The skin is the body's largest organ. It serves various functions, including protection and metabolism. Due to its structure and location, it is more vulnerable to external physical and chemical damage than internal organs. Additionally, certain endogenous diseases can cause pathological changes to appear on the skin and nerves. When skin tissue breaks down or sustains severe trauma, the cells, blood vessels, and nerves across all layers can suffer varying degrees of damage. This often results in pain, itching, sensory disturbances, and other discomforts, causing significant distress to patients. Stem-cell-derived exosome therapy has emerged as a promising treatment for skin injuries due to its safety, non-toxicity, and precision medicine benefits. Research has shown that stem-cell-derived exosomes regulate nerve cells by mediating MicroRNA (miRNA) transport and expression between cells, promoting axon growth. This exosome-driven miRNA exchange serves as a vital mode of intercellular communication, playing a crucial role in nervous system repair. Nerves play a critical role in skin wound healing and tissue regeneration, with sensory and autonomic nerves influencing key skin functions such as inflammation, immune defense, apoptosis, proliferation, and wound repair. Exosomes may aid in treating cutaneous nerve injuries by directly or indirectly promoting axon regeneration, nerve cell proliferation, and the release of protective neurofactors. This exosome-driven miRNA exchange serves as a vital mode of intercellular communication, playing a crucial role in nervous system repair. Nerves play a critical role in skin wound healing and tissue regeneration, with sensory and autonomic nerves influencing key skin functions such as inflammation, immune defense, apoptosis, proliferation, and wound repair. Exosomes may aid in treating cutaneous nerve injuries by directly or indirectly promoting axon regeneration, nerve cell proliferation, and the release of protective neurofactors. exosome nerve nerve regeneration wound wound healing This research received no external funding. Severe damage to skin tissue reaching the reticular layer, such as deep burns, does not regenerate and results in scarring after healing. In contrast, the papillary and epidermal layer damage can undergo regenerative repair. This repair and scar formation process is highly complex and regulated by various cells, the extracellular matrix, cytokines, and neuroimmune mechanisms [ 2 ]. Nerves nourish and regulate the skin, which is crucial to wound healing. During this process, the inflammatory response activates sensory and motor nerves in the dermis, prompting the release of neuropeptides that regulate healing [ 3 ]. One key function is detecting and transmitting exogenous and endogenous danger signals to immune cells, triggering a coordinated immune response. When exposed to external stimuli, the body’s neuro–endocrine–immune network quickly adjusts cellular metabolism, neural excitation, and hormone release while initiating gene regulation to trigger various biological responses [ 5 ]. In skin trauma repair and regulation, nerve factors are as important as the regenerative effects of blood vessels and tissues. Tissue damage or ischemia often accompanies nerve damage, and nerve regeneration occurs alongside wound repair, playing a crucial role in the overall healing process. In the nervous system, they are involved in both physiological and pathological processes. Exosomes promote wound healing and inhibit scar formation by regulating inflammation, cell proliferation and migration, angiogenesis, and collagen deposition during skin wound healing. Additionally, they support neurotherapeutic functions by mediating axon regeneration, Schwann cell activation, vascular regeneration, and inflammation regulation, thereby aiding in the repair of neurological deficits and improving the quantity and quality of nerve fibers. This contributes positively to the repair of skin nerves [ 9 , 10 ]. Severe burns, also known as total burns, are total burns that destroy the skin, subcutaneous tissue, and peripheral nerve structures, resulting in motor and sensory dysfunction. Electrical and chemical burns are often accompanied by irreversible neural axonal damage, leading to chronic peripheral neuropathy [ 21 , 22 ]. Beyond restoring sensory perception, nerve fibers are vital in skin repair and in maintaining dynamic skin homeostasis during the wound-healing process [ 23 ]. Autologous skin grafting is the most effective treatment for cutaneous burns but is limited in patients with insufficient donor skin due to extensive injuries. In contrast, neuritis due to leprosy does not develop proliferative scarring, suggesting that neuromodulation plays a critical role in the healing process of skin wounds. Most studies conclude that nerves promote skin wound regeneration and scar healing. Nerves trigger neurogenic inflammatory responses and activate local inflammatory mediators at the injury site [ 87 ]. They also enhance blood supply to the wound and surrounding tissues by dilating local blood vessels, promoting DNA synthesis, and stimulating the proliferation of endothelial cells, vascular smooth muscle cells, keratinocytes, and fibroblasts (FBs) [ 88 ]. By delivering active proteins and nucleic acids to target cells, these exosomes influence key aspects of the healing process, including the inflammatory response, cell proliferation, tissue remodeling, angiogenesis, and matrix reconstruction. This accelerates wound healing while inhibiting the formation of keloid scars [ 98 , 99 ]. For example, umbilical cord blood MSC-derived exosomes (UMSC-Exos) have been shown to accelerate wound healing and skin regeneration. These exosomes promote fibroblast aggregation and stimulate the secretion of NGF, which supports nerve regeneration in the skin. Research by Zhu et al.

Post-burn pruritus is the pruritus that occurs after burn during the rehabilitation and healing process of burn wounds. The post-burn pruritus is a common and serious complication of burn injury, which severely lowers the quality of life of the patient. Many potential treatments are available for pruritus but there is no consensus of the best single treatment yet. The precise mechanism of post-burn pruritus has not been elucidated, but it appears to have pruritogenic and neuropathic aspects. Clinically, post-burn pruritus tends to be intractable to conventional treatment but rather responds to neuroleptic agents, such as gabapentin and pregabalin. During wound healing, various neuropeptides secreted from the nerves of the skin control epidermal and vascular proliferation and connective tissue cells. When keratinocytes are activated by an itch-inducing substance, they secrete a variety of inflammatory substances that increase the susceptibility of the itch receptor. There are two mechanisms underlying post-burn neuropathic pruritus. The first one is peripheral sensitization. The second one is the intact nociceptor hypothesis. An effective treatment for post-burn pruritus will also be effective in other neuropathic and intractable itching. In this review, we summarized the interaction and mechanism of keratinocytes, immune cells, and nerve fibers related to post-burn pruritus. 29 5 2020 21 11 3880 3880 29 6 2020 © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/ ). Abstract Post-burn pruritus is the pruritus that occurs after burn during the rehabilitation and healing process of burn wounds. The post-burn pruritus is a common and serious complication of burn injury, which severely lowers the quality of life of the patient. Many potential treatments are available for pruritus but there is no consensus of the best single treatment yet. The precise mechanism of post-burn pruritus has not been elucidated, but it appears to have pruritogenic and neuropathic aspects. Clinically, post-burn pruritus tends to be intractable to conventional treatment but rather responds to neuroleptic agents, such as gabapentin and pregabalin. During wound healing, various neuropeptides secreted from the nerves of the skin control epidermal and vascular proliferation and connective tissue cells. When keratinocytes are activated by an itch-inducing substance, they secrete a variety of inflammatory substances that increase the susceptibility of the itch receptor. There are two mechanisms underlying post-burn neuropathic pruritus. Status of Post-Burn Pruritus Post-burn pruritus is the pruritus that occurs during the wound healing process after a burn. The onset of the pruritus may occur within a few days after burn and the prevalence of pruritus after burn is 80–100%, according to reports [ 1 , 2 , 3 ]. The prevalence of pruritus tends to decrease with time, but, in some cases, it has persisted for more than a few years and the prevalence rate has reached 40% even after 12 years [ 4 ]. Cells and Molecules Mechanism Acute phase Keratinocyte Keratinocyte secretes a variety of inflammatory substances which induce pruritus; histamine, calcitonin gene related peptides (CGRP), Substance P, etc. [ 20 ] Mast cell Mast cell releases histamine into post-burn lesion [ 38 ] Histamine Histamine appears to be a key initiator of impulses predominantly in the initial stages of healing after burn, but the role of histamine in post-burn itch is minimal [ 46 ] It helps keratinocyte produce inflammatory agents [ 34 , 37 ] Substance P Calcitonin gene related peptides (CGRP) Substance P and CGRP are the main transduction medias involved in C fiber. Disinhibition in this pathway results in excitability in the CNS [ 25 ] After an injury, the skin-healing process involves three phases: An inflammatory phase, a proliferative phase, and a remodeling phase. During wound healing, various neuropeptides secreted from the nerves of the skin affect epidermal and dermal proliferation and inflammation [ 31 , 32 , 33 ]. When keratinocytes are activated by an itch-inducing substance, they secrete a variety of inflammatory substances that increase the susceptibility of the itch receptor. Histamine can increase keratinocyte production of inflammatory agents such as interleukin-6 (IL-6), IL-8, and C-C motif chemokine ligand 5 (CCL5) [ 34 ]. Mast cells are increased in post-burn hypertrophic scars, and the thicker the scars, the greater the itching [ 38 ]. Thymic After the acute phase of healing, histamine is known to be less important to the mechanism of pruritus. In the chronic phase, it converts to the neuropathic type of pruritus characterized by antihistamine-resistant wounds with sensitized CNS. Increased neuropeptides, such as nerve growth factor, substance P, and the upregulation of calcium channel in the spinal cord, cause CNS sensitization in chronic burns. Thus, the CNS activates autonomously, which shifts maintenance into a chronic phase. Finally, a burn injury can induce synaptic reorganization. The post-burn state has been linked with alterations to the functional topography in the primary somatosensory cortex. Topical 5–10% ketamine, in combination with 5% lidocaine and 5% amitriptyline, is an effective treatment for neuropathic itch [ 55 ]. A combination of topical ketamine-lidocaine-amitriptyline could be an option in post-burn patients for reducing the firing of defective nerves [ 5 ]. Although doxepin is a tricyclic antidepressant (TCA), it has highly potent histamine receptor-blocking properties [ 56 ]. Topical doxepin cream has been used for pruritus of various dermatological disorders. There is a study comparing topical 5% doxepin cream with standard therapy (oral antihistamines, skin moisturizers, and sedatives) on healed pruritic wounds.

Abstract High-quality cutaneous wound healing is associated with rapid wound closure and a comfortable healing process. Currently, exosomes derived from mesenchymal stem cells displayed a prominent therapeutic effect on skin wound closure. But the therapeutic approaches for wound itching are very limited in clinical. Stem cells from human exfoliated deciduous teeth (SHED) may offer a unique exosome resource for cell-free therapeutics in potential clinical applications. Here, we investigated the common mechanisms underlying wound closure and unpleasant sensation of itching, focusing on the contribution of the SHED-derived exosome to immune response and wound itching during healing. The effects of SHED-derived exosomes on inflammatory wound healing were examined using lipopolysaccharide (LPS)-induced wounds in a mouse model. We found prolonged inflammation and distinct itch responses in skin wound tissue during LPS-induced wound healing. SHED-derived exosomes facilitated LPS-induced wound closure and relieved wound itching. Therefore, they are ideal for the treatment of wound healing. Macrophages in skin wound tissues are responsible for autophagy during wound healing. Macrophage autophagy also regulates cell proliferation, migration, and neuronal signal transduction in vitro. SHED-derived exosomes containing miR-1246 enhanced autophagy by regulating macrophage function through the AKT, ERK1/2, and STAT3 signaling pathways. Thus, SHED-derived exosomes promote wound healing with The effects of SHED-derived exosomes on inflammatory wound healing were examined using lipopolysaccharide (LPS)-induced wounds in a mouse model. We found prolonged inflammation and distinct itch responses in skin wound tissue during LPS-induced wound healing. SHED-derived exosomes facilitated LPS-induced wound closure and relieved wound itching. Therefore, they are ideal for the treatment of wound healing. Macrophages in skin wound tissues are responsible for autophagy during wound healing. Macrophage autophagy also regulates cell proliferation, migration, and neuronal signal transduction in vitro. Consequently, as potentially crucial targets, macrophages release multiple inflammatory cytokines and control tissue repair responses, suggesting they could play a role in the development of wound healing and itching. Recently, mesenchymal stem cells (MSCs) have been frequently used in the field of wound healing because of their self-renewal ability, multiple differentiation potential, and microenvironmental regulation [ 13 , 14 ]. Although MSCs accelerate the resolution of wound inflammation and encourage tissue regeneration, it has been suggested that the regenerative functionality is mainly because of their paracrine actions, in which exosomes play an essential role [ 15 – 18 ]. SHED are known to differentiate into neural cells and are capable of high immunoregulatory activity [ 24 , 25 ]. However, the effect and underlying mechanisms of SHED-derived exosomes (SHED-Exo) on wound healing and itching remain unclear. Here, we utilized an experimental mouse model of wound healing to investigate the effects of SHED-Exo on lipopolysaccharide (LPS)-induced wound healing and itching. We confirmed the healing-promoting and itch-suppressing effects of SHED-Exo on the skin and elucidated that macrophage autophagy regulated tissue regeneration and neuron sensitivity. Moreover, SHED-Exo-treated wounds exhibited the most abundant granulation tissue and the shortest wound length. Collectively, these results suggested that SHED-Exo facilitated wound closure and promoted tissue regeneration, and these positive effects may be related to autophagy. SHED-Exo relieve itch responses during wound healing To further investigate whether SHED-Exo regulate itch responses during wound healing, which could be associated with the autophagy level, we observed scratching responses and TRPV4 appearance on day 5 of wound healing. LPS-treated mice displayed a higher number of scratching bouts compared to the control and no-wound animals (Fig. 3 a). Additionally, mice treated with SHED-Exo scratched much less than the LPS-treated mice on the 5th day of healing. Consistent with this result, SHED-Exo inhibited LPS-induced upregulation of TRPV4 expression in the skin, whereas 3-MA reversed the effects of SHED-Exo, indicating that these exosome-mediated effects are involved with autophagy (Fig. 3 b). Collectively, these results suggested that SHED-Exo relieve itching associated with autophagy during wound healing. Fig. 3 SHED-Exo relieve itch responses during wound healing. a Scratching behaviors were observed in mice before and on the 5th day of wound healing. Data are from two independent experiments. n = 7. Interestingly, treatment with 3-MA significantly reversed the effects of SHED-Exo on wound closure and pruritus, suggesting that the effect of SHED-Exo was associated with autophagy. We also found that RAPA mimicked the effects of exosomes, but not dramatically. Therefore, we speculated that autophagy is a likely approach to wound closure and pruritus when the skin is recovering from injury. The type of cells responsible for autophagy during wound healing and whether it influences inflammation at the lesion site were determined. We found that macrophages are the main cell type in the skin during the process of wound healing. The cutaneous wounds were subcutaneously injected with 0.5 mg/kg LPS, 10 mg/kg autophagy inhibitor 3MA, 1 mg/kg autophagy promoter rapamycin, or 10 mg/kg SHED-derived exosomes dissolved in 200 μL PBS. A series of digital photographs of the cutaneous wounds was taken during the wound healing process, and a standard ruler was used as a scale. At the indicated time points, wound size was calculated on photographs using Adobe Photoshop Elements 14 software. Changes in the wound area are expressed as a percentage of the initial wound area. Histological and immunofluorescence analysis After 5 and 10 d of healing, the wound skin

Abstract A variety of dressings is available for the treatment of partial-thickness wounds, but none has strong evidence supporting their beneficial effect on healing. This may be due to variation in the type and depth of wounds in clinical studies. The aim of this study was to use a standardized porcine wound model to compare three dressings commonly used in burn centers for partial-thickness burns. Partial-thickness scalds were made on the flanks of pigs. Wounds were treated with silver sulfadiazine (SSD, flammazine), a hydrofiber dressing, or glycerol-preserved allogeneic (pig) skin. The healing process was monitored for 8 weeks. Macroscopic parameters were the itching behavior, the cosmetic appearance of the scars, and contraction. Microscopic parameters were the inflammatory response, myofibroblast influx, and the numbers of nerves. All wounds were closed on day 14 and wound infection did not occur. Treatment with SSD resulted in significantly more wound contraction compared to treatment with glycerol-preserved pig skin. Animals treated with SSD suffered more from itching (scratching) during the first 2 weeks after wounding. The number of nerves in healing wounds of these animals was significantly higher compared to wounds treated with hydrofiber dressing or allogeneic skin. In our standardized porcine partial-thickness wound model, treatment with SSD resulted in less favorable wound healing. Compared to treatment with glycerol-preserved allogeneic skin, SSD resulted in