Graeme E. Glass

TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells.

With an aging population, skeletal fractures are increasing in incidence, including the typical closed and the less common open fractures in normal bone, as well as fragility fractures in patients with osteoporosis. For the older age group, there is an urgent unmet need to induce predictable bone formation as well as improve implant fixation in situations such as hip joint replacement. Using a murine model of slow-healing fractures, we have previously shown that coverage of the fracture with muscle accelerated fracture healing and increased union strength. Here, we show that cells from muscle harvested after 3 d of exposure to an adjacent fracture differentiate into osteoblasts and form bone nodules in vitro. The osteogenic potential of these cells exceeds that of adipose and skin-derived stromal cells and is equivalent to bone marrow stromal cells. Supernatants from human fractured tibial bone fragments promote osteogenesis and migration of muscle-derived stromal cells (MDSC) in vitro. The main factor responsible for this is TNF-α, which promotes first MDSC migration, then osteogenic differentiation at low concentrations. However, TNF-α is inhibitory at high concentrations. In our murine model, addition of TNF-α at 1 ng/mL at the fracture site accelerated healing. These data indicate that manipulating the local inflammatory environment to recruit, then differentiate adjacent MDSC, may be a simple yet effective way to enhance bone formation and accelerate fracture repair. Our findings are based on a combination of human specimens and an in vivo murine model and may, therefore, translate to clinical care.

Improving lower limb salvage following fractures with vascular injury: a systematic review and new management algorithm.

BACKGROUND Lower limb fractures with vascular injuries are associated with a high rate of secondary amputation. Reducing ischaemic time is vital for limb salvage. However, the optimal sequence of surgical management remains unclear. We aimed to review the literature to establish an evidence-based management algorithm. METHODS All identifiable English language or translated literature related to the surgical sequence of lower limb fractures with vascular injuries was reviewed. RESULTS A total of 101 cases described in 10 publications (median age: 31; range: 2.5-76) were suitable for analysis. The mean MESS was 4.2. The limb-salvage rate with an ischaemic time of less than 6h was 87%, falling to 61% when ischaemic time exceeded 6h. A preoperative angiography caused a significant delay. The rate of re-vascularisation within 6h improved from 46% (33 of 71) to 90% (27 of 30) with the use of a shunt (p=0.04), with a mean ischaemic time of 3.8h (+/-1.7h, 1 standard deviation (SD)) versus 7.6h (+/-3.8h, 1SD) in those re-vascularised using grafts (p<0.001). The amputation rate of 27% was reduced to 13% by using shunts. CONCLUSION Early recognition of vascular injury is vital. Formal angiograms are unnecessary and cause crucial delays. A vascular shunt can significantly reduce ischaemic time, enabling unhurried assessment of the feasibility of limb salvage, debridement of demonstrably non-viable tissue and safe skeletal fixation prior to definitive vascular and soft-tissue repair.

Low‐dose TNF augments fracture healing in normal and osteoporotic bone by up‐regulating the innate immune response

The mechanism by which trauma initiates healing remains unclear. Precise understanding of these events may define interventions for accelerating healing that could be translated to the clinical arena. We previously reported that addition of low‐dose recombinant human TNF (rhTNF) at the fracture site augmented fracture repair in a murine tibial fracture model. Here, we show that local rhTNF treatment is only effective when administered within 24 h of injury, when neutrophils are the major inflammatory cell infiltrate. Systemic administration of anti‐TNF impaired fracture healing. Addition of rhTNF enhanced neutrophil recruitment and promoted recruitment of monocytes through CCL2 production. Conversely, depletion of neutrophils or inhibition of the chemokine receptor CCR2 resulted in significantly impaired fracture healing. Fragility, or osteoporotic, fractures represent a major medical problem as they are associated with permanent disability and premature death. Using a murine model of fragility fractures, we found that local rhTNF treatment improved fracture healing during the early phase of repair. If translated clinically, this promotion of fracture healing would reduce the morbidity and mortality associated with delayed patient mobilization.

The ortho-plastic management of Gustilo grade IIIB fractures of the tibia in children: A systematic review of the literature

BACKGROUND The challenges of managing Gustilo IIIB tibial fractures in children are unique. A multi-disciplinary, evidence based approach is needed. We aimed to evaluate the evidence for the ortho-plastic management of Gustilo grade IIIB open tibial shaft fractures in children based on a review of all published data in order to rationalise the orthopaedic and plastic surgical approach to these complex injuries. METHOD A systematic review of the literature was performed. Gustilo grade IIIB tibial shaft fractures in pre-adolescent and adolescent children were identified and evaluated with regard to both the skeletal and soft tissue management, and the outcome. RESULTS Of 54 children with grade IIIB tibial fractures, a mean union time of 31 weeks included 33 weeks for 42 adolescents and 23 weeks for 12 pre-adolescents. Faster union time in pre-adolescents tended towards significance. Delayed union occurred in 22%, nonunion in 13%, mostly in adolescents. Two of 45 covered by vascularised flaps and 3 of 9 treated without flaps developed deep infection (p=0.028). There was no correlation between method of skeletal fixation and union time. CONCLUSION Gustilo IIIB tibial shaft fractures in pre-adolescents tended towards faster healing with fewer complications, irrespective of the method of skeletal fixation. In adolescents, healing times were similar to adults. Soft tissue closure without flaps was associated with deep infection in one-third of patients, requiring debridement and flap cover. Adequate debridement and flap cover is suggested in all cases, irrespective of age.

The microbiological basis for a revised antibiotic regimen in high-energy tibial fractures: preventing deep infections by nosocomial organisms.

BACKGROUND Deep surgical site infections (SSIs) complicate Gustilo IIIB tibial fractures in 8-13% of cases. Antibiotic prophylaxis typically covers environmental contaminants. However, nosocomial organisms are usually implicated in deep infection. We used the microbiological profile of infected Gustilo IIIB tibial fractures to define a new, dynamic prophylactic regimen which recognises the need for prophylaxis against nosocomial organisms at the time of definitive closure. METHODS The microbiological profiles of Gustilo IIIB tibial fractures presenting over a 2-year period from January 2006 to December 2007 were reviewed. The environmental contaminants were compared with the organisms isolated from deep SSIs and correlated with the prophylactic antibiotic regimen used. RESULTS Fifty-two patients were included. Nine developed a deep tissue infection. The pathogens implicated included resistant Enterococci, Pseudomonas, Enterobacter and MRSA. Standard antibiotic prophylaxis provided cover for these combinations in only one of nine cases. This would have improved to eight of nine cases with the use of teicoplanin and gentamicin, given as a one-time dose during definitive soft-tissue closure. Specimens taken from wound debridement were neither sensitive nor specific for the subsequent development of deep infection and did not predict the organisms responsible. CONCLUSIONS Following high-energy open fracture, a single prophylactic antibiotic regimen directed against environmental wound contaminants does not provide cover for the organisms responsible for deepest SSIs and may have depopulated the niche, promoting nosocomial contamination prior to definitive closure. We advocate a dynamic prophylactic strategy, tailoring a second wave of prophylaxis against nosocomial organisms at the time of definitive wound closure, and at the same time avoiding the potential complications of prolonged antibiotic use.

Bell’s palsy: a summary of current evidence and referral algorithm

Spontaneous idiopathic facial nerve (Bells) palsy leaves residual hemifacial weakness in 29% which is severe and disfiguring in over half of these cases. Acute medical management remains the best way to improve outcomes. Reconstructive surgery can improve long term disfigurement. However, acute and surgical options are time-dependent. As family practitioners see, on average, one case every 2 years, a summary of this condition based on common clinical questions may improve acute management and guide referral for those who need specialist input. We formulated a series of clinical questions likely to be of use to family practitioners on encountering this condition and sought evidence from the literature to answer them. The lifetime risk is 1 in 60, and is more common in pregnancy and diabetes mellitus. Patients often present with facial pain or paraesthesia, altered taste and intolerance to loud noise in addition to facial droop. It is probably caused by ischaemic compression of the facial nerve within the meatal segment of the facial canal probably as a result of viral inflammation. When given early, high dose corticosteroids can improve outcomes. Neither antiviral therapy nor other adjuvant therapies are supported by evidence. As the facial muscles remain viable re-innervation targets for up to 2 years, late referrals require more complex reconstructions. Early recognition, steroid therapy and early referral for facial reanimation (when the diagnosis is secure) are important features of good management when encountering these complex cases.

Why haematomas cause flap failure: an evidence-based paradigm.

BACKGROUND Haematomas compromise flaps in the absence of a pressure effect and pedicle thrombosis. While animal models confirmed the toxic effect of whole blood on adjacently sited random pattern flaps, our understanding of this phenomenon remains incomplete. Our aim was to identify mechanisms by which a subjacent haematoma leads to flap compromise to inform clinical practice. METHODS A literature review was conducted of all peer-reviewed publications relating haematoma to tissue compromise including free transferred tissue, vascularised flap models and brain injury. Clinical correlation was made with free vascularised flaps and rhytidectomy skin flaps. RESULTS Haematomas compromise around 2-4% of free tissue transfers and local flaps. We propose that several mechanisms are responsible. Cytokines, generated by platelet degradation, recruit neutrophils, releasing both reactive oxygen species and proteolytic enzymes. Reactive oxygen species (ROS), including superoxide (O(2)(-)) and hydroxyl (OH-) are also produced by ATP degradation, promoted by NAD+ sequestration. Additionally, the complement cascade is triggered by thrombin. Ferrous ions, freed by complement-mediated lysis of erythrocytes and degradation of haemoglobin also promote generation of ROS. Reactive oxygen species, complement and activated neutrophils cause endothelial cell disruption, leading to activation of pro-thrombotic mechanisms and small vessel occlusion, with consequent tissue ischaemia, which in turn generates further ROS. CONCLUSION Haematomas cause tissue injury by a complex sequence of inter-related biochemical and cellular processes merging on a common pathway of local tissue ischaemia which the overlying tissue is unable to regulate. Emergent evacuation of haematoma must be considered irrespective of envelope tension.

Spring-assisted Cranioplasty for the Correction of Nonsyndromic Scaphocephaly: A Quantitative Analysis of 100 Consecutive Cases

Background: Spring-assisted cranioplasty has been proposed as an alternative to total calvarial remodeling for sagittal craniosynostosis. Advantages include its minimally invasive nature, and reduced morbidity and hospital stay. Potential drawbacks include the need for a second procedure for removal and the lack of published long-term follow-up. The authors present a single-institution experience of 100 consecutive cases using a novel spring design. Methods: All patients treated at the authors’ institution between April of 2010 and September of 2014 were evaluated retrospectively. Patients with isolated nonsyndromic sagittal craniosynostosis were included. Data were collected for operative time, anesthetic time, hospital stay, transfusion requirement, and complications in addition to cephalic index preoperatively and at 1 day, 3 weeks, and 6 months postoperatively. Results: One hundred patients were included. Mean cephalic index was 68 preoperatively, 71 at day 1, and 72 at 3 weeks and 6 months postoperatively. Nine patients required transfusion. Two patients developed a cerebrospinal fluid leak requiring intervention. One patient required early removal of springs because of infection. One patient had a wound dehiscence over the spring and one patient sustained a venous infarct with hemiplegia. Five patients required further calvarial remodeling surgery. Conclusions: The authors’ modified spring design and protocol represents an effective strategy in the management of single-suture sagittal craniosynostosis with reduced total operative time and blood loss compared with alternative treatment strategies. In patients referred within the first 6 months of birth, this technique has become the authors’ procedure of choice. In a minority of cases, especially in the older age groups, further remodeling surgery is required. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Injectable Pore-Forming Hydrogel Scaffolds for Complex Wound Tissue Engineering: Designing and Controlling Their Porosity and Mechanical Properties.

Traumatic soft tissue wounds present a significant reconstructive challenge. The adoption of closed-circuit negative pressure wound therapy (NPWT) has enabled surgeons to temporize these wounds before reconstruction. Such systems use porous synthetic foam scaffolds as wound fillers at the interface between the negative pressure system and the wound bed. The idea of using a bespoke porous biomaterial that enhances wound healing, as filler for an NPWT system, is attractive as it circumvents concerns regarding reconstructive delay and the need for dressing changes that are features of the current systems. Porous foam biomaterials are mechanically robust and able to synthesize in situ. Hence, they exhibit potential to fulfill the niche for such a functionalized injectable material. Injectable scaffolds are currently in use for minimally invasive surgery, but the design parameters for large-volume expansive foams remain unclear. Potential platforms include hydrogel systems, (particularly superabsorbent, superporous, and nanocomposite systems), polyurethane-based moisture-cured foams, and high internal phase emulsion polymer systems. The aim of this review is to discuss the design parameters for such future biomaterials and review potential candidate materials for further research into this up and coming field.

Managing missed lower extremity compartment syndrome in the physiologically stable patient: A systematic review and lessons from a Level I trauma center.

BACKGROUND Decompressing an acute lower extremity compartment syndrome salvages muscle and nerve and preserves limb function. However, reperfusion of ischemic tissue causes a systemic insult that can be life threatening. Hence, the management of missed acute lower limb compartment syndrome remains controversial. The aim of this study was to evaluate the literature and, together with our own experience from a Level 1 trauma center, clarify the management of missed compartment syndrome in the physiologically stable patient. METHODS Pubmed, EMBASE, MEDLINE, the Cochrane database of systematic reviews and the Cochrane central register of controlled trials were searched. Studies were evaluated using the GRADE methodology. In addition, our trauma database was searched (2005 to May 2015) for additional cases, and a multidisciplinary case note review was conducted for all cases identified. This study was registered prospectively on the PROSPERO database (CRD42015026098). RESULTS Our systematic review yielded 9 studies, including one case-controlled study, 3 case series, and 5 case reports with a total of 57 patients and 64 limbs. Overall, study quality was “very low” with the exception of the case-controlled study, which was “low.” Delayed compartment decompression (6–120 hours) resulted in amputation rates of 5 of 24, 8 of 19, 4 of 5, and 2 of 3 limbs. Two patients died of complications associated with late compartment decompression. One compartment syndrome of the buttock was managed nonoperatively. Most surviving limbs exhibited functional deficits. Additionally, our experience comprised 10 cases. Of the six who underwent compartment decompression, the burden of subsequent morbidity included three amputations (one above knee), two complete foot drops, and one episode of severe sepsis. As this experience mirrored the poor outcomes reported in the literature, we managed the four most recent cases nonoperatively. All remain ambulant with incomplete foot drops or limb weakness. CONCLUSION Surgical decompression of missed acute lower limb compartment syndrome yields an early physiological insult and a high late-amputation rate. Managing selected cases nonoperatively may result in less early morbidity and yield superior long-term results, but the evidence remains sparse and of poor quality. LEVEL OF EVIDENCE Systematic review, level III.