Publications by authors named "Ardeshir Bayat"

165 Publications

Novel Rotational Combination Regimen of Skin Topicals Improves Facial Photoaging: Efficacy Demonstrated in Double-Blinded Clinical Trials and Laboratory Validation.

Front Med (Lausanne) 2021 17;8:724344. Epub 2021 Sep 17.

Centre for Dermatology Research, National Institute for Health Research Manchester Biomedical Research Centre, Stopford Building, University of Manchester, Manchester, United Kingdom.

Topical antiaging products are often a first-line intervention to counter visible signs of facial photoaging, aiming for sustained cosmetic improvement. However, prolonged application of a single active topical compound was observed clinically to lead to a plateau effect in improving facial photoaging. In view of this, we set out to reduce this effect systematically using a multi-tiered approach with laboratory evidence and clinical trials. The objective of the study was to evaluate the effects of active topical ingredients applied either alone, in combination, or in a rotational manner on modulation of facial photoaging. The study methodology included , organotypic, and skin explants; biopsy study; as well as clinical trials. We demonstrate for the first time that a pair of known antiaging ingredients applied rotationally, on human dermal fibroblasts, maximized pro-collagen I production. Indeed, rotational treatment with retinol and phytol/glycolic acid (PGA) resulted in better efficacy than application of each active ingredient alone as shown by explants and biopsy study, with penetration of active ingredients confirmed by Raman spectroscopy. Furthermore, two split-face, randomized, double-blinded clinical trials were conducted, one for 12 months to compare treated vs. untreated and the other for 6 months followed by a 2-month regression to compare treated vs. commercially marketed products. In both studies, rotational regimen showed superior results to its matching comparison as assessed by clinical grading and image analysis of crow's feet wrinkles. In conclusion, rotational regimen using retinol and PGA is effective in treating facial photoaging signs with long-lasting benefits.
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http://dx.doi.org/10.3389/fmed.2021.724344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484331PMC
September 2021

Genetics and epigenetics of keloids.

Adv Wound Care (New Rochelle) 2021 Sep 9. Epub 2021 Sep 9.

University of Cape Town, 37716, Medicine, Rondebosch, Western Cape, South Africa;

Significance Keloid scarring is cosmetically disfiguring, psychosocially distressing and potentially physically disabling. It is a financial burden affecting patients and health care systems. The pathophysiology of keloid formation is poorly understood and subsequently treatment options are ill-defined, limited and largely unsatisfactory. Recent advances Increased research on the genetic and epigenetic mechanisms in keloids has broadened our understanding of keloid pathobiology. Epigenetic mechanisms, mainly DNA methylation, histone modification and non-coding RNAs, are currently being widely investigated. Advances in genetic sequencing technology and reduced cost have also aided this endeavour. Studies on blood and patient-derived keloid tissue are being done with therapeutic agents targeting epigenetic and genetic markers with the shared goal of identifying the pathways underlying the initiation and maintenance of keloids. These advances have informed us of multiple complex molecular pathways implicated in keloids which are yet to be fully elucidated. Critical issues Improved understanding of the genetic and epigenetic causes implicated in keloids will enhance our knowledge on this enigmatic disorder and likely lead to the development of therapeutic targets based on the available clinical and experimental studies. Due to the incomplete knowledge of molecular targets involved in keloid scarring pathways, therapeutics is still lagging for this clinically and scientifically important condition. Future directions Focused research on identification of molecular targets and mechanistic pathways implicated in keloids is required to generate novel antifibrotic therapeutic options to decrease or eradicate recurrence of the disease as well as associated morbidity and improve the quality of life of those affected with keloids.
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http://dx.doi.org/10.1089/wound.2021.0094DOI Listing
September 2021

Validation strategies for identifying drug targets in dermal fibrotic disorders.

Drug Discov Today 2021 Oct 3;26(10):2474-2485. Epub 2021 Jul 3.

Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK; Medical Research Council-Wound Healing Unit, Division of Dermatology, University of Cape Town, Cape Town, South Africa. Electronic address:

Fibrotic skin disorders, such as keloid disease (KD), are common clinically challenging disorders with unknown etiopathogenesis and ill-defined treatment strategies that affect millions of people worldwide. Thus, there is an urgent need to discover novel therapeutics. The validation of potential drug targets is an obligatory step in discovering and developing new therapeutic agents for the successful treatment of dermal fibrotic conditions, such as KD. The integration of multi-omics data with traditional and modern technological approaches, such as RNA interference (RNAi) and genome-editing tools, would provide unique opportunities to identify and validate novel targets in KD during early drug development. Thus, in this review, we summarize the current and emerging drug discovery process with a focus on validation strategies of potential drug targets identified in dermal fibrosis.
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http://dx.doi.org/10.1016/j.drudis.2021.06.014DOI Listing
October 2021

The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans.

Nat Biomed Eng 2021 Oct 21;5(10):1115-1130. Epub 2021 Jun 21.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Silicone is widely used in chronic implants and is generally perceived to be safe. However, textured breast implants have been associated with immune-related complications, including malignancies. Here, by examining for up to one year the foreign body response and capsular fibrosis triggered by miniaturized or full-scale clinically approved breast implants with different surface topography (average roughness, 0-90 μm) placed in the mammary fat pads of mice or rabbits, respectively, we show that surface topography mediates immune responses to the implants. We also show that the surface surrounding human breast implants collected during revision surgeries also differentially alters the individual's immune responses to the implant. Moreover, miniaturized implants with an average roughness of 4 μm can largely suppress the foreign body response and fibrosis (but not in T-cell-deficient mice), and that tissue surrounding these implants displayed higher levels of immunosuppressive FOXP3 regulatory T cells. Our findings suggest that, amongst the topographies investigated, implants with an average roughness of 4 μm provoke the least amount of inflammation and foreign body response.
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http://dx.doi.org/10.1038/s41551-021-00739-4DOI Listing
October 2021

Noninvasive Objective Tools for Quantitative Assessment of Skin Scarring.

Adv Wound Care (New Rochelle) 2021 Aug 24. Epub 2021 Aug 24.

Plastic and Reconstructive Surgery Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, England, United Kingdom.

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. 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, confocal microscopy, full-field laser perfusion imaging, and spectrophotometric intracutaneous analysis. 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. 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.
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http://dx.doi.org/10.1089/wound.2020.1387DOI Listing
August 2021

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.

Pharmaceutics 2021 Apr 8;13(4). Epub 2021 Apr 8.

Plastic and Reconstructive Surgery Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester M13 9PT, UK.

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 ( = 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 ( < 0.01). Group 1 was superior to other groups ( < 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 ( < 0.01) by immunohistochemistry and at week-4 ( < 0.05) by QRT-PCR. EGCG increased antioxidant levels (HO-1) at week-4 ( < 0.01) plus elastin at week-8 ( < 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).
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http://dx.doi.org/10.3390/pharmaceutics13040510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068279PMC
April 2021

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

Adv Wound Care (New Rochelle) 2021 Apr 20. Epub 2021 Apr 20.

Plastic and Reconstructive Surgery Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, England, United Kingdom.

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). 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. 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. 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.
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http://dx.doi.org/10.1089/wound.2020.1364DOI Listing
April 2021

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

Int J Mol Sci 2020 Dec 18;21(24). Epub 2020 Dec 18.

Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, Plastic and Reconstructive Surgery Research, University of Manchester, Manchester M13 9PT, UK.

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.
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http://dx.doi.org/10.3390/ijms21249673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766369PMC
December 2020

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

Front Immunol 2020 30;11:552205. Epub 2020 Sep 30.

Plastic and Reconstructive Surgery Research, Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom.

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.
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http://dx.doi.org/10.3389/fimmu.2020.552205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561364PMC
June 2021

Assessment of Transdermal Delivery of Topical Compounds in Skin Scarring Using a Novel Combined Approach of Raman Spectroscopy and High-Performance Liquid Chromatography.

Adv Wound Care (New Rochelle) 2021 01;10(1):1-12

Plastic and Reconstructive Surgery Research, Center for Dermatology Research, NIHR, Manchester Biomedical Research Center, University of Manchester, Manchester, United Kingdom.

The goal of any topical formulation is efficient transdermal delivery of its active components. However, delivery of compounds can be problematic with penetration through tough layers of fibrotic dermal scar tissue. We propose a new approach combining high-performance liquid chromatography (HPLC) and Raman spectroscopy (RS) using a topical of unknown composition against a well-known antiscar topical (as control). Positive detection of compounds within the treatment topical using both techniques was validated with mass spectrometry. RS detected conformational structural changes; the 1,655/1,446 cm ratio estimating collagen content significantly decreased ( < 0.05) over weeks 4, 12, and 16 compared with day 0. The amide I band, known to represent collagen and protein in skin, shifted from 1,667 to 1,656 cm, which may represent a change from β-sheets in elastin to α-helices in collagen. Confirmatory elastin immunohistochemistry decreased compared with day 0, conversely the collagen I/III ratio increased in the same samples by week 12 ( < 0.05, and  < 0.0001, respectively), in keeping with normal scar formation. Optical coherence tomography attenuation coefficient representing collagen deposition was significantly decreased at week 4 compared with day 0 and increased at week 16 ( < 0.05). This study provides a platform for further research on the simultaneous evaluation of the effects of compounds in cutaneous scarring by RS and HPLC, and identifies a role for RS in the therapeutic evaluation and theranostic management of skin scarring. RS can provide noninvasive information on the effects of topicals on scar pathogenesis and structural composition, validated by other analytical techniques.
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http://dx.doi.org/10.1089/wound.2020.1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698991PMC
January 2021

A microbiome and metabolomic signature of phases of cutaneous healing identified by profiling sequential acute wounds of human skin: An exploratory study.

PLoS One 2020 27;15(2):e0229545. Epub 2020 Feb 27.

Plastic & Reconstructive Surgery Research, Division of Musculoskeletal & Dermatological Sciences, NIHR Manchester Biomedical Research Centre (BRC), University of Manchester, Manchester, United Kingdom.

Profiling skin microbiome and metabolome has been utilised to gain further insight into wound healing processes. The aims of this multi-part temporal study in 11 volunteers were to analytically profile the dynamic wound tissue and headspace metabolome and sequence microbial communities in acute wound healing at days 0, 7, 14, 21 and 28, and to investigate their relationship to wound healing, using non-invasive quantitative devices. Metabolites were obtained using tissue extraction, sorbent and polydimethylsiloxane patches and analysed using GCMS. PCA of wound tissue metabolome clearly separated time points with 10 metabolites of 346 being involved in separation. Analysis of variance-simultaneous component analysis identified a statistical difference between the wound headspace metabolome, sites (P = 0.0024) and time points (P<0.0001), with 10 out of the 129 metabolites measured involved with this separation between sites and time points. A reciprocal relationship between Staphylococcus spp. and Propionibacterium spp. was observed at day 21 (P<0.05) with a statistical correlation between collagen and Propionibacterium (r = 0.417; P = 0.038) and Staphylococcus (r = -0.434; P = 0.03). Procrustes analysis showed a statistically significant similarity between wound headspace and tissue metabolome with non-invasive wound devices. This exploratory study demonstrates the temporal and dynamic nature of acute wound metabolome and microbiome presenting a novel class of biomarkers that correspond to wound healing, with further confirmatory studies now necessary.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229545PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046225PMC
May 2020

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

Wound Repair Regen 2020 05 5;28(3):422-426. Epub 2020 Feb 5.

Plastic and Reconstructive Surgery Research, Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, England, UK.

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.
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http://dx.doi.org/10.1111/wrr.12793DOI Listing
May 2020

and Models for Functional Testing of Therapeutic Anti-scarring Drug Targets in Keloids.

Adv Wound Care (New Rochelle) 2019 Dec 6;8(12):655-670. Epub 2019 Nov 6.

Hair and Skin Research Laboratory, Division of Dermatology, Department of Medicine, Faculty of Health Sciences and Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.

Keloids are benign fibro-proliferative raised dermal lesions that spread beyond the original borders of the wound, continue to grow, rarely regress, and are the most common in pigmented individuals after an abnormal wound healing response. The current treatment failure and respective challenges involved highlighting the underlying issue that the etiopathogenesis of keloids is still not well understood. Disease models are required to better understand the disease pathogenesis. It is not possible to establish keloids in animals because of the uniqueness of this disease to human skin. To address this challenge, along these lines, non-animal reproducible models are vital in investigating molecular mechanisms of keloid pathogenesis and therapeutics development. Various non-animal models have been developed to better understand the molecular mechanisms involved in keloid scarring and aid in identifying and evaluating the therapeutic potential of novel drug candidates. In this scenario, the current review aims at describing monocultures, co-cultures, organotypic cultures, and whole skin keloid tissue organ culture models. Current treatment options for keloids are far from securing a cure or preventing disease recurrence. Identifying universally accepted effective therapy for keloids has been hampered by the absence of appropriate disease model systems. Animal models do not accurately mimic the disease, thus non-animal model systems are pivotal in keloid research. The use of these models is essential not only for a better understanding of disease biology but also for identifying and evaluating novel drug targets.
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http://dx.doi.org/10.1089/wound.2019.1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904937PMC
December 2019

Laser Treatment of Traumatic Scars and Contractures: 2020 International Consensus Recommendations.

Lasers Surg Med 2020 02 9;52(2):96-116. Epub 2019 Dec 9.

Miami Dermatology and Laser Institute, Miami, Florida, 33173.

Background And Objectives: There is currently intense multidisciplinary interest and a maturing body of literature regarding laser treatments for traumatic scars, but international treatment guidelines and reimbursement schemes have not yet caught up with current knowledge and practice in many centers. The authors intend to highlight the tremendous potential of laser techniques, offer recommendations for safe and efficacious treatment, and promote wider patient access guided by future high-quality research.

Study Design/materials And Methods: An international panel of 26 dermatologists and plastic and reconstructive surgeons from 13 different countries and a variety of practice backgrounds was self-assembled to develop updated consensus recommendations for the laser treatment of traumatic scars. A three-step modified Delphi method took place between March 2018 and March 2019 consisting of two rounds of emailed questionnaires and supplementary face-to-face meetings. The panel members approved the final manuscript via email correspondence, and the threshold for consensus was at least 80% concurrence among the panel members.

Results: The manuscript includes extensive detailed discussion regarding a variety of laser platforms commonly used for traumatic scar management such as vascular lasers and ablative and non-ablative fractional lasers, special considerations such as coding and laser treatments in skin of color, and 25 summary consensus recommendations.

Conclusions: Lasers are a first-line therapy in the management of traumatic scars and contractures, and patients without access to these treatments may not be receiving the best available care after injury. Updated international treatment guidelines and reimbursement schemes, additional high-quality research, and patient access should reflect this status. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23201DOI Listing
February 2020

Functional Testing of a Skin Topical Formulation : Objective and Quantitative Evaluation in Human Skin Scarring Using a Double-Blind Volunteer Study with Sequential Punch Biopsies.

Adv Wound Care (New Rochelle) 2019 May 3;8(5):208-219. Epub 2019 May 3.

Plastic and Reconstructive Surgery Research, Division of Musuloskeletal and Dermatological Sciences, Centre for Dermatology Research, NIHR Manchester BRC, University of Manchester, Manchester, United Kingdom.

Many topicals claim an efficacious role in skin scar management with limited evidence. Our aim is to present a clear format for functional testing of a skin scarring ointment, using noninvasive and invasive measurements, categorizing findings under the physiological, structural, and mechanical parameters of a scar. A double-blinded, randomized volunteer research study of 45 subjects receiving an ointment composing of natural ingredients against a widely used antiscarring topical used as a positive control with temporal sequential punch biopsies (up to 16 weeks) was evaluated using noninvasive quantitative devices and validated by gene and protein studies. Outcome measures included physiological, mechanical, and structural features of scars. Significant non-invasive findings included an increase in skin hydration ( < 0.05) at week (W) 4, 8, and 12, and elasticity (W16;  = 0.009). These findings were validated by immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). Hyaluronic acid IHC (W4  = 0.014, W12  = 0.034, and W16  = 0.042), qRT-PCR (W16  = 0.049); Collagen I (W16  = 0.034, and 0.049) IHC and qRT-PCR, respectively. Collagen III qRT-PCR (W12  = 0.035, and W16  = 0.32); elastin IHC (W12  = 0.044); and fibronectin IHC (W4  = 0.009, W12  = 0.038, and W16 p = 0.026). Utilizing this model allows for quantitative, objective evaluation of any topical, where previously there has been a paucity of relevant methods to evaluate their effect. The positive effect of a topical formulation with an unknown mechanism of action on early cutaneous scar maturation over progressive sequential time points is now evidenced using noninvasive and invasive techniques with the findings categorized on the basis of scarring parameters.
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http://dx.doi.org/10.1089/wound.2018.0864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855292PMC
May 2019

Understanding Keloid Pathobiology From a Quasi-Neoplastic Perspective: Less of a Scar and More of a Chronic Inflammatory Disease With Cancer-Like Tendencies.

Front Immunol 2019 7;10:1810. Epub 2019 Aug 7.

Plastic and Reconstructive Surgery Research, Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom.

Keloids are considered as benign fibroproliferative skin tumors growing beyond the site of the original dermal injury. Although traditionally viewed as a form of skin scarring, keloids display many cancer-like characteristics such as progressive uncontrolled growth, lack of spontaneous regression and extremely high rates of recurrence. Phenotypically, keloids are consistent with non-malignant dermal tumors that are due to the excessive overproduction of collagen which never metastasize. Within the remit of keloid pathobiology, there is increasing evidence for the various interplay of neoplastic-promoting and suppressing factors, which may explain its aggressive clinical behavior. Amongst the most compelling parallels between keloids and cancer are their shared cellular bioenergetics, epigenetic methylation profiles and epithelial-to-mesenchymal transition amongst other disease biological (genotypic and phenotypic) behaviors. This review explores the quasi-neoplastic or cancer-like properties of keloids and highlights areas for future study.
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http://dx.doi.org/10.3389/fimmu.2019.01810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692789PMC
October 2020

Development of Bioinspired Gelatin and Gelatin/Chitosan Bilayer Hydrofilms for Wound Healing.

Pharmaceutics 2019 Jul 4;11(7). Epub 2019 Jul 4.

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.

In the current study, we developed a novel gelatin-based bilayer wound dressing. We used different crosslinking agents to confer unique properties to each layer, obtaining a bioinspired multifunctional hydrofilm suitable for wound healing. First, we produced a resistant and non-degradable upper layer by lactose-mediated crosslinking of gelatin, which provided mechanical support and protection to overall design. For the lower layer, we crosslinked gelatin with citric acid, resulting in a porous matrix with a great swelling ability. In addition, we incorporated chitosan into the lower layer to harness its wound healing ability. FTIR and SEM analyses showed that lactose addition changed the secondary structure of gelatin, leading to a more compact and smoother structure than that obtained with citric acid. The hydrofilm was able to swell 384.2 ± 57.2% of its dry weight while maintaining mechanical integrity. Besides, its water vapour transmission rate was in the range of commercial dressings (1381.5 ± 108.6 g/m·day). In vitro, cytotoxicity assays revealed excellent biocompatibility. Finally, the hydrofilm was analysed through an ex vivo wound healing assay in human skin. It achieved similar results to the control in terms of biocompatibility and wound healing, showing suitable characteristics to be used as a wound dressing.
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http://dx.doi.org/10.3390/pharmaceutics11070314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680716PMC
July 2019

Microarchitectural analysis of decellularised unscarred and scarred dermis provides insight into the organisation and ultrastructure of the human skin with implications for future dermal substitute scaffold design.

J Tissue Eng 2019 Jan-Dec;10:2041731419843710. Epub 2019 Jun 18.

Plastic and Reconstructive Surgery Research, Division of Musculoskeletal & Dermatological Sciences, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.

The three-dimensional spatial arrangement of dermal tissue plays a crucial role in directing cellular behaviour during wound healing. It is vital to elucidate a better understanding of the three-dimensional dermal architecture of human skin. We sought to understand the configuration in morphological structure of decellularised human dermis between unscarred skin and normotrophic scars. Skin biopsies underwent decellularisation (DNA removal = 88%). Histological analysis showed no change in gross morphology of decellularised unscarred and scarred dermis. Multiphoton and atomic force microscopies showed that collagen fibres in unscarred decellularised dermis were interwoven akin to a mesh-like structure. Collagen fibres in decellularised unscarred dermis were less stiff (mean: 2.155 ± 0.9595 MPa;  < 0.0001) with a rougher (  = 16.5,  = 12.5,  = 198;  < 0.0001) surface topography. Scarred dermis had a higher collagen volume density (papillary dermis,  < 0.0082; reticular dermis,  < 0.0332). The results demonstrate that scaffolds should exhibit a mesh-like structure with a biomimetic surface and low stiffness.
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http://dx.doi.org/10.1177/2041731419843710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582285PMC
June 2019

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.

J Invest Dermatol 2019 08 26;139(8):1680-1690.e16. Epub 2019 Feb 26.

Plastic and Reconstructive Surgery Research, University of Manchester, Manchester, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jid.2019.01.030DOI Listing
August 2019

Multi-dimensional models for functional testing of keloid scars: In silico, in vitro, organoid, organotypic, ex vivo organ culture, and in vivo models.

Wound Repair Regen 2019 07 25;27(4):298-308. Epub 2019 Mar 25.

Hair and Skin Research Laboratory, Division of Dermatology, Department of Medicine, Faculty of Health Sciences and Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.

Keloid scars are described as benign fibro-proliferative dermal outgrowths that commonly occur in pigmented skin post cutaneous injury, and continue to grow beyond the boundary of the original wound margin. There is a lack of thorough understanding of keloid pathogenesis and thus keloid therapeutic options remain ill-defined. In view of the poor response to current therapy and high recurrence rates, there is an unmet need in improving our knowledge and therefore in identifying targeted and effective treatment strategies in management of keloids. Keloid research however, is hampered by a lack of relevant animal models as keloids do not spontaneously occur in animals and are unique to human skin. Therefore, developing novel animal models and nonanimal models for functional evaluation of keloid cells and tissue for better understanding their pathobiology and response to putative candidate therapies are essential. Here, we present the key concepts and relevant emerging research on two-dimensional and three-dimensional cell and tissue models for functional testing of keloid scars. We will describe in detail current models including in vitro mono- and co-cultures, multi-cellular spheroids (organoids) and organotyopic cultures, ex vivo whole skin keloid tissue organ culture models as well as in vivo human patient models. Finally, we discuss the role played by time as the fourth dimension in a novel model that involves sequential temporal biopsies of human patients with keloids (a so called 4D in vivo human model). The use of these unique models will no doubt prove pivotal in identification of new drug targets as well as biomarkers, in functional testing of emerging novel therapeutics, and in enhancing our understanding of keloid disease biology.
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http://dx.doi.org/10.1111/wrr.12705DOI Listing
July 2019

Electrical stimulation disrupts biofilms in a human wound model and reveals the potential for monitoring treatment response with volatile biomarkers.

Wound Repair Regen 2019 01 21;27(1):5-18. Epub 2018 Nov 21.

Plastic & Reconstructive Surgery Research, Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.

Management of biofilm infections relies on time-consuming laboratory techniques and monitoring treatment by subjective clinical evaluations. Due to these limitations, there is a need to explore alternative strategies. The aims of this study were to assess the feasibility of using volatile organic compound (VOC) biomarkers to monitor treatment response and measure anti-biofilm efficacy of electrical stimulation (ES) in vitro and in human cutaneous wound biofilm models. Staphylococcus aureus (MSSA) and Pseudomonas aeruginosa (PA) biofilms were exposed to ES, ciprofloxacin, or both, with efficacy assessed and quantified by fluorescence staining, enumeration, metabolic assays, and biomass quantification; VOCs were measured by gas chromatography-mass spectrometry. In vitro MSSA and PA and ex vivo PA biofilms exposed to ES showed significantly reduced bacterial viability, metabolic activity, and biomass compared to controls (p < 0.05). There was significant variation in the relative abundance of VOCs in in vitro MSSA and PA and in ex vivo PA biofilms exposed to ES and antibiotic (p < 0.05). 2-methyl-1-propanol was associated with MSSA viability (R = 0.93, p < 0.05), biomass (R = 0.97, p < 0.05), and metabolic activity (R = 0.93, p < 0.05) and 3-methyl-1-butanol was associated with PA biomass (R = 0.93, p < 0.05). We showed that ES and VOC biomarkers are possible options for alternative nonpharmacological antimicrobial management of biofilms and noninvasive monitoring of wound infection treatment responses, respectively.
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http://dx.doi.org/10.1111/wrr.12679DOI Listing
January 2019

Validation of biofilm formation on human skin wound models and demonstration of clinically translatable bacteria-specific volatile signatures.

Sci Rep 2018 06 21;8(1):9431. Epub 2018 Jun 21.

Plastic & Reconstructive Surgery Research, Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.

Biofilms are major contributors to delayed wound healing and there is a need for clinically relevant experimental models to assess theranostics. Microorganisms release volatile organic compounds (VOCs) and the ability to identify these in infected cutaneous wounds could lead to efficient non-invasive diagnosis. The aims here were to develop and assess bacterial biofilm formation and identify their VOC profiles in an in vitro model and validate in human ex vivo incisional and excisional cutaneous wound models. Biofilm development was assessed using multiple microscopy techniques with biofilm-forming deficient controls and quantified using metabolic and biomass assays; and VOC production measured by gas chromatography-mass spectrometry. The production of most VOCs was affected by biofilm development and model used. Some VOCs were specific either for planktonic or biofilm growth. The relative abundance of some VOCs was significantly increased or decreased by biofilm growth phase (P < 0.05). Some Staphylococcus aureus and Pseudomonas aeruginosa VOCs correlated with biofilm metabolic activity and biomass (R ≤ -0.5; ≥0.5). We present for the first time bacterial biofilm formation in human ex vivo cutaneous wound models and their specific VOC profiles. These models provide a vehicle for human skin-relevant biofilm studies and VOC detection has potential clinical translatability in efficient non-invasive diagnosis of wound infection.
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http://dx.doi.org/10.1038/s41598-018-27504-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013498PMC
June 2018

Photobiomodulation of a flowable matrix in a human skin ex vivo model demonstrates energy-based enhancement of engraftment integration and remodeling.

J Biophotonics 2018 09 29;11(9):e201800077. Epub 2018 May 29.

School of Biological Sciences and Health/Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.

The use of dermal substitutes to treat skin defects such as ulcers has shown promising results, suggesting a potential role for skin substitutes for treating acute and chronic wounds. One of the main drawbacks with the use of dermal substitutes is the length of time from engraftment to graft take, plus the risk of contamination and failure due to this prolonged integration. Therefore, the use of adjuvant energy-based therapeutic modalities to augment and accelerate the rate of biointegration by dermal substitute engraftments is a desirable outcome. The photobiomodulation (PBM) therapy modulates the repair process, by stimulating cellular proliferation and angiogenesis. Here, we evaluated the effect of PBM on a collagen-glycosaminoglycan flowable wound matrix (FWM) in an ex vivo human skin wound model. PBM resulted in accelerated rate of re-epithelialization and organization of matrix as seen by structural arrangement of collagen fibers, and a subsequent increased expression of alpha-smooth muscle actin (α-SMA) and vascular endothelial growth factor A (VEGF-A) leading to an overall improved healing process. The use of PBM promoted a beneficial effect on the rate of integration and healing of FWM. We therefore propose that the adjuvant use of PBM may have utility in enhancing engraftment and tissue repair and be of value in clinical practice.
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http://dx.doi.org/10.1002/jbio.201800077DOI Listing
September 2018

Novel Proteomic Assay of Breast Implants Reveals Proteins With Significant Binding Differences: Implications for Surface Coating and Biocompatibility.

Aesthet Surg J 2018 Aug;38(9):962-969

University of Manchester, Manchester, United Kingdom.

Background: Silicone elastomer, a ubiquitous biomaterial and main constituent of breast implants, has been used for breast augmentation and reconstruction for over 50 years. Breast implants have direct local and purported systemic effects on normal tissue homeostasis dictated by the chemical and physical presence of the implant.

Objectives: Protein adsorption has been demonstrated to be a key driver of local reactions to silicone. We sought to develop an assay and identify the proteins that coat implants during breast implantation.

Methods: Wound fluid was salvaged from women who had undergone breast reduction and incubated in contact with the surface of 13 commercially available implant surfaces. An in situ digestion technique was optimized to elute bound proteins. Samples were analyzed on an Orbitrap elite analyser, proteins identified in Mascot Demon and analyzed in Progenesis.

Results: A total of 822 proteins were identified, bound to the surfaces of the implants. Extracellular proteins were the most abundant ontology, followed by intracellular proteins. Fibrinogen, a proinflammatory protein and Albumin, an anti-inflammatory protein had significant (P < 0.0001) binding differences between the surfaces studied. Complement C3, C5, and factor H were also shown to have significantly different binding affinities for the implants included in the study (P < 0.05).

Conclusions: We have developed a novel assay of breast implant protein binding and demonstrated significant binding affinities for relevant proteins derived from breast tissue wound fluid.

Level Of Evidence 5:
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http://dx.doi.org/10.1093/asj/sjy018DOI Listing
August 2018

Volatile organic compound detection as a potential means of diagnosing cutaneous wound infections.

Wound Repair Regen 2017 08 31;25(4):574-590. Epub 2017 Aug 31.

Plastic and Reconstructive Surgery Research, Institute of Inflammation and Repair, Centre for Dermatological Research, University of Manchester, Manchester, United Kingdom.

Chronic cutaneous wound infections and surgical site infections (SSIs) present a huge burden on the healthcare system and can lead to increased morbidity and mortality. Current diagnostic methods of identifying and confirming infection involve culture-based and molecular methods. Both techniques are time-consuming and delays commonly lead to untargeted empirical treatment. An ideal diagnostic method would be noninvasive and highly sensitive and detect pathogenic organisms with a high degree of accuracy to allow targeted treatment. Volatile organic compounds (VOCs) are a diverse group of carbon-based molecules produced and released by humans and microorganisms. VOC detection has the potential in aiding cutaneous wound infection diagnostics using noninvasive and time-efficient methods. This review provides a comprehensive update on VOCs produced and emitted by bacteria commonly associated with chronic wounds and SSIs. VOC sampling has the advantage of being painless, time-efficient, noninvasive, and reproducible. VOCs emitted by these organisms are diverse. In vitro studies have identified potential signature volatile profiles, which can be used in detecting these microorganisms. Combining these profiles with volatile profiles emitted from acute, chronic and surgical wounds in vivo could potentially allow identification of bacterial-specific VOCs. VOC detection has the potential for a relatively inexpensive, portable, noninvasive, and reliable clinical diagnostic tool, which could be used in detecting cutaneous wound infections and guiding their optimal management.
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http://dx.doi.org/10.1111/wrr.12563DOI Listing
August 2017

Therapeutic targets in the management of striae distensae: A systematic review.

J Am Acad Dermatol 2017 Sep 24;77(3):559-568.e18. Epub 2017 May 24.

Centre for Dermatological Research, University of Manchester, Manchester, United Kingdom. Electronic address:

Background: Striae distensae are permanent dermal lesions that can cause significant psychosocial distress. A detailed understanding of the numerous treatment modalities available is essential to ensuring optimal patient outcomes.

Objective: Our objective was to evaluate and summarize the different treatment methods for striae distensae by linking their proposed modes of action with the histopathogenesis of the condition to guide patient treatment.

Methods: A systematic review of the literature was performed with no limits placed on publication date. Relevant studies were assigned a level of evidence by the authors.

Results: Ninety-two articles were identified, with 74 being eligible for quality assessment. The majority of treatments aim to increase collagen production. The use of vascular lasers can reduce erythema in striae rubrae by targeting hemoglobin, whereas increasing melanin through methods such as ultraviolet light is a major focus for treatment of striae albae. Despite some topical treatments being widely used, uncertainty regarding their mode of action remains. No treatment has proved to be completely effective.

Limitations: Limitations of the study include low-quality evidence, small sample sizes, and varying treatment protocols and outcome measures, along with concerns regarding publication bias.

Conclusions: Further randomized, controlled trials are needed before definitive conclusions and recommendations can be made.
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http://dx.doi.org/10.1016/j.jaad.2017.02.048DOI Listing
September 2017

Cutaneous wound biofilm and the potential for electrical stimulation in management of the microbiome.

Future Microbiol 2017 03 3;12:337-357. Epub 2017 Mar 3.

Plastic & Reconstructive Surgery Research, Centre for Dermatological Research, University of Manchester, Manchester, UK.

Infection contributes significantly to delayed cutaneous wound healing, which impacts patient care. External application of electrical stimulation (ES) has beneficial effects on wound repair and regeneration. The majority of studies to date have explored ES in relation to planktonic microorganisms, yet evidence indicates that bacteria in chronic wounds reside as antibiotic-resistant polymicrobial biofilms, which contribute to impairing wound healing. Culture-independent sequencing techniques have revolutionized our understanding of the skin microbiome and allowed a more accurate determination of microbial taxa and their relative abundance in wounds allowing a greater understanding of the host-microbial interface. Future studies combining the fields of ES, biofilm and microbiome research are necessary to fully elucidate the use of ES in the management of wound infection.
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http://dx.doi.org/10.2217/fmb-2016-0204DOI Listing
March 2017

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.

Wound Repair Regen 2017 04 20;25(2):164-176. Epub 2017 Feb 20.

Plastic and Reconstructive Surgery Research, Centre for Dermatology Research, University of Manchester, Manchester, United Kingdom.

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.
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http://dx.doi.org/10.1111/wrr.12513DOI Listing
April 2017

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling.

Acta Derm Venereol 2017 Jun;97(6):675-684

Plastic and Reconstructive Surgery Research, Stopford Building, Manchester M13 9PT , United Kingdom.

Keloid disease is a fibroproliferative tumour characterised by aggressive local invasion, evident from a clinically and histologically active migrating margin. During combined laser capture microdissection and microarray analysis-based in situ gene expression profiling, we identified upregulation of the polypeptide growth factor neuregulin-1 (NRG1) and ErbB2 oncogene in keloid margin dermis, leading to the hypothesis that NRG1 contributed to keloid margin migration through ErbB2-mediated signalling. The aim of this study was to probe this hypothesis through functional in vitro studies. Exogenous NRG1 addition to keloid and normal skin fibroblasts altered cytokine expression profiles, significantly increased in vitro migration and keloid fibroblast Src and protein tyrosine kinase 2 (PTK2/FAK) gene expression. ErbB2 siRNA knockdown attenuated both keloid fibroblast migration and Src/PTK2 expression, which were not recovered following NRG1 administration, suggesting the NRG1/ErbB2/Src/PTK2 signaling pathway may be a novel regulator of keloid fibroblast migration, and representing a potential new therapeutic target.
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http://dx.doi.org/10.2340/00015555-2587DOI Listing
June 2017

Enhanced Neurogenic Biomarker Expression and Reinnervation in Human Acute Skin Wounds Treated by Electrical Stimulation.

J Invest Dermatol 2017 03 14;137(3):737-747. Epub 2016 Nov 14.

Plastic Surgery Research Group, Dermatology Research Centre, Institute of Inflammation & Repair, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. Electronic address:

Electrical stimulation (ES) is known to promote cutaneous healing; however, its ability to regulate reinnervation remains unclear. First, we show that ES treatment of human acute cutaneous wounds (n = 40) increased reinnervation. Next, to define neurophysiologic mechanisms through which ES affects repair, microarray analysis of wound biopsy samples was performed on days 3, 7, 10, and 14 after wounding. This identified neural differentiation biomarkers TUBB3 (melanocyte development and neuronal marker) and its upstream molecule FIG4 (phosphatidylinositol (3,5)-bisphosphate 5-phosphatase) as significantly up-regulated after ES treatment. To demonstrate a functional ES-TUBB3 axis in cutaneous healing, we showed increased TUBB3 melanocytes and melanogenesis plus FIG4 and nerve growth factor expression, suggesting higher cellular differentiation. In support of this role of ES to regulate neural crest-derived cell fate and differentiation in vivo, knockdown of FIG4 in neuroblastoma cells resulted in vacuologenesis and cell degeneration, whereas ES treatment after FIG4-small interfering RNA transfection enhanced neural differentiation, survival, and integrity. Further characterization showed increased TUBB3 and protein gene product 9.5 Merkel cells during in vivo repair, after ES. We demonstrate that ES contributes to increased expression of neural differentiation biomarkers, reinnervation, and expansion of melanocyte and Merkel cell pool during repair. Targeted ES-assisted acceleration of healing has significant clinical implications.
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http://dx.doi.org/10.1016/j.jid.2016.09.038DOI Listing
March 2017
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