Autologous skin substitute for hard-to-heal ulcers: retrospective analysis on safety, applicability, and efficacy in an outpatient and hospitalized setting.

Chronic ulcers ((arterio)venous, decubitus, or postoperative) have no tendency to heal within a period of at least 3 months despite optimal therapy according to internationally accepted guidelines. This retrospective study evaluates the safety and efficacy of an autologous, dermal-epidermal skin substitute (SS) for treating ulcers of various origins. Ulcers were treated within 7 Dutch centers over 5 years. Sixty-six ulcers (size: 0.75-150 cm²; duration: 0.25-32 years) with a follow-up time of 24 weeks after a single-skin substitute application were assessed. Wound-bed preparation consisted of vacuum-assisted-closure-therapy (5 days, hospitalized) or application of acellular dermis (5-7 days, outpatient). Time to heal, adverse events, and recurrence 1 year after complete healing were recorded. Complete ulcer healing occurred in 36 of 66 ulcers (55%) at 24 weeks. At that time point, a further 29% of ulcers showed decrease in ulcer size between 50 and 99%. No difference was observed between the hospitalized vs. outpatient treatment with complete healing. There were 32 of 36 healed ulcers that were available for follow-up 1 year after complete closure, of which 27 (84%) were still closed. Only two minor/moderate possibly related adverse events were recorded. This retrospective analysis shows that SS provides a safe and successful treatment for particularly chronic ulcers of various origins.

Simple wound exudate collection method identifies bioactive cytokines and chemokines in (arterio) venous ulcers.

A major challenge for clinicians treating (arterio) venous leg ulcers is to decide between standard therapy and advanced interventions. Here, we developed a simple method to collect human material representative of the ulcer wound bed, which can be used to identify biomarkers for prognostic test development. Superficial surgical debridement was performed using a small vidal curette during the weekly visit to the outpatient clinic. Moist, easily removable debridement material essentially blood free (including necrotic and nonviable slough) was collected from the surface of the ulcer. The amount ranged from 5.5 mg to 78 mg material per ulcer. Seventeen cytokines, chemokines, and growth factors were extracted and analyzed by enzyme-linked immunosorbent assay (concentration range: 0.0005-78 ng/mg total protein). Notably, CXCL8 was by far the most abundant protein present. Inflammatory mediators were more abundant than anti-inflammatory mediators (e.g., interleukin (IL)-10 and transforming growth factor-ß1). Bioactivity assays showed chronic wound extracts to be capable of stimulating fibroblast migration in a chemokine-dependent manner and also capable of stimulating healthy cells within skin substitutes to secrete wound healing mediators (CCL2, CXCL1, CXCL8, IL-6) in an IL-1α dependent manner. Collection of debridement tissue enables investigation of the ulcer environment in an easy noninvasive manner that may be suitable for prognostic test development.

Effectiveness of Preoperative Depilation of the Urethral Donor Site for Phalloplasty: Neourethral Hair Growth and its Effects on Voiding.

BACKGROUND: For transgender men choosing to undergo phalloplasty with urethral lengthening, there is a potential for hair growth in the neourethra. Depilation of the urethral donor site may reduce subsequent intraurethral hair growth. OBJECTIVES: To evaluate the effectiveness of preoperative laser depilation and assess the correlation between urethral hair density and voiding among transgender men undergoing phalloplasty with urethral lengthening. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of 25 transgender men undergoing phalloplasty with urethral lengthening between July 2010 and April 2015 at the VU University Medical Center in Amsterdam. INTERVENTION: Phalloplasty with urethral lengthening using skin with or without preoperative depilation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data on preoperative laser depilation treatments were obtained from the local laser center. Intraurethral images were captured via urethroscopy and used to rate hair density. Images of the contralateral forearm were used as a reference. Hair density was rated in terms of the number of hairs per view as zero, low (1-9), moderate (10-19), or high (≥20). Voiding was assessed using the International Prostate Symptom Score (IPSS) questionnaire, a 24-h voiding diary, and uroflowmetry. RESULTS AND LIMITATIONS: Twenty-five patients underwent urethroscopy. In the depilation group (n = 14) the hair reduction was significant and hair density was downgraded on average by 1.0 points (95% confidence interval [CI] 0.5-1.5). The mean number of laser treatment sessions was 6 (range 2-10). In the no-depilation group (n = 11), hair density did not significantly differ between the urethra and the contralateral arm (mean difference 0.18, 95% CI 0.5-0.9). The majority of the patients reported mild voiding complaints (median IPSS score 7, range 2-28) and had a normal functional bladder capacity and a nonobstructed urinary flow with low postvoid volumes. CONCLUSIONS: Laser epilation treatment reduces hair growth but does not eliminate hair. Voiding complaints do not seem to be related to hair density in the urethra. PATIENT SUMMARY: For skin donor sites used in penis construction for transgender men, the amount of hair growth is reduced by preoperative laser depilation, but hair is still present in the new urethra. Hair in the urethra does not cause urinary voiding complaints.

Comparison of autologous full-thickness gingiva and skin substitutes for wound healing.

Ideally tissue-engineered products should maintain the characteristics of the original tissue. For example, skin represents orthokeratinized epithelium and oral gingiva represents parakeratinized epithelium. The aim of this study was to develop an autologous full-thickness gingiva substitute suitable for clinical applications and to compare it with our autologous full-thickness skin substitute that is routinely used for healing chronic wounds. Autologous full-thickness skin and gingiva substitutes were constructed under identical culture conditions from 3-mm punch biopsies isolated from the upper leg or gingiva tissue, respectively. Both consisted of reconstructed epithelia on acellular dermis repopulated with fibroblasts. To compare the characteristics of the original and reconstructed tissue, differential morphological observations and expression of differentiation markers (keratins 6, 10, and 17 and stratum corneum precursors involucrin, loricrin, and SKALP) were determined. Skin and gingiva substitutes were transplanted onto therapy-resistant leg ulcers or tooth extraction sites in order to determine their effects on wound healing. The tissue-engineered constructs maintained many of the differential histological and immunohistochemical characteristics of the original tissues from which they were derived. The skin substitute was orthokeratinized, and the gingiva substitute was parakeratinized. Transplantation of skin (n = 19) and gingiva substitutes (n = 3) resulted in accelerated wound healing with no adverse effects. As identical culture systems were used to generate both the skin and gingiva substitutes, the differences observed in tissue (immuno)histology can be attributed to intrinsic properties of the tissues rather than to environmental factors (e.g., air or saliva). This study emphasizes the importance of closely matching donor sites with the area to be transplanted. Our results represent a large step forward in the area of clinical applications in oral tissue engineering, which have until now greatly lagged behind skin tissue engineering.

Characterization of In Vitro Reconstructed Human Normotrophic, Hypertrophic, and Keloid Scar Models.

To understand scar pathology, develop new drugs, and provide a platform for personalized medicine, physiologically relevant human scar models are required, which are characteristic of different scar pathologies. Hypertrophic scars and keloids are two types of abnormal scar resulting from unknown abnormalities in the wound healing process. While they display different clinical behavior, differentiation between the two can be difficult-which in turn means that it is difficult to develop optimal therapeutic strategies. The aim of this study was to develop in vitro reconstructed human hypertrophic and keloid scar models and compare these to normotrophic scar and normal skin models to identify distinguishing biomarkers. Keratinocytes and fibroblasts from normal skin and scar types (normotrophic, hypertrophic, keloid) were used to reconstruct skin models. All skin models showed a reconstructed differentiated epidermis on a fibroblast populated collagen-elastin matrix. Both abnormal scar types showed increased contraction, dermal thickness, and myofibroblast staining compared to normal skin and normotrophic scar. Notably, the expression of extracellular matrix associated genes showed distinguishing profiles between all scar types and normal skin (hyaluronan synthase-1, matrix-metalloprotease-3), between keloid and normal skin (collagen type IV), between normal scar and keloid (laminin α1), and between keloid and hypertrophic scar (matrix-metalloprotease-1, integrin α5). Also, inflammatory cytokine and growth factor secretion (CCL5, CXCL1, CXCL8, CCL27, IL-6, HGF) showed differential secretion between scar types. Our results strongly suggest that abnormal scars arise from different pathologies rather than simply being on different ends of the scarring spectrum. Furthermore, such normal skin and scar models together with biomarkers, which distinguish the different scar types, would provide an animal free, physiologically relevant scar diagnostic and drug testing platform for the future.

[Ambulant compression therapy for crural ulcers; an effective treatment when applied skilfully]. / Ambulante compressietherapie voor ulcera cruris; Een effectieve behandeling bij adequate uitvoering.

The incidence of crural ulcers is high. They reduce quality of life considerably and create a burden on the healthcare budget. The key treatment is ambulant compression therapy (ACT). We describe two patients with crural ulcers whose ambulant compression treatment was suboptimal and did not result in healing. When the bandages were applied correctly healing was achieved. If correctly applied ACT should provide sufficient pressure to eliminate oedema, whilst taking local circumstances such as bony structures and arterial qualities into consideration. To provide pressure-to-measure regular practical training, skills and regular quality checks are needed. Knowledge of the properties of bandages and the proper use of materials for padding under the bandage enables good personalised ACT. In trained hands adequate compression and making use of simple bandages and dressings provides good care for patients suffering from crural ulcers in contrast to inadequate ACT using the same materials.

[Treatment of patients with venous leg ulcers: what if compression therapy alone is no longer beneficial?]. / Behandeling van patiënten met een veneus ulcus cruris: wat als compressietherapie alleen niet meer helpt?

Non-healing venous leg ulcers are a cumbersome problem for the patient and the physician. Adequate compression therapy that reduces venous pressure is the cornerstone of treatment. For each patient treatment of superficial venous insufficiency should be considered. Adjuvant surgical, physical or biologic interventions can stimulate healing in case of refractory ulcers Treatment of a venous ulcer needs a tailored approach.

Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial.

BACKGROUND: The prevalence of venous leg ulcers is as high as 1% to 1.5%, and the total costs of this disease are 1% of the total annual health care budget in Western European countries. Treatment modalities are conservative or surgical. Subfascial endoscopic perforating vein surgery (SEPS) combined with superficial vein ligation is performed in many centers to address vein incompetence in patients with chronic venous leg ulcers. Several reports describe good healing and low recurrence rates, although a randomized trial to compare surgical treatment including SEPS and treatment of the superficial venous system to conservative modalities has never been performed. Therefore, a prospective, randomized, multicenter trial was conducted to study whether ambulatory compression therapy with venous surgery is a better treatment than just ambulatory compression therapy in venous leg ulcer patients. METHODS: Patients with an active (open) venous leg ulcer (CEAP C6) qualified for the study. The study consisted of two treatment groups. All patients were treated by standardized ambulatory compression therapy, and half of the patients received SEPS. Concomitant superficial venous incompetence was also treated in the second group. For allocation to both treatment groups, each patient was assigned by a computer program at the randomization center. The primary goal of the study was to compare the ulcer-free period during follow-up in both study groups. Secondary end points were ulcer healing and recurrence rates. RESULTS: From April 1997 until January 2001, 200 ulcerated legs (170 patients) were included in the study in 12 centers in The Netherlands. A total of 97 ulcers were allocated to the surgical group and 103 to the conservative group. Patient characteristics were similar in the two treatment groups at baseline, with the exception of a higher proportion in the conservative group of diabetes mellitus. Healing rates were 83% in the surgical group and 73% in the conservative group (not significant; median time to healing, 27 months). Recurrence rates were the same in both treatment groups (22% surgical vs 23% conservative). During follow-up of a mean of 29 months (median, 27 months) in the surgical group and 26 months (median, 24 months) in the conservative group, we found that in the surgical group, the ulcer-free rate was 72%, whereas in the conservative group this rate was 53% (P = .11; Mann-Whitney test). Patients with recurrent ulceration or medially located ulcers in the surgical group had a longer ulcer-free period than those treated in the conservative group (P = .02 for both). A first-time ulcer and one of the centers also had a positive effect on the ulcer-free period during follow-up (P < .001 and P = .02), independent of the treatment group. Deep vein incompetence did not affect the ulcer-free period. CONCLUSIONS: In conclusion, we suggest that patients with medial and/or recurrent ulceration should receive surgery combined with ambulatory compression therapy. A dedicated center should provide care for those patients.