Sara Ud-Din

Striae distensae: a comprehensive review and evidence‐based evaluation of prophylaxis and treatment

Striae distensae are an extremely common, therapeutically challenging form of dermal scarring. Risk factors have been reported but much remains to be understood about their epidemiology, diagnosis and treatment. Up‐to‐date knowledge of the scientific research and the evidence behind both preventative and therapeutic agents are vital in order to understand striae and to offer patients the best therapeutic alternatives. We present a clinical review of the current literature concerning striae distensae and their prevention and treatment. A systematic review of the literature was undertaken using Medline, Embase and Google Scholar. Articles in English, Spanish, Portuguese, Turkish and French were included. Striae distensae occur in pregnancy, puberty and obesity as well as in numerous medical conditions and following therapeutic interventions. Proposed aetiological mechanisms relate to hormones, physical stretch and structural alterations to the integument. Assessment methods include subjective visual scoring and various imaging modalities. Treatments that we have evaluated include topical agents, used prophylactically or therapeutically, as well as light and laser therapies, which have shown improvements in the appearance of striae. Few high level evidence based medicine randomized controlled trials evaluating treatments for striae distensae exist. Topical therapeutic agents appear to lack efficacy in the prevention of striae distensae.

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.

Strategic management of keloid disease in ethnic skin: a structured approach supported by the emerging literature

Keloid disease (KD) is a common, benign, dermal fibroproliferative growth of unknown aetiology. Lesions tend to grow over time; they often recur following therapy and do not regress spontaneously. KD causes considerable discomfort due to pain, pruritus and inflammation, and a significant psychosocial impact with reduced quality of life. It is unique to humans and occurrence is higher in individuals with dark, pigmented, ethnic skin. There is a strong familial heritability, with a high ethnic predisposition in individuals of African, Asian and Hispanic descent. High recurrence rates and unknown resolution rates present a major problem for both the patient and clinician. Many treatment modalities exist; however, there is no single advocated therapy. Therefore, the aim of this review was to explore the most current literature regarding the range of treatment options for KD and to offer a structured approach in the management of KD, based on evidence and experience, to aid clinicians in their current practice. A focused history involving careful evaluation of the patients symptoms, signs, quality of life and psychosocial well‐being should direct targeted therapy, complemented with regular follow‐up and re‐evaluation. Many treatment modalities, such as intralesional steroid injection, silicone gel application, cryotherapy, lasers, 5‐fluorouracil and, relatively recently, photodynamic therapy, are currently being used in clinical practice for the management of KD. Combination therapies have also been shown to be beneficial. However, there is a lack of robust, randomized, level‐one, evidence‐controlled trials evaluating these treatment options. Management of KD in ethnic pigmented skin remains a clinical challenge. Thus, a strategic approach with structured assessment, targeted therapy and focus on prevention of recurrence is highly recommended. Quality evidence is essential in order to tailor treatment effectively for the ethnic patient presenting with 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.

Topical management of striae distensae (stretch marks): Prevention and therapy of striae rubrae and albae

Striae distensae (SD) are common dermal lesions, with significant physical and psychological impact. Many therapeutic modalities are available but none can completely eradicate SD. The most common therapy is the application of topicals used both therapeutically and prophylactically. Even though there are many commercially available topical products, not all have sufficient level of evidence to support their continued use in SD. The aim here was to assess the evidence for the use of topicals in SD and to propose a structured approach in managing SD. A systematic search of published literature and manufacturer website information for topicals in SD was carried out. The results showed that there are few studies (n = 11) which investigate the efficacy of topicals in management of SD. Trofolastin and Alphastria creams demonstrated level‐2 evidence of positive results for their prophylactic use in SD. Additionally, tretinoin used therapeutically showed varying results whilst cocoa butter and olive oil did not demonstrate any effect. Overall, there is a distinct lack of evidence for each topical formulation. The majority of topicals failed to mention their effect on early vs. later stages of SD (striae rubrae compared to striae albae) and their role in both prevention and treatment. In conclusion, there is no topical formulation, which is shown to be most effective in eradicating or improving SD. A structured approach in identification and targeted management of symptoms and signs with the appropriate topical is required. Randomized controlled trials are necessary to assess the efficacy of topical products for treatment and prevention of different stages of SD.

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.

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.

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.