Cascade catalysis nanozyme for interfacial functionalization in combating implant infections associated with diabetes via sonodynamic therapy and adaptive immune activation.

Innovative solutions are required for the intervention of implant associated infections (IAIs), especially for bone defect patients with chronic inflammatory diseases like diabetes mellitus (DM). The complex immune microenvironment of infections renders implants with direct antibacterial ability inadequate for the prolonged against of bacterial infections. Herein, a synergistic treatment strategy was presented that combined sonodynamic therapy (SDT) with adaptive immune modulation to treat IAIs in diabetes patients. A multifunctional coating was created on the surface of titanium (Ti) implants, consisting of manganese dioxide nanoflakes (MnO2 NFs) with cascade catalytic enzyme activity and a responsive degradable hydrogel containing a sonosensitizer. The reactive oxygen species (ROS) generated by glucose-hydrogen peroxide (H2O2) cascade catalysis and ultrasound (US) activation sonosensitizer helped kill bacteria and release bacterial antigens. Meanwhile, Mn2+ facilitated dendritic cells (DCs) maturation, enhancing antigen presentation to activate both cellular and humoral adaptive immunity against bacterial infections. This approach effectively eliminated bacteria in established diabetic IAIs model and activated systemic antibacterial immunity, providing long-term antibacterial protection. This study presents a non-antibiotic immunotherapeutic strategy for fighting IAIs in chronic diseases.

Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing.

Bone nonunion poses an urgent clinical challenge that needs to be addressed. Recent studies have revealed that the metabolic microenvironment plays a vital role in fracture healing. Macrophages and bone marrow-derived mesenchymal stromal cells (BMSCs) are important targets for therapeutic interventions in bone fractures. Itaconate is a TCA cycle metabolite that has emerged as a potent macrophage immunomodulator that limits the inflammatory response. During osteogenic differentiation, BMSCs tend to undergo aerobic glycolysis and metabolize glucose to lactate. Copper ion (Cu2+) is an essential trace element that participates in glucose metabolism and may stimulate glycolysis in BMSCs and promote osteogenesis. In this study, we develop a 4-octyl itaconate (4-OI)@Cu@Gel nanocomposite hydrogel that can effectively deliver and release 4-OI and Cu2+ to modulate the metabolic microenvironment and improve the functions of cells involved in the fracture healing process. The findings reveal that burst release of 4-OI reduces the inflammatory response, promotes M2 macrophage polarization, and alleviates oxidative stress, while sustained release of Cu2+ stimulates BMSC glycolysis and osteogenic differentiation and enhances endothelial cell angiogenesis. Consequently, the 4-OI@Cu@Gel system achieves rapid fracture healing in mice. Thus, this study proposes a promising regenerative strategy to expedite bone fracture healing through metabolic reprogramming of macrophages and BMSCs.

From hemostasis to proliferation: Accelerating the infected wound healing through a comprehensive repair strategy based on GA/OKGM hydrogel loaded with MXene@TiO2 nanosheets.

The treatment of infected wounds poses a formidable challenge in clinical practice due to the detrimental effects of uncontrolled bacterial infection and excessive oxidative stress, resulting in prolonged inflammation and impaired wound healing. In this study, we presented a MXene@TiO2 (MT) nanosheets loaded composite hydrogel named as GA/OKGM/MT hydrogel, which was formed based on the Schiff base reaction between adipic dihydrazide modified gelatin (GA)and Oxidized Konjac Glucomannan (OKGM), as the wound dressing. During the hemostasis phase, the GA/OKGM/MT hydrogel demonstrated effective adherence to the skin, facilitating rapid hemostasis. In the subsequent inflammation phase, the GA/OKGM/MT hydrogel effectively eradicated bacteria through MXene@TiO2-induced photothermal therapy (PTT) and eliminated excessive reactive oxygen species (ROS), thereby facilitating the transition from the inflammation phase to the proliferation phase. During the proliferation phase, the combined application of GA/OKGM/MT hydrogel with electrical stimulation (ES) promoted fibroblast proliferation and migration, leading to accelerated collagen deposition and angiogenesis at the wound site. Overall, the comprehensive repair strategy based on the GA/OKGM/MT hydrogel demonstrated both safety and reliability. It expedited the progression through the hemostasis, inflammation, and proliferation phases of wound healing, showcasing significant potential for the treatment of infected wounds.

Micronano Titanium Accelerates Mesenchymal Stem Cells Aging through the Activation of Senescence-Associated Secretory Phenotype.

Stem cell senescence is one of the most representative events of organism aging and is responsible for many physiological abnormalities and disorders. In the scenario of orthopedic disease treatment, stem cell aging may affect the implantation outcome and even lead to operation failure. To explore whether stem cell aging will affect the osteointegration effect of titanium implant, a widely used micronano titanium (MNT) was fabricated. We first verified the expected osteointegration effect of the MNT, which could be attributed to the improvement of stem cell adhesion and osteogenic differentiation. Then, we obtained aged-derived bone marrow mesenchymal stem cells (BMSCs) and studied their biological behaviors on MNT both in vitro and in vivo. We found that compared with normal rats, MNT did not significantly improve the osteointegration in aged rats. Compared with normal rats, fewer endogenous stem cells were observed at the implant-host interface, and the expression of p21 (senescence marker) was also higher. We further confirmed that MNT promoted the nuclear localization of NF-κB in senescent stem cells through the activation of p38 MAPK, thereby inducing the occurrence of the senescence-associated secretory phenotype (SASP) and ultimately leading to the depletion of the stem-cell pool at the implant-host interface. However, the activation of p38 MAPK can still promote the osteogenic differentiation of nonsenescent BMSCs. These results showed an interesting paradoxical balance between osteogenesis and senescence on MNT surfaces and also provided insights for the design of orthopedic implants for aging patients.

All-in-One Engineering Multifunctional Nanoplatforms for Sensitizing Tumor Low-Temperature Photothermal Therapy In Vivo.

Low-temperature photothermal therapy (PTT) is a noninvasive method that harnesses the photothermal effect at low temperatures to selectively eliminate tumor cells, while safeguarding normal tissues, minimizing thermal damage, and enhancing treatment safety. First we evaluated the transcriptome of tumor cells at the gene level following low-temperature treatment and observed significant enrichment of genes involved in cell cycle and heat response-related signaling pathways. To address this challenge, we have developed an engineering multifunctional nanoplatform that offered an all-in-one strategy for efficient sensitization of low-temperature PTT. Specifically, we utilized MoS2 nanoparticles as the photothermal core to generate low temperature (40-48 °C). The nanoplatform was coated with DPA to load CPT-11 and Fe2+ and was further modified with PEG and iRGD to enhance tumor specificity (MoS2/Fe@CPT-11-PEG-iRGD). Laser- and acid-triggered release of CPT-11 can significantly increase intracellular H2O2 content, cooperate with Fe2+ ions to increase intracellular lipid ROS content, and activate ferroptosis. Furthermore, CPT-11 induced cell cycle arrest in the temperature-sensitive S-phase, and increased lipid ROS levels contributed to the degradation of HSPs protein expression. This synergistic approach could effectively induce tumor cell death by the sensitized low-temperature PTT and the combination of ferroptosis and chemotherapy. Our nanoplatform can also maximize tumor cell eradication and prolong the survival time of tumor-bearing mice in vivo. The multifunctional approach will provide more possibilities for clinical applications of low-temperature PTT and potential avenues for the development of multiple tumor treatments.

Waste to Wealth: Near-Infrared/pH Dual-Responsive Copper-Humic Acid Hydrogel Films for Bacteria-Infected Cutaneous Wound Healing.

The clinical applications of currently used photosensitizers are limited by high costs, inconvenient preparation, suboptimal biodegradability, and a lack of biological activity. Humic acids (HAs) show photothermal activity and can be used as a photosensitizer for photothermal therapy. In the presence of various functional groups, HAs are endowed with anti-inflammatory and antioxidant activities. The solubility of HAs is dependent on the pH value, which is soluble in neutral to alkaline conditions and undergoes a conformational change to a coiled and compact structure in acidic conditions. Additionally, Cu2+ is an emerging therapeutic agent for cutaneous wounds and can be chelated by HAs to form complexes. In this study, we explore the ability of HAs to modulate the inflammatory response, particularly macrophage polarization, and the potential underlying mechanism. We fabricate a near-infrared (NIR)/pH dual-responsive Cu-HAs nanoparticle (NP)-based poly(vinyl alcohol) (PVA) hydrogel film loaded with SEW2871 (SEW), a macrophage recruitment agent, to treat bacteria-infected cutaneous wounds. The results show that HAs could promote M2 macrophage polarization in a dose-dependent manner. The Cu-HAs NPs successfully eradicated bacterial infection through NIR-induced local hyperthermia. This PVA@Cu-HAs NPs@SEW hydrogel film improves tissue regeneration by promoting M2 macrophage polarization, alleviating oxidative stress, enhancing angiogenesis, and facilitating collagen deposition. These findings highlight the therapeutic potential of PVA@Cu-HAs NPs@SEW hydrogel film for the treatment of bacterially infected cutaneous wound healing.

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer.

The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals in tumor cells are able to avoid various tumor tolerance mechanisms by alleviating the intracellular hypoxia environment. Herein we reported a nanoreactor Cu2-xSe that enabled the conversion of Cu elements between Cu+ and Cu2+ for the generation of O2 and the consumption of intracellular GSH content. Furthermore, to enhance the catalytic and ferroptosis-inducing activities of the nanoreactors, the ferroptosis agonist Erastin was loaded on the ZIF-8 coating on the surface of Cu2-xSe to up-regulate the expression of NOX4 protein, increase the intracellular H2O2 content, catalyze the Cu+ to produce O2 and activate ferroptosis. In addition, the nanoreactors were simultaneously surface functionalized with PEG polymer and folic acid molecules, which ensured the in vivo blood circulation and tumor-specific uptake. In vitro and in vivo experiments demonstrated that the functionalized self-supplying nanoreactors can amplify the ability to generate O2 and consume intracellular GSH via the interconversion of Cu elements Cu+ and Cu2+, and impair the GPX4/GSH pathway and HIF-1α protein expression. At the same time, by alleviating the intracellular hypoxia environment, the expression of miR301, a gene in the secreted exosomes was decreased, which ultimately affected the phenotype polarization of TAMs and increased the content of IFN γ secreted by CD8+ T cells, which further promoted the ferroptosis induced by Erastin-loaded nanoreactors. This combined therapeutic strategy of activating the tumor immune response and ferroptosis via self-supplying nanoreactors provides a potential strategy for clinical application.

Phenotypic and Cellular Characteristics of a Stromal Vascular Fraction/Extracellular Matrix Gel Prepared Using Mechanical Shear Force on Human Fat.

The retention of fat-derived grafts remains a challenge for regenerative medicine. Fat aspirates from patients undergoing liposuction were prepared into standard Coleman fat grafts or further isolated using mechanical shear force to prepare a stromal vascular fraction (SVF)/extracellular matrix (ECM) gel. The retention rate of the SVF/ECM gel was significantly higher than that of the Coleman fat at 3, 14, 28, and 60 days following transplantation on the backs of nude mice. The viscosity of the fat was directly proportional to the shearing force. Although the mechanical isolation did not affect the total number of cells, it significantly decreased the number of living cells. Flow cytometry showed a greater number of mesenchymal stem cells, supra-adventitial (SA)-adipose stromal cells (ASCs), and adipose-derived stem cells but a lower number of endothelial progenitor cells in the SVF/ECM gel than in the Coleman fat. Thus, mechanical isolation of fat can increase the pluripotency of adipocytes, which can improve graft retention in cell therapy.

[Clinicopathologic features and differential diagnoses of non-involuting congenital hemangioma in children].

OBJECTIVE: To investigate the clinicopathologic features and differential diagnoses of non-involuting congenital hemangioma (NICH) in children. METHODS: The clinical, morphologic and immunophenotypic characteristics of 22 cases of NICH were retrospectively analyzed. RESULTS: The mean patients' age at diagnosis was 4.2 years, with a male to female ratio of 1.75:1. The tumors were located in the head and face (5 cases), neck (3 cases), body (6 cases), upper limbs (5 cases), and lower limbs (3 cases). Histologically, the tumor was dominated by rather large lobules of small vessels that were mostly rounded, curved, small and thin-walled, and were lined by endothelial cells surrounded by one or more layers of pericytes. The center of the lobules was occupied by one or more thin or thick walled vessels, which were surrounded by fibrous and fatty tissue, which contained abnormal arterial and venous structures. At the edge of the lobules there were lymphatic vessels. Immunohsitochemical study showed that tumor cells in NICH were positive for CD34 (22/22), CD31 (22/22), SMA (22/22), vimentin (22/22) and Glut1 (0/22). D2-40 expression was located at the edge of the capillary lobules. CONCLUSIONS: NICH is a benign lesion. Clinically and pathologically, it needs to be differentiated from rapidly involuting congenital hemangioma, infantile hemangiomas, tufted angioma, vascular malformation, and others.

[The synthesis and fluorescence properties of doping europium-benzoic acid-phenanthroline complexes].

Eu1-x Lnx (BA)3Phen(Ln: Gd, La, Y; BA: benzoic acid; Phen: phenanthroline; x = 0.0-0.9) complexes are synthesized, and their similar structures showed by IR spectra. Fluorescence spectra indicate that the complexes can emit intense characteristic fluorescence from europium ion and the doping elements can enhance the fluorescence intensities of central europium ion and have co-fluorescence effect.