= -0.623, p=0.099; Th P-Selectin at 6 hrs: R= -0.694 p = 0.056 and POD1: R= -0.713, p=0.047). EBL also significantly correlated with reductions in platelet count at 6 hrs (R= -0.919, p=0.010) and absolute platelet count on POD1 (R= -0.858, p=0.006). Conclusions: We have observed a progressive reduction in platelet activation and fibrin-dependent clot formation throughout scoliosis surgery, particularly in patients with neuromuscular disease. High endothelial injury related to achieving surgical exposure may account for the early drop in response to the extravascular collagen receptor agonist, convulxin. Measures associated with secondary hemostasis, such as the thrombin-stimulated platelet activation and time to maximum clot strength, both demonstrated exhaustion towards the post-operative period. These data suggest that surgically-induced disruption in platelet function may be a key component of the coagulopathic phenomenon described and closely associated with blood loss.

Purpose Complications following total knee arthroplasty (TKA) lead to patient morbidity and cost. While acute phase reactants, such as c-reactive protein (CRP) and fibrinogen, have been used to predict complications following TKA, the extent and duration of changes in albumin levels following TKA are unknown. It is hypothesized that like CRP and fibrinogen, albumin, and the fibrinogen/albumin ratio (FAR) represent useful measures of the acute phase response (APR) following TKA. The purpose of this study was to describe the longitudinal course of albumin and FAR in healthy patients following TKA, relative to established biomarkers, and examine if the variance in albumin or FAR correlates with patient comorbidities. Methods This retrospective cohort study of patients undergoing TKA at a tertiary medical center. CRP, fibrinogen, and albumin values were collected pre- and post-operatively. An age-adjusted Charlson comorbidity index (CCI) was utilized as a measure of patient comorbidity status. Results The median preoperative albumin value was 4.3 g/dL, which dropped to 3.6 g/dL on postoperative day 1 following TKA. The albumin value returned to 93% of the baseline by postoperative week 2. The course of albumin inversely mirrored the course of CRP (r = -0.41). Median preoperative FAR was 0.087 g/L, which rose to 0.130 g/L by postoperative week 2 and returned to baseline by postoperative week 6. While preoperative FAR strongly correlated with postoperative week 2 values (r = 0.74), there was a weak positive correlation between age-adjusted CCI and pre-operative FAR (r = 0.24) in patients undergoing primary TKA. Conclusion Albumin levels follow a predictable postoperative decline that inversely correlates with CRP in healthy patients following TKA. Given the low cost and abundance of laboratories offering albumin levels, direct albumin levels and/or albumin ratios such as FAR may be underutilized biomarkers for monitoring the APR following TKA.

Background:. Stabilization of the medial column is vital in preventing the loss of fixation and malunion in displaced pediatric supracondylar humeral fractures (SCHFs). The preferred percutaneous pin configuration for medial column fixation remains controversial between medial pinning (cross-pinning) and additional lateral-based pinning. The intraoperative internal rotation stress test (IRST) has been proposed to reliably determine the optimal fixation strategy for each unique fracture. This study evaluated the impact of implementing the IRST on both the choice of pin configuration and institution-wide complications in pediatric patients treated operatively for SCHFs. Methods:. Pediatric patients undergoing percutaneous pinning for SCHFs between 2007 and 2017 at a single center were retrospectively reviewed. The IRST was made a universal institutional practice in 2013. Patients were divided into 2 groups for analysis: (1) patients who underwent treatment before the IRST was implemented in 2013 (the pre-IRST group), and (2) patients who were treated after the IRST was implemented in 2013 (the IRST group). Subgroup analysis was completed for patients in the IRST group who were treated with cross-pinning or 3 lateral-based pins. Results:. In this study, 820 patients in the pre-IRST group and 636 patients in the IRST group were included. After the IRST implementation, the rate of loss of fixation fell from 1.2% to 0% (p = 0.003), and the reoperation rate fell from 3.3% to 0.2% (p < 0.001). No cases resulted in a loss of fixation after the adoption of the IRST. The number of patients treated with cross-pinning decreased significantly from 53.2% to 31.6% (p < 0.001) after the IRST implementation, yet cross-pinning continued to be used for more severe fractures. Complication rates within the IRST group were not significantly different (p > 0.05) between cross-pinning and 3 lateral-based pins. Conclusions:. In the largest cohort reported on to date, to our knowledge, institutional implementation of the IRST resulted in a significant reduction in the use of cross-pinning. Although the usage of cross-pinning decreased, cross-pinning was still used frequently in the most severe fractures. The IRST use also resulted in significantly fewer complications such as loss of fixation after institution-wide implementation of the IRST for treating pediatric SCHFs. Level of Evidence:. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND Musculoskeletal infection is a major cause of morbidity in the pediatric population. Despite the canonical teaching that an irritable joint and signs of infection likely represent an infected joint space, recent evidence in the pediatric hip has demonstrated that alternative diagnoses are equally or more likely and that combinations of pathologies are common. The knee is the second most commonly infected joint in children, yet there remains a paucity of available data regarding the epidemiology and workup of the infected pediatric knee. The authors hypothesize that there is heterogeneity of pathologies, including combinations of pathologies, that presents as a potentially infected knee in a child. The authors aim to show the utility of magnetic resonance imaging and epidemiologic and laboratory markers in the workup of these patients. METHODS A retrospective review of all consults made to the pediatric orthopaedic surgery team at a single tertiary care center from September 2009 through December 2015 regarding a concern for potential knee infection was performed. Excluded from the study were patients with penetrating trauma, postoperative infection, open fracture, no C-reactive protein (CRP) within 24 hours of admission, sickle cell disease, an immunocompromised state, or chronic osteomyelitis. RESULTS A total of 120 patients were analyzed in this study. There was marked variability in pathologies. Patients with isolated osteomyelitis or osteomyelitis+septic arthritis were older, had an increased admission CRP, were more likely to be infected with Staphylococcus aureus, required an increased duration of antibiotics, and had an increased incidence of musculoskeletal complications than patients with isolated septic arthritis. CONCLUSIONS When considering a child with an irritable knee, a heterogeneity of potential underlying pathologies and combinations of pathologies are possible. Importantly, the age of the patient and CRP can guide a clinician when considering further workup. Older patients with a higher admission CRP value warrant an immediate magnetic resonance imaging, as they are likely to have osteomyelitis, which was associated with worse outcomes when compared with patients with isolated septic arthritis. LEVEL OF EVIDENCE Level III-retrospective research study.

Bone fractures create five problems that must be resolved: bleeding, risk of infection, hypoxia, disproportionate strain, and inability to bear weight. There have been enormous advancements in our understanding of the molecular mechanisms that resolve these problems after fractures, and in best clinical practices of repairing fractures. We put forth a modern, comprehensive model of fracture repair that synthesizes the literature on the biology and biomechanics of fracture repair to address the primary problems of fractures. This updated model is a framework for both fracture management and future studies aimed at understanding and treating this complex process. This model is based upon the fracture acute phase response (APR), which encompasses the molecular mechanisms that respond to injury. The APR is divided into sequential stages of “survival” and “repair.” Early in convalescence, during “survival,” bleeding and infection are resolved by collaborative efforts of the hemostatic and inflammatory pathways. Later, in “repair,” avascular and biomechanically insufficient bone is replaced by a variable combination of intramembranous and endochondral ossification. Progression to repair cannot occur until survival has been ensured. A disproportionate APR—either insufficient or exuberant—leads to complications of survival (hemorrhage, thrombosis, systemic inflammatory response syndrome, infection, death) and/or repair (delayed- or non-union). The type of ossification utilized for fracture repair is dependent on the relative amounts of strain and vascularity in the fracture microenvironment, but any failure along this process can disrupt or delay fracture healing and result in a similar non-union. Therefore, incomplete understanding of the principles herein can result in mismanagement of fracture care or application of hardware that interferes with fracture repair. This unifying model of fracture repair not only informs clinicians how their interventions fit within the framework of normal biological healing but also instructs investigators about the critical variables and outputs to assess during a study of fracture repair.

Heterotopic ossification (HO), or the pathologic formation of bone within soft tissues, is a significant complication following severe injuries as it impairs joint motion and function leading to loss of the ability to perform activities of daily living and pain. While soft tissue injury is a prerequisite of developing HO, the exact molecular pathology leading to trauma-induced HO remains unknown. Through prior investigations aimed at identifying the causative factors of HO, it has been suggested that additional predisposing factors that favor ossification within the injured soft tissues environment are required. Considering that chondrocytes and osteoblasts initiate physiologic bone formation by depositing nanohydroxyapatite crystal into their extracellular environment, we investigated the hypothesis that deposition of nanohydroxyapatite within damaged skeletal muscle is likewise sufficient to predispose skeletal muscle to HO. Using a murine model genetically predisposed to nanohydroxyapatite deposition (ABCC6-deficient mice), we observed that following a focal muscle injury, nanohydroxyapatite was robustly deposited in a gene-dependent manner, yet resolved via macrophage-mediated regression over 28 days post injury. However, if macrophage-mediated regression was inhibited, we observed persistent nanohydroxyapatite that was sufficient to drive the formation of HO in 4/5 mice examined. Together, these results revealed a new paradigm by suggesting the persistent nanohydroxyapatite, referred to clinically as dystrophic calcification, and HO may be stages of a pathologic continuum, and not discrete events. As such, if confirmed clinically, these findings support the use of early therapeutic interventions aimed at preventing nanohydroxyapatite as a strategy to evade HO formation. Electronic supplementary material The online version of this article (10.1007/s00223-018-0502-5) contains supplementary material, which is available to authorized users.

The rate of venous thromboembolism in children with musculoskeletal infections (MSKIs) is markedly elevated compared with hospitalized children in general. Predictive biomarkers to identify high-risk patients are needed to prevent the significant morbidity and rare mortality associated with thrombotic complications. We hypothesize that overactivation of the acute phase response is associated with the development of pathologic thrombi and we aim to determine whether elevations in C-reactive protein (CRP) are associated with increased rates of thrombosis in pediatric patients with MSKI.A retrospective cohort study measuring CRP in pediatric MSKI patients with or without thrombotic complications.The magnitude and duration of elevation in CRP values correlated with the severity of infection and the development of pathologic thrombosis. In multivariable logistic regression, every 20 mg/L increase in peak CRP was associated with a 29% increased risk of thrombosis (P0.001). Peak and total CRP were strong predictors of thrombosis with area under the receiver-operator curves of 0.90 and 0.92, respectively.Future prospective studies are warranted to further define the discriminatory power of CRP in predicting infection-provoked thrombosis. Pharmacologic prophylaxis and increased surveillance should be strongly considered in patients with MSKI, particularly those with disseminated disease and marked elevation of CRP.Level III.

INTRODUCTION: Severe injury provokes coagulopathy and systemic inflammatory response syndrome (SIRS) that, in concurrence, greatly increase the risk of life-threatening complications including bleeding, thrombosis, and multi-organ dysfunction syndrome (MODS), making it a leading cause of death and disability worldwide. For centuries, surgeons have observed hyperactivation of the enzyme plasmin (hyperfibrinolysis) following severe injury and its detrimental effects on bleeding in these patients. Recently, it has been demonstrated that the function of plasmin extends well beyond fibrinolysis to the modulation of inflammation and coagulation, suggesting it may alter the systemic inflammatory and coagulation response to severe injury. We hypothesize that early hyperactivation of plasmin augments systemic inflammation and coagulopathy following severe injury. METHODS: To test this hypothesis, we used burn as a model of severe injury in which patients develop SIRS and coagulopathy without bleeding, allowing us to study the consequences of plasmin activation aside from hemorrhage. Thirty-one burn patients with >5% total body surface area (TBSA) burns admitted to the Vanderbilt University Medical Center Burn Unit were enrolled upon patient consent along with 10 healthy volunteers. Blood was collected serially for the length of hospital stay beginning upon admission. To study the clinical condition and control study variables, we administered a 30% TBSA burn to mice in a parallel study, collecting blood serially beginning at 1-hour post-burn (N=6/group). Control mice received similar preparation in the absence of a burn. Outputs assessed for humans and mice were the same. Plasma plasmin-antiplasmin complexes (PAPc) were used as a measure for plasmin activation, plasma IL-6, IL-1β, and TNFα were used to measure systemic inflammation, and plasma antithrombin III (ATIII) deficiency and platelet count were used to measure coagulopathy. To study the role of plasmin(ogen) in burn-induced coagulopathy and inflammation in a preliminary experiment, plasminogen+/- mice with 50% normal circulating plasminogen and plasmin activity received a similar burn. Both human and animal studies were previously approved by Vanderbilt University IRB and IACUC respectively. RESULTS: In burn patients without inhalation injury, PAPc levels significantly increased in proportion to the severity of injury measured by %TBSA (p CONCLUSION: Studies in severe injuries and elective surgeries have demonstrated that early inhibition of plasmin activation by antifibrinolytic drugs not only reduced bleeding, but also systemic inflammation. Our results suggest an association between plasmin activation, platelet loss, and systemic inflammation following burn injury in both human and mouse models. While the study in Plg+/- mice implicates plasmin in burn-induced inflammation, future studies will examine the mechanistic role of plasmin activation in burn-induced systemic inflammation and coagulopathy using genetic and pharmacologic tools to manipulate plasmin in a mouse model. While the systemic response to burn injury is similar to that of other severe injuries, future studies will investigate the relationship between plasmin activation, coagulopathy, and SIRS in general trauma. As a critical modulator of hemostasis and inflammation, our findings support plasmin as a potential therapeutic target for regulating trauma-induced coagulopathy and SIRS, beyond inhibition of fibrinolysis. Disclosures Schoenecker: OrthoPediatrics: Consultancy.