Una cicatriz es un parche de piel permanente que crece sobre una herida. Se forma cuando el cuerpo se cura después de una cortadura, un raspón, una quemadura o una llaga. Las cicatrices también pueden resultar tras una cirugía donde se corte la piel, infecciones como la varicela o afecciones de la piel como el acné.

Mejoras después del tratamiento con Factores de Crecimiento

Siete días después de la sensibilización, la oreja y la piel dorsal de los ratones NC / Nga se volvieron a sensibilizar con DNCB al 0,4% y se trataron con PRT al 0,1%, EGF 1 ppm o EGF 5 ppm durante 2 semanas. PRT 0.1% es un tratamiento bien conocido para el trastorno de la piel inmunomediado16 y se utilizó como control terapéutico. El tratamiento con EGF suprimió la inflamación de la piel similar a la AD inducida por DNCB (Fig. 1B, C). El tratamiento con EGF 1 ppm o EGF 5 ppm redujo significativamente el grosor de la oreja el día 21 en comparación con el control (Fig. 1D). Además, EGF disminuyó el puntaje de dermatitis de las lesiones cutáneas inducidas por DNCB en los días 14 y 21 de una manera dependiente de la dosis (Fig. 1F). Las lesiones tipo AD mostraron hiperqueratosis e hiperplasia del epitelio. La tinción con H&E mostró que el grosor epidérmico del oído y la piel dorsal se atenuó con el tratamiento con EGF y PRT 0.1% (Fig. 1B-E). Se observaron epidermis y dermis más gruesas en las lesiones cutáneas del grupo control. Sin embargo, EGF 1 y 5 ppm redujeron significativamente el grosor epidérmico del oído y la piel dorsal en comparación con el grupo de control. Tomados en conjunto, estos hallazgos sugieren que la administración tópica de EGF protege contra la AD inducida por DNCB en ratones NC / Nga.

Publicaciones Científicas

Diabetic Foot Ulcers and Epidermal Growth Factor: Revisiting the Local Delivery Route for a Successful Outcome


Soon after epidermal growth factor (EGF) discovery, some in vivo models appeared demonstrating its property to enhance cutaneous wound healing. EGF was the first growth factor (GF) introduced in the clinical arena as a healing enhancer, exerting its mitogenic effects on epithelial, fibroblastoid, and endothelial cells via a tyrosine kinase membrane receptor. Compelling evidences from the 90s documented that, for EGF, locally prolonged bioavailability and hourly interaction with the receptor were necessary for a successful tissue response. Eventually, the enthusiasm on the clinical use of EGF to steer the healing process was wiped out as the topical route to deliver proteins started to be questioned. The simultaneous in vivo experiments, emphasizing the impact of the parenterally administered EGF on epithelial and nonepithelial organs in terms of mitogenesis and cytoprotection, rendered the theoretical fundamentals for the injectable use of EGF and shaped the hypothesis that locally infiltrating the diabetic ulcers would lead to an effective healing. Although the diabetic chronic wounds microenvironment is hostile for local GFs bioavailability, EGF local infiltration circumvented the limitations of its topical application, thus expanding its therapeutic prospect. Our clinical pharmacovigilance and basic studies attest the significance of the GF local infiltration for chronic wounds healing.

1. Introduction

Diabetic foot ulcers (DFUs) are a major and feared complication among the constellation of the multiorgan diabetic-associated disorders. DFU is defined as a full-thickness wound penetrating through the dermis (the deep vascular and collagenous inner layer of the skin) located below the ankle in a diabetes patient [1]. An astonishing review article by Armstrong and coworkers showed that DFU is not exclusively a limb-threatening condition. The relative 5-year mortality rate after limb amputation is 68% representing a second place only preceded by lung cancer [2]. Furthermore, ulcer recurrence is one of the most important and unsolved challenges in the current approach to diabetic foot disease [3].

The foundation of this complication resides in the inability to orchestrate a physiological multistep healing process. Diabetic subjects are prone to mount a chronification phenotype which is clinically translated in (1) failure for triggering proliferative phase/granulation tissue response, (2) meager or histologically abnormal angiogenesis, (3) impaired wound contraction, and (4) stagnant and aberrant reepithelialization process [4].

Diabetes-related peripheral neuropathy and ischemia-hypoxia owing to macro- and/or microvascular damage are major predisposing factors for DFU debut and its healing failure [5, 6]. At a molecular level, diabetic peripheral neuropathy predisposes to impaired wound healing by provoking an extensive derangement of neuropeptides that definitively controls critical events like inflammation, chemoattraction, vascular permeability, leucocytes adhesion, cytokines expression, endothelial cells proliferation, and growth factors release [7, 8]. By its side, diabetic vascular disease is associated with the most severe DFU adverse outcomes, including lower probability of healing, longer healing times, higher probability of ulcer recurrence, greater risks of amputations, and potentially higher mortality. It is well known that hyperglycemia is the primary trigger of vascular endothelial cells toxicity, which translates in vascular functional impairment, microvascular rarefaction, imperfect angiogenesis, and media and intima thickening [9, 10]. The ensuing hypoxia drives a peculiar clinical, cellular, and molecular signature that eventually aborts the healing process through a variety of deleterious mechanisms. Thus, the physiological relevance of oxygen delivery within the wound matrix is out of discussion [11]. Mounting evidences target the definitive role of epigenetic mechanisms for the onset of aberrant angiogenesis and wound chronicity in diabetes. Likewise, the apparently trivial glycemic levels and the cellular oxygen pressure are not passive bystanders; rather, they actively contribute to the cellular epigenetic blueprint reprogramming rendering a “stagnant transcriptome” [9, 12]. Accordingly, the instrumental molecular pathways routing to wound chronification seems to converge on three main cellular pillars: precocious senescence, proliferative refractoriness, and apoptosis [13, 14]. Again, we deem that epigenetic forces may drive the inability of the tissues to deal with external or intrinsic predisposing factors on the base of wound chronification and local reulcerations [15, 16].

The healing response emerges subsequently to cells exposure to alarm signals once the skin barrier is disrupted. This response is ultimately commanded by growth factors (GFs) which act as soluble messengers, establishing a communication network among the different cells populations and with the extracellular matrix. The paracrine GFs releasing sources include platelets, immune inflammatory cells, fibroblasts, endothelial cells, and keratinocytes [17].

Historical studies implicate an insufficient production and/or activity of GFs and their receptors in the diabetic wound healing failure, which would involve the immobilization of critical reparative ingredients [1820]. Consequently, the topical administration of recombinant human GFs that dates back to almost 40 years ago arose as an encouraging alternative toward torpid healing processes. Nonetheless, the initial expectations with these “magic bullets” vanished away in about a 10-year period. To our understanding, two main factors quenched such excitement: (a) the inputs from basic science that associated GFs to malignant cells promotion and progression (for review see [21]) and (b) the setback that stemmed from clinical trials in which the topical administration of epidermal growth factor (EGF) failed to enhance the healing process of chronic wounds [22] and, unexpectedly, of acute, controlled, and experimentally induced wounds in healthy volunteers [23].

These disappointments warned about the need for additional research in GFs physiology and pharmacology as in the understanding of wound milieu biochemistry. After years of peaks and troughs, EGF and platelet-derived growth factor (PDGF) have remained as the only GFs in the clinical armamentarium for hard-to-heal diabetic wounds. The line of thought that encouraged us to fuel the hypothesis that infiltrating EGF into the lesions would lead to an effective healing was the resultant of recombining different and disperse pieces of knowledge, including those supporting the fact that topical administration is not an ideal delivery route for chronic wounds. Thus, this review manuscript is rather a reflection that links the elementary principles of diabetic chronic wounds biochemistry, with the rationale of reorienting the GFs delivery route for a successful healing outcome. Today after 15 years of experience, the basic science has been validated by the clinical routine.

The literature search was based on key words introduced in PubMed and Bioline International ( data sources, while only articles in English language were downloaded.

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Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice


Atopic dermatitis (AD) is a common inflammatory skin disease characterized by a complex, heterogeneous pathogenesis including skin barrier dysfunction, immunology, and pruritus. Although epidermal growth factor (EGF) is essential for epithelial homeostasis and wound healing, the effect of EGF on AD remains to be explored. To develop a new therapy for AD, the anti-AD potential of EGF was investigated by inducing AD-like skin lesions in NC/Nga mice using 2,4-dinitrochlorobenzene (DNCB). EGF was administrated to NC/Nga mice to evaluate its therapeutic effect on DNCB-induced AD. EGF treatment improved dermatitis score, ear thickness, epidermal hyperplasia, serum total immunoglobulin E level, and transepidermal water loss in NC/Nga mice with DNCB-induced AD. In addition, levels of skin barrier-related proteins such as filaggrin, involucrin, loricrin, occludin, and zonula occludens-1 (ZO-1) were increased by EGF treatment. These beneficial effects of EGF on AD may be mediated by EGF regulation of Th1/Th2-mediated cytokines, mast cell hyperplasia, and protease activated receptor-2 (PAR-2) and thymic stromal lymphopoietin (TSLP), which are triggers of AD. Taken together, our findings suggest that EGF may potentially protect against AD lesional skin via regulation of skin barrier function and immune response.

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AD is a multifactorial skin disease characterized by complex interactions of innate and adaptive immune responses in individuals with genetic, pharmacological, and psychological predisposition1. It is one of the most common chronic inflammatory skin diseases and is characterized by impaired epidermal barrier, eczematous lesions, pruritus, dry skin, abnormal immune responses, and immunoglobulin (Ig) E-mediated allergies to various exogenous antigens2. When type 2 T cells are activated, cytokines such as interleukin (IL)-4, IL-5, IL-10, and IL-13 are secreted to strengthen the humoral immune response3. IL-4 also plays a role in suppressing the function of type 1 T cells. Allergic reaction caused by an imbalance between type 1 and type 2 T cells is believed to cause AD. Other immune cells are also thought to be involved in AD. For instance, mast cells, which are major effector cells of IgE-mediated hypersensitivity reactions, are key factors in the pathogenesis of AD because they are allergen activated through the high-affinity IgE receptor4. Mast cells are regulatory cells in Th2-dominant immune responses. Histamine is a major mediator released from mast cells that mediates pruritus by binding to the histamine H1 receptor in the dermis. Activation of mast cells also causes the release of tryptase, which in turn activates PAR-2, localized on C fiber nerve terminals5. Activated C fibers transmit this information to the central nervous system, where the sensation of itch is perceived.

The epidermal growth factor receptor (EGFR) signaling pathway is crucial in skin development and homeostasis6,7. The EGF family comprises multiple mediators, including transforming growth factor-α, amphiregulin, heparin binding-EGF, and epiregulin, all of which regulate keratinocyte biology810. Recent studies have shown the importance of EGF as a potential therapeutic target for maintaining intestinal epithelial health and inducing recovery of damaged epithelium11,12. In addition, EGFR ligands have been found to be upregulated in chronic inflammatory skin disorders, such as psoriasis, atopic dermatitis, and allergic contact dermatitis13. EGF facilitates epidermal cell regeneration and plays an essential role in the process of dermal wound healing by stimulating the proliferation and migration of keratinocytes. EGF treatment can stabilize mast cell degranulation, thereby reducing the release of granular products in gastric mucosal lesions of rats14. Additionally, production of IL-17A and expression of IL-6 and IL-1β in allergen-induced AD skin have been shown to be attenuated by EGF treatment15. However, the clinical effects and mechanisms of EGF have not been fully elucidated.

In the present study, we evaluated the effects of EGF on AD and propose a mechanism by which EGF regulates allergic inflammation both systemically and at the lesional level. Our findings indicated that EGF upregulates epidermal proteins and downregulates TSLP-mediated mast cell and Th2 cell activation to reduce AD symptoms in NC/Nga mice with DNCB-induced AD.

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