Injectable and in situ foaming shape-adaptive porous Bio-based polyurethane scaffold used for cartilage regeneration.

Irregular articular cartilage injury is a common type of joint trauma, often resulting from intense impacts and other factors that lead to irregularly shaped wounds, the limited regenerative capacity of cartilage and the mismatched shape of the scaffods have contributed to unsatisfactory therapeutic outcomes. While injectable materials are a traditional solution to adapt to irregular cartilage defects, they have limitations, and injectable materials often lack the porous microstructures favorable for the rapid proliferation of cartilage cells. In this study, an injectable porous polyurethane scaffold named PU-BDO-Gelatin-Foam (PUBGF) was prepared. After injection into cartilage defects, PUBGF forms in situ at the site of the defect and exhibits a dynamic microstructure during the initial two weeks. This dynamic microstructure endows the scaffold with the ability to retain substances within its interior, thereby enhancing its capacity to promote chondrogenesis. Furthermore, the chondral repair efficacy of PUBGF was validated by directly injecting it into rat articular cartilage injury sites. The injectable PUBGF scaffold demonstrates a superior potential for promoting the repair of cartilage defects when compared to traditional porous polyurethane scaffolds. The substance retention ability of this injectable porous scaffold makes it a promising option for clinical applications.

Stimuli-responsive microcarriers and their application in tissue repair: A review of magnetic and electroactive microcarrier.

Microcarrier applications have made great advances in tissue engineering in recent years, which can load cells, drugs, and bioactive factors. These microcarriers can be minimally injected into the defect to help reconstruct a good microenvironment for tissue repair. In order to achieve more ideal performance and face more complex tissue damage, an increasing amount of effort has been focused on microcarriers that can actively respond to external stimuli. These microcarriers have the functions of directional movement, targeted enrichment, material release control, and providing signals conducive to tissue repair. Given the high controllability and designability of magnetic and electroactive microcarriers, the research progress of these microcarriers is highlighted in this review. Their structure, function and applications, potential tissue repair mechanisms, and challenges are discussed. In summary, through the design with clinical translation ability, meaningful and comprehensive experimental characterization, and in-depth study and application of tissue repair mechanisms, stimuli-responsive microcarriers have great potential in tissue repair.

Chitosan/polydopamine/octacalcium phosphate composite microcarrier simulates natural bone components to induce osteogenic differentiation of stem cells.

Natural polymers and minerals can be combined to simulate natural bone for repairing bone defects. However, bone defects are often irregular and pose challenges for their repair. To overcome these challenges, we prepared Chitosan/Polydopamine/Octacalcium phosphate (CS/PDA/OCP) microcarriers that mimic bone composition and micro-size to adapt to different bone defect defects. CS/PDA microspheres were prepared by emulsion phase separation method and PDA in-situ polymerization. Finally, it was used to adsorb and immobilize OCP particles, resulting in the preparation of CS/PDA/OCP composite microcarriers. The microcarriers maintain an interconnected porous structure and appropriate porosity, which promotes cell adhesion, proliferation, and nutrient exchange. Subsequently, the protein adsorption capacity, simulated degradation, cell adhesion and proliferation capacity of the composite microcarriers were investigated. Additionally, their ability to simulate mineralization and induce osteogenic differentiation of BMSCs was characterized. The results demonstrated that the composite microcarrier had good biocompatibility and was conducive to cell adhesion and proliferation. Moreover, ALP and ARS staining revealed that the addition of OCP significantly enhanced the osteogenic differentiation of BMSCs. These results indicate that the composite microcarrier has promising prospects for bone repair applications.

The controlled degradation of bacterial cellulose in simulated physiological environment by immobilization and release of cellulase.

Bacterial cellulose (BC) has good network structure, biocompatibility, and excellent mechanical properties, and is widely used in the field of biomaterials. The controllable degradation of BC can further broaden its application. Oxidative modification and cellulases may endow BC with degradability, but these methods inevitably lead to the obvious reduction of its initial mechanical properties and uncontrolled degradation. In this paper, the controllable degradation of BC was realized for the first time by using a new controlled release structure that combines the immobilization and release of cellulase. The immobilized enzyme has higher stability and is gradually released in the simulated physiological environment, and its load can control the hydrolysis rate of BC well. Furthermore, the BC-based membrane prepared by this method retains the favorable physicochemical performance of the original BC, including flexibility and great biocompatibility, and holds good application prospects in drug control release or tissue repair.

Ultrasonic/electrical dual stimulation response nanocomposite bioelectret for controlled precision drug release.

Electret materials have attracted extensive attention because of their permanent polarization and electrostatic effect. However, it is one of problem that needs to be solved in biological application to manipulate the change of surface charge of electret by external stimulation. In this work, a drug-loaded electret with flexibility and no cytotoxicity was prepared under relatively mild conditions. The electret can release the charge through stress change and ultrasonic stimulation, and the drug release can be accurately controlled with the help of ultrasonic and electric double stimulation response. Here, the dipoles like particles of carnauba wax nanoparticles (nCW) are fixed in the matrix based on the interpenetrating polymer network structure, and "frozen" oriented dipolar particles that are treated by thermal polarization and cooled at high field strength. Subsequently, the charge density of the prepared composite electret can reach 101.1 â€‹nC/m2 at the initial stage of polarization and 21.1 â€‹nC/m2 after 3 weeks. In addition, the stimulated change of electret surface charge flow under cyclic tensile stress and cyclic compressive stress can generate a current of 0.187 â€‹nA and 0.105 â€‹nA at most. The ultrasonic stimulation results show that when the ultrasonic emission power was 90% (Pmax â€‹= â€‹1200 â€‹W), the current of 0.472 â€‹nA can be generated. Finally, the drug release characteristics and biocompatibility of the nCW composite electret containing curcumin were tested. The results showed that it not only had the ability to accurately control the release by ultrasound, but also triggered the electrical effect of the material. The prepared drug loaded composite bioelectret provides a new way for the construction, design and testing of the bioelectret. Its ultrasonic and electrical double stimulation response can be accurately controlled and released as required, and it has broad application prospects.

Magnetic Microcarriers with Accurate Localization and Proliferation of Mesenchymal Stem Cell for Cartilage Defects Repairing.

Magnetic biomaterials are widely used in the field of tissue engineering because of their functions such as drug delivery and targeted therapy. In this study, a magnetically responsive composite microcarrier was prepared through in situ polymerization of dopamine with Fe3O4 (MS) to form a complex. The magnetic composite microcarriers are paramagnetic and have certain magnetic responsiveness, suitable pore size porosity for cell growth, and good blood compatibility and biocompatibility. The bone marrow mesenchyml stem cells (BMSCs) were cultured on magnetic composite microcarriers, and a static magnetic field (SMF) was applied. The results showed that BMSCs adhered to the microcarriers proliferated under the action of horizontal and vertical forces. Magnetic composite microcarriers loaded with BMSCs were implanted into the SD rat model of cartilage defect, and a magnet was added to the operative side. After 12 weeks, cartilage regeneration was observed. The results of gross observation and histological immunostaining 1 month, 2 months, and 3 mounths after operation showed that the magnetic composite microcarriers of loaded cells promoted the early maturation of cartilage and collagen secretion, and the effect of cartilage repair was significantly better than that of the control group. Gait analysis showed that implanting magnetic composite microcarriers loaded with stem cells can reduce postoperative pain and promote limb recovery in SD rats. In conclusion, this study suggests that magnetic composite microcarriers are promising tissue-engineered scaffolds for cartilage regeneration and repair.

A Mulberry Diels-Alder-Type Adduct, Kuwanon M, Triggers Apoptosis and Paraptosis of Lung Cancer Cells through Inducing Endoplasmic Reticulum Stress.

The mulberry tree (Morus alba) has been cultivated in China for thousands of years. Mulberry Diels-Alder-type adducts (MDAAs) are characteristic constituents of the genus Morus. The unique structure and diverse bioactivities of MDAAs have attracted the attention of researchers. Kuwanon M (KWM) is an MDAA isolated from the root bark of Morus alba. This research reports the growth inhibitory effects of KWM on human lung cancer cells and its possible mechanism. In A549 and NCI-H292 cells, KWM treatment induced suppression of cell proliferation and migration. The appearance of chromatin condensation, phosphatidyl serine exposure and caspase cleavage indicated the arising of apoptosis. The loss of mitochondrial membrane potential (MMP), release of cytochrome c and dysregulation of Bax/Bcl-2 demonstrated that the KWM-induced apoptosis was through the mitochondrial pathway. Paraptosis was simultaneously detected under KWM treatment, as evidenced by the exhibition of cytoplasmic vacuolation, down-regulation of Alix and up-regulation of endoplasmic reticulum (ER) stress-related proteins. Mechanistically, ER stress induced activation of unfolded protein response (UPR) pathways and activation of the MAPK (JNK and ERK) pathway, all of which were critical for KWM-induced apoptosis and paraptosis. These findings suggested the possibility that KWM might be considered as a potential lung cancer therapeutic agent.

Kuoxin Decoction promotes lymphangiogenesis in zebrafish and in vitro based on network analysis.

Background: Inadequate lymphangiogenesis is closely related to the occurrence of many kinds of diseases, and one of the important treatments is to promote lymphangiogenesis. Kuoxin Decoction (KXF) is an herbal formula from traditional Chinese medicine used to treat dilated cardiomyopathy (DCM), which is associated with lymphangiogenesis deficiency. In this study, we comprehensively verified whether KXF promotes lymphangiogenesis in zebrafish and in vitro based on network analysis. Methods: We performed virtual screening of the active compounds of KXF and potential targets regarding DCM based on network analysis. Tg (Flila: EGFP; Gata1: DsRed) transgenic zebrafish embryos were treated with different concentrations of KXF for 48 h with or without the pretreatment of MAZ51 for 6 h, followed by morphological observation of the lymphatic vessels and an assessment of lymphopoiesis. RT-qPCR was employed to identify VEGF-C, VEGF-A, PROX1, and LYVE-1 mRNA expression levels in different groups. After the treatment of lymphatic endothelial cells (LECs) with different concentrations of salvianolic acid B (SAB, the active ingredient of KXF), their proliferation, migration, and protein expression of VEGF-C and VEGFR-3 were compared by CCK-8 assay, wound healing assay, and western blot. Results: A total of 106 active compounds were identified constituting KXF, and 58 target genes of KXF for DCM were identified. There were 132 pathways generated from KEGG enrichment, including 5 signaling pathways related to lymphangiogenesis. Zebrafish experiments confirmed that KXF promoted lymphangiogenesis and increased VEGF-C and VEGF-A mRNA expression levels in zebrafish with or without MAZ51-induced thoracic duct injury. In LECs, SAB promoted proliferation and migration, and it could upregulate the protein expression of VEGF-C and VEGFR-3 in LECs after injury. Conclusion: The results of network analysis showed that KXF could regulate lymphangiogenesis through VEGF-C and VEGF-A, and experiments with zebrafish confirmed that KXF could promote lymphangiogenesis. Cell experiments confirmed that SAB could promote the proliferation and migration of LECs and upregulate the protein expression of VEGF-C and VEGFR-3. These results suggest that KXF promotes lymphangiogenesis by a mechanism related to the upregulation of VEGF-C/VEGFR-3, and the main component exerting this effect may be SAB.

Epimedokoreanin B inhibits the growth of lung cancer cells through endoplasmic reticulum stress-mediated paraptosis accompanied by autophagosome accumulation.

Epimedokoreanin B (EKB) is a prenylated flavonoid isolated from Epimedium koreanum. In this article, we described the anti-cancerous effects of EKB and its underlying mechanism in human non-small cell lung cancer (NSCLC) A549 and NCI-H292 cells. EKB treatment inhibited cell proliferation and migration accompanied by cytoplasmic vacuolation in both cell lines. The cell death induced by EKB lacked the features of apoptosis like chromatin condensation, phosphatidyl serine exposure and caspase cleavage. The vacuoles stimulated by EKB predominantly derived from endoplasmic reticulum (ER) and mitochondria dilation, which are the characteristics of paraptosis. Down-regulation of Alix and up-regulation of ER stress-related proteins after EKB treatment further supported the occurrence of paraptosis. ER stress inhibitor 4-phenylbutyric acid (4-PBA) and protein synthesis inhibitor cycloheximide (CHX) treatment antagonized the vacuoles formation as well as cell death induced by EKB, indicating that ER stress was involved in EKB induced paraptosis. In addition, autophagosome accumulation accompanied with autophagy flux blocking was observed in EKB treated cells, this was consistent with the occurrence of ER stress. Collectively, EKB was demonstrated as a paraptosis-like cell death inducer in A549 and NCI-H292 cells. The inhibitory effect of EKB on lung cancer cell proliferation was further demonstrated in a zebrafish xenograft model. These findings raise the possibility that paraptosis inducers may be considered as alternative choices for lung cancer therapy.

Huangqi Guizhi Wuwu Decoction Improves Arthritis and Pathological Damage of Heart and Lung in TNF-Tg Mice.

Background: Huangqi Guizhi Wuwu Decoction (HGWD) is a traditional and effective Chinese medicine compound decoction for the treatment of rheumatoid arthritis (RA). However, there is few research on the treatment of rheumatoid cardiopulmonary complications. The present study was to study whether HGWD can alleviate the pathological changes caused by rheumatoid arthritis and cardiopulmonary complications. Methods: Five 3-month-old TNF-Tg mice were treated with HGWD (9.1 g/kg) once a day or the same dose of normal saline lasted for 8 weeks, and wild-type littermates of the same age were used as a negative control, and methotrexate (MTX) was intraperitoneally administered as a positive control. After the treatment, pathological staining was performed on the mouse ankle joints, heart, and lungs. Result: It was found that HGWD reduced the inflammation of the ankle joint synovium in TNF-Tg mice, and reduced myocardial hypertrophy, inflammatory infiltration and fibrosis of heart, as well as lung inflammation and fibrosis. Immunohistochemical staining with anti-TNF-α antibody showed that HGWD reduced the expression of TNF-α in the heart of TNF-Tg mice. Conclusion: In conclusion, HGWD alleviates joint inflammation in TNF-Tg mice and reduces the pathological changes of the heart and lungs.

Bacterial cellulose/soybean protein isolate composites with promoted inflammation inhibition, angiogenesis and hair follicle regeneration for wound healing.

Soybean protein, as a safe and low-cost alternative to animal protein, attracts increasing attention in wound healing. In the present study, beta-conglycinin (7S) and glycinin (11S) with high solubility were obtained through separation of soybean protein. Afterward, 7S or 11S modified bacterial cellulose (BC) composites were produced by self-assembly method. Results confirmed the successful self-assembly of soybean protein isolates on the nanofibers of BC. The surface roughness and hydrophilicity of BC/7S and BC/11S decreased compared with native BC. Soybean protein could be steadily released from BC/7S and BC/11S and BC/11S released more soybean proteins than BC/7S. In vitro, BC/7S and BC/11S supported fibroblasts attachment and promoted fibroblasts proliferation and type I collagen expression. In vivo, BC/7S and BC/11S facilitated wound healing and collagen deposition, enhanced angiogenesis and hair follicle regeneration, as well as reduced scar formation and inflammation in full-thickness skin wounds of rats. Moreover, wounds treated with BC/11S showed a faster wound healing rate and more collagen depositions than those of BC/7S, which may be attributed to the larger considerable amount of soybean protein released by BC/11S. These results indicate that BC/7S and BC/11S are potential candidates for wound dressings.

In-situ self-assembly of bacterial cellulose/poly(3,4-ethylenedioxythiophene)-sulfonated nanofibers for peripheral nerve repair.

Biocompatible and electroactive biomaterials have good potential on peripheral nerve repair. Bacterial cellulose (BC) shows excellent biocompatibility and is easy to modified, however it lacks electroactivity. In this study, biocompatible, conductive, and transparent bacterial cellulose/poly(3,4-ethylenedioxythiophene)-sulfonated nanofibers (BC/PEDOT-SNFs, BPS) composite membranes were prepared through the in-situ polymerization of PEDOT and the doping of SNFs. The polymerization of PEDOT endowed BC with conductivity, making the BPS membranes conducive to the adhesion and proliferation of adipose-derived stem cells (ADSCs). The conductivity of BPS was affected by the SNFs doped, and its value was up to 1.8 × 10-2 S/cm while the sulfonation degree of SNFs reached 93%. Furthermore, nerve conduits made of BPS were implanted in-vivo for 12 weeks, and it great improved the peripheral nerve repair effect. In summary, BPS membranes with excellent conductivity and multiple merits for cells loading, hold great application potential for peripheral nerve repair.

Polylysine-decorated macroporous microcarriers laden with adipose-derived stem cells promote nerve regeneration in vivo.

Cell transplantation is an effective strategy to improve the repair effect of nerve guide conduits (NGCs). However, problems such as low loading efficiency and cell anoikis undermine the outcomes. Microcarriers are efficient 3D cell culture scaffolds, which can also prevent cell anoikis by providing substrate for adhesion during transplantation. Here, we demonstrate for the first time microcarrier-based cell transplantation in peripheral nerve repair. We first prepared macroporous chitosan microcarriers (CSMCs) by the emulsion-phase separation method, and then decorated the CSMCs with polylysine (pl-CSMCs) to improve cell affinity. We then loaded the pl-CSMCs with adipose-derived stem cells (ADSCs) and injected them into electrospun polycaprolactone/chitosan NGCs to repair rat sciatic nerve defects. The ADSCs-laden pl-CSMCs effectively improved nerve regeneration as demonstrated by evaluation of histology, motor function recovery, electrophysiology, and gastrocnemius recovery. With efficient cell transplantation, convenient operation, and the multiple merits of ADSCs, the ADSCs-laden pl-CSMCs hold good potential in peripheral nerve repair.

Preparation, deproteinization, characterization, and antioxidant activity of polysaccharide from Medemia argun fruit.

In this study, the crude polysaccharide from argun palm (Medemia argun) fruit was extracted with hot water and deproteinized by four different methods. Its structure characterization, thermal property and antioxidant activity were investigated by FT-IR spectroscopy, Scanning electron microscope, Congo-red, I2-KI, DPPH• assay, ABTS•+ assay, TGA and DSC analysis. It indicated that the NaCl method was the best method in deproteinization. The argun fruit polysaccharide linked by the ß-glycosidic bonds. The molecular weight of polysaccharide deproteinized with NaCl was 4.46 × 105 Da. It showed that the polysaccharide from argun palm fruit consisted of fructose, arabinose, rhamnose, galactose, glucose, xylose, and galacturonic acid. The result of TGA and DSC assay indicated that argun fruit polysaccharide has a favorable thermal stability. It was proved that, the argun fruit polysaccharide possessed high antioxidant activity and would be a new natural antioxidant.

Microencapsulation of fingered citron extract with gum arabic, modified starch, whey protein, and maltodextrin using spray drying.

The aim of this study was to investigate the characteristics of the Fingered citron extract (FCE) microcapsules powders with different formulations of the encapsulation carrier agents [gum arabic (GA), maltodextrin (MD), modified starch (MS), and whey protein (WP)], which are obtained through spray drying. Encapsulation yield, encapsulation efficiency, moisture content, hygroscopicity, water activity, density properties, Carr's index, cohesiveness, flowability, porosity, wettability, solubility, color, particle size, thermal behavior, relative crystallinity, and micrographs were analyzed. Moreover, chemical structure of the microcapsule powder was identified using Fourier transform infrared spectroscopy (FT-IR). Best results were achieved when Fingered citron extract was encapsulated using gum arabic/maltodextrin/modified starch (GMS) formulation as carrier agents, where it had the highest encapsulation yield (89.39%) and encapsulation efficiency (87.20%). Furthermore, it achieved the best result in density properties, flowability, porosity, wettability, and relative crystallinity. These results have shown that using gum arabic/maltodextrin/modified starch formulation was superior for production of the Fingered citron extract microcapsules powders.

Inflammatory activation of microglia by Staphylococcus aureus caused phenotypic alterations and affected glioblastoma growth.

As the most common type of tumour in brain, glioma has a high rate of morbidity and mortality and easily penetrates the surrounding normal brain parenchyma. The immunosuppressive microenvironment, which is similar to that in other neoplasms, is believed to participate in the tumorigenesis of glioma. Thus, many experts are seeking to exploit microenvironment as a therapeutic target. In the present study, we focused on microglia polarization to investigate the anti-glioma response of microglia inflammatory activation by Staphylococcus aureus in vitro and in vivo. First, we found that intratumor injection of S. aureus delayed glioma growth in C57/BL6 mice. Then, we showed that inflammatory microglia activated by S. aureus inhibited glioma cell proliferation, migration, and invasion. This inhibition was likely related to the phenotypic switch observed in microglia. In intracranial tumour models, the microglia activated by S. aureus exerted antitumour efficacy and prolonged animal survival. Taken together, our results suggest that microglia activated by S. aureus have antitumour efficacy, which may be a potential therapeutic agent for glioma. SIGNIFICANCE OF THE STUDY: In this study, we mainly demonstrated the antitumour efficacy of microglia after activated by S. aureus. Firstly, we found that intratumor injection of S. aureus inhibited the tumour growth in intracranial orthotopic glioma model. In addition, we found that the microglia around the glioma may exert antitumour efficacy, and its phenotype may be altered by stimulation of S. aureus. Our data manifested that S. aureus did not directly suppress cell proliferative, migration, and invasion capacity, but by activating microglia. And in mice GL261 GBMs, injection of microglia after cocultured with S. aureus inhibited tumour growth and prolonged animal survival.

Overexpression of STAT1 suppresses angiogenesis under hypoxia by regulating VEGF­A in human glioma cells.

Hypoxia is common in Glioblastoma (GBM). By regulating the 'hypoxia signaling cascade', hypoxia affects several processes including cell proliferation, invasion, and angiogenesis. Some studies have revealed that signal transducer and activator of transcription (STAT), including STAT1, is abnormal under hypoxia in several cancers. Here, we investigated the role of STAT1 under hypoxia in glioma progression. We found that STAT1 was downregulated under a hypoxic condition in U251 and U373. STAT1 overexpression can not only decrease proliferation, migration and invasion in U251 and U373 but also inhibit tube formation of HBMECs. Moreover, overexpression of STAT1 decreased tumor growth and prolonged the overall survival of xenograft mice. We also showed that STAT1 overexpression inhibited the expression of HIF-1α and VEGF-A. Our work suggests that STAT1 plays a pivotal role as a tumor suppressor in glioma under hypoxia, and it could be a potential new therapeutic target in glioma.

Synthesis and characterization of bright green terbium coordination complex derived from 1,4-bis(carbonylmethyl)terephthalate: Structure and luminescence properties.

A photoluminescent terbium (Tb) complex involving a novel benzoic-acid compound with a unique coordinated structure, namely 1,4-bis(carbonylmethyl)terephthalate (BCMT), has been designed and synthesized. The new coordinate structure and energy-transfer mechanism between the ligand and Tb(III) ions were investigated in detail. The results demonstrated that the BCMT-Tb(III) complex shows strong fluorescence intensity (4×106a.u.) and long fluorescence lifetime (1.302ms), owing to the favorable degree of energy matching between the triplet excited level of the ligand and the resonant level of Tb(III) ions. Based on the analysis of three-dimensional luminescence spectra, the as-prepared Tb(III) complex can be effectively excited in the range of 250-310nm, and it shows high color purity, with a bright green appearance.