Natural Polymers - Based Hydrogel Dressings for Wound Healing.

SIGNIFICANCE: Acute wounds such as severe burns and chronic wounds like diabetic ulcers present a significant threat to human health. Wound dressings made from natural polymers offer inherent properties that effectively enhance wound healing outcomes and reduce healing time. RECENT ADVANCES: Numerous innovative hydrogels are being developed and translated to the clinic to successfully treat various wound types. This underscores the substantial potential of hydrogels in the future wound care market. Economically, annual sales of wound care products are projected to reach $15-22 billion by 2024. CRITICAL ISSUES: While chitosan-, cellulose-, and collagen-based hydrogel dressings are currently commercially available, scaling up and manufacturing hydrogels for commercial products remains a challenging process. Additionally, ensuring the sterility and stability of the chemical or biological components comprising the hydrogel are critical considerations. FUTURE DIRECTIONS: In light of the persistent increase in wound fatalities and the resulting economic and social impacts, as well as the importance of educating the public about dietary health and disease, there should be increased investment in new wound care dressings, particularly hydrogels derived from natural products. With numerous researchers dedicated to advancing preclinical hydrogels, the future holds promise for more innovative and more personalized hydrogel wound dressings.

[Recording and identification of depolarization-activated current in intercalated cells].

The depolarization-activated current of intercalated cells in the distal nephron was detected for the first time, and the type of ion channel mediating the current was identified based on electrophysiological and pharmacological properties. The whole-cell current of distal nephron in kidney of C57BL/6J mice was recorded by Axon MultiClamp 700B patch-clamp system, and the effects of several K+ channel inhibitors on the depolarization-activated current in intercalated cells were observed. In addition, the immunofluorescence technique was used to investigate the localization of the channel in intercalated cells. The results showed that when K+ concentration of the bath solution was equal to intracellular fluid (140 mmol/L K+), the depolarization-activated current could be recorded in intercalated cells, but this current was not observed in the principal cells. The depolarization-activated current detected in the intercalated cells could be blocked by Kv4.1 inhibitors. The immunofluorescence experiment showed that the fluorescence of Kv4.1 protein was only present in intercalated cells and not observed in principal cells. Kv4.1 protein immunofluorescence was observed in the luminal and basolateral membrane of intercalated cells, but the fluorescence intensity of luminal membrane was higher than that of basolateral membrane. We conclude that the depolarization-activated current detected in intercalated cells is mediated by Kv4.1 and this channel is mainly expressed in the luminal membrane of intercalated cells.

Safety and efficacy of the DragonFly system for transcatheter valve repair of degenerative mitral regurgitation: one-year results of the DRAGONFLY-DMR trial.

BACKGROUND: Severe degenerative mitral regurgitation (DMR) can cause a poor prognosis if left untreated. For patients considered at prohibitive surgical risk, transcatheter edge-to-edge repair (TEER) has become an accepted alternative therapy. The DragonFly transcatheter valve repair system is an innovative evolution of the mitral TEER device family to treat DMR. AIMS: Herein we report on the DRAGONFLY-DMR trial (ClinicalTrials.gov: NCT04734756), which was a prospective, single-arm, multicentre study on the safety and effectiveness of the DragonFly system. METHODS: A total of 120 eligible patients with prohibitive surgical risk and DMR ≥3+ were screened by a central eligibility committee for enrolment. The study utilised an independent echocardiography core laboratory and clinical event committee. The primary endpoint was the clinical success rate, which measured freedom from all-cause mortality, mitral valve reintervention, and mitral regurgitation (MR) >2+ at 1-year follow-up. RESULTS: At 1 year, the trial successfully achieved its prespecified primary efficacy endpoint, with a clinical success rate of 87.5% (95% confidence interval: 80.1-92.3%). The rates of major adverse events, all-cause mortality, mitral valve reintervention, and heart failure hospitalisation were 9.0%, 5.0%, 0.8%, and 3.4%, respectively. MR ≤2+ was 90.4% at 1 month and 92.0% at 1 year. Over time, left ventricular reverse remodelling was observed (p<0.05), along with significant improvements in the patients' functional and quality-of-life outcomes, shown by an increase in the New York Heart Association Class I/II from 32.4% at baseline to 93.6% at 12 months (p<0.001) and increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score of 31.1±18.2 from baseline to 12 months (p<0.001). CONCLUSIONS: The DRAGONFLY-DMR trial contributes to increasing evidence supporting the safety and efficacy of TEER therapy, specifically the DragonFly system, for treating patients with chronic symptomatic DMR 3+ to 4+ at prohibitive surgical risk.

Polyurethane foam dressing with non-adherent membrane improves negative pressure wound therapy in pigs.

OBJECTIVE: Negative pressure wound therapy (NPWT) is considered to be an effective technique to promote the healing of various wounds. The aim of this study was to evaluate different wound dressings combined with NPWT in treating wounds in Wuzhishan pigs. METHOD: Excisions were made in the backs of the pigs and were covered with polyvinyl alcohol (PVA) dressing, polyurethane (PU) dressing or PU dressing with non-adherent membrane (PU-non-ad). NPWT was applied to the wound site. In the control group, basic occlusive dressing (gauze) without NPWT was applied. On days 0, 3, 7, 14, 21 and 28 post-surgery, the wound size was measured during dressing change, and wound healing rate (WHR) was calculated. In addition, blood perfusion within 2cm of the surrounding wound was measured by laser doppler flowmetry. Dressing specimen was collected and microbiology was analysed. Granulation tissues from the central part of the wounds were analysed for histology, vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) mRNA expression. RESULTS: The PU-non-ad-NPWT significantly (p<0.01) accelerated wound healing in the pigs. Further pathological analysis revealed that the non-adherent membrane effectively protected granulation tissue formation in PU-NPWT treated wounds. The blood perfusion analysis suggested that the non-adherent membrane improved the blood supply to the wound area. Microbiological analysis showed that non-adherent membrane decreased the bacterial load in the PU-NPWT dressing. VEGF and CD31 mRNA expression was upregulated in the wound tissue from the PU-non-ad-NPWT treated groups. CONCLUSION: In this study, the PU dressing with non-adherent membrane was an ideal dressing in NPWT-assisted wound healing.

Exploring m6A-linked aging genes in osteoarthritis and broad cancer spectrum: Prospects for diagnostic and therapeutic advancements.

Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts individuals and healthcare systems worldwide. However, the exploration of N6-methyladenosine (m6A)-related aging genes in OA pathogenesis remains largely underexplored. This study aimed to elucidate the role of m6A-related aging genes in OA and to develop a robust diagnostic model based on their expression profiles. Leveraging publicly available gene expression datasets, we conducted consensus clustering to categorize OA into distinct subtypes, guided by the expression patterns of m6A-related aging genes. Utilizing XGBoost, a cutting-edge machine learning approach, we identified key diagnostic genes and constructed a predictive model. Our investigation extended to the immune functions of these genes, shedding light on potential therapeutic targets and underlying regulatory mechanisms. Our analysis unveiled specific OA subtypes, each marked by unique expression profiles of m6A-related aging genes. We pinpointed a set of pivotal diagnostic genes, offering potential therapeutic avenues. The developed diagnostic model exhibited exceptional capability in distinguishing OA patients from healthy controls. To corroborate our computational findings, we performed quantitative real-time polymerase chain reaction analyses on two cell lines: HC-OA (representing adult osteoarthritis cells) and C-28/I2 (representative of normal human chondrocytes). The gene expression patterns observed were consistent with our bioinformatics predictions, further validating our initial results. In conclusion, this study underscores the significance of m6A-related aging genes as promising biomarkers for diagnosis and prognosis, as well as potential therapeutic targets in OA. Although these findings are encouraging, further validation and functional analyses are crucial for their clinical application.

Clinical efficacy of blood derivatives on wound healing: A systematic review and network meta-analysis.

This study aims to evaluate the clinical effects of different blood derivatives on wound healing using network meta-analysis. PubMed, Embase, OVID, Web of Science, SCOPUS and Cochrane Central were searched to obtain studies about blood derivatives on wound healing until October 2023. R 4.2.0 and Stata 15.0 softwares were used for data analysis. Forty-four studies comprising 5164 patients were included. The results of network meta-analysis showed that the healing area from high to low was GF + ORCCB, ORCCB, GF, PRF, Unnas paste dressing, APG, PRP injection, PRP, PRP + thrombin gel, PPP, HPL, CT. The healing time from low to high was PRP + thrombin gel, GF, PRP, PC + K, PC, APG, PRF, CT, Silver sulfadiazine ointment. The number of patients cured from high to low was APG, PRP injection, PRP, Aurix, PRF, Leucopatch, HPL, Antimicrobial Ointment Dressing, CT, 60 µg/cm2 repifermin, 120 µg/cm2 repifermin, AFG, PPP. The order of analgesic effect from high to low was AFG, Aminogam gel, PRF, PRP, Oxidised oil, APG, GF, CT. The order of the number of wound infection cases from low to high is APG, 20 µg/cm2 repifermin, 60 µg/cm2 repifermin, PRP, LeucoPatch, CT, PPP, Antiseptic ointment dressing. Healing area: GF + ORCCB had the best effect; Healing time: PRP + thrombin gel took the shortest time. The number of cured patients and the reduction of wound infection: APG has the best effect. Analgesic effect: AFG has the best effect. More studies with large sample sizes are needed to confirm the above findings.

The Role of Stem Cell on Wound Healing After Revascularization-Healing Following Revascularization-Unlocking Skin Potential.

Wound healing is a complex and dynamic process involving a series of cellular and molecular events. Revascularization, the restoration of blood flow to ischemic or damaged tissue, is a key step in wound healing. Adequate vascularization has been recognized as a necessary factor for successful tissue regeneration. In the later stage of revascularization and tissue remodeling in wound healing, stem cells regulate other repair cells and matrix formation by influencing the maturation of blood vessels. The reductive oxidation (REDOX) state may be a key mechanism through stem/progenitor cells to influence endothelial cells to mature blood vessels and improve the quality of healing. Mitochondria may play an important role in this process.

Correlation of bioactive components of platelet rich plasma derived from human female adult peripheral blood and umbilical cord blood with age.

Platelet-rich plasma (PRP) has gained significant attention in the field of regenerative medicine due to its potential therapeutic applications. However, few studies have reported the components, especially anti-ageing-related components, of PRP derived from umbilical cord blood (UCB). It is essential to understand the influence of age on the composition and efficacy of PRP to optimize its clinical use. The present study compared the concentrations of bioactive components in PRP from healthy female adults and UCB-derived PRP. PRP was obtained from blood samples from females in four age groups (12 per group): neonates (UCB donors) and adults aged 18-25, 26-45, and 46-65 years, respectively. The concentrations of epidermal growth factor, basic fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1, platelet-derived growth factor-AA (PDGF-AA), PDGF-AB/BB, vascular endothelial growth factor A, RANTES, TIMP-1, TIMP-2, GDF11, and clusterin and activity of superoxide dismutase, catalase, and glutathione peroxidase (GPx) in the PRP samples were determined and compared among groups. Pairwise comparisons between the groups showed statistically significant differences in the concentrations of some bioactive components of PRP, such as FGF-2, PDGF-AB/BB, and clusterin, and GPx activity. UCB-derived PRP contains various active ingredients such as VEGF-A, CAT activity, and TIMP-2. Contrary to expectations, UCB-derived PRP did not show higher concentrations of the anti-ageing protein GDF11. Because UCB is a rich source of bioactive components with low immunogenicity, its use in PRP preparation is an important research direction for future studies.

A composite hydrogel with antibacterial and promoted cell proliferation dual properties for healing of infected wounds.

Wound infection remains a major challenge for health professionals, because it delays wound healing and increases the overall cost and morbidity. Therefore, the development of new biomaterials with new antibacterial properties and healing effects remains a dire clinical need. To solve this problem, we developed silver nanoparticles embedded in γ-cyclodextrin metal-organic frameworks (Ag@MOF) and platelet-rich plasma (PRP)-loaded hydrogel systems based on methacrylated silk fibroin (SFMA) and methacrylate hyaluronic acid (HAMA) as Ag+ ion and growth factor delivery vehicles for inhibiting the growth of drug-resistant bacteria and promoting wound healing. The prepared SFMA/HAMA hydrogel demonstrated good rheological properties, swelling capability, appropriate mechanical properties and controllable biodegradability. The SFMA/HAMA/Ag@MOF/PRP hydrogel showed sustained release profiles of Ag+ ions and EGF. The SFMA/HAMA/Ag@MOF hydrogel have good inherent antibacterial properties against both gram-negative bacteria and gram-positive bacteria. The prepared hydrogel showed excellent cytocompatibility and could stimulate the growth and proliferation rate of NIH-3T3 cells. In vivo experiments showed that SFMA/HAMA/Ag@MOF/PRP hydrogel treatment enhanced the healing of full-thickness wounds, reduced inflammatory cell infiltration, and promoted re-epithelialization and collagen synthesis. All results indicated that the prepared hydrogel has tremendous potential to reduce wound infections and improve wound healing.

Histological characteristics of exercise-induced skeletal muscle remodelling.

This study aims to analyse the pathological features of skeletal muscle injury repair by using rats to model responses to different exercise intensities. Eighty-four rats were randomly divided into five groups for treadmill exercise. The short-term control, low-intensity, medium-intensity and high-intensity groups underwent gastrocnemius muscle sampling after 6, 8 and 12 weeks of exercise. The long-term high-intensity group underwent optical coherence tomography angiography and sampling after 18 weeks of exercise. RNA sequencing was performed on the muscle samples, followed by the corresponding histological staining. Differentially expressed genes were generally elevated at 6 weeks in the early exercise stage, followed by a decreasing trend. Meanwhile, the study demonstrated a negative correlation between time and the gene modules involved in vascular regulation. The modules associated with muscle remodelling were positively correlated with exercise intensity. Although the expression of many genes associated with common angiogenesis was downregulated at 8, 12 and 18 weeks, we found that muscle tissue microvessels were still increased, which may be closely associated with elevated sFRP2 and YAP1. During muscle injury-remodelling, angiogenesis is characterized by significant exercise time and exercise intensity dependence. We find significant differences in the spatial distribution of angiogenesis during muscle injury-remodelling, which be helpful for the future achievement of spatially targeted treatments for exercise-induced muscle injuries.

Effective regeneration of rat sciatic nerve using nanofibrous scaffolds containing rat ADSCs with controlled release of rhNGF and melatonin molecules for the treatment of peripheral injury model.

Different therapeutic strategies have been designed and developed for the repair and regeneration of peripheral nerve injury (PNI) tissue as a result of advancements in tissue engineering and regenerative medicine. Due to its versatility, controlled delivery and administration of multifunctional therapeutic agents can be regarded of as an effective strategy in treating nerve injury. In this study, melatonin (Mel) molecules and recombinant human nerve growth factor (rhNGF) were loaded on the surface and in the core of polycaprolactone/chitosan (PCL/CS) blended nanofibrous scaffold. To simulate the in vivo microenvironment, a dual-delivery three-dimensional (3-D) nanofibrous matrix was developed and the in vitro neural development of stem cell differentiation process was systematically examined. The microscopic technique with acridine orange and ethidium bromide (AO/EB) fluorescence staining method was used to establish the adipose-derived stem cells (ADSCs) differentiation and cell-cell communications, which demonstrated that the effective differentiation of the ADSCs with nanofibrous matrix. As investigated observations, ADSCs differentiation was further evident through cell migration assay and gene expression analysis. According to the biocompatibility analysis, the nanofibrous matrix did not trigger any adverse immunological reactions. Based on these characteristics, a 5-week in vivo investigation examined the potential of the developed nanofibrous matrix in the regeneration of sciatic nerve of rats. Additionally, compared to the negative control group, the electrophysiological and walking track analyses demonstrated improved sciatic nerve regeneration. This study demonstrates the nanofibrous matrix's ability to regenerate peripheral nerves.

Risk factors analysis and nomogram construction for postoperative pulmonary infection in elderly patients with hip fractures.

PURPOSE: The purpose of this study was to predict the probability of postoperative pulmonary infection in elderly patients with hip fractures by developing and validating a precise model. METHODS: The clinical data of 1008 elderly hip fracture patients undergoing surgical treatment in Shanghai Tenth Peoples' Hospital were retrospectively selected. A univariate analysis and multivariate regression were used to analyze the independent risk factors for postoperative pulmonary infection in elderly patients with hip fractures. A risk prediction model was established, and a nomogram was drawn. The area under the ROC curve and Hosmer‒Lemeshow test were used to evaluate the predictive effect of the model. RESULTS: The multivariate regression analysis indicated that age > 73, time from fracture to surgery (d) > 4 days, smoking, ASA ≥ III level, COPD, hypoproteinemia, red cell distribution width > 14.8%, mechanical ventilation time > 180 min, and stay in the ICU were independent risk factors for postoperative pulmonary infection in elderly patients. The AUCs of the model were 0.891 and 0.881, 0.843, respectively, in the two verification groups. For the Hosmer‒Lemeshow test, the P values were 0.726 in the modeling group and 0.497 and 0.231 in the verification group (P > 0.05). CONCLUSION: Overall, this study uncovered different independent risk factors for postoperative pulmonary infection in patients with hip fractures. The nomogram can effectively predict the occurrence of postoperative pulmonary infection.

Application of platelet-rich plasma (PRP) in lips rejuvenation.

BACKGROUND: In recent years, minimally invasive and non-invasive rejuvenation methods have been welcomed. PRP has been used widely for skin rejuvenation, but there are few studies on PRP for lip rejuvenation. OBJECTIVE: The objective of this study was to investigate the preliminary effects of PRP for lip rejuvenation. METHODS: Between October 2018 and April 2023, 15 participants with lip aging (1 male, 14 females; range 27-58 years) were treated with PRP. The follow-up time was 3 to 24months. After 3 to 6 times treatments, beauty seekers and experienced physicians jointly evaluated effectiveness of treatment. The assessment included improvements in the colour, wrinkles, and skin texture of the lips before and after treatment. RESULTS: According to the beauty seekers and Surgeons 'evaluation, the aging characteristics of the lips of the 15 beauty seekers have been improved to varying degrees. The most obvious improvement was that the color of the lips which became more vivid. There was no swelling, bruising, scar hyperplasia and other complications. A participant was evaluated using the VISIA skin detector. The patient's lip color and discoloration improved after treatment. Of the 15 participants treated. 3 participants experienced mild pain or discomfort during the injection process. There was no swelling, bruising, scar hyperplasia and other complications. CONCLUSION: The results of this study revealed promising evidence of PRP as an effective option on lip rejuvenation. However, large, multi-center, controlled, long term, pilot studies are required to confirm the preliminary results of our study.

Oligomeric ß-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway.

Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aß1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aß1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aß1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aß1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aß1-42-induced suppression was confirmed in Aß-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aß1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aß1-42 reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aß1-42 impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets.

CNTN1 Aggravates Neuroinflammation and Triggers Cognitive Deficits in Male Mice by Boosting Crosstalk between Microglia and Astrocytes.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

Transconjunctival fat repositioning blepharoplasty: is excess fat herniation a prerequisite?

BACKGROUND: The fat repositioning technique has been widely used for the treatment of tear trough deformity, and there is a strong belief that excess fat herniation is a prerequisite for the procedure. OBJECTIVE: The purpose of this study was to evaluate its effect in patients with minimal or no excess fat herniation. METHODS: A total of 232 patients underwent the procedure and met the inclusion criteria. Of them, 198 were primary cases, and 34 had a history of fat removal for blepharoplasty. The amount of infraorbital fat was evaluated preoperatively by palpation. Release of the tear trough ligament and fat redistribution were sequentially performed as previously described. Surgical outcome was assessed based on Hirmand's grading system and the FACE-Q scales. RESULTS: Tear trough deformities were eliminated in more than 85% of cases. Aesthetic results were comparable between the primary and secondary surgery groups. The percentage of patients who complained of extremely or moderately severe tear trough deformities decreased from 86.3% preoperatively to 34.0% postoperatively. The scores of the lower eyelid FACE-Q decreased significantly (P<0.05). Patients were satisfied with their decision to undergo blepharoplasty (78.2±18.7). Undercorrection of the tear trough occurred in 30 patients. Other complications included 12 cases of transient conjunctiva bleeding, 2 cases of eyelid numbness, and 6 cases of dry eye. These resolved spontaneously. CONCLUSION: Fat repositioning is a feasible and effective technique for the treatment of tear trough deformities in patients with minimal or no excess orbital fat herniation provided that a fat pad is palpable. LEVEL OF EVIDENCE: 4.

Donor-Derived Transmission of Scedosporiosis in Kidney Transplant Recipients from a Systemic lupus erythematosus donor.

Donor-derived infection (DDI) associated with Scedosporium spp is extremely rare, and results in a very poor prognosis. The present study reports a probable DDI due to Scedosporium boydii (S. boydii) from a donor with neuropsychiatric systemic lupus erythematosus. Two recipients developed Scedosporiosis after kidney transplantation from the same donor. Recipient 1 died of central nervous system infection due to S. boydii based on the clinical presentations, and the positive metagenomic next-generation sequencing (mNGS) and culture results for the cerebrospinal fluid. The other recipient with urinary tract obstruction due to S. boydii, which was identified through the positive culture and mNGS results of the removed stents, was successfully treated by stent replacement and voriconazole administration. Undiagnosed disseminated donor infection and the transmission of S. boydii should be given attention, particularly when the donor and recipients have primary immunodeficiency disease. The screening of donors and recipients for S. boydii using mNGS may be helpful in guiding antifungal prophylaxis and treatment recipients, due to its higher sensitivity and shorter diagnostic time relative to other traditional techniques.

Weakly acidic microenvironment of the wound bed boosting the efficacy of acidic fibroblast growth factor to promote skin regeneration.

The pH value within the wound microenvironment influences indirectly and directly all biochemical reactions taking place in the process of skin wound healing. Currently, it is generally believed that a low pH value, such as it is found on normal skin, is favorable for wound regeneration, while some investigations have shown that in fact alkaline microenvironments are required for some healing processes. The role of growth factors in promoting wound healing requires a specific microenvironment. In wound microenvironments of different pH, growth factors with different isoelectric points may have different effects. To explore whether the application of FGF with different isoelectric points in wounds with different pH values interferes with the healing process to different degrees, GelMA hydrogels with different pH values were prepared to maintain the wounds microenvironment with the same pH values, in which aFGF and bFGF were loaded as well. The results show that GelMA hydrogels of different pH values maintained the same pH of the wound microenvironment sustainably on the 4th day. Moreover, aFGF and bFGF promoted skin wound healing to varying degrees in different pH wound microenvironments. In particular, aFGF significantly promoted wound re-epithelialization in a weak acidic microenvironment, while bFGF promoted collagen synthesis and deposition in the early stage of weak acid wounds. In addition, aFGF plays a superior role in inhibiting inflammation in weak acidic wounds.

Mesenchymal Stem Cell Aggregation-Released Extracellular Vesicles Induce CD31+ EMCN+ Vessels in Skin Regeneration and Improve Diabetic Wound Healing.

The blood vessel system is essential for skin homeostasis and regeneration. While the heterogeneity of vascular endothelial cells has been emergingly revealed, whether a regeneration-relevant vessel subtype exists in skin remains unknown. Herein, a specialized vasculature in skin featured by simultaneous CD31 and EMCN expression contributing to the regeneration process is identified, the decline of which functionally underlies the impaired angiogenesis of diabetic nonhealing wounds. Moreover, enlightened by the developmental process that mesenchymal condensation induces angiogenesis, it is demonstrated that mesenchymal stem/stromal cell aggregates (CAs) provide an efficacious therapy to enhance regrowth of CD31+ EMCN+ vessels in diabetic wounds, which is surprisingly suppressed by pharmacological inhibition of extracellular vesicle (EV) release. It is further shown that CAs promote secretion of angiogenic protein-enriched EVs by proteomic analysis, which directly exert high efficacy in boosting CD31+ EMCN+ vessels and treating nonhealing diabetic wounds. These results add to the current knowledge on skin vasculature and help establish feasible strategies to benefit wound healing under diabetic condition.