Oliver Kloeters

Chronic wound pathogenesis and current treatment strategies : a unifying hypothesis

Summary: Most chronic wounds can be classified into three major types: pressure ulcers, venous ulcers, and diabetic ulcers. The authors propose a unifying hypothesis of chronic wound pathogenesis based on four main causative factors: local tissue hypoxia, bacterial colonization of the wound, repetitive ischemia-reperfusion injury, and an altered cellular and systemic stress response in the aged patient. Traditional strategies for the treatment of chronic wounds have shown limited success. The authors explore potential treatment regimens specifically aimed at each individual determinant of chronic wound pathogenesis. Furthermore, they explore a combined therapeutic approach that collectively targets all the components of chronic wound pathology. These innovative ideas and therapies could be of substantial interest for clinicians and researchers, while further offering significant benefit to patients with chronic wounds.

Hypertrophic scar model in the rabbit ear: a reproducible model for studying scar tissue behavior with new observations on silicone gel sheeting for scar reduction

Hypertrophic scarring poses a clinically relevant problem as it can be cosmetically disfiguring and functionally debilitating. A lack of animal models has hindered an understanding of the pathogenesis and development of new treatment strategies therefore has largely been empiric. Our group has developed a unique hypertrophic scar (HS) model in the rabbit ear. The model has been reproducible, quantifiable, and measurable over a time period of 1 month. We describe the development as well as the reliability and responsiveness of this model to different therapeutic agents, such as TGF‐β blockade, silicone occlusion, and application of collagen‐synthesis inhibitors. Moreover, it has given insights into the mechanism of action of silicone sheeting occlusive treatment and ultimately suggests that the epidermis plays a critical role in the development of HS. Additionally, we will present new data supporting the importance of the epidermis and further clarify the mechanism of action of silicone sheeting. When a semi‐occlusive polyurethane film was left in place for an additional time period, scar formation was reduced. HSs of this model covered with silicone sheets and five layers of Tegaderm® showed a significant scar reduction by 80% compared with wounds with only one layer of Tegaderm®. The HS model in the rabbit ear is a highly reliable, responsive, and practical model for studying scar tissue behavior. Furthermore, our data suggest that the degree and the duration of occlusion are most important for reducing scar tissue formation.

Hydrated keratinocytes reduce collagen synthesis by fibroblasts via paracrine mechanisms.

Regulating collagen metabolism can control hypertrophic scars in cutaneous wounds. Hypertrophic scars can be reduced by occlusive dressings such as silicone sheeting; however, their mechanism is still unknown. We hypothesized that hydration of keratinocytes reduces the collagen secretion of fibroblasts by modifying the cytokine levels. Stratified human epidermal keratinocytes and confluent human dermal fibroblasts were co‐cultured serum free for 72 hours. Keratinocytes were either kept at the air interface or hydrated. Messenger RNA (mRNA) levels of interleukin‐1 (IL‐1)α, IL‐1β, tumor necrosis factor α (TNF‐α), keratinocyte growth factor (KGF), and procollagen‐1 were analyzed by real‐time reverse transcription‐polymerase chain reaction. Secretion of cytokines into conditioned media was quantified by enzyme‐linked immunosorbent assay and collagen content by Western blot. The content of collagen‐I decreased by 44% in the presence of hydrated keratinocytes. Co‐culture with air‐treated keratinocytes decreased collagen‐I only by 23%. Co‐cultured hydrated keratinocytes had significantly higher TNF‐α mRNA (172%) than hydrated keratinocytes. At the protein level, there was an overall trend toward increased TNF‐α levels in hydrated cultures. IL‐1β secretion decreased significantly under hydration (42% monoculture, 58% co‐culture). Co‐culture stimulated a 240% increase of KGF mRNA in fibroblasts compared with monocultured fibroblasts. Fibroblasts secreted 4.5‐fold more KGF in hydrated co‐cultures and sixfold more KGF in air‐treated co‐cultures. Hydration of keratinocytes modifies important paracrine interactions between keratinocytes and fibroblasts and reduces collagen‐1, which supports the hypothesis that hydration of the epidermis and restoration of water barrier function play an important role in scar formation.

Risk factors for compartment syndrome in traumatic brachial artery injuries: an institutional experience in 139 patients.

BACKGROUND The brachial artery is the most common vascular injury encountered in upper extremity trauma. If not treated promptly, it can result in compartment syndrome (CS) and long-term disability. Here, we report an institutional experience of traumatic brachial artery injuries and establish risk factors for the development of upper extremity CS in this setting. METHODS A retrospective review of 139 patients with traumatic brachial artery injury from 1985 to 2001 at a single institution. Patients were divided into two cohorts, those with evidence of CS and those without CS (NCS), for comparison. RESULTS One hundred thirty-nine patients presented with traumatic brachial artery injuries (mean age, 28.4 years). Twenty-nine patients (20.9%) were diagnosed with upper extremity CS, and 28 of these patients underwent fasciotomy on recognition of their CS. Seven patients (6.4%) in the NCS cohort underwent fasciotomy as a result of absent distal pulses on initial examination. Mean follow-up was 51.6 days. Two patients required revision of their arterial repair, and one patient underwent amputation. The risk of CS was increased in the presence of combined arterial injuries (p = 0.03), combined nerve injuries (p = 0.04), motor deficits (p < 0.0001), fractures, and increased intraoperative blood loss (p = 0.001). Multivariate logistic regression performed on these variables revealed that elevated intraoperative blood loss, combined arterial injury, and open fracture were independent risk factors for the development of CS (OR 1.12, 5.79, and 2.68, respectively). CONCLUSION Prompt evaluation and management of traumatic brachial artery injuries is important to prevent CS, which can lead to functional deficits. In the setting of combined arterial injury, open fracture, and significant intraoperative blood loss, prophylactic fasciotomy should be considered.

Suprathel―Acetic Acid Matrix Versus Acticoat and Aquacel as an Antiseptic Dressing: An In Vitro Study

Background:The treatment of burn wounds is still a challenge regarding the management of antiseptic wound conditioning. Especially, in the United States, silver-containing dressings, such as Acticoat and Aquacel are frequently used. Because silver-containing dressings have well-known drawbacks such as an antimicrobial lack against Pseudomonas aeruginosa, we sought to develop an alternative dressing method. In previous studies, we could demonstrate the excellent antiseptic properties of acetic acid against common burn unit germs, and in another study, the feasibility and suitability of a Suprathel–acetic acid matrix as an antiseptic dressing. Materials and Methods:This study was designed to test the in vitro antimicrobial effect of a Suprathel–acetic acid matrix versus Acticoat and Aquacel. To cover the typical bacterial spectrum of a burn unit, the following Gram-negative and Gram-positive bacteria strains were tested: Escherichia coli, extended-spectrum beta-lactamase–positive Klebsiella pneumoniae, P. aeruginosa, Acinetobacter baumannii, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus. Results:The tests showed an excellent bactericidal effect of the Suprathel–acetic acid matrix particularly with problematic Gram-negative bacteria such as Proteus vulgaris, P. aeruginosa, and Acinetobacter baumannii. The efficiency was superior to that of Acicoat and Aquacel. Conclusions:Our results support the notion, that the Suprathel–acetic acid matrix has an excellent bactericidal effect and therefore seems to be suitable as a local antiseptic agent in the treatment of burn wounds.

The use of a semiocclusive dressing reduces epidermal inflammatory cytokine expression and mitigates dermal proliferation and inflammation in a rat incisional model

Occlusive wound dressings are utilized clinically to accelerate wound healing and improve the final appearance of scars. In vivo and in vitro evidence suggests that one mechanism for this effect is maintenance of normal hydration in the epidermis, although the molecular signals remain uncharacterized. We sought to elucidate histological changes and some of the molecular signals involved in this effect in a rat model of wound semiocclusion. We utilized a rat linear incision model with surgical tape occlusion. Histological stains and quantitative real‐time PCR analysis were used to characterize the cellular and molecular effects of semiocclusion on the wound healing response. Semioccluded wounds demonstrated decreased epidermal thickness and cellularity and less mitotic epidermal activity when compared with nonoccluded control wounds. Associated dermal cellularity was similarly attenuated by semiocclusion. Finally, levels of proinflammatory cytokines interleukin‐1‐α and tumor necrosis factor‐α were significantly decreased on postoperative day 3 at the transcriptional level when compared with nonoccluded wounds. Semiocclusive wound treatments significantly decrease epidermal thickness, cellularity, mitotic activity, and dermal cellularity as well as transcriptional levels of important epidermal mediators of inflammation in a rat incisional wound model.

A prognostic model for the risk of development of upper extremity compartment syndrome in the setting of brachial artery injury.

A potentially devastating sequela of brachial artery injury in the setting of upper extremity trauma is the development of compartment syndrome (CS). We performed a retrospective review of 139 trauma patients with brachial artery injury from 1985–2001. Objective characteristics of each case were extracted and analyzed using multivariate logistic regression. Three variables were found to be significant in the final model: estimated intraoperative blood loss as a continuous variable, and presence of a multiple arterial injury and presence of an open fracture as categorical variables. Odds ratio were 1.12, 5.79, and 2.68, respectively. We used these variables to create a summative score for the development of CS with weights assigned proportional to the adjusted odds ratio. Odds of having CS for subjects in group 2 and group 3 are 5.3 and 15.1 times the odds for subjects in group 1, respectively. Applying multivariate regression analysis to the largest series of brachial artery injuries to date, we have developed a predictive scoring model of CS.

Alteration of Smad3 signaling in ischemic rabbit dermal ulcer wounds

Impaired reepithelialization is a hallmark of chronic, ischemic wounds; however, the pathogenesis of the delayed reepithelialization in these wounds remains poorly understood. Transforming growth factor β is involved in both the normal and hypoxic wound‐healing response and exogenous overexpression of Smad3, which has been known to accelerate reepithelialization. Recently, it was shown in the rabbit ear dermal ulcer model that Ad‐Smad3 injection enhanced reepithelialization and granulation tissue formation suggesting a positive effect of Smad3 on wound healing. However, little is known about the role of Smad3 in the ischemic wound healing process. In this study, we examined the effect of Smad3 in an ischemic wound model. Ad‐Smad3 or Ad‐LacZ (108 pfu/wound) was injected into either ear of white New Zealand rabbits. Twenty‐four hours later, these ears were rendered ischemic using an established model, and four 7 mm full‐thickness punch wounds were made on each ear. Histological evaluation showed a significant increase in reepithelialization parameters in Ad‐Smad3–transfected wounds (p<0.01). In contrast, granulation tissue parameters were not affected by Smad3 in ischemia. Smad4 and Smad7 mRNA‐expression was not affected by Smad3 overexpression. Connective tissue growth factor protein was up‐regulated under ischemic conditions but was unaffected by Smad3 transfection in both ischemic and nonischemic wounds. Our results suggest an enhancing effect of Smad3 on reepithelialization in an ischemic wound model that, in turn, might provide novel therapeutic options. Furthermore, the lack of alteration of Smad‐dependent intermediates by Smad3 overexpression suggests the activation of Smad‐independent pathways in ischemia.

Die chirurgische Behandlung des alten Patienten

Medizinischer Fortschritt und verbesserte Lebensbedingungen fuhren zu drastischen Veranderungen in der Zusammensetzung unserer Gesellschaft. Haben die uber 65-Jahrigen derzeit noch einen Anteil von 19% an der Gesamtbevolkerung, so wird im Jahr 2050 annahernd jeder dritte Burger in Deutschland 65 Jahre oder alter sein (Eisenmenger et al., 2006). Die Behandlung von alten Patienten wird daher sowohl aus medizinisch-therapeutischer Sicht als auch aus okonomischen Erwagungen heraus zwangslaufig eine immer wichtigere Rolle spielen.

Aufnahme und Erstversorgung des Schwerbrandverletzten

Im klinischen Alltag haben sich zwei Scores zur orientierenden Einschatzung der Verletzungsschwere und der damit verbundenen Uberlebenswahrscheinlichkeit eines Brandverletzten durchgesetzt. Der Banx-Index berucksichtigt ausschlieslich die verbrannte Korperoberflache (VKOF) und das Lebensalter des Patienten und prognostiziert eine Uberlebenswahrscheinlichkeit kleiner 10% sobald die Summe beider Werte 100 uberschreitet. Wesentlich differenzierter und damit prognostisch verlasslicher ist der ABSI-Score (Abbreviated Burn Severity Index), der anhand mehrerer Faktoren uber einen ermittelten Punktwert eine feinere Skalierung der Uberlebenswahrscheinlichkeit ermoglicht. Dennoch bleiben auch beim ABSI-Score Faktoren wie Adipositas, Nikotin- und Alkoholabusus des Patienten unberucksichtigt. Das Vorliegen solcher Faktoren hat in Untersuchungen groser Brandverletztenzentren eine deutliche Verschlechterung der Uberlebenswahrscheinlichkeit des Patienten nachgewiesen [1,2]