No abstract

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 skinderived 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.

Intracapsular tonsillar reduction with an endoscopic microdebrider relieves OSDB as effectively as conventional tonsillectomy, but results in less postoperative pain and a more rapid recovery.

Significance Fibrosis, a hallmark of many clinical disorders, occurs because of uncontrolled myofibroblast activity. We studied Dupuytren's disease, a common hereditable fibrotic condition that causes the fingers to irreversibly curl toward the palm. We found that freshly isolated tissue from Dupuytren's patients contained macrophages and released proinflammatory protein mediators (cytokines). Of the cytokines, only TNF selectively converted normal fibroblasts from the palm of patients with Dupuytren's disease into myofibroblasts via activation of the Wnt signaling pathway. Conversely, blockade of TNF resulted in reversal of the myofibroblast phenotype. Therefore, TNF inhibition may prevent progression or recurrence of Dupuytren's disease.

SignificanceWhile stem cell therapy has become the standard of care for hematological disorders, challenges remain for the treatment of solid organ injuries. Targeting endogenous cells would overcome many hurdles associated with exogenous stem cell therapy. Alarmins are released upon tissue damage, and here we describe how upregulation of a physiological pathway by exogenous administration of a single dose of HMGB1, either locally or systemically, promotes tissue repair by targeting endogenous stem cells. We show that HMGB1 complexed with CXCL12 transitions stem cells that express CXCR4 from G0 to GAlert. These primed cells rapidly respond to appropriate activating factors released upon injury. HMGB1 promotes healing even if administered 2 wk before injury, thereby expanding its translational benefit for diverse clinical scenarios.

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.

Early vascularized soft tissue closure has long been recognized to be essential in achieving eventual infection free union. The question of whether muscle or fasciocutaneous tissue is superior in terms of promoting fracture healing remains unresolved. Here we review the experimental and clinical evidence for the different tissue types and advocate that the biological role of flaps should be included as a key consideration during flap selection.

We have consistently demonstrated that power-assisted adenoidectomy is precise, rapid, and safe.