Multifunctional Fluoropolymer-Engineered Magnetic Nanoparticles to Facilitate Blood-Brain Barrier Penetration and Effective Gene Silencing in Medulloblastoma.

Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma.

Fluorine-modified polymers reduce the adsorption of immune-reactive proteins to PEGylated gold nanoparticles.

Aim: To investigate the influence of fluorine in reducing the adsorption of immune-reactive proteins onto PEGylated gold nanoparticles. Methods: Reversible addition fragmentation chain transfer polymerization, the Turkevich method and ligand exchange were used to prepare polymer-coated gold nanoparticles. Subsequent in vitro physicochemical and biological characterizations and proteomic analysis were performed. Results: Fluorine-modified polymers reduced the adsorption of complement and other immune-reactive proteins while potentially improving circulatory times and modulating liver toxicity by reducing apolipoprotein E adsorption. Fluorine actively discouraged phagocytosis while encouraging the adsorption of therapeutic targets, CD209 and signaling molecule calreticulin. Conclusion: This study suggests that the addition of fluorine in the surface coating of nanoparticles could lead to improved performance in nanomedicine designed for the intravenous delivery of cargos.

Nanomedicines are based around the delivery of therapies by tiny, nanosized delivery vehicles. This method offers a much better way of specifically targeting life-threatening diseases. For fast delivery, nanomedicines can be injected into the blood (intravenously); however, this often leads to an unwanted and exaggerated immune response. The immune system is activated by proteins in the blood that attach themselves to nanoparticles through various chemical interactions (the protein corona effect). Fluorine is a chemical routinely used in surfactants such as firefighting foam and more recently in molecular imaging and nanoparticles designed for the delivery of therapies aimed at cancer. While fluorine has great potential to improve the cellular uptake of therapies, little is known about whether it can also help camouflage the nanoparticles against the immune system responses. Here, using fluorinated polymer-coated gold nanoparticles, the authors demonstrate that fluorine reduces uptake by immune cells and is highly effective at reducing the binding of immune system-initiating proteins. This work successfully illustrates the rationale for more widespread investigation of fluorine during the development of polymer-coated nanoparticles designed for the intravenous delivery of nanomedicines.

The naringin/carboxymethyl chitosan/sodium hyaluronate/silk fibroin scaffold facilitates the healing of diabetic wounds by restoring the ROS-related dysfunction of vascularization and macrophage polarization.

Chronic diabetic wounds remain a globally recognized clinical challenge, which occurs mainly due to the disturbances of wound microenvironmental induced by high concentrations of reactive oxygen species (ROS). Impairments in angiogenesis and inflammation in the wound microenvironment ultimately impede the normal healing process. Therefore, targeting macrophage and vascular endothelial cell dysfunction is a promising therapeutic strategy. In our study, we fabricated artificial composite scaffolds composed of naringin/carboxymethyl chitosan/sodium hyaluronate/silk fibroin (NG/CMCS/HA/SF) to promote wound healing. The NG/CMCS/HA/SF scaffold demonstrated favorable anti-inflammatory, anti-oxidative, and pro-angiogenic properties in both in vitro and in vivo experiments, effectively promoting the healing of diabetic wounds. The positive therapeutic effects observed indicate that the composite scaffolds have great potential in clinical wound healing applications.

Tailored Fluorosurfactants through Controlled/Living Radical Polymerization for Highly Stable Microfluidic Droplet Generation.

Droplet-based microfluidics represents a disruptive technology in the field of chemistry and biology through the generation and manipulation of sub-microlitre droplets. To avoid droplet coalescence, fluoropolymer-based surfactants are commonly used to reduce the interfacial tension between two immiscible phases to stabilize droplet interfaces. However, the conventional preparation of fluorosurfactants involves multiple steps of conjugation reactions between fluorinated and hydrophilic segments to form multiple-block copolymers. In addition, synthesis of customized surfactants with tailored properties is challenging due to the complex synthesis process. Here, we report a highly efficient synthetic method that utilizes living radical polymerization (LRP) to produce fluorosurfactants with tailored functionalities. Compared to the commercialized surfactant, our surfactants outperform in thermal cycling for polymerase chain reaction (PCR) testing, and exhibit exceptional biocompatibility for cell and yeast culturing in a double-emulsion system. This breakthrough synthetic approach has the potential to revolutionize the field of droplet-based microfluidics by enabling the development of novel designs that generate droplets with superior stability and functionality for a wide range of applications.

Epidermal Stem Cell Derived Exosomes Alleviate Excessive Autophagy Induced Endothelial Cell Apoptosis by Delivering miR200b-3p to Diabetic Wounds.

The dysfunction of endothelial cells caused by hyperglycemia is observed as a decrease in neovascularization in diabetic wound healing. Studies have found that epidermal stem cells (EpiSCs) can promote the angiogenesis of full-thickness wounds. To further explain the therapeutic effect of EpiSCs, EpiSC-derived exosomes (EpiSC-EXOs) are considered the main substance contributing to stem cell effectivity. In our study, EpiSCs and EpiSC-EXOs were supplied to the dorsal wounds of db/db mice. Results showed that EpiSCs could colonize in the wound area and both EpiSCs and EpiSC-EXOs could accelerate diabetic wound healing by promoting angiogenesis. In vitro, persistent high glucose led to the malfunction and apoptosis of endothelial cells. The apoptosis induced by high glucose is due to excessive autophagy and was alleviated by EpiSC-EXOs. RNA sequencing of EpiSC-EXOs showed that miR200b-3p was enriched in EpiSC-EXOs and alleviated the apoptosis of endothelial cells. Synapse defective rho GTPase homolog 1 was identified the target of miR200b-3p and affected the phosphorylation of ERK to regulate intracellular autophagy and apoptosis. Furthermore, animal experiments validated the angiogenic effect of miR200b-3p. Collectively, our results verified the effect of EpiSC-EXOs on apoptosis caused by hyperglycemia in endothelial cells through the miR200b-3p/synapse defective rho GTPase homolog 1 /RAS/ERK/autophagy pathway, providing a theoretical basis for EpiSC in treating diabetic wounds.

Vector enabled CRISPR gene editing - A revolutionary strategy for targeting the diversity of brain pathologies.

Brain pathologies are considered one of the greatest contributors of death and disability worldwide. Neurodegenerative Alzheimer's disease is the second leading cause of death in adults, whilst brain cancers including glioblastoma multiforme in adults, and pediatric-type high-grade gliomas in children remain largely untreatable. A further compounding issue for patients with brain pathologies is that of long-term neuropsychiatric sequela - as a symptom or arising from high dose therapeutic intervention. The major challenge to effective, low dose treatment is finding therapeutics that successfully cross the blood-brain barrier and target aberrant cellular processes, while having minimum effect on essential cellular processes, and healthy bystander cells. Following over 30 years of research, CRISPR technology has emerged as a biomedical tour de force with the potential to revolutionise the treatment of both neurological and cancer related brain pathologies. The aim of this review is to take stock of the progress made in CRISPR technology in relation to treating brain pathologies. Specifically, we will describe studies which look beyond design, synthesis, and theoretical application; and focus instead on in vivo studies with translation potential. Along with discussing the latest breakthrough techniques being applied within the CRISPR field, we aim to provide a prospective on the knowledge gaps that exist and challenges that still lay ahead for CRISPR technology prior to successful application in the brain disease treatment field.

Intestinal mucosal flora of the intestine-kidney remediation process of diarrhea with deficiency kidney-yang syndrome in Sishen Pill treatment: Association with interactions between Lactobacillus johnsonii, Ca2+-Mg2+-ATP-ase, and Na+-K+-ATP-ase.

This study aims to investigate the effect of Sishen Pill on the characteristics of gut mucosal microbiota in diarrhea mice with deficiency kidney-yang syndrome. Fifteen Kunming male mice were randomly divided into Normal control group (C), Model self-healing group (X) and Sishen Pill group (S), with 5 mice/cages. Hematoxylin eosin (HE) staining was used to observe the kidney structure. Serum Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase were detected by enzyme-linked immunosorbent assay (ELISA), Analysis of intestinal mucosal flora using third-generation high-throughput sequencing. The relative abundance results in the three groups revealed that the dominant bacterial genera: Lactobacillus, Muribaculum and Candidatus-Arthromitus; bacterial species: Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus murinus, and Lactobacillus intestinalis, and differences in the presence of major microbiota between the X and S groups. A positive correlation between Lactobacillus johnsonii and both Ca2+-Mg2+-ATP-ase and Na+-K+-ATP-ase was found via correlation analysis. Sishen Pill also changed the manufacture of other secondary metabolites, as well as the metabolism of carbohydrates, glycans, energy, lipids, and other amino acids, and xenobiotics biodegradation and metabolism. In conclusion, Sishen Pill improved kidney structure, energy metabolism and the diversity and structure of intestinal mucosal flora. In addition, Lactobacillus johnsonii may be a characteristic species of Sishen Pill in treating diarrhea with kidney-yang deficiency syndrome.

Magnetic iron oxide nanoparticles for brain imaging and drug delivery.

Central nervous system (CNS) disorders affect as many as 1.5 billion people globally. The limited delivery of most imaging and therapeutic agents into the brain is a major challenge for treatment of CNS disorders. With the advent of nanotechnologies, controlled delivery of drugs with nanoparticles holds great promise in CNS disorders for overcoming the blood-brain barrier (BBB) and improving delivery efficacy. In recent years, magnetic iron oxide nanoparticles (MIONPs) have stood out as a promising theranostic nanoplatform for brain imaging and drug delivery as they possess unique physical properties and biodegradable characteristics. In this review, we summarize the recent advances in MIONP-based platforms as imaging and drug delivery agents for brain diseases. We firstly introduce the methods of synthesis and surface functionalization of MIONPs with emphasis on the inclusion of biocompatible polymers that allow for the addition of tailored physicochemical properties. We then discuss the recent advances in in vivo imaging and drug delivery applications using MIONPs. Finally, we present a perspective on the remaining challenges and possible future directions for MIONP-based brain delivery systems.

Melatonin influences the biological characteristics of keloid fibroblasts through the Erk and Smad signalling pathways.

Background: Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs). Methods: Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs. Results: Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways. Conclusions: Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.

Single-stage transplantation combined with epidermal stem cells promotes the survival of tissue-engineered skin by inducing early angiogenesis.

BACKGROUND: The composite transplantation of a split-thickness skin graft (STSG) combined with an acellular dermal matrix (ADM) is a promising repair method for full-thickness skin defects. Due to delayed vascularization of the ADM, no currently available engineered skin tissue is able to permanently cover full-thickness skin defects via a single-stage procedure. Epidermal stem cells (EpSCs) have been found to promote angiogenesis in the wound bed. Whether EpSCs can induce early angiogenesis of dermal substitutes and promote the survival of single-stage tissue-engineered skin transplantation needs to be further studied. METHODS: In vitro, rat vascular endothelial cells (RVECs) were treated with the supernatant of EpSCs cultured in ADM and stimulated for 48 h. RVECs were analysed by RNA sequencing and tube formation assays. For the in vivo experiment, 75 rats were randomly divided into five groups: ADM, ADM + EpSCs (AE), STSG, ADM + STSG (AS), and ADM + STSG + EpSCs (ASE) groups. The quality of wound healing was estimated by general observation and H&E and Masson staining. The blood perfusion volume was evaluated using the LDPI system, and the expression of vascular markers was determined by immunohistochemistry (IHC). RESULTS: The active substances secreted by EpSCs cultured in ADM promoted angiogenesis, as shown by tube formation experiments and RNA-seq. EpSCs promoted epithelialization of the ADM and vascularization of the ADM implant. The ASE group showed significantly increased skin graft survival, reduced skin contraction, and an improved cosmetic appearance compared with the AS group and the STSG control group. CONCLUSIONS: In summary, our findings suggest that EpSCs promote the formation of new blood vessels in dermal substitutes and support one-step transplantation of tissue-engineered skin, and thereby provide new ideas for clinical application.

Analysis of miR-203a-3p/SOCS3-mediated induction of M2 macrophage polarization to promote diabetic wound healing based on epidermal stem cell-derived exosomes.

BACKGROUND: The development of therapeutic strategies to improve wound healing in individual diabetic patients remains challenging. Stem cell-derived exosomes represent a promising nanomaterial, and microRNAs (miRNAs) can be isolated from them. It is important to identify the potential therapeutic role of specific miRNAs, given that miRNAs can play a therapeutic role. METHODS: qPCR, flow cytometry, and western blotting were used to verify the effect of epidermal stem cell-derived exosomes (EpiSC-EXOs) on M2 macrophage polarization and SOCS3 expression. By screening key miRNAs targeting SOCS3 in EpiSC-EXOs by high-throughput sequencing, we verified the mechanism in vitro. Finally, an animal model was used to verify the effect of promoting healing. RESULTS: The use of EpiSC-EXOs reduced SOCS3 expression and promoted M2 macrophage polarization. The abundant miR-203a-3p present in the EpiSC-EXOs specifically bound to SOCS3 and activated the JAK2/STAT3 signaling pathway to induce M2 macrophage polarization. Treatment of the db/db mouse wound model with miR-203a-3p agomir exerted a pro-healing effect. CONCLUSIONS: Our results demonstrated that the abundant miR-203a-3p present in EpiSC-EXOs can promote M2 macrophage polarization by downregulating SOCS3 and suggested that diabetic wounds can obtain better healing effects through this mechanism.

Bioinformatics analysis and identification of dysregulated POSTN in the pathogenesis of keloid.

Keloid is a benign fibro-proliferative dermal tumour formed by an abnormal scarring response to injury and characterised by excessive collagen accumulation and invasive growth. The pathophysiology of keloids is complex, and the treatment for keloids is still an unmet medical need. Here, we investigated the transcriptional gene that influences keloid development by comparing keloid, non-lesioned keloid skin and normal skin as well as keloid fibroblast and normal fibroblast (GSE83286, GSE92566, GSE44270). Based on the analysis, 146 up-regulated genes and 48 down-regulated genes were found in keloid tissue compared with normal skin and keloid no-lesioned skin. Eleven genes were further identified by overlapping the DEGs from keloid tissue described previously with DEGs in keloid fibroblast. The overlapped genes included PRR16, SFRP2, EDIL3, GERM1, POSTN, PDE3A, GALNT5, F2RL2, EYA4, ZFHX4, and AIM2. POSTN is the most crucial node in PPI network, which mainly correlate to collagen-related genes. Moreover, siRNA knockdown identified POSTN is a crucial regulatory gene that regulates keloid fibroblast migration and collagen I, collagen III expression level. In conclusion, our study identified 11 hub genes that play crucial role in keloid formation and provided insights for POSTN to be the therapeutic target for keloid through bioinformatic analysis of three datasets. Additionally, our results would support the development of future therapeutic strategies.

Correlation Between Kidney Function and Intestinal Biological Characteristics of Adenine and Folium SennaeInduced Diarrhea Model in Mice.

BACKGROUND: This study investigated the correlation among kidney function, intestinal enzyme activities, and microbial activity of adenine and Folium sennae-induced diarrhea model in mice, which provided a basis for clinical treatment of kidney-intestinal correlation. METHODS: We performed different doses of adenine combined with Folium sennae intragastric administration to establish the animal model of diarrhea. We assessed thymus and spleen indexes, serum creatinine, urea nitrogen and uric acid contents, intestinal contents and mucosal enzyme activities, and microbial activity. RESULTS: After modeling, mice presented increased serum creatinine and decreased urea nitrogen. Uric acid showed different changes in the different model groups. The thymus index in the model mice was trending downward, whereas the spleen index was the opposite. Moreover, model mice induced a non-significant increase in xylanase activity of the intestinal contents and mucosa compared to the control performance. Sucrase content of the intestinal contents increased considerably in the model groups but decreased in the intestinal mucosa. Lactase and amylase induced different trends in the different modeling methods. As well, the microbial activity of intestinal contents increased significantly, while that of intestinal mucosa decreased. CONCLUSION: Adenine combined with Folium sennae successfully replicated diarrhea in mice models. Using 50 mg/ (kg/day) adenine for 14 days in combination with 10 g/(kg/day) Folium sennae decoction for 7 days caused kidney function injury in diarrhea mice. In addition, kidney function injury was accompanied by changing in intestinal functional enzyme activity and microbial activity.

The early association of water irrigation with negative pressure wound therapy does not more efficiently reduce the depth of the alkali infiltration progress into the burn.

Water irrigation is an efficacious decontaminating method for dermis exposures to corrosive agents and hence has been widely applied to treat especially alkali burns. Nevertheless, once alkali has infiltrated the deep subcutaneous tissue, washing the tissue surface with water irrigation does not attenuate the damage progress. Therefore, significant efforts have been devoted to promising strategies aimed at removing the deeply infiltrated lye. According to a recent report, the negative pressure wound therapy (NPWT) reduces the pH value of the exudate from alkali-provoked burns thus accelerating wound healing. However, it remains to be ascertained whether or not NPWT coupled with water irrigation, that is, iNPWT, more effectively hinders the alkali injury deepening. In this study, we compared the effectiveness of an early application of water irrigation with or without NPWT in preventing the progressive deepening of the alkali burn in an animal model. Our histological examination results showed no appreciable difference in tissue injury depth, dermal retention, inflammatory cell infiltration, re-epithelization, and cellular function between iNPWT and water irrigation alone treatments. Thus, our results prove that the more expensive NPWT coupled with water irrigation does not more effectively hinder the alkali's injury deepening. Hence, iNPWT use should be more cautious in clinical practice.

Photoacoustic Imaging Probes for Theranostic Applications.

Photoacoustic imaging (PAI), an emerging biomedical imaging technology, capitalizes on a wide range of endogenous chromophores and exogenous contrast agents to offer detailed information related to the functional and molecular content of diseased biological tissues. Compared with traditional imaging technologies, PAI offers outstanding advantages, such as a higher spatial resolution, deeper penetrability in biological tissues, and improved imaging contrast. Based on nanomaterials and small molecular organic dyes, a huge number of contrast agents have recently been developed as PAI probes for disease diagnosis and treatment. Herein, we report the recent advances in the development of nanomaterials and organic dye-based PAI probes. The current challenges in the field and future research directions for the designing and fabrication of PAI probes are proposed.

Diarrhea with deficiency kidney-yang syndrome caused by adenine combined with Folium senna was associated with gut mucosal microbiota.

The present study aims to study and analyze the characteristics of gut mucosal microbiota in diarrhea mice with deficiency kidney-yang syndrome. Ten male mice were randomly divided into the control group and the model group. Diarrhea mice model with deficiency kidney-yang syndrome was established by adenine combined with Folium sennae. The kidney structure was observed by hematoxylin-eosin (HE) staining. Serum Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase were detected by enzyme-linked immunosorbent assay (ELISA). The characteristics of gut mucosal microbiota were analyzed by performing third-generation high-throughput sequencing. The results showed that the model mice exhibit obvious structural damage to the kidney. Serum Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase levels showed a decreased trend in the model group. The diversity and community structure of the gut mucosal microbiota improved in the model group. Dominant bacteria like Candidatus Arthromitus, Muribaculum, and Lactobacillus reuteri varied significantly at different taxonomic levels. The characteristic bacteria like Bacteroides, Erysipelatoclostridium, Anaerotignum, Akkermansia muciniphila, Clostridium cocleatum, Bacteroides vulgatus, and Bacteroides sartorii were enriched in the model group. A correlation analysis described that Erysipelatoclostridium was positively correlated with Na+-K+-ATP-ase and Ca2+-Mg2+-ATP-ase levels, while Anaerotignum exhibited an opposite trend. Together, adenine combined with Folium sennae damaged the structure of the kidney, affected energy metabolism, and caused disorders of gut mucosal microbiota in mice. Bacteroides, Erysipelatoclostridium, and Anaerotignum showed significant inhibition or promotion effects on energy metabolism. Besides, Akkermansia muciniphila, Clostridium cocleatum, Bacteroides vulgatus, and Bacteroides sartorii might be the characteristic species of gut mucosal microbiota responsible for causing diarrhea with deficiency kidney-yang syndrome.

Negative-Pressure Wound Therapy Improves Take Rate of Skin Graft in Irregular, High-Mobility Areas: A Randomized Controlled Trial.

BACKGROUND: Tie-over bolster dressing to secure a skin graft is associated with low graft take rates in irregular, high-mobility areas and suboptimal recipient wound beds. Negative-pressure wound therapy has become a well-established method to secure the graft, with a graft take rate of this method reported to be 96.7 percent. However, comparative efficacies between the two methods on irregular, high-mobility areas are yet to be determined. METHODS: Patients eligible for skin graft were randomly assigned to receive either negative-pressure wound therapy or tie-over bolster dressing between December of 2014 and December of 2015. The primary outcome was determined by the take rate of skin grafts between postoperative days 5 and 7. The secondary outcomes were dressing time and postoperative complications, including hematoma, seroma, infection, displacement, and necrosis. RESULTS: A total of 86 patients were assigned to receive either negative-pressure wound therapy ( n = 43) or tie-over bolster dressing ( n = 43) for skin graft treatment. Negative-pressure wound therapy significantly improved the take rate of grafts as compared with tie-over bolster dressing (97.2 versus 90.2 percent; p = 0.005). The improvements came from the grafts in irregular, high-mobility areas in the respective groups (97.6 versus 81.7 percent; p < 0.001). Negative-pressure wound therapy reduced skin graft displacement as a postoperative complication as compared with tie-over bolster dressing (one versus nine patients; p = 0.007). Dressing time using negative-pressure wound therapy was significantly shorter compared with tie-over bolster dressing (15.2 ± 4.2 versus 27.4 ± 4.3 minutes; p = 0.001). CONCLUSION: Negative-pressure wound therapy can improve the take rate of skin grafts in irregular, high-mobility areas and shorten the dressing time. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Nanomaterial integrated 3D printing for biomedical applications.

3D printing technology, otherwise known as additive manufacturing, has provided a promising tool for manufacturing customized biomaterials for tissue engineering and regenerative medicine applications. A vast variety of biomaterials including metals, ceramics, polymers, and composites are currently being used as base materials in 3D printing. In recent years, nanomaterials have been incorporated into 3D printing polymers to fabricate innovative, versatile, multifunctional hybrid materials that can be used in many different applications within the biomedical field. This review focuses on recent advances in novel hybrid biomaterials composed of nanomaterials and 3D printing technologies for biomedical applications. Various nanomaterials including metal-based nanomaterials, metal-organic frameworks, upconversion nanoparticles, and lipid-based nanoparticles used for 3D printing are presented, with a summary of the mechanisms, functional properties, advantages, disadvantages, and applications in biomedical 3D printing. To finish, this review offers a perspective and discusses the challenges facing the further development of nanomaterials in biomedical 3D printing.

Bioinformatic Analysis Reveals Hub Immune-Related Genes of Diabetic Foot Ulcers.

Diabetic foot ulcer (DFU) is a complex and devastating complication of diabetes mellitus that are usually stagnant in the inflammatory phase. However, oral wound healing, which is characterized by a rapid and scarless healing process, is regarded an ideal model of wound healing. Thus, we performed a comprehensive bioinformatics analysis of the previously published data regarding oral ulcers and DFUs and found that compared to oral wound healing, the activated pathways of DFUs were enriched in cellular metabolism-related pathways but lacked the activation of inflammatory and immune-related pathways. We also found that CXCL11, DDX60, IFI44, and IFI44L were remarkable nodes since they had the most connections with other members of the module. Meanwhile, CXCL10, IRF7, and DDX58 together formed a closed-loop relationship and occupied central positions in the entire network. The real-time polymerase chain reaction and western blot was applied to validate the gene expression of the hub immune-related genes in the DFU tissues, it was found that CXCL11, IFI44, IFI44L, CXCL10 and IRF7 have a significant difference compared with normal wound tissues. Our research reveals some novel potential immune-related biomarkers and provides new insights into the molecular basis of this debilitating disease.

Exosomes Derived from Epidermal Stem Cells Improve Diabetic Wound Healing.

Diabetic foot ulceration is a major diabetic complication with unmet needs. We investigated the efficacy of epidermal stem cells and epidermal stem cells-derived exosomes (ESCs-Exo) in improving impaired diabetic wound healing and their mechanisms of action. In vitro experiments showed that ESCs-Exo enhanced the proliferation and migration of diabetic fibroblasts and macrophages and promoted alternative or M2 macrophage polarization. In wounds of db/db mice, treatment with both epidermal stem cells and ESCs-Exo, when compared with fibroblast exosomes and PBS control, accelerated wound healing by decreasing inflammation, augmenting wound cell proliferation, stimulating angiogenesis, and inducing M2 macrophage polarization. Multiplex protein quantification of wound lysates revealed TGFß signaling influenced by ESCs-Exo. High-throughput sequencing of small RNAs contained in the ESCs-Exo showed higher proportions of microRNAs than those contained in fibroblast exosomes. In silico functional analysis showed that the ESCs-Exo microRNAs‒target genes were primarily involved in homeostatic processes and cell differentiation and highlighted regulatory control of phosphatidylinositol-3 kinase/protein kinase B and TGFß signaling pathways. This was also validated in vitro. Collectively, our results indicate that epidermal stem cells and ESCs-Exo are equally effective in promoting impaired diabetic wound healing and that ESCs-Exo treatment may be a promising and technically advantageous alternative to stem cell therapies.