3D printing of Ceffe-infused scaffolds for tailored nipple-like cartilage development.

The reconstruction of a stable, nipple-shaped cartilage graft that precisely matches the natural nipple in shape and size on the contralateral side is a clinical challenge. While 3D printing technology can efficiently and accurately manufacture customized complex structures, it faces limitations due to inadequate blood supply, which hampers the stability of nipple-shaped cartilage grafts produced using this technology. To address this issue, we employed a biodegradable biomaterial, Poly(lactic-co-glycolic acid) (PLGA), loaded with Cell-Free Fat Extract (Ceffe). Ceffe has demonstrated the ability to promote angiogenesis and cell proliferation, making it an ideal bio-ink for bioprinting precise nipple-shaped cartilage grafts. We utilized the Ceffe/PLGA scaffold to create a porous structure with a precise nipple shape. This scaffold exhibited favorable porosity and pore size, ensuring stable shape maintenance and satisfactory biomechanical properties. Importantly, it could release Ceffe in a sustained manner. Our in vitro results confirmed the scaffold's good biocompatibility and its ability to promote angiogenesis, as evidenced by supporting chondrocyte proliferation and endothelial cell migration and tube formation. Furthermore, after 8 weeks of in vivo culture, the Ceffe/PLGA scaffold seeded with chondrocytes regenerated into a cartilage support structure with a precise nipple shape. Compared to the pure PLGA group, the Ceffe/PLGA scaffold showed remarkable vascular formation, highlighting the beneficial effects of Ceffe. These findings suggest that our designed Ceffe/PLGA scaffold with a nipple shape represents a promising strategy for precise nipple-shaped cartilage regeneration, laying a foundation for subsequent nipple reconstruction.

Temporal control in shell-core structured nanofilm for tracheal cartilage regeneration: synergistic optimization of anti-inflammation and chondrogenesis.

Cartilage tissue engineering offers hope for tracheal cartilage defect repair. Establishing an anti-inflammatory microenvironment stands as a prerequisite for successful tracheal cartilage restoration, especially in immunocompetent animals. Hence, scaffolds inducing an anti-inflammatory response before chondrogenesis are crucial for effectively addressing tracheal cartilage defects. Herein, we develop a shell-core structured PLGA@ICA-GT@KGN nanofilm using poly(lactic-co-glycolic acid) (PLGA) and icariin (ICA, an anti-inflammatory drug) as the shell layer and gelatin (GT) and kartogenin (KGN, a chondrogenic factor) as the core via coaxial electrospinning technology. The resultant PLGA@ICA-GT@KGN nanofilm exhibited a characteristic fibrous structure and demonstrated high biocompatibility. Notably, it showcased sustained release characteristics, releasing ICA within the initial 0 to 15 days and gradually releasing KGN between 11 and 29 days. Subsequent in vitro analysis revealed the potent anti-inflammatory capabilities of the released ICA from the shell layer, while the KGN released from the core layer effectively induced chondrogenic differentiation of bone marrow stem cells (BMSCs). Following this, the synthesized PLGA@ICA-GT@KGN nanofilms were loaded with BMSCs and stacked layer by layer, adhering to a 'sandwich model' to form a composite sandwich construct. This construct was then utilized to repair circular tracheal defects in a rabbit model. The sequential release of ICA and KGN facilitated by the PLGA@ICA-GT@KGN nanofilm established an anti-inflammatory microenvironment before initiating chondrogenic induction, leading to effective tracheal cartilage restoration. This study underscores the significance of shell-core structured nanofilms in temporally regulating anti-inflammation and chondrogenesis. This approach offers a novel perspective for addressing tracheal cartilage defects, potentially revolutionizing their treatment methodologies.

Enhancing long-segmental tracheal restoration: A self-repairing hydrogel loaded with chondrocytokines for sutureless anastomosis and cartilage regeneration.

Artificial tracheal substitutes encounter significant challenges during long-segmental tracheal defects (LSTD) reconstruction, notably early postoperative anastomotic stenosis and tracheal chondromalacia. Mitigating early anastomotic stenosis by creating a compliant sutureless substitute is pivotal. Enhancing its chondrogenic capacity is equally critical for sustained healthy tracheal cartilage regeneration. This study proposes a self-healing hydrogel for sutureless tracheal anastomosis to mitigate anastomotic stenosis, enriched with kartogenin (KGN) and transforming growth factor-ß1 (TGFß1) to bolster chondrogenic properties. Initially, two precursor solutions were prepared: 1) aldehyde-modified hyaluronic acid with sulfonation and ß-cyclodextrin-CHO loaded with KGN; 2) hydrazide-grafted gelatin loaded with TGFß1. Coextrusion of these solutions resulted in a gelated G + TGFß1/sH-CD + KGN hydrogel, characterized by a robust covalent bonding network of acylhydrazones between hydrazide and aldehyde groups, imparting excellent self-healing properties. The G + TGFß1/sH-CD + KGN hydrogels, showcasing favorable cytocompatibility, excellent injectability, and rapid gelation, were loaded with bone marrow stem cells. These were customized into O-shaped rings and assembled into a malleable tracheal substitute using our established ring-to-tube method. This resultant compliant substitute facilitated sutureless anastomosis of LSTD in a rabbit model, attributed to the Schiff base reaction between the hydrogel's carbonyl group and the tissue's amino group. Notably, the tracheal substitute reduced early postoperative anastomotic stenosis, maintained tracheal patency, alleviated sputum blockage, promoted reepithelization, and increased the survival rate of the experimental rabbits. The sustained release of chondrocytokines resulted in excellent tracheal cartilage regeneration. Employing chondrocytokines-loaded hydrogels with self-healing properties represents a significant advancement in sutureless tracheal anastomosis and tracheal cartilage regeneration, holding promising potential in inhibiting early postoperative anastomotic stenosis and tracheal chondromalacia when treating LSTD.

The Development of Immunotherapy for the Treatment of Recurrent Glioblastoma.

Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neuro-oncology, and the survival status of patients after relapse usually means rapid deterioration, thus becoming the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulating the body's immune system to recognize and attack cancer cells, which could be used in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma. This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and especially focus on rGBM.

Frontiers of Hydroxyapatite Composites in Bionic Bone Tissue Engineering.

Bone defects caused by various factors may cause morphological and functional disorders that can seriously affect patient's quality of life. Autologous bone grafting is morbid, involves numerous complications, and provides limited volume at donor site. Hence, tissue-engineered bone is a better alternative for repair of bone defects and for promoting a patient's functional recovery. Besides good biocompatibility, scaffolding materials represented by hydroxyapatite (HA) composites in tissue-engineered bone also have strong ability to guide bone regeneration. The development of manufacturing technology and advances in material science have made HA composite scaffolding more closely related to the composition and mechanical properties of natural bone. The surface morphology and pore diameter of the scaffold material are more important for cell proliferation, differentiation, and nutrient exchange. The degradation rate of the composite scaffold should match the rate of osteogenesis, and the loading of cells/cytokine is beneficial to promote the formation of new bone. In conclusion, there is no doubt that a breakthrough has been made in composition, mechanical properties, and degradation of HA composites. Biomimetic tissue-engineered bone based on vascularization and innervation show a promising future.

[Preparation and properties of fiber-based conductive composite scaffolds for peripheral nerve regeneration].

Objective: To explore the preparation method, physical and chemical properties, and biocompatibility of a conductive composite scaffold based on polypyrrole/silk fibroin (PPy/SF) fiber with "shell-core" structure, and to provide a preliminary research basis for the application in the field of tissue engineered neuroscience. Methods: The conductive fibers with "shell-core" structure were prepared by three-dimensional printing combined with in-situ polymerization. PPy/SF fiber-based conductive composite scaffolds were formed by electrospinning. In addition, core-free PPy conductive fibers and SF electrospinning fibers were prepared. The stability, biomechanics, electrical conductivity, degradation performance, and biological activity of each material were tested to analyze the comprehensive properties of fiber-based conductive composite scaffolds. Results: Compared with pure core-free PPy conductive fibers and SF electrospinning fibers, the PPy/SF fiber-based conductive composite scaffolds with "shell-core" structure could better maintain the stability performance, enhance the mechanical stretchability of the composite scaffolds, maintain long-term electrical activity, and improve the anti-degradation performance. At the same time, PPy/SF conductive composite scaffolds were suitable for NIH3T3 cells attachment, conducive to cell proliferation, and had good biological activity. Conclusion: PPy/SF fiber-based conductive composite scaffolds meet the needs of conductivity, stability, and biological activity of artificial nerve grafts, and provide a new idea for the development of a new generation of high-performance and multi-functional composite materials.

Expression of neuropeptide Y is increased in an activated human HSC cell line.

Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian central and peripheral nervous systems. Transgenic mice overexpressing NPY in noradrenergic neurons have increased level of hepatic triglycerides, fatty acids and cholesterol, which contributed to the development of hepatosteatosis. However, the roles of NPY in the activation of hepatic stellate cells (HSCs) and the underlying mechanisms remain unclear. This study aimed to investigate the expression and secretion of NPY in human immortalized HSC LX-2 cells and the regulatory function of NPY on the fibrogenic response in LX-2 cells, to explore the potential association between NPY and LX-2 activation. The results showed an increase in the expression and secretion of NPY(1-36) in activated LX-2 cells. Both endogenous and exogenous NPY(1-36) induced the phosphorylation of mTOR, p70S6K, and 4EBP1 and promoted the fibrogenic response via NPY Y1 receptor subtype (NPY1R), as these responses were blocked by either an NPY1R antagonist (BIBP3226) or NPY1R knockdown. Moreover, NPY(1-36) serum levels were increased in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) and presented a positive relationship with MELD scores in LC patients. These findings suggest that immortalized HSCs LX-2 have the potential to produce NPY(1-36). High serum levels of NPY(1-36) is correlated with hepatic dysfunction in cirrhotic patients.

Sirt1 enhances tau exon 10 inclusion and improves spatial memory of Htau mice.

Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule binding repeats, named 3R-tau and 4R-tau, respectively. Dysregulation of tau exon 10 splicing could cause neurofibrillary degeneration. Acetylation is one of the major post-translational protein modifications in the cell by attachment of the acetyl group to either the α-amino group of the N-terminus of proteins or to the ε-amino group of lysine residues. Sirt1, one member in mammalian Sirtuin family, deacetylates protein and is associated closely with age-related diseases including Alzheimer's disease. However, the role of Sirt1 in tau exon 10 splicing remains elusive. In the present study, we determined the role of Sirt1 in tau exon 10 splicing. We found that activation of Sirt1 by resveratrol enhanced tau exon 10 inclusion, leading to 4R-tau expression. Sirt1 interacted with splicing factor 9G8, deacetylated it at Lys24, and suppressed its function in promoting tau exon 10 exclusion. Moreover, resveratrol improved learning and spatial memory in Htau mice. These findings suggest that Sirt1 may serve as a new drug target for Alzheimer's Disease related tauopathies and resveratrol may be used to correct dysregulated tau exon 10 with 3R-tau > 4R-tau.