Efficacy of Alkaline Phosphatase in Critically Ill Patients with COVID-19: A Multicentre Investigator-Initiated Double-Blind Randomised Placebo-Controlled Trial.

BACKGROUND: Efforts to identify therapies to treat hospitalised patients with COVID-19 are being continued. Alkaline phosphatase (AP) dephosphorylates pro-inflammatory adenosine triphosphate (ATP) into anti-inflammatory adenosine. METHODS: In a randomised controlled trial, we investigated the safety and efficacy of AP in patients with SARS-CoV-2 infection admitted to the ICU. AP or a placebo was administered for four days following admission to the ICU. The primary outcome was the duration of mechanical ventilation. Mortality in 28 days, acute kidney injury, need for reintubation, safety, and inflammatory markers relevant to the described high cytokine release associated with SARS-CoV-2 infection were the secondary outcomes. RESULTS: Between December 2020 and March 2022, 97 patients (of the intended 132) were included, of which 51 were randomised to AP. The trial was terminated prematurely based on meeting the threshold for futility. Compared to the placebo, AP did not affect the duration of mechanical ventilation (9.0 days vs. 9.3 days, p = 1.0). No safety issues were observed. After 28 days, mortality was 9 (18%) in the AP group versus 6 (13%) in the placebo group (p = 0.531). Additionally, no statistically significant differences between the AP and the placebo were observed for the other secondary outcomes. CONCLUSIONS: Alkaline phosphatase (AP) therapy in COVID-19 ICU patients showed no significant benefits in this trial.

Kinetics of Inflammatory Mediators in the Immune Response to Burn Injury: Systematic Review and Meta-Analysis of Animal Studies.

Burns are often accompanied by a dysfunctional immune response, which can lead to systemic inflammation, shock, and excessive scarring. The objective of this study was to provide insight into inflammatory pathways associated with burn-related complications. Because detailed information on the various inflammatory mediators is scattered over individual studies, we systematically reviewed animal experimental data for all reported inflammatory mediators. Meta-analyses of 352 studies revealed a strong increase in cytokines, chemokines, and growth factors, particularly 19 mediators in blood and 12 in burn tissue. Temporal kinetics showed long-lasting surges of proinflammatory cytokines in blood and burn tissue. Significant time-dependent effects were seen for IL-1ß, IL-6, TGF-ß1, and CCL2. The response of anti-inflammatory mediators was limited. Burn technique had a profound impact on systemic response levels. Large burn size and scalds further increased systemic, but not local inflammation. Animal characteristics greatly affected inflammation, for example, IL-1ß, IL-6, and TNF-α levels were highest in young, male rats. Time-dependent effects and dissimilarities in response demonstrate the importance of appropriate study design. Collectively, this review presents a general overview of the burn-induced immune response exposing inflammatory pathways that could be targeted through immunotherapy for burn patients and provides guidance for experimental set-ups to advance burn research.

Short- and Long-term Outcomes of an Acellular Dermal Substitute versus Standard of Care in Burns and Reconstructions: A Phase I/II Intrapatient Randomized Controlled Trial.

OBJECTIVE: Dermal substitutes promote dermal regeneration and improve scar quality, but knowledge gaps remain regarding their efficacy and indications for use. The authors investigated the safety and short- and long-term efficacy of an acellular dermal substitute in patients with full-thickness wounds. METHODS: This intrapatient randomized controlled, open-label, phase I (safety) and phase II (efficacy) study compared treatment with Novomaix (Matricel GmbH), a dermal collagen/elastin-based scaffold, with split-thickness skin graft (STSG) only. The primary safety outcome was graft take at 5 to 7 days postsurgery. Postsurgical scar quality was assessed by measuring elasticity, color, and scores on the Patient and Observer Scar Assessment Scale at 3 months, 12 months, and 6 years. RESULTS: Twenty-five patients were included, of which 24 received treatment allocation. Graft take and wound healing were statistically significantly lower/delayed in the dermal matrix group compared with STSG alone (P < .004). Serious adverse events were delayed epithelialization in four dermal matrix and three STSG study areas. At 12 months postsurgery, skin extension (P = .034) and elasticity (P = .036) were better for the dermal matrix group compared with the group receiving STSG alone. Other scar quality parameters at 12 months and 6 years did not differ between treatment arms. CONCLUSIONS: The dermal substitute was a safe treatment modality for full-thickness wounds. Compared with STSG alone, time to wound healing was slightly increased. Nevertheless, scar quality at 12 months seemed somewhat improved in the wounds treated with the dermal substitute, indicative of enhanced scar maturation. In the long term, final scar quality was similar for both treatment modalities.

Hydrosurgical and conventional debridement of burns: randomized clinical trial.

BACKGROUND: Tangential excision of burned tissue followed by skin grafting is the cornerstone of burn surgery. Hydrosurgery has become popular for tangential excision, with the hypothesis that enhanced preservation of vital dermal tissue reduces scarring. The aim of this trial was to compare scar quality after hydrosurgical versus conventional debridement before split-skin grafting. METHODS: A double-blind randomized within-patient multicentre controlled trial was conducted in patients with burns that required split-skin grafting. One wound area was randomized to hydrosurgical debridement and the other to Weck knife debridement. The primary outcome was scar quality at 12 months, assessed with the observer part of the Patient and Observer Scar Assessment Scale (POSAS). Secondary outcomes included complications, scar quality, colour, pliability, and histological dermal preservation. RESULTS: Some 137 patients were randomized. At 12 months, scars of the hydrosurgical debrided wounds had a lower POSAS observer total item score (mean 2.42 (95 per cent c.i. 2.26 to 2.59) versus 2.54 (95 per cent c.i. 2.36 to 2.72; P = 0.023)) and overall opinion score (mean 3.08 (95 per cent c.i. 2.88 to 3.28) versus 3.30 (95 per cent c.i. 3.09-3.51); P = 0.006). Patient-reported scar quality and pliability measurements were significantly better for the hydrosurgically debrided wounds. Complication rates did not differ between both treatments. Histologically, significantly more dermis was preserved with hydrosurgery (P < 0.001). CONCLUSION: One year after surgery scar quality and pliability was better for hydrosurgically debrided burns, probably owing to enhanced histological preservation of dermis. REGISTRATION NUMBER: Trial NL6085 (NTR6232 (http://www.trialregister.nl)).

The impact of incisional negative pressure wound therapy on scar quality and patient-reported outcomes: A within-patient-controlled, randomised trial.

Literature provides a moderate level of evidence for the beneficial effects of incisional negative pressure wound therapy (iNPWT) on scar quality. The purpose of this study was to establish if iNPWT results in improved scar outcomes in comparison to the standard of care. Therefore, a within-patient randomised controlled, open-label trial was conducted in transgender men undergoing gender-affirming mastectomies. A unilateral side was randomised to receive iNPWT (PICO™, Smith&Nephew) without suction drains and contrastingly the standard dressing (Steri-Strips™) with suction drain. Scar quality and questionnaires were bilaterally measured by means of objective assessments and patient-reported outcome measures (PROM) at 1, 3 and 12 months. Objective scar outcomes were scar pliability (Cutometer®), colouration (DSM-II) and scar width (3-D imaging). PROM outcomes were related to scars (POSAS and SCAR-Q) and body satisfaction (BODY-Q). From 85 included patients, 80 were included for analyses. No significant difference between treatments was seen in the quantitative outcomes of scar pliability, colour, and width. For qualitative scar outcomes, several significant findings for iNPWT were found for several subscales of the POSAS, SCAR-Q, and BODY-Q. These effects could not be substantiated with linear mixed-model regression, signifying no statically more favourable outcome for either treatment option. In conclusion, this study demonstrated that some PROM outcomes were more favourable for the iNPWT compared to standard treatment. In contrast, the quantitative outcomes showed no beneficial effects of iNPWT on scar outcomes. This suggests that iNPWT is of little benefit as a scar-improving therapy.

Patient-reported scar quality of donor-sites following split-skin grafting in burn patients: Long-term results of a prospective cohort study.

BACKGROUND: Skin grafting is the current gold standard for treatment of deeper burns. How patients appraise the donor-site scar is poorly investigated. The aim of this study was to evaluate long-term patient-reported quality of donor-site scars after split skin grafting and identify possible predictors. METHODS: A prospective cohort study was conducted. Patients were included in a Dutch burn centre during one year. Patient-reported quality of donor-site scars and their worst burn scar was assessed at 12 months using the Patient and Observer Scar Assessment Scale (POSAS). Mixed model analyses were used to identify predictors of scar quality. RESULTS: This study included 115 donor-site scars of 72 patients with a mean TBSA burned of 11.2%. The vast majority of the donor-site scars (84.4%) were rated as having at least minor differences with normal skin (POSAS item score ≥2) on one or more scar characteristics and the overall opinion on 80.9% of the donor-site scars was that they deviated from normal skin 12 months after surgery. The overall opinion on the donor-site scar was 3.2 ± 2.1 vs. 5.1 ± 2.4 on the burn scar. A younger age, female gender, a darker skin type, and location on the lower leg were predictors of reduced donor-site scar quality. In addition, time to re-epithelization was associated with scar quality. CONCLUSION: This study provided new insights in long-term scar quality of donor-sites. Donor-site scars differed from normal skin in a large part of the population 12 months after surgery. Results of this study can be used to inform patients on the long-term outcomes of their scars and to tailor preventive or therapeutic treatment options.

A systematic review evaluating the influence of incisional Negative Pressure Wound Therapy on scarring.

Pathological scars can result in functional impairment, disfigurement, a psychological burden, itch, and even chronic pain. We conducted a systematic review to investigate the influence of incisional Negative Pressure Wound Therapy (iNPWT) on scarring. PubMed, EMBASE and CINAHL were searched for preclinical and clinical comparative studies that investigated the influence of iNPWT on scarring-related outcomes. Individual studies were assessed using the OHAT Risk of Bias Rating Tool for Human and Animal studies. The body of evidence was rated using OHAT methodology. Six preclinical studies and nine clinical studies (377 patients) were identified. Preclinical studies suggested that iNPWT reduced lateral tension on incisions, increased wound strength, and reduced scar width upon histological assessment. Two clinical studies reported improved patient-reported scar satisfaction as measured with the PSAS (1 year after surgery), POSAS, and a VAS (both 42, 90, and 180 days after surgery). Five clinical studies reported improved observer-reported scar satisfaction as measured with the VSS, SBSES, OSAS, MSS, VAS, and POSAS (7, 15, 30, 42, 90, 180, and 365 days after surgery). Three clinical studies did not detect significant differences at any point in time (POSAS, VAS, and NRS). Because of imprecision concerns, a moderate level of evidence was identified using OHAT methodology. Preclinical as well as clinical evidence indicates a beneficial influence of iNPWT on scarring. Moderate level evidence indicates that iNPWT decreases scar width and improves patient and observer-reported scar satisfaction.

Burns in the elderly: a nationwide study on management and clinical outcomes.

BACKGROUND: In modern-day burn care, advanced age remains an important predictor for mortality among burn victims. In this study, we compared the complete treatment trajectory (including pre-hospital and surgical treatment) and the outcomes between an elderly burn population and a younger adult burn population. METHODS: In this nationwide study, data from the Dutch Burn Repository were used. This is a uniform national registration for Dutch specialized burn care. All adult patients that were admitted to one of the three Dutch burn centres from the period 2009 to 2015 were included in the analysis. Burn patients were considered as elderly when ≥65 years of age, and were then further subdivided into three age categories: 65-74, 75-85 and 85+ years. Younger adults in the age category 18-64 years were used as the reference group.Surgical management was studied comprehensively and included timing of surgery, the number of procedures and details on the surgical technique, especially the technique used for debridement and the grafting technique that was applied.For the comparison of clinical outcome, the following parameters were included: mortality, wound infections, length of stay/TBSA (total body surface area) burned, discharge disposition and secondary reconstructions. RESULTS: During the study period, 3155 adult patients were included (elderly, n = 505). Burn severity, reflected by the median TBSA, varied between 3.2-4.0% and was comparable, but aetiology and pre-hospital care were different between elderly and the younger adult reference group.Surgical treatment was initiated significantly faster in elderly burn patients (p < 0.001). Less selective techniques for surgical debridement were used in the elderly burns patients (hydrosurgery, 42.0% vs 23.5-22.6%), and on the other hand more avulsion (5.3% vs 7.3-17.6%) and primary wound closure (6.7% vs 24.5%). The most frequently used grafting technique was meshed skin grafts (79.2-88.6%); this was not related to age.Mortality increased rapidly with a higher age and showed a high peak in the 85+ category (23.8%). Furthermore, considerable differences were found in hospital discharge disposition between the elderly and the reference group. CONCLUSIONS: In conclusion, elderly burn patients who require specialized burn care are vulnerable and medically challenging. Differences in aetiology, comorbidity, physiology and the management prior to admission possibly affect the initial surgical management and result in significantly worse outcomes in elderly. Elderly patients need optimal, timely and specialized burn care to enhance survival after burn injuries.

Topical treatment for facial burns.

BACKGROUND: Burn injuries are an important health problem. They occur frequently in the head and neck region. The face is the area central to a person's identity that provides our most expressive means of communication. Topical interventions are currently the cornerstone of treatment of burns to the face. OBJECTIVES: To assess the effects of topical interventions on wound healing in people with facial burns of any depth. SEARCH METHODS: In December 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated the effects of topical treatment for facial burns were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, risk of bias assessment and GRADE assessment of the certainty of the evidence. MAIN RESULTS: In this first update, we included 12 RCTs, comprising 507 participants. Most trials included adults admitted to specialised burn centres after recent burn injuries. Topical agents included antimicrobial agents (silver sulphadiazine (SSD), Aquacel-Ag, cerium-sulphadiazine, gentamicin cream, mafenide acetate cream, bacitracin), non-antimicrobial agents (Moist Exposed Burn Ointment (MEBO), saline-soaked dressings, skin substitutes (including bioengineered skin substitute (TransCyte), allograft, and xenograft (porcine Xenoderm), and miscellaneous treatments (growth hormone therapy, recombinant human granulocyte-macrophage colony-stimulating factor hydrogel (rhGMCS)), enzymatic debridement, and cream with Helix Aspersa extract). Almost all the evidence included in this review was assessed as low or very low-certainty, often because of high risk of bias due to unclear randomisation procedures (i.e. sequence generation and allocation concealment); lack of blinding of participants, providers and sometimes outcome assessors; and imprecision resulting from few participants, low event rates or both, often in single studies. Topical antimicrobial agents versus topical non-antimicrobial agents There is moderate-certainty evidence that there is probably little or no difference between antimicrobial agents and non-antimicrobial agents (SSD and MEBO) in time to complete wound healing (hazard ratio (HR) 0.84 (95% confidence interval (CI) 0.78 to 1.85, 1 study, 39 participants). Topical antimicrobial agents may make little or no difference to the proportion of wounds completely healed compared with topical non-antimicrobial agents (comparison SSD and MEBO, risk ratio (RR) 0.94, 95% CI 0.68 to 1.29; 1 study, 39 participants; low-certainty evidence). We are uncertain whether there is a difference in wound infection (comparison topical antimicrobial agent (Aquacel-Ag) and MEBO; RR 0.38, 95% CI 0.12 to 1.21; 1 study, 40 participants; very low-certainty evidence). No trials reported change in wound surface area over time or partial wound healing. There is low-certainty evidence for the secondary outcomes scar quality and patient satisfaction. Two studies assessed pain but it was incompletely reported. Topical antimicrobial agents versus other topical antimicrobial agents It is uncertain whether topical antimicrobial agents make any difference in effects as the evidence is low to very low-certainty. For primary outcomes, there is low-certainty evidence for time to partial (i.e. greater than 90%) wound healing (comparison SSD versus cerium SSD: mean difference (MD) -7.10 days, 95% CI -16.43 to 2.23; 1 study, 142 participants). There is very low-certainty evidence regarding whether topical antimicrobial agents make a difference to wound infection (RR 0.73, 95% CI 0.46 to 1.17; 1 study, 15 participants). There is low to very low-certainty evidence for the proportion of facial burns requiring surgery, pain, scar quality, adverse effects and length of hospital stay. Skin substitutes versus topical antimicrobial agents There is low-certainty evidence that a skin substitute may slightly reduce time to partial (i.e. greater than 90%) wound healing, compared with a non-specified antibacterial agent (MD -6.00 days, 95% CI -8.69 to -3.31; 1 study, 34 participants). We are uncertain whether skin substitutes in general make any other difference in effects as the evidence is very low certainty. Outcomes included wound infection, pain, scar quality, adverse effects of treatment and length of hospital stay. Single studies showed contrasting low-certainty evidence. A bioengineered skin substitute may slightly reduce procedural pain (MD -4.00, 95% CI -5.05 to -2.95; 34 participants) and background pain (MD -2.00, 95% CI -3.05 to -0.95; 34 participants) compared with an unspecified antimicrobial agent. In contrast, a biological dressing (porcine Xenoderm) might slightly increase pain in superficial burns (MD 1.20, 95% CI 0.65 to 1.75; 15 participants (30 wounds)) as well as deep partial thickness burns (MD 3.00, 95% CI 2.34 to 3.66; 10 participants (20 wounds)), compared with antimicrobial agents (Physiotulle Ag (Coloplast)). Miscellaneous treatments versus miscellaneous treatments Single studies show low to very low-certainty effects of interventions. Low-certainty evidence shows that MEBO may slightly reduce time to complete wound healing compared with saline soaked dressing (MD -1.7 days, 95% CI -3.32 to -0.08; 40 participants). In addition, a cream containing Helix Aspersa may slightly increase the proportion of wounds completely healed at 14 days compared with MEBO (RR 4.77, 95% CI 1.87 to 12.15; 43 participants). We are uncertain whether any miscellaneous treatment in the included studies makes a difference in effects for the outcomes wound infection, scar quality, pain and patient satisfaction as the evidence is low to very low-certainty. AUTHORS' CONCLUSIONS: There is mainly low to very low-certainty evidence on the effects of any topical intervention on wound healing in people with facial burns. The number of RCTs in burn care is growing, but the body of evidence is still hampered due to an insufficient number of studies that follow appropriate evidence-based standards of conducting and reporting RCTs.

Course of scar quality of donor sites following split skin graft harvesting: Comparison between patients and observers.

There exists little to no data on the development of donor-site scars that remain after split skin graft harvesting. The objectives of this study were to (a) examine changes in characteristics of donor-site scar quality over time and (b) assess the agreement between patient-reported and observer-reported donor-site scar quality in a burn population. A prospective cohort study was conducted including patients who underwent split skin grafting for their burn injury. Patients and observers completed the Patient and Observer Scar Assessment Scale (POSAS) for the first harvested donor site at 3 and 12 months post-surgery. This study included 80 patients with a median age of 34 years. At 3 months post-surgery, the patients scored the POSAS items itch and color as most deviant from normal skin, both improved between 3 and 12 months (3.1 vs 1.5 and 5.0 vs 3.5, respectively [P < .001]). Other scar characteristics did not show significant change over time. The patients' overall opinion score improved from 3.9 to 3.2 (P < .001). Observers rated the items vascularization and pigmentation most severe, only vascularization improved significantly between both time points. Their overall opinion score decreased from 2.7 to 2.3 (P < .001). The inter-observer agreement between patients and observers was considered poor (ICC < 0.4) at both time points. Results of current study indicate that observers underestimate the impact of donor-site scars. This has to be kept in mind while guiding therapy and expectations. LEVEL OF EVIDENCE: II, prospective cohort study.

Evaluation of measurement properties of health-related quality of life instruments for burns: A systematic review.

BACKGROUND: Health-related quality of life (HRQL) is a key outcome in the evaluation of burn treatment. Health-related quality of life instruments with robust measurement properties are required to provide high-quality evidence to improve patient care. The aim of this review was to critically appraise the measurement properties of HRQL instruments used in burns. METHODS: A systematic search was conducted in Embase, MEDLINE, CINAHL, Cochrane, Web of Science, and Google scholar to reveal articles on the development and/or validation of HRQL instruments in burns. Measurement properties were assessed using the Consensus-based Standards for the selection of health Measurement Instruments methodology. A modified Grading of Recommendations, Assessment, Development, and Evaluation analysis was used to assess risk of bias (prospero ID, CRD42016048065). RESULTS: Forty-three articles covering 15 HRQL instruments (12 disease-specific and 3 generic instruments) were included. Methodological quality and evidence on measurement properties varied widely. None of the instruments provided enough evidence on their measurement properties to be highly recommended for routine use; however, two instruments had somewhat more favorable measurement properties. The Burn-Specific Health Scale-Brief (BSHS-B) is easy to use, widely accessible, and demonstrated sufficient evidence for most measurement properties. The Brisbane Burn Scar Impact Profiles were the only instruments with high-quality evidence for content validity. CONCLUSION: The Burn Specific Health Scale-Brief (burn-specific HRQL) and the Brisbane Burn Scar Impact Profile (burn scar HRQL) instruments have the best measurement properties. There is only weak evidence on the measurement properties of generic HRQL instruments in burn patients. Results of this study form important input to reach consensus on a universally used instrument to assess HRQL in burn patients. LEVEL OF EVIDENCE: Systematic review, level III.

Allogeneic platelet-rich plasma (PRP) is superior to platelets or plasma alone in stimulating fibroblast proliferation and migration, angiogenesis, and chemotaxis as relevant processes for wound healing.

BACKGROUND: Platelet-rich plasma (PRP) is frequently used in the treatment of acute and chronic wounds. One of the major problems concerning the use of PRP is the absence of a well-characterized and standardized product, which leads to a high variety in study outcomes. Therefore, more studies on the composition and standardization of PRP in wound healing are needed. STUDY DESIGN AND METHODS: Platelet concentrates derived from healthy blood donors were made in plasma (PC-plasma) or platelet additive solution (PC-PAS). The effects of PC-plasma, PC-PAS, and plasma were then tested on proliferation, differentiation, and migration of fibroblasts, as well as sprouting of endothelial cells in fibrin gels and chemotaxis of white blood cells (WBCs). RESULTS: PC-plasma stimulates the migration and proliferation of human dermal fibroblasts more than plasma or platelets alone. Furthermore, platelet factors decrease the expression of α-smooth muscle actin in dermal fibroblast cultures. PC-plasma also stimulates sprouting of endothelial cells. Finally, PC-plasma also acts as a strong chemoattractant for WBCs. CONCLUSIONS: Allogeneic PC-plasma has beneficial effects on various aspects of wound healing in vitro and is superior to plasma or platelets alone. PC-plasma is an attractive candidate for further in vivo evaluation.

Preexpansion in Phalloplasty Patients: Is It Effective?

BACKGROUND: Phalloplasty is performed as genital gender-affirming surgery in transmasculine persons. It requires the harvest of sizeable autologous fasciocutaneous flaps, which is associated with donor-site morbidity and extensive scarring. Flap preexpansion has been used to facilitate wound closure and reduce scarring, but the efficacy of flap preexpansion in phalloplasty is unclear. The objective of this study was to assess the safety and effectiveness of preexpansion before phalloplasty. METHODS: Transmasculine persons who underwent phalloplasty between December 2006 and July 2014 at our institution were identified and invited to participate. A chart review was performed to obtain patient demographics and expander-related complications. Outcomes regarding the donor-site scar (Patient Observer Scar Assessment Scale, scar size, patient satisfaction) were measured at the outpatient clinic and compared between transmasculine persons treated with and transmasculine persons treated without preexpansion. RESULTS: Of 33 transmasculine persons who underwent phalloplasty, 17 underwent preexpansion. Phalloplasty techniques included the use of the radial forearm free flap, the anterolateral thigh flap, or a combination of both. In total, 34 tissue expanders were placed in the forearm (n = 12) and/or thigh (n = 22). Complications occurred in 18 (52.9%) of 34 tissue expanders and in 13 (76.5%) of 17 transmasculine persons. Seven reoperations were performed because of extrusion (n = 2), infection (n = 2), port failure (n = 2), or leakage (n = 1). Sixteen transmasculine persons visited our clinic for scar assessment (8 with and 8 without preexpansion). Primary closure was achieved in 4 (31%) of 13 expanded donor sites. Relative scar size was reduced when the wound could be closed primarily, but overall scar size, quality, and satisfaction did not differ significantly between groups. CONCLUSION: Donor-site expansion before phalloplasty was associated with high rates of expander-related complications and expander failure. Primary closure of the donor site was achieved in less than a third of the cases. Primary closure may potentially lead to smaller scars and greater satisfaction; however, we concluded that the potential advantages of preexpansion do not outweigh the high risk of complications and lack of success.

A Cultured Autologous Dermo-epidermal Skin Substitute for Full-Thickness Skin Defects: A Phase I, Open, Prospective Clinical Trial in Children.

BACKGROUND: The management of deep partial-thickness and full-thickness skin defects remains a significant challenge. Particularly with massive defects, the current standard treatment, split-thickness skin grafting, is fraught with donor-site limitations and unsatisfactory long-term outcomes. A novel, autologous, bioengineered skin substitute was developed to address this problem. METHODS: To determine whether this skin substitute could safely provide permanent defect coverage, a phase I clinical trial was performed at the University Children's Hospital Zurich. Ten pediatric patients with acute or elective deep partial- or full-thickness skin defects were included. Skin grafts of 49 cm were bioengineered using autologous keratinocytes and fibroblasts isolated from a patient's small skin biopsy specimen (4 cm), incorporated in a collagen hydrogel. RESULTS: Graft take, epithelialization, infection, adverse events, skin quality, and histology were analyzed. Median graft take at 21 days postoperatively was 78 percent (range, 0 to 100 percent). Healed skin substitutes were stable and skin quality was nearly normal. There were four cases of hematoma leading to partial graft loss. Histology at 3 months revealed a well-stratified epidermis and a dermal compartment comparable to native skin. Mean follow-up duration was 15 months. CONCLUSIONS: In the first clinical application of this novel skin substitute, safe coverage of skin defects was achieved. Safety and efficacy phase II trials comparing the novel skin substitute to split-thickness skin grafts are ongoing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Monitoring 111In-labelled polyisocyanopeptide (PIC) hydrogel wound dressings in full-thickness wounds.

Wounds often result in scarring, prolonged morbidity, and loss of function. New interactive and modifiable hydrogel wound dressings are being developed for these injuries. Polyisocyanopeptide (PIC) gel is a promising thermosensitive hydrogel having several characteristics that can facilitate wound repair, including ease of application/removal and strain-stiffening properties that mimic extracellular matrix components. However, it is unknown whether the PIC gel remains in the wound for a clinically relevant time period. Therefore, PIC polymers were functionalized with a DTPA group allowing labelling with Indium-111 (111In). Following application of this radiolabelled gel to splinted and non-splinted murine full-thickness skin wounds the signal was monitored using SPECT/CT imaging for 7 days. The SPECT signal from the PIC gel was highly stable and covered the complete wound area. Non-bound 111In-EDTA was rapidly cleared via the kidneys to the urine. The impact of PIC gels on wound repair was further studied visually and histologically. Radiolabelled PIC gel was observed to move both over and under the skin, while histological analysis demonstrated that part of the gel became encapsulated within the wound repair tissue, but did not delay wound closure or otherwise impair wound healing. This work illustrates for the first time the use of 111In-labelled PIC gels for diagnostic and monitoring purposes and describes the use of PIC in the (non-)splinted murine skin wound model. It was found that PIC gels remained in splinted and non-splinted full-thickness skin wounds during wound repair. This warrants the continuation of developing the PIC gel into a clinically advanced wound dressing.

Thermosensitive biomimetic polyisocyanopeptide hydrogels may facilitate wound repair.

Changing wound dressings inflicts pain and may disrupt wound repair. Novel synthetic thermosensitive hydrogels based on polyisocyanopeptide (PIC) offer a solution. These gels are liquid below 16 °C and form gels beyond room temperature. The architecture and mechanical properties of PIC gels closely resemble collagen and fibrin, and include the characteristic stiffening response at high strains. Considering the reversible thermo-responsive behavior, we postulate that PIC gels are easy to apply and remove, and facilitate healing without eliciting foreign body responses or excessive inflammation. Biocompatibility may be higher in RGD-peptide-functionalized PIC gels due to enhanced cell binding capabilities. Full-thickness dorsal skin wounds in mice were compared to wounds treated with PIC gel and PIC-RGD gel for 3 and 7 days. No foreign body reactions and similar wound closure rates were found in all groups. The level of macrophages, myofibroblasts, epithelial migration, collagen expression, and blood vessels did not significantly differ from controls. Surprisingly, granulocyte populations in the wound decreased significantly in the PIC gel-treated groups, likely because foreign bacteria could not penetrate the gel. RGD-peptides did not further improve any effect observed for PIC. The absence of adverse effects, ease of application, and the possibilities for bio-functionalization make the biomimetic PIC hydrogels suitable for development into wound dressings.

Long-term scar quality after hydrosurgical versus conventional debridement of deep dermal burns (HyCon trial): study protocol for a randomized controlled trial.

BACKGROUND: Deep dermal burns require tangential excision of non-viable tissue and skin grafting to improve wound healing and burn-scar quality. Tangential excision is conventionally performed with a knife, but during the last decade hydrosurgery has become popular as a new tool for tangential excision. Hydrosurgery is generally thought to be a more precise and controlled manner of burn debridement leading to preservation of viable tissue and, therefore, better scar quality. Although scar quality is considered to be one of the most important outcomes in burn surgery today, no randomized controlled study has compared the effect of these two common treatment modalities with scar quality as a primary outcome. The aim of this study is, therefore, to compare long-term scar quality after hydrosurgical versus conventional tangential excision in deep dermal burns. METHODS/DESIGN: A multicenter, randomized, intra-patient, controlled trial will be conducted in the Dutch burn centers of Rotterdam, Beverwijk, and Groningen. All patients with deep dermal burns that require excision and grafting are eligible. Exclusion criteria are: a burn wound < 50 cm2, total body surface area (TBSA) burned > 30%, full-thickness burns, chemical or electrical burns, infected wounds (clinical symptoms in combination with positive wound swabs), insufficient knowledge of the Dutch or English language, patients that are unlikely to comply with requirements of the study protocol and follow-up, and patients who are (temporarily) incompetent because of sedation and/or intubation. A total of 137 patients will be included. Comparable wound areas A and B will be appointed, randomized and either excised conventionally with a knife or with the hydrosurgery system. The primary outcome is scar quality measured by the observer score of the Patient and Observer Scar Assessment Scale (POSAS); a subjective scar-assessment instrument, consisting of two separate six-item scales (observer and patient) that are both scored on a 10-point rating scale. DISCUSSION: This study will contribute to the optimal surgical treatment of patients with deep dermal burn wounds. TRIAL REGISTRATION: Dutch Trial Register, NTR6232 . Registered on 23 January 2017.

Early intervention by Captopril does not improve wound healing of partial thickness burn wounds in a rat model.

The Renin Angiotensin System is involved in fibrotic pathologies in various organs such as heart, kidney and liver. Inhibition of this system by angiotensin converting enzyme antagonists, such as Captopril, has been shown beneficial effects on these pathologies. Captopril reduced the inflammatory reaction but also directly influenced the fibrotic process. Prolonged and excessive inflammatory response is a major cause of hypertrophic scar formation in burns. We therefore evaluated the effect of Captopril on the healing of partial thickness burn wounds in a rat model. Partial thickness contact burns were inflicted on the dorsum of the rats. The rats received either systemic or local treatment with Captopril. The inflammatory reaction and wound healing (scar) parameters were investigated and compared to control animals. In this study we could not detect positive effects of either administration route with Captopril on the inflammatory reaction, nor on wound healing parameters. The local treatment showed reduced wound closure in comparison to the systemic treatment and the control group. Early Captopril treatment of burn wounds did not show the beneficial effects that were reported for fibrotic disorders in other tissues. To influence the fibrotic response Captopril treatment at a later time point, e.g. during the remodeling phase, might still have beneficial effects.

Sustainable effectiveness of single-treatment autologous fat grafting in adherent scars.

Following severe injury, not just the skin but also the subcutis may be destroyed. Consequently, the developing scar can become adherent to underlying structures. Reconstruction of the subcutis can be achieved by autologous fat grafting. Our aim was to evaluate the long-term scar outcome after single-treatment autologous fat grafting using a comprehensive scar evaluation protocol. Scar assessment was performed preoperatively in 40 patients. A 12-month follow-up assessment was performed in 36 patients, using the Cutometer, the Patient and Observer Scar Assessment Scale, and DSM II ColorMeter. The Cutometer parameters elasticity and maximal extension improved with 28 and 22% (both p < 0.001), respectively. Nearly all scores of the scar assessment scale decreased significantly, which corresponds to improved scar quality. In addition, the mean melanin score was ameliorated over time. Thus, we demonstrated the sustainable effectiveness of single-treatment autologous fat grafting in adherent scars, indicated by improved pliability, and overall scar quality.