Aligned nanofibrillar collagen scaffolds - Guiding lymphangiogenesis for treatment of acquired lymphedema.

Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

Otfrid Foerster (1873-1941)--self-taught neurosurgeon and innovator of reconstructive peripheral nerve surgery.

Otfrid Foerster (1873-1941) became a self-taught neurosurgeon during and after WW I, playing a critical role in the development of peripheral nerve reconstruction. Although best known for describing dermatomes, he published over 300 articles on the nervous system. Confronted by thousands of nerve injuries during WW I, as well as poor results and disinterest from his surgical colleagues, Foerster began performing neurolysis and tension-free nerve repairs himself under emergency conditions. He pioneered grafting motor nerve defects by expendable cutaneous nerves (e.g., sural) and performed intraplexal neurotizations and various nerve transfers, such as the pectoral, subscapular, long thoracic, and thoracodorsal nerves in brachial plexus injuries. Foerster championed rehabilitation, recognizing the potential of electrostimulation and physiotherapy to influence cortical reorganization (brain plasticity) and improve recovery after nerve injury. Foerster died from tuberculosis in 1941, leaving a rich reconstructive peripheral nerve legacy; his innovative and visionary spirit serves as a role model.

Burn-induced heart failure: lipopolysaccharide binding protein improves burn and endotoxin-induced cardiac contractility deficits.

BACKGROUND: Burn injury is frequently complicated by bacterial infection. Following burn injury, exposure to endotoxin produces a measurable decrease in cardiomyocyte sarcomere contractile function. Lipopolysaccharide-binding protein (LBP) is an acute phase protein that potentiates the recognition of lipopolysaccharide (LPS) by binding to the lipid A moiety of LPS. In this study, we sought to determine the effect of recombinant rat LBP (rLBP) on cardiomyocyte sarcomere function after burn or sham injury in the presence or absence of bacterial endotoxin. METHODS: Rats underwent a full-thickness 30% total body surface area scald or sham burn. At 24 h post-injury, cardiomyocytes were isolated, plated at 50,000 cells/well, and incubated with 50 µg/mL LPS and rLBP or chloramphenicol acetyltransferase (BVCat, an irrelevant control protein produced using the same expression system as rLBP) at concentrations by volume of 1%, 5%, 10%, and 30%. Subsets of cardiomyocytes were incubated with 5% rat serum or 30% rLBP and blocking experiments were conducted using an LBP-like synthetic peptide (LBPK95A). In vitro sarcomere function was measured using a variable rate video camera system with length detection software. RESULTS: Co-culture of burn and sham injury derived cardiomyocytes with high-dose rLBP in the presence of LPS resulted in a significant reduction to the functional impairment observed in peak sarcomere shortening following exposure to LPS alone. LBP-like peptide LBPK95A at a concentration of 20 µg/mL, in the presence of LPS, abolished the ability of 30% rLBP and 5% rat serum to restore peak sarcomere shortening of cardiomyocytes isolated following burn injury to levels of function exhibited in the absence of endotoxin exposure. CONCLUSIONS: In the setting of LPS challenge following burn injury, rLBP at high concentrations restores cardiomyocyte sarcomere contractile function in vitro. Rather than potentiating the recognition of LPS by the cellular LPS receptor complex, rLBP at high concentrations likely results in an inhibitory binding effect that minimizes the impact of endotoxin exposure on cardiomyocyte function following thermal injury.

Burn-induced organ dysfunction: vagus nerve stimulation improves cardiac function.

INTRODUCTION: Many studies have demonstrated the existence of an anti-inflammatory, parasympathetic pathway, termed as the inflammatory reflex. Burn-induced heart failure has been investigated in many previous studies. Proinflammatory cytokines, such as TNF-alpha, IL-1beta, and IL-6, have been shown to play a key pathogenetic role and vagus nerve stimulation attenuates proinflammatory cytokine production. This study was designed to evaluate postburn alterations of cardiac functional parameters after vagal electrostimulation. MATERIAL AND METHODS: A 30% total body surface area standardized, full-thickness rat burn model was used. Electric stimulation of the vagus nerve was performed. The following functional cardiac parameters were measured by ventricular microcatheterization: Maximal and minimal left ventricular pressure, mean left ventricular pressure, end-diastolic pressure (EDP), positive and negative pressure rise and fall (+/-dP/dt), cardiac contractility index, and assessment of the heart rate. RESULTS: Vagus nerve stimulation improved maximal and minimal left ventricular pressure values compared with burn-only animals. End-diastolic pressure was elevated significantly in stimulated animals; however, EDP values were comparable with those in sham-injured animals. Analyzing positive and negative pressure development, +/-dP/dt was restored to levels measured in sham-injured animals but not to control animal levels. No variations in heart rate were found. CONCLUSION: We as well as others have shown that inflammation after burn injury is a key pathogenetic element, and this study provides new evidence that cardiac function is also improved by vagus nerve stimulation. These results lead us to consider novel therapeutic options for the treatment of postburn cardiac dysfunction.

Burn-induced organ dysfunction: vagus nerve stimulation attenuates organ and serum cytokine levels.

INTRODUCTION: The interaction of the CNS and the immune system is well known. A parasympathetic anti-inflammatory pathway has recently been described. Both electrical and pharmacological parasympathetic stimulation attenuate proinflammatory mediator generation. Burn induces abacterial cytokine generation and we sought to evaluate whether parasympathetic stimulation after experimental burn decreases cardiodepressive mediator generation. MATERIAL AND METHODS: A 30% TBSA full-thickness rat burn model was used. After microsurgical preparation of the cervical portion of the vagus nerve, we performed electric vagus nerve stimulation. Serum was harvested and organ samples of heart and liver were homogenized. Samples were subjected to sandwich-ELISA specific for TNF-alpha, IL-1beta and IL-6. Heart rate measurements were done using left ventricular microcatheterization. Statistical analysis was done using Student's t-tests and analysis of variance (ANOVA). RESULTS: Burn induced a significant rise of TNF-alpha, IL-1beta and IL-6 in organ homogenates and serum. After cervical vagal electrostimulation, serum and organ homogenate levels of proinflammatory cytokines were markedly reduced compared to burn controls. Left ventricular microcatheter assessment demonstrated no cardiodepressive effect of the vagal stimulation itself. CONCLUSION: Our results encourage further research regarding the neuroimmunologic background of burn, possibly leading to the development of a novel therapeutic approach to burn-induced organ dysfunction and immunodysregulation.