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Dupuytren’s disease is a progressive fibroproliferative disorder of the hand. In the nodular stage of Dupuytren’s disease, pain might limit daily hand activities and progress to finger contractures. Focused electromagnetic high-energetic extracorporeal shockwave therapy (ESWT) may reduce pain in Dupuytren’s nodules (Tubiana N). In this prospective, randomized, blinded, placebo-controlled single center trial, we enrolled 52 patients (mean age, 58.2 ± 9.2) with painful nodular Dupuytren disease Tubiana N. Randomization was done to either (group A) 3 treatments with focused electromagnetic high-energetic ESWT (2000 shots, 3 Hz, 0.35 mmJ/mm2/hand, Storz Duolith SD1, n = 27) or (group B) placebo ESWT (2000 shots, 3 Hz, 0.01 mJ/mm2/hand, n = 25) in a weekly interval. Primary outcome was the level of pain on a visual analogue scale (VAS 0–10) at 3/6/12/18 months, secondary outcomes were patient-related outcome measures (DASH score, MHQ score, URAM scale), grip strength, patient’s satisfaction, and Dupuytren’s disease progression over 18 months follow-up. Focused ESWT significantly improved outcomes. Pain was reduced from 3.6 ± 1.8 to 1.9 ± 1.2 at three, to 1.4 ± 0.7 at six, to 1.7 ± 1.6 after 12 months and 1.9 ± 0.8 after 18 months in the intervention group (47% reduction, p p ClinicalTrials.gov Identifier: NCT01184586).

Introduction: Extracorporeal shock waves (ESWs) have been shown to have a positive effect on skin wound healing; however, little is known on the regeneration of the microcirculation and angiogenesis as well as the different application modes. Methods: A total of 40 BALB/c mice were provided with dorsal skin fold chambers and were divided into 3 therapy groups (n = 30) and one control group (n = 10). The 3 therapy groups were treated with shock waves at different pulse rates (500–1,000 pulses/min) and application frequencies (day 0 and day 6 or day 0 only). Photographic documentation and intravital microscopy were carried out on day 1, 2, 4, and 6 after wounding. Results: Using the newly developed Diver Box, shock waves could be applied in vivo without mechanical tissue damage. Shock wave therapy to skin wounds demonstrated to induce faster wound closure rates in the beginning than controls in groups with higher pulse rates and frequencies of the shock waves. Furthermore, the regeneration of microcirculation and perfusion in the healing skin was significantly improved after the application of, in particular, higher pulse rates as given by increased numbers of perfused capillaries and functional vessel density. The study of inflammation showed, especially in high-pulse ESW groups, higher leukocyte counts, and rolling leukocytes over time until day 6 as a response to the induction of inflammatory reaction after ESW application. Angiogenesis showed a marked increase in positive areas as given by sprouts, coils, and recruitments in all ESW groups, especially between days 4 and 6. Conclusion: The major findings of this trial demonstrate that ESW therapy to skin wounds is effective and safe. This is demonstrated by the initially faster wound closure rate, but later the same wound closure rate in the treatment groups than in controls. Furthermore, during the regeneration of microcirculation and perfusion in the healing skin, a significant improvement was observed after the application of, in particular, higher ESW pulse rates, suggesting an ESW-related increase in nutrient and oxygen supply in the wound tissue.

Zusammenfassung Hintergrund Das Facelift ist mittlerweile der vierthäufigste ästhetische Eingriff beim Mann. Die Gesichtsalterung verläuft bei Männern und Frauen sehr unterschiedlich. Somit werden individuelle Techniken angewendet, da ein einheitliches Konzept für die operative Gesichtsstraffung beim Mann bisher fehlt. Ziel der Studie ist es, ein genderspezifisches, speziell für Männer entwickeltes Facelift-Konzept zu evaluieren. Material und Methoden Frauen und Männer (je n = 10) wurden einem dreidimensionalen Gesichtsscan und einer anschließenden Simulation eines V-förmigen Liftvektors (Standardlift) und einem neuen Facelift-Konzept speziell für Männer in doppelter T-Form (Male Lift) unterzogen. In einer Online-Umfrage mit 262 Teilnehmern wurden sowohl die simulierten als auch die unveränderten Bilder präsentiert und die Attribute Männlichkeit, Weiblichkeit, Attraktivität und Jugendlichkeit abgefragt. Statistische Modelle wurden verwendet, um entsprechende Attribute der Straffungen sowie weitere Faktoren zu identifizieren und Unterschiede der Simulationen zu ermitteln. Ergebnisse Verjüngende Veränderungen im Gesicht sind generell mit einer deutlichen Verbesserung der Attribute Jugendlichkeit und Attraktivität im Vergleich zu unveränderten Kontrollgesichtern verbunden. Wie erwartet führt ein Male Lift zur Maskulinisierung, während ein Standardlift zur Feminisierung führt; unabhängig vom Geschlecht der Probanden. Das Male Lift zeigte höhere Werte für das Attribut Attraktivität bei männlichen, ebenso wie das Standardlift bei weiblichen Probanden. Das für Frauen entwickelte und somit für Frauen auch besser geeignete Standardlift ist mit einer deutlich höheren Wahrscheinlichkeit für das Attribut Jugendlichkeit verbunden, während dies beim neu eingeführten Male Lift-Konzept nicht so stark ausgeprägt beurteilt wird. Schlussfolgerung Das neue Facelift-Konzept für männliche Patienten ist signifikant mit den Merkmalen Männlichkeit und Attraktivität verbunden, während das für Frauen geeignete Standardlift mit deutlich höheren Bewertungen der Attribute Weiblichkeit und Jugendlichkeit einhergeht. Die Ergebnisse der SIMALIFT-Studie sind der erste Beweis für die Notwendigkeit einer differenzierteren, geschlechtsspezifischen Herangehensweise an ein Facelift.

Zusammenfassung Hintergrund Trotz Brandschutzmaßnahmen und Aufklärung erleiden ca. 0,5 Millionen Menschen pro Jahr in Deutschland Verbrennungen. Im Jahr 2018 mussten fast 2000 Schwerstbrandverletzte in deutschen Verbrennungszentren behandelt werden. Brandverletzungen stellen eine schwerwiegende Erkrankung mit hoher Mortalität und langfristigen Folgen für den Patienten dar. Methodik und Ergebnisse Ziel dieses Übersichtsartikels ist es, eine Zusammenfassung der derzeit gültigen Leitlinie zur Behandlung von Verbrennungen im Erwachsenenalter (https://www.awmf.org/leitlinien/detail/ll/044–001.html) zu präsentieren, wobei der Fokus auf folgenden Aspekten liegt: 1. der Akutbehandlung der Brandwunde am Unfallort, 2. der Entscheidungsfindung zur Verlegung in ein Brandverletztenzentrum, 3. der chirurgischen Wundversorgung mit Debridement und Hauttransplantation und 4. der Nachsorge. Die S2k-Leitlinie basiert auf aktueller Literatur und dem Konsens von 11 an der Behandlung Brandverletzter beteiligter Fachgesellschaften. Zusammenfassung Dieser Übersichtsartikel enthält gewichtete Empfehlungen zur Behandlung von Brandwunden erwachsener Patienten in Deutschland. Der Artikel soll Ärzten und medizinischem Personal in der Akutsituation vor Ort und in der Klinik die Entscheidung über die notwendige Behandlung erleichtern. Hiermit soll die Behandlungsqualität für Patienten verbessert werden.

Wounds and tissue defects of the hand and foot often lead to severe functional impairment of the affected extremity. Next to general principles of wound healing, special functional and anatomic considerations must be taken into account in the treatment of wounds in these anatomical regions to achieve a satisfactory reconstructive result. In this article, we outline the concept of wound healing and focus on the special aspects to be considered in wounds of the hand and foot. An overview of different treatment and dressing techniques is given with special emphasis on the reconstruction of damaged structures by plastic surgical means.

The literature reports many cases of cutaneous malignancy in the setting of skin tattoos. In this study, we review the reported incidence of and risk factors for tattoo-associated skin cancer. A PubMed literature review was performed for all cases of tattoo-associated skin cancer, including squamous cell carcinoma, basal cell carcinoma, malignant melanoma, keratoacanthoma, and other rare skin malignancies (source: PubMed/until June 2017). The authors identified 51 publications and 63 total cases of tattoo-associated skin cancer. We also report on a single new case of tattoo-associated skin cancer observed at one of our co-authors’ institutions. Among these 64 total cases, 58% were associated with black and blue inks and 34% were associated with red ink. Overall, while the strength of association remains unclear, the literature reports many cases of tattoo-associated skin cancer. Among these cases, black, blue, and red inks were particularly worrisome for their carcinogenic potential. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Objective:Oxytocin (OXY) has significant effects on mammalian behavior. Next to its role in lactation and social interactions, it is described to support better wound healing as well. However, direct OXY effects on wound healing and the regeneration of the microvascular network are still not clarified. We therefore examined the effects of OXY and an OXY receptor antagonist [atosiban (ATO)] on skin wound healing, focusing on epithelialization and neovascularization.Methods:Skin wound healing has been assessed using intravital fluorescence microscopy in a model of full dermal thickness wounds in the dorsal skin fold chamber of hairless mice. Animals received repetitive low or high doses of OXY or ATO. Morphological and cellular characterization of skin tissue repair was performed by histology and in vitro cell assays.Results:The assessment of skin tissue repair using this therapy regimen showed that OXY and ATO had no major influence on epithelialization, neovascularization, wound cellularity, or inflammation. Moreover, OXY and ATO did neither stimulate nor deteriorate keratinocyte or fibroblast migration and proliferation.Conclusion:In summary, this study is the first to demonstrate that OXY application does not impair skin wound healing or cell behavior. However, until now, the used transmitter system seems not to be clarified in detail, and it might be proposed that it is associated with the stress response of the organism to various stimuli.

Zusammenfassung Zielsetzung In Deutschland wird die Habilitation in der Humanmedizin und den Gesundheitswissenschaften von etwa 850 Kandidatinnen und Kandidaten jahrlich erfolgreich abgeschlossen. Demgegenuber steht eine nur begrenzte Anzahl akademischer Positionen. Zudem haben sich die Bildungs- und Gesellschaftsstrukturen in den letzten Jahren erheblich verandert, was die Bedeutung des spezifisch deutschen Qualifikationsnachweises infrage stellte. Ziel war es daher, ein aktuelles Meinungsbild der Mitglieder von medizinischen Habilitationskommissionen zu den Voraussetzungen, Verfahren und zur generellen Bedeutung der medizinischen Habilitation zu erfragen sowie potentielle Reformwunsche aus Sicht der Kommission selbst zu erfassen. Methodik Die Untersuchung wurde als online-Umfrage zu sozio-biographischen Merkmalen und zu subjektiven Einschatzungen bzgl. den Bedingungen, Stellenwert, Karrierewegen sowie Reformwunschen der Habilitation durchgefuhrt. Ergebnisse Die Umfrageteilnehmer schatzten den Stellenwert der Habilitation mit 71,3 % als uberwiegend hoch ein. In der medizinischen Auffassung der Humboldt-Trias (Forschung, Lehre, Krankenversorgung) wurden Forschung (94,3 %) und Lehre (89,7 %) als wichtigste Habilitationsvoraussetzungen bewertet. Auf die Frage der Motivation wurde daher auch von 91,0 % die Freude an der Forschung, mit 78,2 % die Freude an der Lehre und mit 65,5 % die besseren beruflichen Zukunftschancen angegeben. Eine Gleichstellung der Habilitation mit einem Ph.D. wird von den Befragten klar abgelehnt (58,6 %). Eine Abschaffung der Habilitation steht mehrheitlich auser Frage, jedoch bestehen klare Wunsche zur Reform, welche vorzugsweise interne Hurden wie die Abhangigkeit von Ordinarien und mehr Transparenz im Verfahren, aber auch die Forderung einer bundeseinheitlichen Habilitationsordnung betreffen. Schlussfolgerung Die medizinische Habilitation hat trotz kontroverser Diskussionen nach Ansicht der Habilitationskommissionen noch immer ihre Bedeutung und wird trotz einiger Kritikpunkte als zeitgemas eingestuft. Es bestehen jedoch klare Hinweise zur Reform, welche sowohl lokaler, nationaler und internationaler Erneuerungen bedurfen, um eine Chancengleichheit der Kandidaten herzustellen und damit entsprechende Karriereoptionen zu eroffnen.

Background: In response to tissue damage, angiogenesis is an extremely dynamic process that is finely regulated by signals from cells, the surrounding extracellular matrix (ECM), and derived mediators. As the only process, angiogenesis remains of decisive importance in the context of the entire wound healing process and is subject to constant change. The dissolution of the endothelial basement membrane, the migration of endothelial cells, and the development of new capillary vessels during wound healing depend not only on the cells and cytokines present, but also on the production and organization of ECM components in the immediate wound. Summary: Angiogenesis in wound healing can be divided into two main phases. During the pro-angiogenic phase at the beginning of wound healing, excessive neo-formation of blood vessels, some of which are poorly differentiated, occurs, which restore blood flow and thus nutritive perfusion as quickly as possible. This is followed by an anti-angiogenic phase in which the initially established vascular network undergoes a maturing process, which, however, is accompanied by a significant reduction in the number of vessels. Key Messages: Although many mechanisms and specific cell functions in wound healing have already been described, many underlying pathophysiological processes remain unknown. Because angiogenesis and its maturation is a very fast but also very long-lasting process, the understanding of the underlying mechanisms is of crucial importance. This article will give an overview of the current understanding and controversy in this sub-step of wound healing.

Background Extracorporeal shock wave treatment (ESWT) has proven its clinical benefits in different fields of medicine. Tissue regeneration and healing is improved after shock wave treatment. Even in the case of burn wounds angiogenesis and re-epithelialization is accelerated, but ESWT in extensive burn wounds is impracticable. Hypothesis High energy ESWT influences cutaneous microcirculation at body regions remote from application site. Methods Eighteen Sprague Dawley rats were randomly assigned to two groups and received either high energy ESWT (Group A: total 1000 impulses, 10 J) or placebo shock wave treatment (Group B: 0 impulses, 0 J), applied to the dorsal lower leg of the hind limb. Ten minutes later microcirculatory effects were assessed at the contralateral lower leg of the hind limb (remote body region) by combined Laser-Doppler-Imaging and Photospectrometry. Results In Group A cutaneous capillary blood velocity was significantly increased by 152.8% vs. placebo ESWT at the remote body location (p = 0.01). Postcapillary venous filling pressure remained statistically unchanged (p > 0.05), while cutaneous tissue oxygen saturation increased by 12.7% in Group A (p = 0.220). Conclusion High energy ESWT affects cutaneous hemodynamics in body regions remote from application site in a standard rat model. The results of this preliminary study indicate that ESWT might be beneficial even in disseminated and extensive burn wounds by remote shock wave effects and should therefore be subject to further scientific evaluation.

A 46-year-old man presented with clinical signs of nerve compression syndrome of his right ulnar nerve as confirmed by nerve conduction studies. Unexpectedly, clinical examination and magnetic resonance imaging (MRI) revealed a subcutaneous tumor of 5×2 cm above the ulnar groove. Surgical exploration and histopathology of biopsies demonstrated the nerve distended and entrapped into an eosinophilic, inflammatory tissue. This rare condition is consistent with localized eosinophilic fasciitis, with no systemic manifestations. There are reports of isolated forearm versions of the disease. However, none occurred with the entrapment of a peripheral nerve appearing as a peripheral nerve tumor, yet. Consequentially, the presented patient would not have benefitted from further surgical neurolysis or tumor debulking, as eosinophilic fasciitis is an inflammatory and systemic disease. The patient’s symptoms decreased spontaneously after 4 weeks of postsurgical treatment, including nonsteroidal anti-inflammatory drugs (NSAIDs). Altogether, this case proved the necessity to regard even rare diseases as a potential cause of entrapment of peripheral nerves. This should lead surgeons to critical, differential diagnostic thinking and suggest that systemic diseases may be encountered during surgery due to their capability to mimic peripheral nerve tumors.

Introduction. Acellular dermal matrices (ADMs) are now commonly used for breast reconstruction surgery. There are various products available: ADMs derived from human (HADM), porcine (PADM), or bovine (BADM) sources. Detailed long-term follow-up studies are necessary to detect differences in complication rates between these products. Material and Methods. From 2010 to 2015, forty-one patients underwent 52 ADM-breast reconstructions in our clinic, including oncologic breast reconstructions and breast augmentation revisions (n=52). 15x HADMs (Epiflex®/DIZG), 21x PADMs (Strattice®/LifeCell), and 16x BADMs (Tutomesh®/RTI Surgical) were implanted. Retrospective data collection with median follow-up of 36 months (range: 12–54 months) was performed. Results. Overall complication rate was 17% after ADM implantation (HADM: 7%; PADM: 14%; BADM: 31%). In a composite endpoint of complications and Red Breast Syndrome, a lower event probability was observed between BADMs, PADMs, and HADMs (44%, 19%, and 7%, resp.; p=0.01 for the trend). Furthermore, capsular contracture occurred in 6%, more frequently as compared to the current literature. Conclusions. When ADM-based reconstruction is indicated, the authors suggest primarily the use of HADMs and secondary the use of PADMs. It is shown that BADMs have the highest complication probability within our patient cohort; nevertheless, BADMs convey physical advantages in terms of flexibility and better aesthetic outcomes. The indication for the use of ADMs should be filled for each case individually.

The most common complication after implantation of foreign material is infection, leading to implant failure and severe patient discomfort. Smoldering-infections proceed inapparently and might not get verified by radiological diagnostics. Early identification of this type of infection might significantly reduce the rate of complications. Therefore, we manufactured a microsensor strip in a hybrid of thin-film and laminate technology in a wafer-level process. It comprises electrochemical, amperometric microsensors for glucose, oxygen and lactate as well as an integrated reference electrode. Microsensors have been implanted in the mouse dorsal skin fold chamber, which got inoculated with a human-pathogen bacterial strain. A selective signal could be measured for all parameters and time points. The infection led to measurable changes of the wound environment as given by a decrease of the oxygen- as well as the glucose-concentration while the lactate concentration increased markedly over time. The given results in this study are the first hints on a promising new tool and should therefore be interpreted as a proof of the principle to show the functionality of the microsensors in an in vivo setting. These microsensors could be used to monitor smoldering infections of implantable foreign materials reducing foreign implant associated complications.

Background: The integrity of healthy skin plays a crucial role in maintaining physiological homeostasis of the human body. The skin is the largest organ system of the body. As such, it plays pivotal roles in the protection against mechanical forces and infections, fluid imbalance, and thermal dysregulation. At the same time, it allows for flexibility to enable joint function in some areas of the body and more rigid fixation to hinder shifting of the palm or foot sole. Many instances lead to inadequate wound healing which necessitates medical intervention. Chronic conditions such as diabetes mellitus or peripheral vascular disease can lead to impaired wound healing. Acute trauma such as degloving or large-scale thermal injuries are followed by a loss of skin organ function rendering the organism vulnerable to infections, thermal dysregulation, and fluid loss. Methods: For this update article, we have reviewed the actual literature on skin wound healing purposes focusing on the main phases of wound healing, i.e., inflammation, proliferation, epithelialization, angiogenesis, remodeling, and scarring. Results: The reader will get briefed on new insights and up-to-date concepts in skin wound healing. The macrophage as a key player in the inflammatory phase will be highlighted. During the epithelialization process, we will present the different concepts of how the wound will get closed, e.g., leapfrogging, lamellipodial crawling, shuffling, and the stem cell niche. The neovascularization represents an essential component in wound healing due to its fundamental impact from the very beginning after skin injury until the end of the wound remodeling. Here, the distinct pattern of the neovascularization process and the special new functions of the pericyte will be underscored. At the end, this update will present 3 topics of high interest in skin wound healing issues, dealing with scarring, tissue engineering, and plasma application. Conclusion: Although wound healing mechanisms and specific cell functions in wound repair have been delineated in part, many underlying pathophysiological processes are still unknown. The purpose of the following update on skin wound healing is to focus on the different phases and to brief the reader on the current knowledge and new insights. Skin wound healing is a complex process, which is dependent on many cell types and mediators interacting in a highly sophisticated temporal sequence. Although some interactions during the healing process are crucial, redundancy is high and other cells or mediators can adopt functions or signaling without major complications.

Erythropoietin (EPO) is the main regulator of red blood cell production but there exists also a variety of nonhematopoietic properties. More recent data show that EPO is also associated with the protection of tissues suffering from ischemia and reperfusion injury as well as with improved regeneration in various organ systems, in particular the skin. This review highlights the mechanisms of EPO in the different stages of wound healing and the reparative processes in the skin emphasizing pathophysiological mechanisms and potential clinical applications. There is clear evidence that EPO effectively influences all wound-healing phases in a dose-dependent manner. This includes inflammation, tissue, and blood vessel formation as well as the remodeling of the wound. The molecular mechanism is predominantly based on an increased expression of the endothelial and inducible nitric oxide (NO) synthase with a consecutive rapid supply of NO as well as an increased content of vascular endothelial growth factor (VEGF) in the wound. The improved understanding of the functions and regulatory mechanisms of EPO in the context of wound-healing problems and ischemia/reperfusion injury, especially during flap surgery, may lead to new considerations of this growth hormone for its regular clinical application in patients.

Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO-mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n= 11–14, P< 0.05) and decreased right ventricular wall stress (n= 8, P< 0.05) assessed by pressure-volume loops after 6 weeks. MI-EPO hearts exhibited smaller infarction size (20.1 ± 1.1%versus 27.8 ± 1.2%; n= 6–8, P< 0.001) and greater capillary density (338.5 ± 14.7 versus 259.8 ± 9.2 vessels per mm; n= 6–8, P< 0.001) than MIC hearts. Direct EPO injection reduced post-MI myocardial apoptosis by approximately 41% (0.27 ± 0.03%versus 0.42 ± 0.03%; n= 6, P= 0.005). The chemoattractant SDF-1 was up-regulated significantly assessed by quantitative realtime PCR and immunohistology. c-Kit+ and CD34+ stem cells were significantly more numerous in MI-EPO than in MIC at 24 hrs in peripheral blood (n= 7, P< 0.05) and 48 hrs in the infarcted hearts (n= 6, P< 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI-EPO hearts (n= 7, P< 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c-Kit+ and CD34+ stem cells via the enhanced expression of chemoattractant SDF-1.

The hematopoietic growth factor erythropoietin (EPO) attracts attention due to its all-tissue-protective pleiotropic properties. We studied the effect of EPO on dermal regeneration using intravital microscopy in a model of full dermal thickness wounds in the skin-fold chamber of hairless mice. Animals received repetitive low doses or high doses of EPO (RLD-EPO or RHD-EPO) or a single high dose of EPO (SHD-EPO). SHD-EPO accelerated wound epithelialization, reduced wound cellularity, and induced maturation of newly formed microvascular networks. In contrast, RHD-EPO impaired the healing process, as indicated by delayed epithelialization, high wound cellularity, and lack of maturation of microvascular networks. Also, RHD-EPO caused an excessive erythrocyte mass and rheological malfunction, further deteriorating vessel and tissue maturation. Moreover, RHD-EPO altered fibroblast and keratinocyte migration in vitro, while both cell types exposed to RLD-EPO, and, in particular, to SHD-EPO showed accelerated wound scratch closure. In summary, our data show that a single application of a high dose of EPO accelerates and improves skin wound healing.

The KyberSept trial in septic patients showed that antithrombin (AT) reduced 90-day mortality significantly in a subgroup of patients not receiving concomitant heparin for thrombosis prophylaxis. Microvascular thrombosis is a key pathophysiologic mechanism during sepsis, ischemia/reperfusion and disseminated intravascular coagulation (DIC). Therefore, this study investigated the antithrombotic property of AT as potential monotherapy in an experimental endotoxemia model in order to omit concomitant heparin.Using a light/dye injury model in the ear and the cremaster muscle preparation of mice, we quantitatively assessed microvascular thrombus formation in a total of 30 endotoxemic mice by means of intravital fluorescence microscopy. Before thrombus induction animals received a single i.v. bolus of AT (100 or 250 IU/kg), heparin (100 IU/kg) or saline (NaCl).In NaCl-treated endotoxemic animals, light/dye exposure led to complete thrombotic occlusion in arterioles and venules within450 s in the ear model. Heparin delayed thrombotic vessel occlusion by more than 50%. AT significantly prolonged times until thrombotic vessel occlusion in a dose-dependent manner and more effectively than heparin (p0.05 vs. NaCl and heparin). This anti-coagulative effect of AT was especially pronounced in arterioles. Upon light/dye exposure to cremaster muscle preparations in endotoxemic mice AT also caused a 4-fold delay in microvascular thrombus growth with 827+/-77 s until complete thrombotic occlusion.We could characterize for the first time AT-mediated antithrombotic activity during endotoxemia in two models of phototoxicity-induced microvascular thrombosis. Our results clearly demonstrate an additional AT mechanism of action that may be responsible for beneficial effects observed during endotoxemia and DIC. This AT profile may allow future high-dose AT application without giving heparin for thrombosis prophylaxis, an intriguing strategy that is to be tested under clinical conditions.

Elucidation of the precise mechanisms and therapeutic options of extracorporeal shock wave therapy (ESWT) is only at the beginning. Although immediate real-time effects of ESWT on cutaneous hemodynamics have recently been described, the dose response to different ESWT energies in cutaneous microcirculation has never been examined. Thirty-nine Sprague-Dawley rats were randomly assigned to three groups that received either focused high-energy shock waves (group A: total of 1000 impulses, 10 J) to the lower leg of the hind limb, focused low-energy shock waves (group B: total of 300 impulses, 1 J) or placebo shock wave treatment (group C: 0 impulses, 0 J) using a multimodality shock wave delivery system (Duolith SD-1 T-Top, Storz Medical, Tagerwilen, Switzerland). Immediate microcirculatory effects were assessed with the O2C (oxygen to see) system (LEA Medizintechnik, Giessen, Germany) before and for 20 min after application of ESWT. Cutaneous tissue oxygen saturation increased significantly higher after high-energy ESWT than after low-energy and placebo ESWT (A: 29.4% vs. B: 17.3% vs. C: 3.3%; p = 0.003). Capillary blood velocity was significantly higher after high-energy ESWT and lower after low-energy ESWT versus placebo ESWT (group A: 17.8% vs. group B: -22.1% vs. group C: -5.0%, p = 0.045). Post-capillary venous filling pressure was significantly enhanced in the high-energy ESWT group in contrast to the low-energy ESWT and placebo groups (group A: 25% vs. group B: 2% vs. group C: -4%, p = 0.001). Both high-energy and low-energy ESWT affect cutaneous hemodynamics in a standard rat model. High-energy ESWT significantly increases parameters of cutaneous microcirculation immediately after application, resulting in higher tissue oxygen saturation, venous filling pressure and blood velocity, which suggests higher tissue perfusion with enhanced oxygen saturation, in contrast to low-energy as well as placebo ESWT. Low-energy ESWT also increased tissue oxygen saturation, albeit to a lower extent, and decreases both blood velocity and venous filling pressure. Low-energy ESWT reduced tissue perfusion, but improved oxygen saturation immediately after the application.

Purpose Microvascular thrombosis during septic conditions is of essential clinical relevance, but the pathomechanisms are not yet completely understood. The purpose of this study was to study the distinguished differentiation of the interactions of inflammation and coagulation using antithrombin (AT), a mediator of anticoagulation and anti-inflammation. Methods Using a thrombosis model in a cremaster muscle preparation of male C57Bl/6J mice (n = 83), we quantitatively assessed microvascular thrombus formation by using intravital fluorescence microscopy. Experimental groups consisted of animals treated with AT or with tryptophan49-blocked AT (TrypAT), which exerts only anticoagulant but no anti-inflammatory effects. To further see whether endothelial glycosaminoglycan (GAG) binding with consecutive prostacyclin (PGI2) release is mandatory for the anticoagulant process of AT, animals were administered heparin or indomethacin either alone or in combination with AT. Results The antithrombotic capacity of AT significantly differs in the experimental groups in which anti-inflammation was antagonized. This is given by the significantly prolonged occlusion times (p

SummaryA recently published post-hoc analysis of a trial using high-dose antithrombin (AT) in septic patients (KyberSept) revealed significant reduction of lethality when no concomitant heparin was administered, whereas patients with the combination of heparin and AT did not benefit in terms of survival. Therefore, it seems feasible to study the capability of AT in prevention of microvascular thrombus formation to avoid concomitant application of heparin and AT. Using fluorescence microscopy and a light/dyeinjury mouse ear model, the kinetics of thrombus formation were analyzed quantitatively in vivo upon single iv bolus of saline (control), heparin (100 IU/kg), hirudin (1 mg/kg) or AT (25, 50, 100 or 250 IU/kg) (N=7 animals per group each). In controls, light/dye-injury induced complete thrombotic occlusion in all arterioles and venules studied. Heparin and hirudin prevented thrombotic vessel occlusion in 62% and 43% of arterioles and 11% and 28% of venules. AT-250 was found to be more effective than heparin and hirudin, because thrombus formation was completely banned in all arterioles and venules. AT-100 and AT-50 were also capable of significantly blocking thrombus formation in both arterioles and venules. In blood vessels, which finally clogged, the time for development of complete vessel occlusion was delayed after heparin, hirudin and AT-25, but in particular after AT-50 and AT-100. In conclusion, AT-mediated antithrombotic activity has been characterized in a model of phototoxicity-induced microvascular thrombosis formation, demonstrating thatAT delays and prevents thrombus formation in arterioles and venules at least comparably effective as heparin and hirudin.

Background. ESWT has proven clinical benefit in dermatology and plastic surgery. It promotes wound healing and improves tissue regeneration, connective tissue disorders, and inflammatory skin diseases. However, a single treatment session or long intervals between sessions may reduce the therapeutic effect. The present study investigated the effects of fractionated repetitive treatment in skin microcirculation.Methods. 32 rats were randomly assigned to two groups and received either fractionated repetitive high-energy ESWT every ten minutes or placebo shock wave treatment, applied to the dorsal lower leg. Microcirculatory effects were continuously assessed by combined laser Doppler imaging and photospectrometry.Results. In experimental group, cutaneous tissue oxygen saturation was increased 1 minute after the first application and until the end of the measuring period at 80 minutes after the second treatment(P<0.05). The third ESWT application boosted the effect to its highest extent. Cutaneous capillary blood flow showed a significant increase after the second application which was sustained for 20 minutes after the third application(P<0.05). Placebo group showed no statistically significant differences.Conclusions. Fractionated repetitive extracorporeal shock wave therapy (frESWT) boosts and prolongs the effects on cutaneous hemodynamics. The results indicate that frESWT may provide greater benefits in the treatment of distinct soft tissue disorders compared with single-session ESWT.

Background: Although the etiology of capsular contracture after breast augmentation has not yet been definitively clarified, the literature contains numerous reports placing the blame on a foreign body reaction. We have developed a procedure for covalently activating a silicone surface with an anti-Fas antibody, which might suppress the foreign body reaction on the silicone surface. Objectives: The authors evaluate whether surrounding tissue might be influenced by anti-Fas antibody coating on silicone disks in comparison to untreated silicone disks in an in vivo model. Methods: During this study, 4-mm anti–Fas-coated silicone disks were implanted subcutaneously in the paravertebral region of mice (C57/BL6). Silicone disks passing the activation coating process without anti-Fas antibody incubation were defined as the control group. Twelve weeks after implantation, the disks were removed and the surrounding tissue examined. Results: The tissue surrounding the silicone disks in the experimental group showed significantly increased levels of collagen type 3, elevated levels of matrix metalloproteinase 9, markedly decreased levels of transforming growth factor β2, and a reduced CD68 expression in the pericapsular tissue. Conclusions: The first in vivo data reveal that the tissue surrounding a silicone surface can be influenced by the vectored binding of an anti-Fas antibody.

The most common implanted material in the human body consists of silicone. Breast augmentation and breast reconstruction using silicone-based implants are procedures frequently performed by reconstructive and aesthetic surgeons. A main complication of this procedure continues to be the development of capsular contracture (CC), displaying the result of a fibrotic foreign body reaction after the implantation of silicone. For many years, experimental and clinical trials have attempted to analyze the problem of its etiology, treatment, and prophylaxis. Different theories of CC formation are known; however, the reason why different individuals develop CC in days or a month, or only after years, is unknown. Therefore, we hypothesize that CC formation, might primarily be induced by immunological mechanisms along with other reasons. This article attempts to review CC formation, with special attention paid to immunological and inflammatory reasons, as well as actual prophylactic strategies. In this context, the word "biocompatibility" has been frequently used to describe the overall biological innocuousness of silicone in the respective studies, although without clear-cut definitions of this important feature. We have therefore developed a new five-point scale with distinct key points of biocompatibility. Hence, this article might provide the basis for ongoing discussion in this field to reduce single-publication definitions as well as increase the understanding of biocompatibility.

Background Local cold therapy for burns is generally recommended to relief pain and limit tissue damage, however, there is limited data of its physiological benefit. This study aimed to evaluate pathophysiological effects of cold therapy in superficial burn on microcirculation, edema formation, and histomorphology. Methods In 12 volunteers (8f, 4m; aged 30.4 ± 14.1 years) circumscribed superficial burn was induced on both hand back and either left untreated as control (control-group) or treated by local-cold-application (cold-treatment-group). Prior to burn (t0), immediately (t1), 15 min (t2), and 30 min (t3) following cold therapy, following parameter was evaluated using intravital-microscopy; epidermal-thickness (ET), granular-cell-size (GCS), individual-blood-cell-flow (IBCF), and functional-capillary-density (FCD). Results Both ET and GCS increased significantly more in control-group and slightly in cold-treatment-group in t1, while turns to insignificant t2 onwards. IBCF and FCD raised up in control-group compared to dramatically decrease in cold-treatment-group in t1. In t2 both parameter remains in control-group and increased in cold-treatment-group. Comparison of both groups for IBCF and FCD indicates significant difference in t1 and t2, however, insignificant in t0 and t3. Conclusions Microcirculation, edema formation, and histomorphology of superficial burn has been significantly influenced through immediate cold therapy, however, this alterations are transient and turns to ineffective after 30 min.

The most genuine interest in plastic surgery with all its subcategories is the correction or restoration of body form and function. For this, plastic surgery is based on a myriad of different techniques that are uniquely associated with this area of expertise but also originate from other medical specialties. Because plastic and reconstructive surgery is one of the most interdisciplinary medical specialties, it makes it necessary for the reconstructive surgeon to keep up to date with new techniques, but also to refine and critically appraise the currently available methods. The restoration of complex soft-tissue injuries combined with severe closed or open fractures resulting from severe trauma poses a significant clinical challenge. These injuries are often associated with significant clinical complications including wound infection, soft-tissue loss, compartment syndrome, non-union fractures, pain, stiffness, protracted course of treatment, joint contracture, osteomyelitis, chronic pain syndromes, and amputation of the respective extremity. A solid and cooperative team approach is indispensable to obtain initial tissue integrity as well as the respective organ function of the patient based on the complexity of the respective injury, complications which may arise, as well as the diversity of treatment options.

Introduction Hydrogen sulfide (H 2 S) known as a gasotransmitter is increasingly recognized for its anti-adhesive, anti-inflammatory and vasoactive properties. Due to these properties, we analysed anti-thrombotic effects of H 2 S and the participation of the nitric oxide synthase (NOS)-pathway. Materials and Methods In individual venules of the ear of hairless SKH1-hr mice, thrombus formation was induced using a phototoxic light/dye-injury model and intravital fluorescence microscopy. Animals were treated intravenously with the H 2 S donor Na 2 S or NaCl as control. In a second setting, the NOS inhibitor L-NAME was applied intraperitoneally as a bolus 12 h prior to Na 2 S treatment and thrombus induction. Blood and ear tissue were sampled after microscopy for assessment of plasma concentrations of soluble (s)P-selectin, sE-selectin, sVCAM-1 and sICAM-1 and expression of endothelial (e)NOS and inducible (i)NOS, respectively. Results When mice were treated with Na 2 S, venular thrombus formation was significantly delayed versus that in animals of the NaCl-treated control group. While plasma levels of pro-thrombotic adhesion molecules were not affected by Na 2 S, immunohistochemistry of the vessel walls showed a significant up-regulation of eNOS and iNOS expression within the Na 2 S-treated group. The delay of thrombus formation in the Na 2 S-group was partly but significantly reverted by application of L-NAME. Conclusions The anti-thrombotic efficacy of H 2 S involves the NOS-pathway and may be of preventive and therapeutic value for clinical disorders with increased risk of thrombotic events.

This study assessed the concept of whether delivery of magnetic nanobeads (MNBs)/adenoviral vectors (Ad)-encoded hVEGF gene (Ad(hVEGF)) could regenerate ischaemically damaged hearts in a rat acute myocardial infarction model under the control of an external magnetic field. Adenoviral vectors were conjugated to MNBs with the Sulfo-NHS-LC-Biotin linker. In vitro transduction efficacy of MNBs/Ad-encoded luciferase gene (Ad(luc)) was compared with Ad(luc) alone in human umbilical vein endothelial cells (HUVECs) under magnetic field stimulation. In vivo, in a rat acute myocardial infarction (AMI) model, MNBs/Ad(hVEGF) complexes were injected intravenously and an epicardial magnet was employed to attract the circulating MNBs/Ad(hVEGF) complexes. In vitro, compared with Ad(luc) alone, MNBs/Ad(luc) complexes had a 50-fold higher transduction efficiency under the magnetic field. In vivo, epicardial magnet effectively attracted MNBs/Ad(hVEGF) complexes and resulted in strong therapeutic gene expression in the ischemic zone of the infarcted heart. When compared to other MI-treated groups, the MI-M(+)/Ad(hVEGF) group significantly improved left ventricular function (p

The therapy of extensive and deep burn wounds is still a challenging task for reconstructive plastic surgery. The outcome is generally not satisfactory, neither from the functional nor from the aesthetic aspect. Several available skin substitutes are used but there is need for optimization of new skin substitutes which have to be tested in vitro as well as in vivo . Here, we show that the dorsal skin fold chamber preparation of mice is well suited for the testing of skin substitutes in vivo . Dermal skin constructs consisting of matriderm ® covered with a collagen type I gel were inserted into full thickness skin wounds in the skin fold chambers. The skin substitutes integrated well into the adjacent skin and got epithelialized from the wound edges within 11 days. The epithelialization by keratinocytes is the prerequisite that also cell-free dermal substitutes might be used in the case of the lack of sufficient areas to gain split thickness skin grafts. Further advantage of the chambers is the lack of wound contraction, which is common but undesired in rodent wound healing. Furthermore, this model allows a sophisticated histological as well as immunohistochemical analysis. As such, we conclude that this model is well suited for the analysis of tissue engineered skin constructs. Besides epithelialization the mode and extend of neovascularization and contraction of artificial grafts may be studied under standardized conditions.

The possible different therapeutic efficacy of human mesenchymal stem cells (hMSC) derived from umbilical cord blood (CB), adipose tissue (AT) or bone marrow (BM) for the treatment of myocardial infarction (MI) remains unexplored. This study was to assess the regenerative potential of hMSC from different origins and to evaluate the role of CD105 in cardiac regeneration. Male SCID mice underwent LAD-ligation and received the respective cell type (400.000/per animal) intramyocardially. Six weeks post infarction, cardiac catheterization showed significant preservation of left ventricular functions in BM and CD105(+)-CB treated groups compared to CB and nontreated MI group (MI-C). Cell survival analyzed by quantitative real time PCR for human GAPDH and capillary density measured by immunostaining showed consistent results. Furthermore, cardiac remodeling can be significantly attenuated by BM-hMSC compared to MI-C. Under hypoxic conditions in vitro, remarkably increased extracellular acidification and apoptosis has been detected from CB-hMSC compared to BM and CD105 purified CB-derived hMSC. Our findings suggests that hMSC originating from different sources showed a different healing performance in cardiac regeneration and CD105(+) hMSC exhibited a favorable survival pattern in infarcted hearts, which translates into a more robust preservation of cardiac function.

Einleitung: Hauptprobleme des Tissue Engineerings von komplexen Gewebestrukturen liegen in den nur eingeschränkten Möglichkeiten, Zellen dreidimensional in einer Matrix anzuordnen, den erwünschten Zelltyp in einem hohen Reinheitsgrad zu platzieren und in der nur unzureichenden Versorgung[for full text, please go to the a.m. URL], 127. Kongress der Deutschen Gesellschaft für Chirurgie

Laser printing based on laser-induced forward transfer (LIFT) is a new biofabrication technique for the arrangement of biological materials or living cells in well-defined patterns. In the current study, skin cell lines (fibroblasts/keratinocytes) and human mesenchymal stem cells (hMSC) were chosen for laser printing experiments due to their high potential in regeneration of human skin and new application possibilities of stem cell therapy. To evaluate the influence of LIFT on the cells, their survival rate, their proliferation and apoptotic activity, and the DNA damages and modifications of their cell surface markers were assessed and statistically evaluated over several days. The cells survived the transfer procedure with a rate of 98% +/- 1% standard error of the mean (skin cells) and 90% +/- 10% (hMSC), respectively. All used cell types maintain their ability to proliferate after LIFT. Further, skin cells and hMSC did not show an increase of apoptosis or DNA fragmentation. In addition, the hMSC keep their phenotype as proven by fluorescence activated cell sorting (FACS) analysis. This study demonstrates LIFT as a suitable technique for unharmed computer-controlled positioning of different cell types and a promising tool for future applications in the ex vivo generation of tissue replacements.

Autoimmune pancreatitis (AIP) is a rare cause of chronic pancreatitis and mimics pancreatic cancer. Although there is strong interest in research, etiology and pathophysiology of AIP are still unknown. Therefore, we analyzed a total of 92 MRL/Mp-mice of either sex, which are prone to develop AIP, in four different age groups (8–12, 16–20, 24–28, and 32–40 wk). Using intravital fluorescence microscopy, histology, laboratory analysis, and Western blot, onset, severity, and pathophysiological mechanisms of AIP were evaluated. Female animals showed in vivo an age-dependent increase of intrapancreatic leukocyte accumulation, as well as a loss in functional capillary perfusion. In contrast, intrapancreatic inflammation in male mice was less pronounced and not age dependent. Furthermore, pancreatic tissue specimen of female animals exhibited major organ destruction with significantly higher values of mean pathological scores (1.5 ± 0.3 vs. ≤0.2; P < 0.05), as well as significantly increased CD4-, CD8-, CD11b-, and CD138-positive cells compared with male animals of the same age. Interestingly, there was a significant positive correlation between intravascular leukocyte adherence and the histopathological score of the pancreas, indicating a determining role of the innate immune system for the late onset of AIP. The present study shows that the onset of AIP is characterized by an inflammatory response and microcirculatory failure, most probably constituting initiators and propagators of this autoimmune disease.

In skin wound healing apoptosis is an essential prerequisite. Erythropoietin (EPO) is reported to improve skin wound healing and to stimulate angiogenesis, however, exerts anti-apoptotic properties which could interfere with the dermal regeneration process. Therefore, the present study re-evaluates the impact of EPO on skin wound healing. In a new in vivo model of dermal wound healing, a full dermal thickness wound was created in the dorsal skinfold chamber of hairless SKH-1-hr mice, which daily received either saline or EPO over 12 days. Additional experiments were performed using the pan-caspase inhibitor zVAD-fmk to specify as to whether EPO affects wound healing mainly by its anti-apoptotic properties. Wounds of EPO- and zVAD-treated animals showed a significantly delayed re-epithelialization and significantly higher densities of newly formed vascular networks versus controls. Wound histology revealed increased cellularity in EPO- and zVAD-treated animals at day 12, indicating provisional wound matrix. Newly formed vessels of EPO-, but not zVAD-treated wounds failed to mature, i.e. shrink in diameter, but even expanded in caliber over time. EPO did not affect proliferation and migration of keratinocytes and fibroblasts in vitro. In summary, we could show for the first time that EPO prolongates dermal wound healing by interfering with vascular and tissue maturation, substantially by its anti-apoptotic property. Thus, EPO-application should be carefully considered if there is need for wound healing.

Wound healing, which is of pivotal importance to the surgeon, represents a complex and highly coordinated process. However, it is still not clarified to which extent surgical trauma correlates with impairment of skin healing processes. Therefore, we investigated the significance of surgical stress on dermal wound healing in an established animal model of major abdominal surgery. Using intravital fluorescence microscopy we analyzed the healing kinetics of full dermal thickness wounds in the ears of SKH1-hr-mice. Partial hepatectomy (pHx) simulated major surgical trauma, while laparotomy only served as sham-operation (sham). Animals without abdominal surgery served as controls (control). Surgical trauma was quantified by systemic cytokine concentrations. Laparotomy wounds were analyzed for biomechanical qualities and collagen deposition. Morphological characterization of the regenerating skin was performed by histology/immunohistochemistry. Paracrine effects of surgical stress were assessed by in vitro cell assays. PHx and to some extent also sham-operation caused a transient rise in systemic TNF-alpha and IL-6 levels and led to a failure in gain of body weight, most probably reflecting the host’s overall response to surgery. Wound closure in pHx-animals was delayed versus controls and sham-operated animals, as indicated in vivo by the significantly lower values of epithelialization and neovascularization over 10 days. Serum of pHx- and sham-operated animals caused a significant alteration of proliferation and migration of fibroblasts in vitro. Ear wound histology further revealed provisional wound matrix (increased cellularity and leukocyte content of granulation tissue) with reduced microvessel density. Moreover, pHx-laparotomy wounds showed a reduced bursting strength coexisting with significantly decreased collagen content. Our study demonstrates the dependency of skin healing upon the extent of surgical trauma-associated paracrine effects. Therefore, much effort should be paid to the development of strategies limiting surgery-associated perturbations of dermal regeneration.

The skin fold chamber is one of the most accepted animal models for studying the microcirculation both in health and disease. Here we describe for the first time the alternative use of the skin fold chamber in mice for intravital microscopic investigation of skin regeneration after creating a full dermal thickness wound. The dorsal skin fold chamber was implanted in hairless SKH1-hr mice and a full dermal thickness wound (area approximately 4 mm2) was created. By means of intravital fluorescence microscopy, the kinetics of wound healing were analyzed for 12 days post wounding with assessment of epithelialization and nutritive perfusion. The morphology of the regenerating skin was characterized by hematoxylin-eosin histology and immunohistochemistry for proliferation and microvessel density. The model allows the continuous visualization of wound closure with complete epithelialization at day 12. Furthermore, a sola cutis se reficientis could be described by an inner circular ring of vessels at the wound margin surrounded by outer radial passing vessels. Inner circular vessels presented initially with large diameters and matured towards diameters of less than 15 microm for conversion into radial spreading outer vessels. Furthermore, wound healing showed all diverse core issues of skin repair. In summary, we were able to establish a model for the analysis of microcirculation in the healing skin of the mouse. This versatile model allows distinct analysis of new vessel formation and maturation in regenerating skin as well as evaluation of skin healing under different pathologic conditions.

A randomized controlled study (KyberSept-Trial [1]) in patients with severe sepsis showed that anti-thrombin-III significantly reduced lethality in a subgroup of septic patients not receiving concomitant heparin for thrombosis prophylaxis. Therefore, the present study investigated the antithrombotic property of ATIII in an animal study as potential monotherapy in order to omit concomitant heparin therapy. In a light/dye injury model of microvascular thrombosis at the ear of the mouse, we investigated a total of 30 homozygous (SKH1-hr) hairless mice of either sex (10–12 weeks old with a body weight (bw) of 22–40 g) under ip anaesthesia with ketamine/xylazine (90/25 mg/kg bw). Intravital fluorescence microscopy allowed quantitative analysis of the kinetics of thrombus formation in arterioles and venules. Prior to thrombus induction all animals received a single intravenous bolus of hirudin (1 mg/kg bw) or ATIII in dosages of 25, 50, 100 or 250 U/kg bw. Control animals received equivalent volumes of physiologic saline (n=5 animals per group). In saline-treated controls, complete thrombotic occlusion could be induced in 100% of all arterioles (9/9) and venules (40/40) studied. Hirudin prevented thrombotic vessel occlusion in 56% of the arterioles (5/9) and 39% of the venules (9/23). ATIII-250 was found more effective than hirudin, as thrombus formation was banned in all arterioles (13/13) and venules (24/24) (p