Methods, Mechanisms, and Application Prospects for Enhancing Extracellular Vesicle Uptake.

Extracellular vesicles (EVs) are considered to be a new generation of bioinspired nanoscale drug delivery systems due to their low immunogenicity, natural functionality, and excellent biocompatibility. However, limitations such as low uptake efficiency, insufficient production, and inhomogeneous performance undermine their potential. To address these issues, numerous researchers have put forward various methods and applications for enhancing EV uptake in recent decades. In this review, we introduce various methods for the cellular uptake of EVs and summarize recent advances on the methods and mechanisms for enhancing EV uptake. In addition, we provide further understanding regarding enhancing EV uptake and put forward prospects and challenges for the development of EV-based therapy in the future.

Healing with precision: A multi-functional hydrogel-bioactive glass dressing boosts infected wound recovery and enhances neurogenesis in the wound bed.

Chronic skin wounds, especially infected ones, pose a significant clinical challenge due to their increasing incidence and poor outcomes. The deteriorative microenvironment in such wounds, characterized by reduced extracellular matrix, impaired angiogenesis, insufficient neurogenesis, and persistent bacterial infection, has prompted the exploration of novel therapeutic strategies. In this study, we developed an injectable multifunctional hydrogel (GEL/BG@Cu + Mg) incorporating Gelatin-Tannic acid/ N-hydroxysuccinimide functionalized polyethylene glycol and Bioactive glass doped with copper and magnesium ions to accelerate the healing of infected wounds. The GEL/BG@Cu + Mg hydrogel composite demonstrates good biocompatibility, degradability, and rapid formation of a protective barrier to stop bleeding. Synergistic bactericidal effects are achieved through the photothermal properties of BG@Cu + Mg and sustained copper ions release, with the latter further promoting angiogenesis. Furthermore, the hydrogel enhances neurogenesis by stimulating axons and Schwann cells in the wound bed through the beneficial effects of magnesium ions. Our results demonstrate that the designed novel multifunctional hydrogel holds tremendous promise for treating infected wounds and allowing regenerative neurogenesis at the wound site, which provides a viable alternative for further improving clinical outcomes.

AgNPs loaded adenine-modified chitosan composite POSS-PEG hybrid hydrogel with enhanced antibacterial and cell proliferation properties for promotion of infected wound healing.

Wound healing is a dynamic and complex process, it's urgent to develop new wound dressings with excellent performance to promote wound healing at the different stages. Here, a novel composite hydrogel dressing composed by silver nanoparticles (AgNPs) impregnated adenine-modified chitosan (CS-A) and octafunctionalized polyhedral oligomeric silsesquioxane (POSS) of benzaldehyde-terminated polyethylene glycol (POSS-PEG-CHO) solution was presented to solve the problem of wound infection. Modification of chitosan with adenine, not only can improve the water solubility of chitosan, but also introduce bioactive substances to promote cell proliferation. CS-A and POSS-PEG-CHO were cross-linked by Schiff-base reaction to form the injectable self-healing hydrogel. On this basis, AgNPs were added into the hydrogel, which endows the hydrogel with better antibacterial activity. Moreover, this kind of hydrogel exhibits excellent cell proliferation properties. Studies demonstrated that the hydrogel can significantly accelerate the closure of infected wounds. The histological analysis and immunofluorescence staining demonstrated that the wounds treated with the composite hydrogel exhibited fewer inflammatory cells, more collagen deposition and angiogenesis, faster regeneration of epithelial tissue. Above all, adenine-modified chitosan composite hydrogel with AgNPs loaded was considered as a dressing material with great application potential for promoting the healing of infected wounds.

MiR-145-5p overexpression rejuvenates aged adipose stem cells and accelerates wound healing.

Adipose-derived stem cells (ADSCs) have been widely applied in translational and regenerative medicine. During aging, there is a recognized functional decline in ADSCs, which compromises their therapeutic effectiveness. Currently, the mechanisms of aging-induced stem cell dysfunction remain unclear, hence there is a need to elucidate these mechanisms and propose strategies for reversing this functional impairment. In this study, we found that ADSCs isolated from old donors (O-ADSCs) presented inferior phenotypes and decreased miR-145-5p levels compared to those from young donors (Y-ADSCs). To interrogate the role of miR-145-5p in ADSCs, gain- and loss-of-function assays were performed. The results indicated that miR-145-5p overexpression in O-ADSCs promoted cellular proliferation and migration, while reducing cell senescence. Further study demonstrated that miR-145-5p could regulate ADSCs function by targeting bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER), which is a crucial modulator in angiogenesis. Moreover, in vivo experiments showed that miR-145-5p-overexpressing O-ADSCs accelerated wound healing by promoting wound re-epithelialization and angiogenesis. Collectively, this study indicates that miR-145-5p works as a positive regulator for optimizing O-ADSCs function, and may be a novel therapeutic target for restoring aging-associated impairments in stem cell function.

Surgical interventions for ingrown toenail.

BACKGROUND: Paronychia is a prevalent clinical disease affecting the soft tissue surrounding the nails. Most cases of toenail paronychia are commonly associated with ingrown toenails. While conservative treatment is effective for mild cases of ingrown toenails, surgical intervention becomes necessary for moderate to severe cases, particularly when granulomas form. OBJECTIVE: To provide a systematic understanding of these classic and modified procedures for surgeons to select the appropriate surgical interventions for patients suffering from moderate to severe ingrown toenails and discuss this technology's advantages and limitations for dermatologic surgery. METHODS: A literature search was performed using PubMed/MEDLINE and Google Scholar databases. Studies discussing surgical intervention for ingrown toenails were included. Moreover, the surgical steps were meticulously depicted by detailed schematic diagrams. RESULTS: These surgical techniques can be divided into three categories: matrix resection, debulking of periungual soft tissues, and the rotational flap technique. Each approach possesses distinct advantages and limitations. CONCLUSION: For moderate to severe cases, surgical interventions may exhibit superior outcomes, faster recovery times, and lower recurrence rates. The surgeon must possess a comprehensive understanding and proficient skillset in various surgical techniques for ingrown toenails.

Biomimetic hybrid nanovesicles improve infected diabetic wound via enhanced targeted delivery.

Infected diabetic wounds have been raising the global medical burden because of its high occurrence and resulting risk of amputation. Impaired endothelium has been well-documented as one of the most critical reasons for unhealed wounds. Recently, endothelial cell-derived nanovesicles (NVs) were reported to facilitate angiogenesis, whereas their efficacy is limited in infected diabetic wounds because of the complex niche. In this study, extrusion-derived endothelial NVs were manufactured and then hybridized with rhamnolipid liposomes to obtain biomimetic hybrid nanovesicles (HNVs). The HNVs were biocompatible and achieved endothelium-targeted delivery through membrane CXCR4-mediated homologous homing. More importantly, the HNVs exhibited better penetration and antibacterial activity compared with NVs, which further promote the intrinsic endothelium targeting in infected diabetic wounds. Therefore, the present research has established a novel bioactive delivery system-HNV with enhanced targeting, penetration, and antibacterial activity-which might be an encouraging strategy for infected diabetic wound treatment.

Multifunctional ADM hydrogel containing endothelial cell-exosomes for diabetic wound healing.

Non-healing wound, with limited treatment options, remains a prevalent complication of diabetes mellitus. The underlying causes wherein include oxidative stress injury, bacterial infection, cellular dysfunction, and persistent inflammation. Acellular Dermal Matrix (ADM), a wound dressing composed of natural extracellular matrix and abundant bioactive factors, has been successfully developed to treat various wounds, including burns and diabetic ulcers. Protocatechualdehyde (PA) & trivalent iron ion (Fe3+) complex (Fe3+@PA) exhibits potential antioxidant and antibacterial properties. In this study, we developed a dual hydrogel network by combining Fe3+@PA complex-modified ADM with light-cured gelatin (GelMA), supplemented with exosomes derived from human umbilical vein endothelial cells (HUVEC-Exos), to create an ADM composite hydrogel system (ADM-Fe3+@PA-Exos/GelMA) with antioxidant, antibacterial, and cell-promoting functions for diabetic wound treatment. Through in vitro experiments, we investigated the biosafety, antioxidant and antibacterial properties of ADM composite hydrogel. Furthermore, we examined the protective effects of ADM composite hydrogel on diabetic wound. The above experiments collectively demonstrate that our ADM-Fe3+@PA-Exos/GelMA hydrogel promotes diabetic wound healing by eliminating bacterial infection, reduced the reactive oxygen species (ROS) levels, protecting cells against oxidative stress damage, promotingcollagen deposition and angiogenesis, which provides a promising strategy to optimize ADM for diabetic wound treatment.

White adipose tissue-derived small extracellular vesicles: A new potential therapeutic reagent for accelerating diabetic wound healing.

Small extracellular vesicles (sEVs) from adipose-derived stem cells (ADSCs) have gained great attention and have been widely used in cell-free therapies for treating diabetic non-healing wounds in recent years. However, further clinical application of ADSC-sEVs have been limited due to their unsolvable defects, including cumbersome extraction procedure, high cost, low yield, etc. Thus, we urgently need to find one therapeutic reagent that could not only accelerate diabetic wound healing as ADSC-sEVs but also overcome these shortcomings. As the extraction process of adipose tissue-derived sEVs (AT-sEVs) is quite simple and labor saving, we put our focus on the efficiencies of white adipose tissue-derived sEVs (WAT-sEVs) and brown adipose tissue-derived sEVs (BAT-sEVs) in diabetic wound repair. After successfully isolating WAT-sEVs and BAT-sEVs by ultracentrifugation, we thoroughly characterized them and compared their diabetic wound healing capabilities both in vitro and in vivo. According to our study, AT-sEVs possess similar competence in diabetic wound healing as compared with ADSC-sEVs. While the effect of BAT-sEVs is not as stable as WAT-sEVs and ADSC-sEVs, the repair efficiency is also slightly lower than the other two sEVs in some cases. In summary, we are the first to discover that WAT-sEVs show great potential in diabetic wound repair. With advantages that are specific to tissue-derived sEVs (Ti-sEVs) such as time- and cost-saving, high-yield, and simple isolation procedure, we believe WAT-sEVs could serve as a novel reliable cell-free therapy for clinical diabetic wound treatment.

Knockdown of long noncoding RNA SAN rejuvenates aged adipose-derived stem cells via miR-143-3p/ADD3 axis.

BACKGROUND: Senescent adipose-derived stem cells (ASCs) exhibit reduced therapeutic efficacy during wound healing. Transcriptional regulation factors including long noncoding RNAs (lncRNAs) reportedly have essential roles in stem cell aging. However, the mechanisms of which lncRNAs influence mesenchymal stem cell aging and how it works need further investigation. METHODS: The expression patterns of lncRNA senescence-associated noncoding RNA (SAN) and miR-143-3p in ASCs obtained from old and young volunteer donors were detected by quantitative polymerase chain reaction. ASCs with overexpression or knockdown of SAN and γ-adducin (ADD3) were constructed by lentiviral transduction. Mimic and inhibitor were used to manipulate the cellular level of miR-143-3p in ASCs. The effects of these RNAs on ASCs proliferation, migration and cellular senescence were examined by EdU, transwell and senescence-activated ß-galactosidase (SA-ß-gal) staining assays. Wound scratch and tube formation assays were conducted to evaluate the capacities of ASCs in promoting fibroblasts migration and endothelial cells angiogenesis. Furthermore, dual-luciferase assays and rescue experiments were performed to identify the RNA interactions. Finally, the therapeutic effects of SAN-depleted aged ASCs were evaluated in a skin injury model. RESULTS: The lncRNA SAN (NONHSAT035482.2) was upregulated in aged ASCs; it controlled cellular senescence in ASCs. lncRNA SAN knockdown in ASCs led to ASC functional enhancement and the inhibition of cellular senescence; it also promoted the effects of conditioned medium (CM) on endothelial cell tube formation and fibroblast migration. Mechanistic analysis showed that SAN serves as a sponge for miR-143-3p, thereby regulating the expression of ADD3. The application of SAN-depleted aged ASCs increased re-epithelialization, collagen deposition, neovascularization and led to accelerated skin wound closure, compared with transplantation of aged ASCs. CONCLUSION: The lncRNA SAN mediates ASC senescence by regulating the miR-143-3p/ADD3 pathway, providing a potential target for rejuvenation of senescent ASCs and enhancement of wound repair.

Exosomal miR-125b-5p derived from adipose-derived mesenchymal stem cells enhance diabetic hindlimb ischemia repair via targeting alkaline ceramidase 2.

INTRODUCTION: Ischemic diseases caused by diabetes continue to pose a major health challenge and effective treatments are in high demand. Mesenchymal stem cells (MSCs) derived exosomes have aroused broad attention as a cell-free treatment for ischemic diseases. However, the efficacy of exosomes from adipose-derived mesenchymal stem cells (ADSC-Exos) in treating diabetic lower limb ischemic injury remains unclear. METHODS: Exosomes were isolated from ADSCs culture supernatants by differential ultracentrifugation and their effect on C2C12 cells and HUVECs was assessed by EdU, Transwell, and in vitro tube formation assays separately. The recovery of limb function after ADSC-Exos treatment was evaluated by Laser-Doppler perfusion imaging, limb function score, and histological analysis. Subsequently, miRNA sequencing and rescue experiments were performed to figure out the responsible miRNA for the protective role of ADSC-Exos on diabetic hindlimb ischemic injury. Finally, the direct target of miRNA in C2C12 cells was confirmed by bioinformatic analysis and dual-luciferase report gene assay. RESULTS: ADSC-Exos have the potential to promote proliferation and migration of C2C12 cells and to promote HUVECs angiogenesis. In vivo experiments have shown that ADSC-Exos can protect ischemic skeletal muscle, promote the repair of muscle injury, and accelerate vascular regeneration. Combined with bioinformatics analysis, miR-125b-5p may be a key molecule in this process. Transfer of miR-125b-5p into C2C12 cells was able to promote cell proliferation and migration by suppressing ACER2 overexpression. CONCLUSION: The findings revealed that miR-125b-5p derived from ADSC-Exos may play a critical role in ischemic muscle reparation by targeting ACER2. In conclusion, our study may provide new insights into the potential of ADSC-Exos as a treatment option for diabetic lower limb ischemia.

Mitochondrial dysfunction and oxidative stress in diabetic wound.

Diabetic wounds nowadays have become a major health challenge with the changes of the disease spectrum. Mitochondria are closely associated with stubborn nonhealing diabetic wounds for their vital role in energy metabolism, redox homeostasis, and signal transduction. There is significant mitochondrial dysfunction and oxidative stress in diabetic wounds. However, the contribution of mitochondrial dysfunction in oxidative stress induced nonhealing diabetic wound is still not fully understood. In this review, we will briefly summarize the current knowledge of the reported signaling pathways and therapeutic strategies involved in mitochondrial dysfunction in diabetic wounds. The findings provide further understanding of strategies that focus on mitochondria in diabetic wound treatment.

Exosomes derived from oral squamous cell carcinoma tissue accelerate diabetic wound healing.

It is a widespread and difficult problem that refractory diabetic wounds have a poor local environment and prolonged inflammatory irritation. Tumor cell-derived exosomes play an important role in the development of tumors, as they can promote tumor cell proliferation, migration, and invasion and enhance tumor cell activity. However, tumor tissue-derived exosomes (Ti-Exos) have been less studied, and it is unclear how they affect wound healing. In this study, we extracted Ti-Exos from human oral squamous carcinoma and paracancerous tissue by ultracentrifugation, size exclusion chromatography, and ultrafiltration and performed exosome characterization. In vitro, the oral squamous cell carcinoma tissue-derived exosomes (OSCC Ti-Exos) promoted the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts. In addition, in vivo experiments showed that the OSCC Ti-Exos accelerated the healing of diabetic wounds and were safe in mice. In contrast, there was no promoting effect of paracancerous tissue-derived exosomes either in vivo or in vitro. In conclusion, OSCC Ti-Exos promoted the healing of diabetic wounds, demonstrated preliminary biosafety in mice, and have promise as therapeutic applications.NEW & NOTEWORTHY Diabetic wound healing has become a public health issue that lacks effective treatment. We collected oral squamous cell carcinoma samples and paracancerous tissue and extracted Ti-Exos for verification. In vitro assays revealed that OSCC Ti-EVs could enhance the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts in diabetic cell model. In vivo assays also verified that OSCC Ti-Exos could promote diabetic wound healing, demonstrated preliminary biosafety in mice, and have promise as therapeutic applications.

Microneedle Patches with Antimicrobial and Immunomodulating Properties for Infected Wound Healing.

Treatment of infected wounds remains a challenge owing to antibiotic resistance; thus, developing smart biomaterials for the healing of infected wounds is urgently needed. In this study, a microneedle (MN) patch system with antimicrobial and immunomodulatory properties is developed to promote and accelerate infected wound healing. In the MN patch (termed PFG/M MNs), a nanoparticle with polydopamine (PDA)-loaded iron oxide is grafted with glucose oxidase (GOx) and hyaluronic acid (HA) and then integrated into the tips, and amine-modified mesoporous silica nanoparticles (AP-MSNs) are incorporated into the bases. Results show that PFG/M MNs eradicate bacterial infections and modulate the immune microenvironment, combining the advantages of chemodynamic therapy, photothermal therapy, and M2 macrophage polarization from Fe/PDA@GOx@HA in the tips as well as anti-inflammatory effect of AP-MSNs from the MN bases. Thus, the PFG/M MN system is a promising clinical candidate for promoting infected wound healing.

On-skin biosensors for noninvasive monitoring of postoperative free flaps and replanted digits.

Severe soft tissue defects and amputated digits are clinically common injuries. Primary treatments include surgical free flap transfer and digit replantation, but these can fail because of vascular compromise. Postoperative monitoring is therefore crucial for timely detection of vessel obstruction and survival of replanted digits and free flaps. However, current postoperative clinical monitoring methods are labor intensive and highly dependent on the experience of nurses and surgeons. Here, we developed on-skin biosensors for noninvasive and wireless postoperative monitoring based on pulse oximetry. The on-skin biosensor was made of polydimethylsiloxane with gradient cross-linking to create a self-adhesive and mechanically robust substrate that interfaces with skin. The substrate was shown to exhibit appropriate adhesion on one side for both high-fidelity measurements of the sensor and low risk of peeling injury to delicate tissues. The other side demonstrated mechanical integrity to facilitate flexible hybrid integration of the sensor. Validation studies using a model of vascular obstruction in rats demonstrated the effectiveness of the sensor in vivo. Clinical studies indicated that the on-skin biosensor was accurate and more responsive than current clinical monitoring methods in identifying microvascular conditions. Comparisons with existing monitoring techniques, including laser Doppler flowmetry and micro-lightguide spectrophotometry, further verified the sensor's accuracy and ability to identify both arterial and venous insufficiency. These findings suggest that this on-skin biosensor may improve postoperative outcomes in free flap and replanted digit surgeries by providing sensitive and unbiased data directly from the surgical site that can be remotely monitored.

Injectable self-healing chitosan-based POSS-PEG hybrid hydrogel as wound dressing to promote diabetic wound healing.

Promoting the healing of diabetic wounds remains a major challenge in scientific research today. A star-like eight-arm cross-linker octafunctionalized POSS of benzaldehyde-terminated polyethylene glycol (POSS-PEG-CHO) was synthesized, and crosslinked with hydroxypropyltrimethyl ammonium chloride chitosan (HACC) via Schiff base reaction to obtain Chitosan-based POSS-PEG hybrid hydrogels. The designed composite hydrogels exhibited strong mechanical strength, injectability, excellent self-healing efficiency, good cytocompatibility and antibacterial properties. Furthermore, the composite hydrogels could accelerate cells migration and proliferation, as expected by remarkably promoting wound healing in diabetic mice. The wounds treated with the composite hydrogels displayed faster regeneration of epithelial tissue, fewer inflammatory cells, more collagen deposition and higher expression level of VEGF. Therefore, Chitosan-based POSS-PEG hybrid hydrogel has great application potential as a dressing for promoting the healing of diabetic wounds.

Tissue-derived extracellular vesicles: Isolation, purification, and multiple roles in normal and tumor tissues.

Extracellular vesicles (EVs) are particles released from cells, and their lipid bilayer membrane encloses large amounts of bioactive molecules that endow EVs with intercellular or inter-tissue communicational abilities. Tissue-derived extracellular vesicles (Ti-EVs) are EVs directly separated from the interstitial space of tissue. They could better reflect the actual physiological or pathological state of the tissue microenvironment compared with cell line-derived EVs and biofluid EVs, indicating their potential roles in elucidating the underlying mechanism of pathogenesis and guiding the diagnosis, therapeutic targeting, and cell-free treatment of diseases. However, there have been a relatively limited number of investigations of Ti-EVs. In this review, we have summarized general procedures for Ti-EVs isolation, as well as some caveats with respect to operations after the isolation step, such as purification and storage. In addition, we have also briefly concluded the current research trends on EVs from various normal and tumor tissues, aiming to cast new light on the future research direction of Ti-EVs.

Tumor tissue derived extracellular vesicles promote diabetic wound healing.

The diabetic wound nowadays remains a major public health challenge, which is characterized by overproduced reactive oxygen species (ROS). However, the current therapy for diabetic wounds is limited for reliable data in the general application. The growth of tumors has been revealed to share parallels with wound healing. Extracellular vesicles (EVs) derived from breast cancer have been reported to promote cell proliferation, migration and angiogenesis. The tumor tissue-derived EVs (tTi-EVs) of breast cancer performance a feature inheritance from original tissue and might accelerate the diabetic wound healing. We wonder whether the tumor-derived EVs are able to accelerate diabetic wound healing. In this study, tTi-EVs were extracted from breast cancer tissue via ultracentrifugation and size exclusion. Subsequently, tTi-EVs reversed the H2O2-induced inhibition of fibroblast proliferation and migration. Moreover, tTi-EVs significantly accelerated wound closure, collagen deposition and neovascularization, and finally promoted wound healing in diabetic mice. The tTi-EVs also reduced the level of oxidative stress in vitro and in vivo. Besides, the biosafety of tTi-EVs were preliminarily confirmed by blood tests and morphological analysis of major organs. Collectively, the present study proves that tTi-EVs can suppress oxidative stress and facilitate diabetic wound healing, which puts forward a novel function of tTi-EVs and provides potential treatment for diabetic wounds.

Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress.

Diabetic wounds are a serious complication of diabetes mellitus (DM) that can lead to persistent infection, amputation, and even death. Prolonged oxidative stress has been widely recognized as a major instigator in the development of diabetic wounds; therefore, oxidative stress is considered a promising therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of Keap1 by siRNA reversed the increase in Keap1 levels, promoted the nuclear translocation of Nrf2, and increased the expression of HO-1, an antioxidant protein. To explore therapeutic delivery strategies, milk-derived exosomes (mEXOs) were developed as a novel, efficient, and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs by sonication, and the obtained mEXOs-siKeap1 were found to promote HUVEC proliferation and migration while relieving oxidative stress in MGO-treated HUVECs. Meanwhile, in a mouse model of diabetic wounds, injection of mEXOs-siKeap1 significantly accelerated diabetic wound healing with enhanced collagen formation and neovascularization. Taken together, these data support the development of Keap1 knockdown as a potential therapeutic strategy for diabetic wounds and demonstrated the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system. The therapeutic effect of siKeap1-loaded mEXOs on diabetic wound healing was assessed. First, we found that the expression of Keap1 was upregulated in the wounds of diabetic mice and in human umbilical vein endothelial cells (HUVECs) pretreated with methylglyoxal (MGO). Next, we extracted exosomes from raw milk by differential centrifugation and loaded siKeap1 into milk-derived exosomes by sonication. The in vitro application of the synthetic complex (mEXOs-siKeap1) was found to increase the nuclear localization of Nrf2 and the expression of the antioxidant protein HO-1, thus reversing oxidative stress. Furthermore, in vivo mEXOs-siKeap1 administration significantly accelerated the healing rate of diabetic wounds (Scheme 1). Scheme 1 Schematic diagram. A Synthesis of mEXOs-siKeap1 complex. B Mechanism of mEXOs-siKeap1 in vitro. C The treatment effect of mEXOs-siKeap1 on an in vivo mouse model of diabetic wounds.

The circ_0002538/miR-138-5p/plasmolipin axis regulates Schwann cell migration and myelination in diabetic peripheral neuropathy.

Circular RNAs (circRNAs) play a vital role in diabetic peripheral neuropathy. However, their expression and function in Schwann cells in individuals with diabetic peripheral neuropathy remain poorly understood. Here, we performed protein profiling and circRNA sequencing of sural nerves in patients with diabetic peripheral neuropathy and controls. Protein profiling revealed 265 differentially expressed proteins in the diabetic peripheral neuropathy group. Gene Ontology indicated that differentially expressed proteins were mainly enriched in myelination and mitochondrial oxidative phosphorylation. A real-time polymerase chain reaction assay performed to validate the circRNA sequencing results yielded 11 differentially expressed circRNAs. circ_0002538 was markedly downregulated in patients with diabetic peripheral neuropathy. Further in vitro experiments showed that overexpression of circ_0002538 promoted the migration of Schwann cells by upregulating plasmolipin (PLLP) expression. Moreover, overexpression of circ_0002538 in the sciatic nerve in a streptozotocin-induced mouse model of diabetic peripheral neuropathy alleviated demyelination and improved sciatic nerve function. The results of a mechanistic experiment showed that circ_0002538 promotes PLLP expression by sponging miR-138-5p, while a lack of circ_0002538 led to a PLLP deficiency that further suppressed Schwann cell migration. These findings suggest that the circ_0002538/miR-138-5p/PLLP axis can promote the migration of Schwann cells in diabetic peripheral neuropathy patients, improving myelin sheath structure and nerve function. Thus, this axis is a potential target for therapeutic treatment of diabetic peripheral neuropathy.

Ingrown Toenail Treated by the Modified Howard-Dubois Technique: Long-Term Follow-Up Results.

Background: According to the Mozena classification system, stage IIb and stage III ingrown toenail cases are considered as severe ones; however, limited options are available for treatment. Aims: To lower the recurrence rate and achieve primary intention healing in severe ingrown toenail cases by the modified Howard-Dubois technique. Methods: Forty patients were included in this study. In this procedure, a fish-mouth like soft tissue along the nail groove to the tip of the toe was resected, the upper surface of the distal phalanx was flattened and the nail bed matrix was remodelled. The European Quality of Life (EuroQol) questionnaire and Surgical Satisfaction Questionnaire were used to assess the outcomes. Results: There were no recurrences observed during the follow-up period. Healing time from surgery to back to school or work was 10.82 days on an average (range: 7-23 days). According to the results of EuroQol questionnaire, improvements were achieved in the areas of mobility (50%), looking after myself (10%), doing usual activities (35%), having pain or discomfort (95%) and feeling worried, sad, or unhappy (55%). According to the results of Surgical Satisfaction Questionnaire, 38 (95%) patients indicated that they would undergo the surgery again if they 'had to do it all over again' and 36 (90%) patients said that they would recommend the procedure to others. Conclusions: This modified Howard-Dubois technique was an effective, safe and cosmetic alternation for the treatment of ingrown toenail in severe or relapsed cases.