Suppressed inflammatory gene expression during human hypertrophic scar compared to normotrophic scar formation.

Hypertrophic scar formation is a result of adverse cutaneous wound healing. The pathogenesis of hypertrophic scar formation is still poorly understood. A problem next to the lack of suitable animal models is that often normal skin is compared to hypertrophic scar (HTscar) and not to normotrophic scar (NTscar) tissue. Another drawback is that often only one time period after wounding is studied, while scar formation is a dynamic process over a period of several months. In this study, we compared the expression of genes involved in inflammation, angiogenesis and extracellular matrix (ECM) formation and also macrophage infiltration in biopsies obtained before and up to 52 weeks after standard surgery in five patients who developed HTscar and six patients who developed NTscar. It was found that HTscar formation coincided with a prolonged decreased expression of inflammatory genes (TNFα, IL-1α, IL-1RN, CCL2, CCL3, CXCL2, CXCR2, C3 and IL-10) and an extended increased expression of ECM-related genes (PLAU, Col3A1, TGFß3). This coincided with a delayed but prolonged infiltration of macrophages (type 2) in HTscar tissue compared to NTscar tissue. These findings were supported by immunohistochemical localization of proteins coding for select genes named above. Our study emphasizes that human cutaneous wound healing is a dynamic process that is needed to be studied over a period of time rather than a single point of time. Taken together, our results suggest innate immune stimulatory therapies may be a better option for improving scar quality than the currently used anti-inflammatory scar therapies.

Time course of the angiogenic response during normotrophic and hypertrophic scar formation in humans.

Previous research suggests that in hypertrophic scars (HSs), an excess of microvessels is present compared with normotrophic scars (NSs). The aim of our study was to quantify vascular densities in HSs and normotrophic scars and to provide an insight into the kinetics of changes in the expression of angiogenic factors in time during wound healing and HS formation. Human presternal wound healing after cardiothoracic surgery through a sternotomy incision was investigated in a standardized manner. Skin biopsies were collected at consecutive time points, i.e., during surgery and 2, 4, 6, 12, and 52 weeks postoperatively. The expression levels of angiopoietin-1, angiopoietin-2, Tie-2, vascular endothelial growth factor, and urokinase-type plasminogen activator were measured by real-time reverse transcription-polymerase chain reaction. Quantification of angiogenesis and cellular localization of the proteins of interest were based on immunohistochemical analysis. Microvessel densities were higher in the HSs compared with the normotrophic scars 12 weeks (p=0.017) and 52 weeks (p=0.030) postoperatively. Angiopoietin-1 expression was lower in the hypertrophic group (p<0.001), which, together with a nonsignificant increase of angiopoietin-2 expression, represented a considerable decrease in the angiopoietin-1/angiopoietin-2 ratio in the hypertrophic group 4 weeks (p=0.053), 12 weeks (p<0.001), and 52 weeks (p<0.001) postoperatively. The expression of urokinase-type plasminogen activator was up-regulated during HS formation (p=0.008). Vascular endothelial growth factor expression was not significantly different when comparing both groups. In summary, the differential expression of angiopoietin-1, angiopoietin-2, and urokinase-type plasminogen activator in time is associated with an increased vascular density in HSs compared with normotrophic scars.

Therapeutic hotline: An alternative adjuvant treatment after ear keloid excision using a custom-made methyl methacrylate stent.

The efficacy of most pressure devices developed for treatment of ear keloids is limited by the insufficient control of the applied pressure, sometimes causing pain and repeated bleeding with a subsequently increased risk of infections and cosmetic problems. The present study aims to describe the efficacy of the custom-made methyl methacrylate stent in patients that were surgically treated for ear keloids and afterward underwent pressure therapy. The recurrence rate of the ear keloids was evaluated after at least 12 months. Adjuvant treatment with the methyl methacrylate stent resulted in an 83% success rate in our experience with 23 patients that completed the intended therapeutic duration of 18 months. No cases of severe complications were seen during or after the treatment. Furthermore, all the items of the Patient and Observer Scar Assessment Scale resulted in a statistically significant improvement of the scar (p < 0.05). Postoperative pressure therapy with the custom-made methyl methacrylate stent seems efficacious, safe, and is usable for keloids of both the helix and the earlobe.

Perioperative conditions affect long-term hypertrophic scar formation.

Corticosteroids are widely used as treatment for excessive scarring by intralesional injection with variable success rates. It is conceivable that systemically administered corticosteroids affect a wider range of inflammatory processes that influence wound healing and may be more successful in preventing hypertrophic scar formation. To study this presumption, we have used a standardized model of presternal scars caused by cardiothoracic surgery through a median sternotomy incision. During cardiac surgery with cardiopulmonary bypass, 1 mg/kg dexamethasone was administered preoperatively, and 0.5 mg/kg 8 hours postoperatively. The presternal scars were evaluated prospectively 2, 4, 6, 12, and 52 weeks postoperatively at standardized measuring points. The height and width of the scars were measured 12 and 52 weeks postoperatively using both a slide caliper and a 7.5-MHz ultrasound probe. Cardiopulmonary bypass was used in 31 of the 43 participants. Eleven patients (35%) in the dexamethasone group developed clinical hypertrophic scars compared with 4 patients (33%) in the control group. These differences were not statistically significant. However, cranial scars became significantly wider in the dexamethasone group compared with the control group (P = 0.04). Twelve weeks postoperatively scars were significantly higher in the dexamethasone group, both cranial (P = 0.05) and caudal (P = 0.03). The differences in scar width and height were mainly present in patients that developed hypertrophic scars. The present results suggest that administration of high-dose perioperative dexamethasone does not prevent hypertrophic scar formation. Its use together with the cardiopulmonary bypass, however, did affect scar dimensions negatively up to 52 weeks after surgery. These findings contribute to the concept of the involvement of perioperative immunologic responses in the etiology of hypertrophic scar formation.

Double balloon endoscopy associated pancreatitis: a description of six cases.

AIM: To perform a single-center analysis of all double balloon endoscopy (DBE) related cases of pancreatitis identified prospectively from a recorded DBE-complication database. METHODS: From November 2003 until January 2007, 603 DBE procedures were performed on 412 patients, with data on complications recorded in a database. The setting was a tertiary care center offering DBE. DBE was performed from the antegrade or retrograde route. Outcome measurements included age, gender, medication, indication, DBE-endoscope type, insertion depth, procedure duration, findings, interventions, post-procedural abdominal pain, and post-procedural hospitalization. RESULTS: This is the largest single-center study reporting on post-DBE pancreatitis prospectively. Six patients (1.0%) developed post-DBE pancreatitis, all after antegrade DBE. There was no association with gender, duration of the procedure or type of endoscope. The mean age was 51.9 years (range 25-78). Four patients had severe pancreatitis. Of these, two had inflammatory signs in the body-tail region, one had pancreatitis in the tail region, and the total pancreas was involved in one. CONCLUSION: The incidence of post-DBE pancreatitis in our series is higher than previously reported. We found no relation with DBE-endoscope type. The inflammatory changes occurred in the body-tail region of the pancreas, suggesting that post-DBE pancreatitis is caused by repetitive mechanical strain on the pancreas.

Formation of hypertrophic scars: evolution and susceptibility.

Formation of hypertrophic scars is a common complication of wound healing, and at present little is known about the incidence and risk factors. Our aim was to analyse the incidence, progression, and regression of postoperative hypertrophic scars over time and to identify risk factors of hypertrophic scars. Patients who had had bilateral reduction mammoplasty or median sternotomy incision were included in the study. All patients were examined at 3 and 12 months postoperatively. We recorded: height, weight, allergy status, smoking status, skin type, tanning, and shape of the scar 3 and 12 months postoperatively. Of the 204 patients who were included, 122 (60%) developed a hypertrophic scar within 12 months of operation. Of these patients, 117 (96%) developed a hypertrophic scar within 3 months of operation. Twelve months postoperatively, 66/204 patients (32%) had a hypertrophic scar. In 31 of the 66 of the patients with a hypertrophic scar 3 months postoperatively (47%), the hypertrophic scar(s) regressed after 3 and 12 months. Smoking and age were associated with formation of hypertrophic scars. In conclusion, 60% of patients developed hypertrophic scars postoperatively, typically during the first three months. Most hypertrophic scars that are present after three months are still hypertrophic after 12 months. Young, non-smoking patients are more susceptible to formation of hypertrophic scars.

Mapping the maze of minimally invasive surgery simulators.

BACKGROUND: Conforming to, among other considerations, legal and ethical concerns for patient safety, there is an increasing demand to assess a surgeon's skills prior to performance in the operating room in pursuit of higher-quality treatment. Training in minimally invasive surgery (MIS) must therefore be intensified, including team training. New methods to train and assess minimally invasive surgical skills are gaining interest. The goal of this review is to provide instructors with an overview of available MIS training tools. In this review, we discuss currently available simulators for MIS training. Applicability, validity, and construction of simulators are reviewed. Also, some of the leading training programs and assessment methods in MIS are reviewed. METHODS: A literature search was performed on studies evaluating surgical task performance on a simulator, reviewing satisfaction with laparoscopic training programs, or validating simulators or assessment methods. RESULTS: Simulators may be divided into simple box trainers and computer-based systems, such as virtual and augmented simulators. All have advantages and disadvantages. An overview is provided of currently available training systems, validity, trainee assessment, and the importance of training programs in MIS. CONCLUSIONS: No simulator yet provides the ability to train the entire set of required psychomotor skills or procedures for MIS. A multiyear training program combining various simulators for multiple-level training, including team training, should be constructed.

Macrophages in skin injury and repair.

After recruitment to the wound bed, monocytes differentiate into macrophages. Macrophages play a central role in all stages of wound healing and orchestrate the wound healing process. Their functional phenotype is dependent on the wound microenvironment, which changes during healing, hereby altering macrophage phenotype. During the early and short inflammatory phase macrophages exert pro-inflammatory functions like antigen-presenting, phagocytosis and the production of inflammatory cytokines and growth factors that facilitate the wound healing process. As such, the phenotype of wound macrophages in this phase is probably the classically activated or the so-called M1 phenotype. During the proliferative phase, macrophages stimulate proliferation of connective, endothelial and epithelial tissue directly and indirectly. Especially fibroblasts, keratinocytes and endothelial cells are stimulated by macrophages during this phase to induce and complete ECM formation, reepithelialization and neovascularization. Subsequently, macrophages can change the composition of the ECM both during angiogenesis and in the remodelling phase by release of degrading enzymes and by synthesizing ECM molecules. This suggests an important role for alternatively activated macrophages in this phase of wound healing. Pathological functioning of macrophages in the wound healing process can result in derailed wound healing, like the formation of ulcers, chronic wounds, hypertrophic scars and keloids. However, the exact role of macrophages in these processes is still incompletely understood. For treating wound repair disorders more should be elucidated on the role of macrophages in these conditions, especially their functional phenotype, to find more therapeutic opportunities. This review summarizes macrophage function in skin injury repair, thereby providing more insight in macrophage function in wound healing and possible interventions in this process.

Topical calcipotriol for preventive treatment of hypertrophic scars: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To evaluate the efficacy of topical application of calcipotriol to healing wounds in preventing or reducing hypertrophic scar formation and to investigate the biochemical properties of the epidermis associated with hypertrophic scar formation. DESIGN: Randomized, double-blind, placebo-controlled trial using the reduction mammoplasty wound-healing model. SETTING: University Medical Center Groningen. Patients Thirty women who underwent bilateral reduction mammoplasty. Interventions For 3 months, scar segments were treated with either topical calcipotriol or placebo. MAIN OUTCOME MEASURES: Three weeks, 3 months, and 12 months postoperatively, the scars were evaluated and punch biopsy samples were collected for immunohistochemical analysis. RESULTS: No significant difference in the prevalence of hypertrophic scars was observed between the placebo- and calcipotriol-treated scars. Only scars with activated keratinocytes 3 weeks postoperatively became hypertrophic (P = .001). CONCLUSIONS: Topical application of calcipotriol during the first 3 months of wound healing does not affect the incidence of hypertrophic scar formation. We observed a strong association between keratinocyte activation and hypertrophic scar formation. Trial Registration trialregister.nl Identifier: NTR1486.

Potential cellular and molecular causes of hypertrophic scar formation.

A scar is an expected result of wound healing. However, in some individuals, and particularly in burn victims, the wound healing processes may lead to a fibrotic hypertrophic scar, which is raised, red, inflexible and responsible for serious functional and cosmetic problems. It seems that a wide array of subsequent processes are involved in hypertrophic scar formation, like an affected haemostasis, exaggerated inflammation, prolonged reepithelialization, overabundant extracellular matrix production, augmented neovascularization, atypical extracellular matrix remodeling and reduced apoptosis. Platelets, macrophages, T-lymphocytes, mast cells, Langerhans cells and keratinocytes are directly and indirectly involved in the activation of fibroblasts, which in turn produce excess extracellular matrix. Following the chronology of normal wound healing, we unravel, clarify and reorganize the complex molecular and cellular key processes that may be responsible for hypertrophic scars. It remains unclear whether these processes are a cause or a consequence of unusual scar tissue formation, but raising evidence exists that immunological responses early following wounding play an important role. Therefore, when developing preventive treatment modalities, one should aim to put the early affected wound healing processes back on track as quickly as possible.

Prevention and curative management of hypertrophic scar formation.

Although hypertrophic scarring commonly occurs following burns, many aspects such as incidence of and optimal treatment for scar hypertrophy remain unclear. This review will focus on hypertrophic scar formation after burn in particular, exploring multiple treatment options and describing their properties as well as effectiveness. To evaluate treatment efficacy and scar development, clinical scar assessment is of eminent importance. Furthermore, recommendations regarding the classification of hypertrophy in the daily practice and in clinical trials are implemented.

Recurrence of plantar fibromatosis after plantar fasciectomy: single-center long-term results.

BACKGROUND: Plantar fibromatosis is a rare, hyperproliferative, benign lesion of the plantar aponeurosis with an unknown cause. Surgical treatment is associated with a high recurrence rate and risk of complications. The goal of this study was to determine the recurrence rate of plantar fibromatosis after plantar fasciectomy at the authors' institute during the past three decades and the factors associated with an increased risk for recurrence. METHODS: The study group contained 27 patients with plantar fibromatosis, who underwent 40 operations on 33 feet, including 13 right (39 percent) and 20 left (61 percent) feet. RESULTS: The overall recurrence rate was 60 percent. Treating a primary lesion with total plantar fasciectomy was associated with the lowest (25 percent) and local resection of the lesion was associated with the highest recurrence rate (100 percent). There seemed to be a relation between the existence of multiple nodules in one foot and a higher recurrence rate. The recurrence of a primary lesion treated with fasciectomy combined with postoperative radiotherapy seemed to be lower in comparison with the recurrence rate after surgery only. CONCLUSIONS: Surgical treatment of plantar fibromatosis is associated with a high recurrence rate and indicated only when the lesions are highly symptomatic and conservative measures fail. Total plantar fasciectomy is the most successful treatment in this study, particularly for primary lesions. The role of postoperative radiotherapy should be evaluated further. A prospective multicenter study comparing different surgical procedures will be needed to determine the type of operation that most effectively eliminates plantar fibromatosis.