Controlling Inflammation Pre-Emptively or at the Time of Cutaneous Injury Optimises Outcome of Skin Scarring.

Inflammation plays an active role during the wound healing process. There is a direct association between the extent of injury as well as inflammation and the amount of subsequent cutaneous scarring. Evidence to date demonstrates that high levels of inflammation are associated with excessive dermal scarring and formation of abnormal pathological scars such as keloids and hypertrophic scars. In view of the multiple important cell types being involved in the inflammatory process and their influence on the extent of scar formation, many scar therapies should aim to target these cells in order to control inflammation and by association help improve scar outcome. However, most current treatment strategies for the management of a newly formed skin scar often adopt a watch-and-wait approach prior to commencing targeted anti-inflammatory therapy. Moreover, most of these therapies have been evaluated in the remodelling phase of wound healing and the evaluation of anti-inflammatory treatments at earlier stages of healing have not been fully explored and remain limited. Taken together, in order to minimise the risk of developing a poor scar outcome, it is clear that adopting an early intervention prior to skin injury would be optimal, however, the concept of pre-emptively priming the skin prior to injury has not yet been thoroughly evaluated. Therefore, the aim of this review was to evaluate the available literature regarding scar therapies that aim to target inflammation which are commenced prior to when a scar is formed or immediately after injury, with a particular focus on the role of pre-emptive priming of skin prior to injury in order to control inflammation for the prevention of poor scarring outcome.

Noninvasive Objective Tools for Quantitative Assessment of Skin Scarring.

Significance: Many treatments are utilized in the management of skin scarring; however, difficulties arise due to the high rates of recurrence and the identification of treatment efficacy in each patient, in particular, in the case of raised dermal scarring. Therefore, evaluation of treatments and the provision of objective scar assessment pre-therapy and post-therapy is of paramount importance to identify changes in scar characteristics using noninvasive devices. Recent Advances: There have been a number of emerging noninvasive objective quantitative devices, which assess specific scar parameters such as pliability, volume, color, perfusion, and depth. These can include three-dimensional imaging, optical coherence tomography, in vivo confocal microscopy, full-field laser perfusion imaging, and spectrophotometric intracutaneous analysis. Critical Issues: Clinical assessment and grading scales are most commonly used to assess scarring; however, there is a need for more objective quantitative measures to monitor their maturation and response to therapy. Currently, there is no consensus as to which objective measuring device is most optimal when assessing skin scarring. There is a need for a predictor tool that allows early implementation of treatment and addresses diagnosis, therapy, and prognosis. Future Directions: Validation of noninvasive objective scar assessment tools is essential as well as further development of technologies. There are currently more modalities that assess physical scar characteristics and only few that measure the physiological parameters. Therefore, the development of a technology that quantifies the metabolic and cellular activity in skin scars is necessary to allow for bespoke strategies for each patient.

Classification of Distinct Endotypes in Human Skin Scarring: S.C.A.R.-A Novel Perspective on Dermal Fibrosis.

Significance: Skin scarring is a permanent, irreversible end point of cutaneous injury. However, not everyone will acquire the same exact scar type. Skin scarring is generally recognized as complex with significant variability in individuals' scar type and response to treatment. Despite these tangible differences in treatment response, to date there has been no simplified approach in defining spectrum of skin scarring in relation to prediction and outcome post-treatment. Thus, in this study we propose that skin scarring consists of distinct endotypes, which is characterized by their specific pathology. Four distinct scar endotypes can be observed: (1) Stretched (flat), (2) Contracted, (3) Atrophic (depressed), and (4) Raised scarring, which can be abbreviated to S.C.A.R. endotypes. Each of these endotypes can certainly include subphenotypes and each phenotype can be present in more than one endotype. To define these endotypes, we also present a structured approach in assessment of all relevant parameters in skin scar evaluation including clinical (scar symptoms and signs) and nonclinical parameters (device measurements of structural, mechanical, and physiological properties of scars as well as gene and protein laboratory studies). Recent Advances: Scars can be phenotypically characterized based on a multitude of parameters assessed; however, not all scar types will share all the same characteristics. This leads to the question of whether skin scarring is a single disease entity with varying phenotypic characteristics or should be classed as several disease entities that have certain similar parameters. We suggest the latter and propose distinct scarring phenotypes arise mainly owing to genetic and environmental susceptibilities associated with the development of each specific scar endotype. Characteristic features of skin scarring, however, can be objectively and quantitively evaluated and used as an aid in the theranostic goal-directed management of scarring. Critical Issues: The concept of identifying different endotypes is key in formulating personalized treatments with improved outcomes beyond what is achieved with current nonspecific approaches in scar management. This approach has gained interest and significant traction in several other medical conditions including asthma, rheumatoid arthritis, and atopic dermatitis. Future Directions: To begin identifying distinct endotypic features in skin scarring, it is important to have a better understanding of underlying pathological mechanisms leading to further insight into the heterogeneous nature of skin scarring endotypes. This approach may lead to improved theranostic outcomes and further understanding of the pathophysiology of the complex nature of human skin scarring.

Pre-Emptive Priming of Human Skin Improves Cutaneous Scarring and Is Superior to Immediate and Delayed Topical Anti-Scarring Treatment Post-Wounding: A Double-Blind Randomised Placebo-Controlled Clinical Trial.

The concept of pre-emptive priming of skin pre-surgery offers a novel approach in optimizing cutaneous scarring outcome. We previously showed an anti-scarring topical (epigallocatechin-3-gallate (EGCG)) is effective in improving skin scarring when applied post-surgery. The objective was to deliver an active compound at the optimal time in order to maximize its impact and improve cutaneous scarring. Therefore, pre-emptive application of anti-scarring topical pre-surgery compared with post-surgery can potentially be superior on scarring outcome. This double-blinded randomized placebo-controlled trial compares the effects of pre-emptive priming of skin with an anti-scarring topical pre-surgery versus post-surgery. Healthy volunteers (n = 40) were split into 4-groups; each undergoing different modes of application versus placebo: Group-1 = priming (7Days) pre-injury, Group-2 = priming (3D) pre-injury, Group-3 = immediate (0D) day-of-injury, Group-4 = delayed application (14D) post-injury. Excisional skin-biopsies in upper-arms were evaluated weekly with multiple quantitative devices over 8-weeks. Histological, immunohistochemical, mRNA sequencing and QRT-PCR studies were performed on tissue-biopsies. EGCG reduced mast cells at weeks-4 and 8 by gene and protein analyses (p < 0.01). Group 1 was superior to other groups (p < 0.01) in both clinical (blood flow) and laboratory parameters (elastin and immune marker expression). Additionally, there was down-regulation of angiogenic-markers by mRNA-sequencing and of CD31 and VEGF-A at weeks-4 and 8 (p < 0.01) by immunohistochemistry and at week-4 (p < 0.05) by QRT-PCR. EGCG increased antioxidant levels (HO-1) at week-4 (p < 0.01) plus elastin at week-8 (p < 0.01). In conclusion, pre-emptive priming of skin pre-injury has significant beneficial effects on surgically induced skin scarring shown by reducing mast cells, blood flow and angiogenesis plus increasing elastin content. This clinical trial was registered with ISRCTN (ISRCTN70155584).

A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis.

Scars are generated in mature skin as a result of the normal repair process, but the replacement of normal tissue with scar tissue can lead to biomechanical and functional deficiencies in the skin as well as psychological and social issues for patients that negatively affect quality of life. Abnormal scars, such as hypertrophic scars and keloids, and cutaneous fibrosis that develops in diseases such as systemic sclerosis and graft-versus-host disease can be even more challenging for patients. There is a large body of literature suggesting that inflammation promotes the deposition of scar tissue by fibroblasts. Mast cells represent one inflammatory cell type in particular that has been implicated in skin scarring and fibrosis. Most published studies in this area support a pro-fibrotic role for mast cells in the skin, as many mast cell-derived mediators stimulate fibroblast activity and studies generally indicate higher numbers of mast cells and/or mast cell activation in scars and fibrotic skin. However, some studies in mast cell-deficient mice have suggested that these cells may not play a critical role in cutaneous scarring/fibrosis. Here, we will review the data for and against mast cells as key regulators of skin fibrosis and discuss scientific gaps in the field.

Mast Cells in Skin Scarring: A Review of Animal and Human Research.

Mast cells (MCs) are an important immune cell type in the skin and play an active role during wound healing. MCs produce mediators that can enhance acute inflammation, stimulate re-epithelialisation as well as angiogenesis, and promote skin scarring. There is also a link between MCs and abnormal pathological cutaneous scarring, with increased numbers of MCs found in hypertrophic scars and keloid disease. However, there has been conflicting data regarding the specific role of MCs in scar formation in both animal and human studies. Whilst animal studies have proved to be valuable in studying the MC phenomenon in wound healing, the appropriate translation of these findings to cutaneous wound healing and scar formation in human subjects remains crucial to elucidate the role of these cells and target treatment effectively. Therefore, this perspective paper will focus on evaluation of the current evidence for the role of MCs in skin scarring in both animals and humans in order to identify common themes and future areas for translational research.

Keloid scarring or disease: Unresolved quasi-neoplastic tendencies in the human skin.

Keloids are benign fibroproliferative dermal scars of unknown etiopathogenesis resulting in an exophytic protuberant growth with persistent and progressive peri-lesional expansile behavior. Keloids are likened to benign neoplastic lesions due to their aggressive clinical behavior, genotypic-phenotypic tissue characteristics, and resistance to treatment. Keloids are traditionally viewed as scars on the healing spectrum; however, keloids are a distinct pathology provoked by cutaneous injury rather than a continuum. In order to elucidate the etiopathogenesis of keloids, the distinction between scar and disease must be made. Therefore, we hypothesize that the link between keloids and their quasi-neoplastic tendencies distinguish it as a disease rather than a scar alone. The biomarker expression profile in these diseases highlight the striking parallels between keloids and both benign and malignant mesenchymal tumors. Signaling pathways common to these diseases have been found to guide the matrix composition of keloids. This hypothesis underscores the need to identify keloids not as a scar but as a disease in order to develop targeted therapy, which can lead to enhanced diagnosis and theranosis.

A Double-Blind, Randomized Trial Shows the Role of Zonal Priming and Direct Topical Application of Epigallocatechin-3-Gallate in the Modulation of Cutaneous Scarring in Human Skin.

BACKGROUND: Epigallocatechin-3-gallate (EGCG), a polyphenol, influences cutaneous wound healing because of its antiangiogenic, anti-inflammatory, and antioxidant properties. We previously showed the role of EGCG in scarring in ex vivo human scar models. Here, we evaluate direct application of topical EGCG compared with zonal priming, a unique concept in the immediate treatment of the zone of injury at the time of wounding before scar formation. TRIAL DESIGN: Double-blind randomized controlled trial. METHODS: We assessed EGCG application compared with placebo over 1-6 weeks in scars created in 62 human volunteers using quantitative noninvasive devices, immunohistochemical analysis, mRNA sequencing, and quantitative real-time reverse transcriptase-PCR of tissue biopsy samples. RESULTS: EGCG reduced mast cells at weeks 1-3, as evidenced by gene and protein analyses (P ≤ 0.01). M2 macrophages were increased with EGCG compared with placebo. EGCG application by zonal priming significantly down-regulated VEGFA and CD31 at week 1 and at 1-2 weeks after direct application (P ≤ 0.01). Direct EGCG application also reduced scar thickness at weeks 1-3 (P = 0.001) and increased scar elasticity at week 4 (P = 0.01). Increased hydration was evident both noninvasively and by increased hyaluronic acid levels (P < 0.01) at week 3. CONCLUSIONS: We show the beneficial role of both zonal priming and direct EGCG application in scar therapy with positive effects on scar thickness, erythema, hydration, and elasticity. Trial register: International standard randomized controlled trial, registration number ISRCTN 18643079; July 16, 2018.

Non-animal models of wound healing in cutaneous repair: In silico, in vitro, ex vivo, and in vivo models of wounds and scars in human skin.

Tissue repair models are essential to explore the pathogenesis of wound healing and scar formation, identify new drug targets/biomarkers and to test new therapeutics. However, no animal model is an exact replicate of the clinical situation in man as in addition to differences in the healing of animal skin; the response to novel therapeutics can be variable when compared to human skin. The aim of this review is to evaluate currently available non-animal wound repair models in human skin, including: in silico, in vitro, ex vivo, and in vivo. The appropriate use of these models is extremely relevant to wound-healing research as it enables improved understanding of the basic mechanisms present in the wound healing cascade and aid in discovering better means to regulate them for enhanced healing or prevention of abnormal scarring. The advantage of in silico models is that they can be used as a first in virtue screening tool to predict the effect of a drug/stimulus on cells/tissues and help plan experimental research/clinical trial studies but remain theoretical until validated. In vitro models allow direct quantitative examination of an effect on specific cell types alone without incorporating other tissue-matrix components, which limits their utility. Ex vivo models enable immediate and short-term evaluation of a particular effect on cells and its surrounding tissue components compared with in vivo models that provide direct analysis of a stimulus in the living human subject before/during/after exposure to a stimulus. Despite clear advantages, there remains a lack of standardisation in design, evaluation and follow-up, for acute/chronic wounds and scars in all models. In conclusion, ideal models of wound healing research are desirable and should mimic not only the structure but also the cellular and molecular interactions, of wound types in human skin. Future models may also include organ/skin-on-a-chip with potential application in wound healing research.

Non-invasive objective devices for monitoring the inflammatory, proliferative and remodelling phases of cutaneous wound healing and skin scarring.

Objective evaluation of cutaneous wounds through the use of non-invasive devices is important for diagnosis, monitoring treatment response and can lead to the development of improved theranostic strategies. The need for objective monitoring of wound healing and scar formation is evident as this enables accurate diagnosis, evaluation and prognosis for clinicians and allows for the standardisation and validation of methodology for researchers. Therefore, this review provides an overview of the current application of non-invasive objective technologies for the assessment of wound healing through the different phases of repair. We propose that cutaneous healing parameters can be split into three core domains: anatomical, mechanical and physiological. These categories can be further subdivided with respect to specific phases of healing. There is no single instrument, which can measure all the parameters of healing simultaneously; thus, it is important to choose the correct device for the particular healing characteristics being monitored. However, multiprobe systems, which include a number of devices connected to one main unit, are useful as they enable multiple measurements of different parameters. Many of the devices have not been validated against histological examination. Additionally, some of the instruments have not been evaluated in all wound or scar types and may not be useful throughout all phases of cutaneous wound healing. In conclusion, non-invasive objective devices are useful in the assessment of cutaneous wound healing, as these tools can link the treatment and diagnosis by evaluating response to treatment and thus could aid as a marker for healing and scar maturation.

Noninvasive device readouts validated by immunohistochemical analysis enable objective quantitative assessment of acute wound healing in human skin.

Objective evaluation of cutaneous wounds through use of noninvasive devices has important implications for diagnosis, monitoring treatment efficacy, progression and may lead to development of improved theranostic treatment strategies. However, there is a lack of validation in the use of certain devices in wound repair, where objective measurements taken by noninvasive devices have been corroborated by immunohistochemical analysis. Thus, data from three acute wound-healing studies in healthy volunteers using three noninvasive objective devices were further evaluated by immunohistochemistry. One hundred ten participants had 5-mm diameter skin biopsies to their arms. Spectrophotometric intracutaneous analysis (SIAscopy), full-field laser perfusion imaging, and three-dimensional imaging provided quantitative measurements of melanin, hemoglobin, collagen, blood flow, and wound size; all of which were validated by immunohistochemistry. Full-field laser perfusion imaging showed blood flow increased to D7 and decreased by 40% to D14. SIAscopy showed that hemoglobin increased to D7 and reduced to D14. CD31 analysis corroborated this by showing a 76% increase in blood vessel density to D7 and a reduction by 14% to D14. Three-dimensional imaging showed that wound surface area reduced by 50% from day 7 to day 14. Alpha-smooth muscle Actin (Alpha-SMA) staining supported these trends by showing increased levels by 72% from D0 to D14 (corresponding to wound contraction). Collagen, measured by SIAscopy, decreased to D7 and increased to D14, which was validated by collagen III analysis. Additionally, collagen I increased by 14% from D0 to D14. SIAscopy measurements for melanin showed an increase at D7 and a slight reduction to D14, while melanogenesis increased by 46.7% from D0 to D14. These findings show the utility of noninvasive objective devices in the quantitative evaluation of wound-healing parameters in human skin as corroborated by immunohistochemistry. This may contribute to the development of prognostic parameters for assessment of response to wound therapy.

Angiogenesis is induced and wound size is reduced by electrical stimulation in an acute wound healing model in human skin.

Angiogenesis is critical for wound healing. Insufficient angiogenesis can result in impaired wound healing and chronic wound formation. Electrical stimulation (ES) has been shown to enhance angiogenesis. We previously showed that ES enhanced angiogenesis in acute wounds at one time point (day 14). The aim of this study was to further evaluate the role of ES in affecting angiogenesis during the acute phase of cutaneous wound healing over multiple time points. We compared the angiogenic response to wounding in 40 healthy volunteers (divided into two groups and randomised), treated with ES (post-ES) and compared them to secondary intention wound healing (control). Biopsy time points monitored were days 0, 3, 7, 10, 14. Objective non-invasive measures and H&E analysis were performed in addition to immunohistochemistry (IHC) and Western blotting (WB). Wound volume was significantly reduced on D7, 10 and 14 post-ES (p = 0.003, p = 0.002, p<0.001 respectively), surface area was reduced on days 10 (p = 0.001) and 14 (p<0.001) and wound diameter reduced on days 10 (p = 0.009) and 14 (p = 0.002). Blood flow increased significantly post-ES on D10 (p = 0.002) and 14 (p = 0.001). Angiogenic markers were up-regulated following ES application; protein analysis by IHC showed an increase (p<0.05) in VEGF-A expression by ES treatment on days 7, 10 and 14 (39%, 27% and 35% respectively) and PLGF expression on days 3 and 7 (40% on both days), compared to normal healing. Similarly, WB demonstrated an increase (p<0.05) in PLGF on days 7 and 14 (51% and 35% respectively). WB studies showed a significant increase of 30% (p>0.05) on day 14 in VEGF-A expression post-ES compared to controls. Furthermore, organisation of granulation tissue was improved on day 14 post-ES. This randomised controlled trial has shown that ES enhanced wound healing by reduced wound dimensions and increased VEGF-A and PLGF expression in acute cutaneous wounds, which further substantiates the role of ES in up-regulating angiogenesis as observed over multiple time points. This therapeutic approach may have potential application for clinical management of delayed and chronic wounds.

Regenerative healing, scar-free healing and scar formation across the species: current concepts and future perspectives.

All species have evolved mechanisms of repair to restore tissue function following injury. Skin scarring is an inevitable and permanent endpoint for many postnatal organisms except for non-amniote vertebrates such as amphibians, which are capable of tissue regeneration. Furthermore, mammalian foetuses through mid-gestation are capable of rapid wound repair in the absence of scar formation. Notably, excessive cutaneous scar formation, such as hypertrophic and keloid scars, is a species limited clinical entity as it occurs only in humans, although wounds on the distal limbs of horses are also prone to heal with fibroproliferative pathology known as equine exuberant granulation tissue. Currently, there are no reliable treatment options to eradicate or prevent scarring in humans and vertebrates. The limited number of vertebrate models for either hypertrophic or keloid scarring has been an impediment to mechanistic studies of these diseases and the development of therapies. In this viewpoint essay, we highlight the current concepts of regenerative, scar-free and scar-forming healing compared across a number of species and speculate on areas for future research. Furthermore, in-depth investigative research into the mechanisms of scarless repair may allow for the development of improved animal models and novel targets for scar prevention. As the ability to heal in both a scarless manner and propensity for healing with excessive scar formation is highly species dependent, understanding similarities and differences in healing across species as it relates to the regenerative process may hold the key to improve scarring and guide translational wound-healing studies.

New insights on keloids, hypertrophic scars, and striae.

This article presents an overview of the literature regarding treatments for keloid disease, hypertrophic scars, and striae distensae in dark pigmented skin. Striae, keloid, and hypertrophic scarring present a challenging problem for both the clinician and patient. No single therapy is advocated for hypertrophic scars, keloid scars, or striae distensae. New therapies have shown promise in the treatment of hypertrophic and keloid scars, and in patients with dark pigmented skin. This article provides guidance on the assessment and determination of patients' suitability for certain treatment options, as well as advice on the follow-up of patients affected with problematic scarring and striae.

Electrical Stimulation and Cutaneous Wound Healing: A Review of Clinical Evidence.

Electrical stimulation (ES) has been shown to have beneficial effects in wound healing. It is important to assess the effects of ES on cutaneous wound healing in order to ensure optimization for clinical practice. Several different applications as well as modalities of ES have been described, including direct current (DC), alternating current (AC), high-voltage pulsed current (HVPC), low-intensity direct current (LIDC) and electrobiofeedback ES. However, no one method has been advocated as the most optimal for the treatment of cutaneous wound healing. Therefore, this review aims to examine the level of evidence (LOE) for the application of different types of ES to enhance cutaneous wound healing in the skin. An extensive search was conducted to identify relevant clinical studies utilising ES for cutaneous wound healing since 1980 using PubMed, Medline and EMBASE. A total of 48 studies were evaluated and assigned LOE. All types of ES demonstrated positive effects on cutaneous wound healing in the majority of studies. However, the reported studies demonstrate contrasting differences in the parameters and types of ES application, leading to an inability to generate sufficient evidence to support any one standard therapeutic approach. Despite variations in the type of current, duration, and dosing of ES, the majority of studies showed a significant improvement in wound area reduction or accelerated wound healing compared to the standard of care or sham therapy as well as improved local perfusion. The limited number of LOE-1 trials for investigating the effects of ES in wound healing make critical evaluation and assessment somewhat difficult. Further, better-designed clinical trials are needed to improve our understanding of the optimal dosing, timing and type of ES to be used.

A double-blind controlled clinical trial assessing the effect of topical gels on striae distensae (stretch marks): a non-invasive imaging, morphological and immunohistochemical study.

Striae distensae (SD) are cutaneous lesions often presenting post-pregnancy with atrophy and flattening of the epidermis. SD is poorly understood and treatment remains ill-defined. Our aim was to assess the effect of topical application of silicone gel compared with placebo on SD using non-invasive devices and by immunohistochemical analysis of sequential tissue biopsies in a double-blind controlled trial. Twenty volunteers massaged silicone and placebo gels into separate sides of the abdomen, daily for 6 weeks. Objective non-invasive imaging plus subjective self-assessment of SD were performed on days 0, 21, 42, 90, in addition to tissue biopsies on days 0 and 42. Non-invasive imaging demonstrated an increase in melanin and a decrease in haemoglobin, collagen and pliability over the 6-week period on both sides. Additionally, collagen levels in SD were significantly higher (p value = 0.001) and melanin levels lower (p value = 0.048) with silicone gel compared with placebo. Histological analysis revealed epidermal flattening with a reduction of rete ridges in SD on both sides. Vascular count significantly decreased with placebo gel (p = 0.002). Corroborating the clinical results, melanin levels increased, whilst collagen type 1 and elastin decreased on both sides. Non-invasive techniques showed that the application of silicone gel increased collagen levels and reduced pigmentation compared with placebo. However, both clinical and histological data revealed that melanin increased whilst collagen, elastin and pliability decreased over the 6-week period with both gels. Furthermore, vascularity significantly decreased with placebo gel. These findings provide preliminary evidence of the utility of topical gels in the clinical management of SD.

Identification of steroid sensitive responders versus non-responders in the treatment of keloid disease.

Intralesional corticosteroid injection is a well-recognised treatment modality for keloid disease (KD). Approximately 50% of KD cases are considered non-responders (or steroid resistant) with no consensus or indicators in detecting steroid-sensitive cases. In view of the undesirable side effects, uncertainty in timing and regularity of steroid treatment, we planned to identify responders and non-responders to target treatment more effectively. A scar injection proforma was developed capturing a detailed history focusing on symptoms and signs (redness, appearance, contour, texture, distortion and severity) associated with KD. The cause, site, number of keloid scars and scar recurrence were recorded as the lesions were injected on a monthly basis. A detailed description of response to steroid injection was documented and photographs were taken. Demographic data were collected on 65 patients (11 to 74 years with mean age 34.7 years, 60% were females, 50% were Caucasian). 77% (n = 50) were classified as steroid responders and showed improvement in symptoms and signs within 3 months. There was a statistically significant correlation between patients with higher contour scores of KD prior to treatment (p = 0.013) and frequency of injections (p = 0.003). Thus, the odds of being a responder were greater for patients with more than one injection and with higher contour scores. This preliminary case series has provided early evidence in enabling identification of steroid responders versus non-responders within a 3-month period. Selection of KD non-responders to steroid treatment can avoid potentially painful injection, its subsequent side effects and unnecessary continuation of redundant therapy and follow-up.

Significant reduction of symptoms of scarring with electrical stimulation: evaluated with subjective and objective assessment tools in a prospective noncontrolled case series.

INTRODUCTION: Fenzian wave (FW) electrical stimulation has been shown to influence cutaneous wound healing. The authors previously published a case series investigating the effect of FW on symptomatic abnormal skin scars (raised dermal scars [RDS]) using spectrophotometric intracutaneous analysis (SIAscopy). In addition, a human volunteer sequential biopsy study in acute cutaneous wounds was conducted, which demonstrated that FW increased vascularity. The aim of this study was to evaluate the effectiveness of FW on symptomatic RDS using full-field laser perfusion imaging (FLPI) to assess changes in dermal blood flow. METHODS: Eighteen patients with RDS and long-term pain and pruritus participated.Time points analyzed were day 0, weeks 1 and 2, and months 1 and 2. Symptoms were monitored using a subjective numerical rating scale. Additionally, a Manchester Scar Scale and digital photographywere used. Objective noninvasive measures captured quantitative data: SIAscopy to measure melanin, hemoglobin and collagen levels, and FLPI to assess the dermal blood flow. RESULTS: There were statistically significant reductions in pain scores (from day 0 to month 1, P = 0.007) and pruritus scores (from day 0 to week 1, P = 0.007; and day 0 to month 1, P = 0.002). The trend for melanin levels demonstrated an increase from day 0 to week 1, hemoglobin levels showed an increase from day 0 to week 2, and hemoglobin flux increased from day 0 to week 2 (not statistically significant). CONCLUSION: This report demonstrates that FW electrical stimulation significantly reduces the symptoms of pain and pruritus in patients with RDS. This unique treatment has the potential for management of symptomatic skin scarring. .

Photodynamic therapy: an innovative approach to the treatment of keloid disease evaluated using subjective and objective non-invasive tools.

Optimal management for keloid disease (KD) is ill defined, with surgical excision resulting in recurrence rates over 50 %. Photodynamic therapy (PDT) uses light to activate a photosensitiser localised in diseased tissues. Two recent case studies and in vitro studies on keloid-derived fibroblasts indicate potential use of PDT in treating KD. Therefore, we hypothesized that there may be a role for PDT in the treatment of KD. Twenty KD patients were divided into three groups; existing keloid scar, post-surgical debulking and post-total surgical excision. Patients underwent three treatments of PDT at weekly intervals. Methyl aminolevulinate photosensitiser applied 3 h prior to PDT, administered at 37 J/cm(2). Non-invasive measures provided quantitative data for pliability, haemoglobin, melanin, collagen and flux. Pain and pruritus scores were measured and patients' were monitored for KD recurrence. All patients had reduced pain and pruritus scores. Haemoglobin flux (p = 0.032), collagen (p = 0.066) and haemoglobin levels (p = 0.060) decreased from week 1 to 3 in all except one patient where measurements were taken and pliability increased significantly (p = 0.001). Increases in pliability were significantly related to decreases in flux (p = 0.001). Only one patient with a keloid in a stress-prone anatomical location experienced recurrence of KD. All other patients had no recurrence at 9-month follow-up. Minimal side effects were reported. In conclusion, PDT reduces scar formation in KD evidenced by decreased blood flow, increased pliability, decreased collagen and haemoglobin levels. These findings indicate potential utility of PDT in the treatment of KD.

Electrical stimulation increases blood flow and haemoglobin levels in acute cutaneous wounds without affecting wound closure time: evidenced by non-invasive assessment of temporal biopsy wounds in human volunteers.

Recent studies highlighted the beneficial effects of a novel electrical stimulation waveform, the degenerate wave (DW), on skin fibroblasts and symptomatic skin scarring. However, no study to date has investigated the role of DW on acute cutaneous wounds. Therefore, we evaluated this in a trial using a temporal punch biopsy model. Twenty healthy volunteers had a biopsy performed on day 0 (left arm) and day 14 (right arm). On day 14, DW was applied. Participants were randomised into two groups. Objective non-invasive assessments were performed on days 0, 7, 14, 60 and 90 using spectrophotometric intracutaneous analysis and full-field laser perfusion imaging. There were statistically significant increases in mean flux on day 14 (P = 0.027) in the post-DW arm. Haemoglobin levels increased on day 7 for the post-DW arm compared to without DW (P = 0.088). Differences in melanin levels were higher post-DW on the left arm between randomised groups on day 90 (P = 0.033). Haemoglobin levels in the vascular ring increased significantly from day 7 to 90 (P < 0.001 for post-DW and without DW arms). This study, for the first time, shows that DW increases blood flow and haemoglobin levels in acute healing wounds without affecting wound closure time and may have potential application in enhancing acute cutaneous healing.