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Enhancement of Wound Healing by Topical Treatment with Epidermal Growth Factor

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Abstract

Experimental studies in animals have demonstrated that the topical application of epidermal growth factor accelerates the rate of epidermal regeneration of partial-thickness wounds and second-degree burns. We conducted a prospective, randomized, double-blind clinical trial using skin-graft-donor sites to determine whether epidermal growth factor would accelerate the rate of epidermal regeneration in humans. Paired donor sites were created in 12 patients who required skin grafting for either burns or reconstructive surgery. One donor site from each patient was treated topically with silver sulfadiazine cream, and one was treated with silver sulfadiazine cream containing epidermal growth factor (10 micrograms per milliliter). The donor sites were photographed daily, and healing was measured with the use of planimetric analysis. The donor sites treated with silver sulfadiazine containing epidermal growth factor had an accelerated rate of epidermal regeneration in all 12 patients as compared with that in the paired donor sites treated with silver sulfadiazine alone. Treatment with epidermal growth factor significantly decreased the average length of time to 25 percent and 50 percent healing by approximately one day and that to 75 percent and 100 percent healing by approximately 1.5 days (P less than 0.02). Histologic evaluation of punch-biopsy specimens taken from the centers of donor sites three days after the onset of healing supported these results. We conclude that epidermal growth factor accelerates the rate of healing of partial-thickness skin wounds. Further studies are required to determine the clinical importance of this finding.
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... The first human recombinant FGF-2 was reported in 1988 [8]. In 1989, Brown et al. reported in the New England Journal of Medicine that epidermal growth factor significantly accelerated the rate of healing of partial thickness skin wounds in a randomized clinical trial [9]. The development of growth factor products targeted at promoting wound healing has been thriving ever since and the clinical application of growth factors has become popular. ...
... However, one must point out that out of the 229 studies considered, only 3 were conducted outside China (i.e. in Japan) and reported in English, while the remaining 226 articles, including 7 reported in English and 219 in Chinese, were all carried out within China and reported by Chinese researchers. During the screening period, one randomized clinical trial conducted in the USA showed that epidermal growth factor accelerated skin-graft-donor sites wound healing significantly [9]. However, the types of outcome measurements in this study could not be combined with those from other included studies to conduct meta-analysis. ...
Article
Background: Promoting wound healing is crucial to restore the vital barrier function of injured skin. Growth factor products including epidermal growth factor (EGF), fibroblast growth factor (FGF) and granulocyte-macrophage colony stimulating factor (GM-CSF) have been used for decades although no systematic evaluation exists regarding their effectiveness and safety issues in treating acute skin wounds. This has resulted in a lack of guidelines and standards for proper application regimes. Therefore, this systematic review and meta-analysis was performed to critically evaluate the effectiveness and safety of these growth factors on skin acute wounds and provide guidelines for application regimes. Methods: We searched PubMed/Medline (1980-2020), Cochrane Library (1980-2020), Cochrane CENTRAL (from establishment to 2020), ClinicalTrials.gov (from establishment to 2020), Chinese Journal Full-text Database (CNKI, 1994-2020), China Biology Medicine disc (CBM, 1978-2019), Chinese Scientific Journal Database (VIP, 1989-2020) and Wanfang Database (WFDATA, 1980-2019). Randomized controlled trials (RCTs), quasi-RCTs and controlled clinical trials treating patients with acute skin wounds from various causes and with those available growth factors were included. Results: A total of 7573 papers were identified through database searching; 229 papers including 281 studies were kept after final screening. Administering growth factors significantly shortened the healing time of acute skin wounds, including superficial burn injuries [mean difference (MD) = -3.02; 95% confidence interval (CI):-3.31 ~ -2.74; p < 0.00001], deep burn injuries (MD = -5.63; 95% CI:-7.10 ~ -4.17; p < 0.00001), traumata and surgical wounds (MD = -4.50; 95% CI:-5.55 ~ -3.44; p < 0.00001). Growth factors increased the healing rate of acute skin wounds and decreased scar scores. The incidence of adverse reactions was lower in the growth factor treatment group than in the non-growth factor group. Conclusions: The studied growth factors not only are effective and safe for managing acute skin wounds, but also accelerate their healing with no severe adverse reactions.
... The inspiration for its discovery as an EGFR agonist originated from the traditional use of Pereskia bleo in wounds and related ailments, including ulcers, gastritis, haemorrhoids, cold sore, and atopic dermatitis (Abdul-Wahab et al., 2012;Sharif et al., 2013;de Castro Campos Pinto and Scio, 2014;Zareisedehizadeh et al., 2014;Zareisedehizadeh et al., 2022). This is because EGF is clinically approved in several countries for treating chronic wounds such as diabetic foot ulcers (Brown et al., 1989;Harding et al., 2002;Gurtner et al., 2008;Bui et al., 2019). Hence, bleogen pB1 could be a bioactive principle in Pereskia bleo responsible for its traditional use in wound healing. ...
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Corneal scarring reduces corneal transparency, compromises vision, and is a major cause of vision loss worldwide. Epidermal growth factor (EGF), which is the prototypic member of the EGF receptor (EGFR) agonists, is present in tears to provide repair and regeneration. Recently, we discovered bleogen pB1 in the cactus plant Pereskia bleo and showed that it is a non-canonical and hyperstable EGFR agonist with EGF-like wound healing properties for diabetic rats. Here, we apply bleogen pB1 to accelerate corneal wound healing in rats. To assess the corneal healing effects of bleogen pB1, we induced an acute alkali burn to the right eye of male Wistar rats. After five consecutive ophthalmic applications, fluorescein staining and opacity scores of the bleogen pB1-treated, and the positive control EGF-treated groups improved significantly compared to the saline control group. Immunohistochemical analyses revealed that infiltrated CD68 ⁺ macrophages and the expression of the myofibroblast marker alpha smooth muscle actin (α-SMA) were significantly decreased in the bleogen pB1- and the EGF-treated groups. By employing a differential gene expression analysis of bleogen pB1- and EGF-treated keratinocytes through RNA-seq, we demonstrated that bleogen pB1 or EGF treatments can affect the expression of genes associated with inflammatory responses and extracellular matrix remodeling. Taken together, our results indicate that the plant-derived EGFR agonist bleogen pB1 can produce similar effects to those of EGF in accelerating corneal wound healing as well as in reducing persistent inflammation and myofibroblast accumulation in the cornea.
... The primary action attributed to EGF is to promote proliferation of mesenchymal, glial and epithelial cells. EGFs has been well documented to have mitogenic and chemotactic effects on fibroblasts (Brown et al., 1989). EGF appears to have little effect on promoting PLF (Periodontal ligament formation) mitogenesis, chemotaxis or matrix synthesis in PLFs. ...
... Subsequently, the receptor is internalized by clathrin-coated endocytosis and EGF enters the cell to exert its effects (e.g., activation of stem cell proliferation and migration) [29]. Activation of the EGF receptor or HER-1 leads to increased production of specific proteins related to the endothelium, keratinocytes, and corneal epithelial differentiation in vivo and in vitro [30,31]. Another role of EGF on mesenchymal stem cells (MSCs) has been reported in partial wounds and surgical incisions by increasing proliferation and subsequently improving the tensile strength of the dermis [32]. ...
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Tissue engineering (TE) is currently considered a cutting‐edge discipline that offers the potential for developing treatments for health conditions that negatively affect quality of life. This interdisciplinary field typically involves the combination of cells, scaffolds, and appropriate induction factors for the regeneration and repair of damaged tissue. Cell fate decisions, such as survival, proliferation, or differentiation, critically depend on various biochemical and biophysical factors provided by the extracellular environment during developmental, physiological, and pathological processes. Therefore, understanding the mechanisms of action of these factors is critical to accurately mimic the complex architecture of the extracellular environment of living tissues and improve the efficiency of TE approaches. In this review, we recapitulate the effects that biochemical and biophysical induction factors have on various aspects of cell fate. While the role of biochemical factors, such as growth factors, small molecules, Extracellular Matrix (ECM) components and cytokines, has been extensively studied in the context of TE applications, it is only recently that we have begun to understand the effects of biophysical signals such as surface topography, mechanical and electrical signals. These biophysical cues could provide a more robust set of stimuli to manipulate cell signaling pathways during the formation of the engineered tissue. Furthermore, the simultaneous application of different types of signals appears to elicit synergistic responses that are likely to improve functional outcomes, which could help translate results into successful clinical therapies in the future. This article is protected by copyright. All rights reserved.
... media/76010/download). To the best of our knowledge the first clinical intervention with a recombinant human GF dates back to 1989, when Brown and co-workers topically administered EGF to accelerate the epidermal regeneration of skin graft donor sites in burn patients [95]. Experimental studies at that time, however, began to emphasize that certain pharmacokinetic requisites had to be met, for an effective outcome with EGF topical administration [96]. ...
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Diabetes mellitus remains as a pandemic disease, associated to progressive and irreversible complications including lower extremity ulcerations, derived from a predisposition to ischemia, neuropathy and an intrinsic wound healing failure. The molecular operators supporting wound chronicity remain elusive, but a local deficit of growth factors is invoked as a common cause for proliferative arrest, apoptosis, and cells senescence. The prodegradative environment of these lesions contributes to reduce growth factors availability and receptors’ physiology. The introduction of growth factors in the clinical arena was precocious since critical pieces of chronicity pathophysiology had not been identified. The topical administration of these agents failed by the effect of local proteolysis, narrow bioavailability window, inadequate diffusion, and a harsh polymicrobial biofilm. To circumvent these pharmacodynamic limitations, we envisioned an intra-ulcer infiltrative delivery route for epidermal growth factor (EGF), based on the rationale derived from experimental evidences. The clinical development program with this procedure has comprised from a proofof- concept to post-marketing studies in poor-prognosis, ischemic, neuropathic, and neuroischemic wounds, involving more than 300 000 patients along 20 years. Pharmacovigilance studies demonstrated that infiltrated EGF is therapeutically effective and safe to circumvent the limitations of the classic topical administration. This pharmacological intervention has remained as an adjuvant therapy to conventional treatments and wound care protocols. Generation of EGF nanovesicles is envisioned as a promising future direction to trigger the re-epithelialization of stagnant, non-resurfaced diabetic wounds upon topical administration.
... Further, studies of the exogenous application of EGFR have also reported improved epithelialization during wound repair by enhancing the migration of human skin fibroblasts [20,21]. In this framework, the PI3K/AKT signaling pathway is critical for many physiological and pathological conditions, such as cell proliferation, angiogenesis, metabolism, differentiation, and survival [22]. ...
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Objective: This study focused on investigating the effects of microRNA551b-5p (miR-551b-5p) on severe acute pancreatitis. Methods: Initially, quantitative real-time polymerase chain reaction (qPCR) is employed to determine the expression of miR-551b-5p in differentiated human umbilical vein endothelial cells (HUVECs). Further, the effects of aberrantly expressed miR-551b-5p in HUVECs Transwell assay. The expressions of proteins associated with severe acute pancreatitis capillary leakage syndrome are determined by Western blot, FITC-phalloidin, and immunofluorescence stainings. Finally, the correlative factor and the target genes of miR-551b-5p, as well as their contributions, are assessed. Results: We observed that overexpression of miR-551b-5p distinctly promoted the expression of EGFR, AKT3, and AQP5, while it suppressed the expression of JAM3, AQP1, and occludin. Functionally, the cytoskeleton of the miR-551b-5p overexpression was relatively loose with apparent vacuoles, and overexpression of miR-551b-5p increased the permeability of HUVECs. Conclusion: miR-551b-5p overexpression promoted changes in vascular endothelial permeability via upregulation of the EGFR/AKT3 pathway and downregulation of occludin and JAM3.
... This compound has also been shown to increase the infiltration of leukocytes and macrophages in wounds and enhancing healing (Inui et al., 1995;Dutta, 2015). Chitosan exerts its effect by increasing production of growth factors such as colony stimulating factor (CSF) and platelet-derived growth factor (PDGF) (Brown et al., 1989;Inui et al., 1995;Ueno et al., 2001), decreasing interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), and tumor necrosis factor-a (TNF-a) (Chung et al., 2012) production by basophils and pro-inflammatory markers by osteoblasts (Kim et al., 2011). The compound has also been reported to decrease nitric oxide production by macrophages in vitro (Yang et al., 2010). ...
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In this study, we formulated Thymoquinone-loaded nanocomposites (TQ-NC) using high-pressure homogenizer without sodium tripolyphosphate. The TQ-NC were characterized and their anti-inflammatory determinedby the response of the LPS-stimulated macrophage RAW 264.7 cells in the production of inflammatory cytokines, nitric oxide, prostaglandin E2, tumor necrosis factor-α, interleukin-6, and interleukin-1β. The physicochemical properties of TQ-NC were determined using different machines. TQ was fully incorporated in the highly thermal stable nanoparticles. The nanoparticles showed rapid release of TQ in the acidic medium of the gastric juice. In medium of pH 6.8, TQ-NC exhibited sustained release of TQ over a period of 100 h. The results suggest that TQ-NC nanoparticles have potential application as parenterally administered therapeutic compound. TQ-NC effectively reduce production of inflammatory cytokines by the LPS-stimulated RAW 264.7 cells, indicating that they have anti-inflammatory properties. In conclusion, TQ-NC nanoparticles have the characteristics of efficient carrier for TQ and an effective anti-inflammatory therapeutic compound.
... 60 Jacob et al indicated that EGF was significantly down-regulated in atopic dermatitis patients, and this lowexpression state may impair anti-inflammatory immune response and proliferation in the skin. [61][62][63][64] Duan et al revealed that EGF was localized within p63 + basal cells in health controls, and there was a down-regulation of EGF in NP tissues. 65 While, Ding et al reported an elevated level of EGF in the sinus mucosa of CRSwNP patients. ...
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Background: The aim of this study is to investigate the potential key genes related to Chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: Datasets GSE36830 and GSE72713 were obtained from Gene Expression Omnibus. Dataset GSE36830 was used to identify differentially expressed genes in CRSwNP patients. GO, KEGG analysis, and PPI network analysis were applied to further investigate the function of DEGs in CRSwNP. GSEA was also performed to explore the mechanisms of DEGs. Dataset GSE72713 was applied to validate the key gene. Moreover, to detect the expression of target gene, nasal polyp tissues and middle turbinate specimens were collected from CRSwNP patients (n = 20) and controls (n = 20), respectively. RT-PCR, Western blot, and immunofluorescence staining were applied. HE and AB-PAS staining were used to assess the infiltration of inflammatory cells. The proliferation and migration ability of human nasal epithelial cells (HNEpCs) were tested via Cell Counting kit-8, wound healing assay and Transwell migration assay. Air-liquid interface was used to culture primary human nasal epithelial cells (pHNECs) from health controls and nasal polyp tissues of CRSwNP patients. Results: A total of 1035 DEGs were identified, and 661 genes were up-regulated and 374 genes were down-regulated. According to PPI network analysis, the top 10 scored genes were identified. Among them, only EGF was down-regulated in CRSwNP. Meanwhile, GSEA result shows that EGF is significantly enriched in WNT activated receptor activity. CCK-8, wound healing assay, and transwell migration assay indicated that recombinant human EGF can promote the proliferation and migration of HNEpCs in vitro. Immunofluorescence staining shows that rhEGF can increase the expression of ZO-1 in pHNECs from nasal polyp tissues. Conclusion: Bioinformatics analysis and in vitro experiments were used to explore the pathogenesis of CRSwNP, and the results showed that EGF may play an important role in the protection of nasal epithelial barrier.
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Objective In the microenvironment of wound sites, naturally occurring growth factors are crucial for cell migration, opsonisation, chemotaxis, differentiation and angiogenesis. Exogenous growth factors, such as platelet-rich plasma (PRP) and adipose tissue, also improve healing. Method In the present within-subject study, we described the effects of PRP and adipose tissue extract (ATE) on skin graft donor site wound healing in patients requiring split-thickness skin grafts. Each patient, having at least two donor sites, received both control (no growth factor) and experimental (PRP or ATE) treatments. Wounds were evaluated on days 5, 7, 10, 15, 30 and 60. Digital photography and spectral images were used to analyse haemoglobin and melanin content, and re-epithelialisation area. Pain was assessed by visual analogue scale. Scar characteristics were scored on days 30 and 60. Biomaterial samples were analysed for growth factor and protein content. Results The study included 24 patients (18 male and six female; mean age: 59.1 years). PRP was topically applied to wounds in 11 patients (13 donor sites) and ATE in 13 patients (15 sites). ATE-treated donor sites exhibited significantly accelerated wound re-epithelialisation on days 5 and 7 compared with control sites (p=0.003 and 0.04, respectively). PRP accelerated healing on day 7 compared with control sites (p=0.001). Additionally, the application of ATE improved scar quality on days 30 and 60 (p=0.0005 and 0.02, respectively). Pain scores did not differ significantly between treatments. Conclusion In this study, both growth factor sources stimulated wound healing. ATE is an alternative source of growth factors that promote early wound healing and improve scar quality.
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Background: The inflammatory lesions of acne leave scars which greatly affect patients' quality of life. Treatment options targeting both acne and acne scars are still lacking. Objectives: To evaluate the clinical efficacy of epidermal growth factor ointment (EGFO) on acne and acne scars. Methods: The study design was 12-week, prospective, split-face, single-blinded. The 36 patients with mild to moderate acne vulgaris applied EGFO on one side of the face and the vehicle ointment on the other side twice daily. The patients were assessed every 4 weeks by acne lesion and scar counts, investigator's global assessment for acne (IGA) and scar (SGA), and the ECCA scar grading scale. Biopsies were performed before and after treatment. Results: Acne and acne scars were significantly improved on EGFO-treated sides, while control sides were not. Acne lesion and scar counts were significantly reduced after 4 weeks, while IGA, SGA, and ECCA grade significantly decreased after 8 weeks. Immunohistochemistry showed decreased expression of keratin 16, NF-κB p65, IL-1α, and IL-8, and increased expression of TGF-β1, elastin, and collagen type 1, 3 after treatment. Conclusions: EGFO can be a treatment option targeting acne and acne scars.
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