Dolores Wolfram

Hypertrophic scars and keloids--a review of their pathophysiology, risk factors, and therapeutic management

BACKGROUND Hypertrophic scars and keloids result from an abnormal fibrous wound healing process in which tissue repair and regeneration‐regulating mechanism control is lost. These abnormal fibrous growths present a major therapeutic dilemma and challenge to the plastic surgeon because they are disfiguring and frequently recur. OBJECTIVE To provide updated clinical and experimental information on hypertrophic scars and keloids so that physicians can better understand and properly treat such lesions. METHODS A Medline literature search was performed for relevant publications and for diverse strategies for management of hypertrophic scars and keloids. CONCLUSION The growing understanding of the molecular processes of normal and abnormal wound healing is promising for discovery of novel approaches for the management of hypertrophic scars and keloids. Although optimal treatment of these lesions remains undefined, successful healing can be achieved only with combined multidisciplinary therapeutic regimens. The authors have indicated no significant interest with commercial supporters.

Surgery for Foreign Body Reactions due to Injectable Fillers

Background: An increasing number of soft tissue fillers have been introduced to the beauty market and these filler substances are widely used as non-toxic, non-immunogenic and relatively harmless injectable alternatives to surgical rejuvenation. Generally, facial fillers are injectable – or surgically insertable – products that are used to fill up the volume loss in the aging face. Depending on bioavailability, chemical composition and degradation, fillers can be classified as temporary or permanent, organic or inorganic and autologous or heterologous. Objective: A plethora of new products has swamped the beauty market since face rejuvenation has become socially acceptable as well as affordable to a wider population, but adverse reactions cannot be excluded. We present 4 patients with complications after injection of facial fillers [including Artecoll®(polymethylmethacrylate microspheres), Restylane® (hyaluronic acid), DermaLive® (hyaluronic acid plus acrylic hydrogel particles) and Newfill® (polylactic acid)] and surgical correction. Results: Surgical intervention led to good aesthetic and functional results after multiple unsuccessful conservative therapies. Conclusion: We recommend that only physicians familiar with the injection techniques and the biological and chemical characteristics of the various injectable products should perform such interventions. Especially permanent fillers should be used with utmost reticence in cosmetic surgery and we would recommend their application only in reconstructive procedures. Additionally, documentation and reporting of all adverse effects must be mandatory.

Altered systemic serologic parameters in patients with silicone mammary implants

BACKGROUND The most common local complication in patients with silicone mammary implants (SMIs) is excessive peri-SMI connective tissue capsule formation and its subsequent contracture. However, considerable controversy remains as to whether these implants also cause systemic side effects. The present study was undertaken to identify possible alterations of serological markers in SMI patients that may herald systemic side effects. METHODS We investigated several systemic serological parameters in 143 individuals, 93 of whom had received SMIs and 50 were controls. The patients were grouped according to the severity of capsular contracture (Baker scores I-IV) and the duration of SMI implants (less than 1 year, between 1 and 5 years, more than 5 years). We also included control groups (female blood donors, nurses with possible professional silicone exposure). Patients with breast cancer and subsequent SMI-reconstruction were excluded from the study since they are generally considered immunocompromised. The following parameters were determined: anti-neutrophil cytoplasmatic autoantibodies (cANCA), anti-nuclear autoantibodies (ANA), anti-cardiolipin antibodies (CL-Ab), rheumatoid factor (RF), complement components (C3, C4), circulating immune complexes (CIC), procollagen III (a marker of active fibrosis), anti-polymer antibodies (APA) and soluble intercellular adhesion molecule-1 (sICAM-1). RESULTS The following parameters were increased in the sera of SMI patients: CIC, procollagen III, APA, sICAM-1. CONCLUSIONS We found a set of parameters in serum that correlate with fibrosis development and the duration of the implants in otherwise healthy SMI carriers. Future studies will clarify whether these serological abnormalities will be useful in predicting clinical disease, and also further assess the sensitivity and specificity of these parameters. Our present recommendation as a result of this study is that SMI patients with persistent abnormal serological parameters should be monitored closely by a clinical team that includes rheumatologists.

The superficial inferior epigastric artery (SIEA) flap: indications for breast reconstruction.

The lower abdominal skin and fat have become a standard for breast reconstruction because the abdominal tissue can mimic the breast to a high degree. With todays increasing focus on safety and routine of microsurgical interventions, more attention must be paid to donor-site morbidity. The superficial inferior epigastric artery (SIEA) free flap is the least invasive microsurgical procedure for breast reconstruction because this operative technique does not require harvesting of the rectus muscle or the abdominal fascia. A total of 11 breast reconstructions were performed with this technique and had an average follow-up of 23 months. The anatomy, operative technique, and various indications for the SIEA flaps are demonstrated.

Insights from computational modeling in inflammation and acute rejection in limb transplantation

Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection.

Mechanisms and mediators of inflammation: potential models for skin rejection and targeted therapy in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) is an effective treatment option for patients suffering from limb loss or severe disfigurement. However, postoperative courses of VCA recipients have been complicated by skin rejection, and long-term immunosuppression remains a necessity for allograft survival. To widen the scope of this quality-of-life improving procedure minimization of immunosuppression in order to limit risks and side effects is needed. In some aspects, the molecular mechanisms and dynamics of skin allograft rejection seem similar to inflammatory skin conditions. T cells are key players in skin rejection and are recruited to the skin via activation of adhesion molecules, cytokines, and chemokines. Blocking these molecules has not only shown success in the treatment of inflammatory dermatoses, but also prolonged graft survival in various models of solid organ transplantation. In addition to T cell recruitment, ectopic lymphoid structures within the allograft associated with chronic rejection in solid organ transplantation might contribute to the strong alloimmune response towards the skin. Selectively targeting the molecules involved offers exciting novel therapeutic options in the prevention and treatment of skin rejection after VCA.

Differentiation between acute skin rejection in allotransplantation and T-cell mediated skin inflammation based on gene expression analysis.

Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments.

Differences between patients and medical professionals in the evaluation of aesthetic outcome following breast reconstruction with implants.

BACKGROUND AND AIM Most studies on breast reconstruction evaluate different surgical techniques, types of implant or time of reconstruction. Moreover, evaluations are usually performed either by surgeons or by patients, but are rarely compared. We conducted a study on aesthetic outcome following breast reconstruction with implants comparing the evaluation by patients versus medical professionals. METHODS Forty-seven patients, who had a breast reconstruction with implants between 2001 and 2010 (median follow-up 71 months), underwent a clinical examination, standardized photo documentation and filled out a questionnaire to evaluate their aesthetic result (rate 1 very good to 5 very poor). Photo documentation was independently evaluated by 18 medical professionals using the same evaluation instrument and the results were compared. Gender and patient aspects were taken into account. RESULTS We found statistically significant differences between patients and medical professional ratings. The patient evaluation was better through all categories as compared to the evaluation by medical personnel. The degree of medical education or gender aspects did not significantly affect the professional ratings. Age at reconstruction, length of follow-up or primary versus secondary reconstruction did not seem to make a difference in the evaluations of the patients versus the medical professionals.. CONCLUSION The differences between patient and expert opinion in rating of aesthetic results indicate that patient satisfaction is influenced by multiple factors and not only by good aesthetic outcome. Patient evaluation should therefore be carefully considered in treatment and outcome studies of breast reconstruction..

Immunophenotypic characterization of human T cells after in vitro exposure to different silicone breast implant surfaces

The most common complication of silicone breast implants is capsular contracture (massive scar formation around the implant). We postulate that capsular contracture is always a sequel to inflammatory processes, with both innate and adaptive immune mechanisms participating. In general, fibroblasts and macrophages have been used as cell types to evaluate in vitro the biocompatibility of breast implant surfaces. Moreover, also T cells have been found at the implant site at the initial stage of fibrous capsule formation. However, only few studies have addressed the influence of surfaces with different textures on T-cell responses. The aim of the present study was to investigate the immune response of human peripheral blood mononuclear cells (PBMC) to commercially available silicone breast implants in vitro. PBMC from healthy female blood donors were cultured on each silicone surface for 4 days. Proliferation and phenotype of cultured cells were assessed by flow cytometry. Cytokine levels were determined by multiplex and real-time assay. We found that silicone surfaces do not induce T-cell proliferation, nor do they extensively alter the proportion of T cell subsets (CD4, CD8, naïve, effector memory). Interestingly, cytokine profiling identified matrix specific differences, especially for IL-6 and TNF-α on certain surface topographies that could lead to increased fibrosis.

Cardiac Arrest Disrupts Caspase-1 and Patterns of Inflammatory Mediators Differently in Skin and Muscle Following Localized Tissue Injury in Rats: Insights from Data-Driven Modeling

Background Trauma often cooccurs with cardiac arrest and hemorrhagic shock. Skin and muscle injuries often lead to significant inflammation in the affected tissue. The primary mechanism by which inflammation is initiated, sustained, and terminated is cytokine-mediated immune signaling, but this signaling can be altered by cardiac arrest. The complexity and context sensitivity of immune signaling in general has stymied a clear understanding of these signaling dynamics. Methodology/principal findings We hypothesized that advanced numerical and biological function analysis methods would help elucidate the inflammatory response to skin and muscle wounds in rats, both with and without concomitant shock. Based on the multiplexed analysis of inflammatory mediators, we discerned a differential interleukin (IL)-1α and IL-18 signature in skin vs. muscle, which was suggestive of inflammasome activation in the skin. Immunoblotting revealed caspase-1 activation in skin but not muscle. Notably, IL-1α and IL-18, along with caspase-1, were greatly elevated in the skin following cardiac arrest, consistent with differential inflammasome activation. Conclusion/significance Tissue-specific activation of caspase-1 and the NLRP3 inflammasome appear to be key factors in determining the type and severity of the inflammatory response to tissue injury, especially in the presence of severe shock, as suggested via data-driven modeling.