Autophagy is the key to making chronic wounds acute in skin wound healing

Abstract

As a highly regulated and dynamically balanced intracellular degradation mechanism, macroautophagy/autophagy plays an essential housekeeping role in different successive stages of skin wound healing; from the homeostasis and inflammatory stages to the proliferative and remodeling stages. Under both progressive and defective skin wound healing conditions, autophagy operates at different levels with a precise extent of activity, at the interface of inflammation, stress signaling and cell metabolism through a complex spatiotemporal cascade of molecular and cellular events. Depending on the wound healing conditions autophagic activity is fine-tuned and differentially modulated at each stage of skin wound healing in order to cope with stage-specific requirements. Here, we postulate that under favorable conditions autophagy may act as the key modulator of skin wound healing by making chronic wounds acute. Enhancing autophagy through the topical application of pro-autophagy biologics in an appropriate hydrating vehicle/moisturizing base such as hydrogels, onto a chronic skin wound may provide moisture and immune modulation, thus contributing to rapid and efficient skin wound healing. A moist environment is more conducive to skin wound healing as it helps to not only accelerate cell proliferation and migration, and extracellular matrix reorganization, but also promotes autophagy and reduces the incidence of inflammation. Abbreviation : AKT: AKT serine/threonine protein kinase; ECM: extracellular matrix; FN1: fibronectin 1; LAM: laminin; MMPs: matrix metallopeptidases; MMP2: matrix metallopeptidase 2; MRSA: methicillin-resistant Staphylococcus aureus ; MTOR: mechanistic target of rapamycin kinase; PI3K: phosphoinositide 3-kinase; TNF/TNF-α: tumor necrosis factor.

Successful Management of Chronic Wounds by an Autophagy-Activating Magnetized Water-Based Gel in Elderly Patients: A Case Series

“…In the five elderly patients described in this study, each presenting with wounds that had not responded to conventional treatments, the application of the magnetized water gel yielded encouraging healing outcomes, demonstrating its promising efficacy in wound management. These proof-of-concept findings are in line with the theory proposed by Mijaljica et al, which identifies autophagy as a critical mechanism in transitioning chronic wounds into an acute healing phase [ 9 ]. In addition to activating autophagy, it is also possible that the magnetized water gel may enhance moisture retention, thereby fostering an ideal environment for cell proliferation, migration, and extracellular matrix reorganization, all while simultaneously mitigating inflammation.…”

“…Autophagy, a highly conserved cellular recycling process, has a complex and multifaceted role across the wound healing process [ 8 ]. In the initial inflammatory stage, it functions as an innate defense mechanism against pathogens that could impede healing while also tempering inflammation to prevent excessive tissue damage [ 9 ]. As healing transitions into the proliferative phase, autophagy facilitates extracellular matrix deposition and promotes the proliferation and differentiation of endothelial cells, fibroblasts, and keratinocytes [ 9 ].…”

“…In the initial inflammatory stage, it functions as an innate defense mechanism against pathogens that could impede healing while also tempering inflammation to prevent excessive tissue damage [ 9 ]. As healing transitions into the proliferative phase, autophagy facilitates extracellular matrix deposition and promotes the proliferation and differentiation of endothelial cells, fibroblasts, and keratinocytes [ 9 ]. Through these mechanisms, autophagy is pivotal for re-epithelialization and the ultimate restoration of skin barrier integrity [ 10 ].…”

“…Recently, we have shown that the topical application of magnetized saline water can stimulate autophagy in intact skin [11]. Starting from the assumption that autophagy may facilitate multiple aspects of wound healing [8][9][10], we hypothesized that activating this process via a topical gel containing 95% magnetized saline water could aid in healing difficult-to-treat wounds where autophagy is frequently impaired. In this case series, we document the successful management of five non-infected, difficult-to-heal wounds in elderly patients using a topical autophagy-stimulating gel containing 95% magnetized saline water.…”

Functional Microneedle Patch for Wound Healing and Biological Diagnosis and Treatment

“…In addition, the blood vessels atrophy and the granulation tissue degrades over time, eventually leaving the wound site free of blood vessels and cells, with a coloration similar to the surrounding skin. [ 18 ] In short, the ideal wound healing is that the skin tissue can recover its original normal structure, function and even its original appearance after damage. [ 19 ] However, skin lesions do not always follow the timely and coordinated course described above.…”