M2 macrophage-derived exosome-functionalized topological scaffolds regulate the foreign body response and the coupling of angio/osteoclasto/osteogenesis.

Designing scaffolds that can regulate the innate immune response and promote vascularized bone regeneration holds promise for bone tissue engineering. Herein, electrospun scaffolds that combined physical and biological cues were fabricated by anchoring reparative M2 macrophage-derived exosomes onto topological pore structured nanofibrous scaffolds. The topological pore structure of the fiber and the immobilization of exosomes increased the nanoscale roughness and hydrophilicity of the fibrous scaffold. In vitro cell experiments showed that exosomes could be internalized by target cells to promote cell migration, tube formation, osteogenic differentiation, and anti-inflammatory macrophage polarization. The activation of fibrosis, angiogenesis, and macrophage was elucidated during the exosome-functionalized fibrous scaffold-mediated foreign body response (FBR) in subcutaneous implantation in mice. The exosome-functionalized nanofibrous scaffolds also enhanced vascularized bone formation in a critical-sized rat cranial bone defect model. Importantly, histological analysis revealed that the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation. This study elaborated on the complex processes within the cell microenvironment niche during fibrous scaffold-mediated FBR and vascularized bone regeneration to guide the design of implants or devices used in orthopedics and maxillofacial surgery. STATEMENT OF SIGNIFICANCE: How to design scaffold materials that can regulate the local immune niche and truly achieve functional vascularized bone regeneration still remain an open question. Here, combining physical and biological cues, we proposed new insight to cell-free and growth factor-free therapy, anchoring reparative M2 macrophage-derived exosomes onto topological pore structured nanofibrous scaffolds. The exosomes functionalized-scaffold system mitigated foreign body response, including excessive fibrosis, tumor-like vascularization, and macrophage activation. Importantly, the biofunctional scaffolds regulated the coupling effect of angiogenesis, osteoclastogenesis, and osteogenesis by stimulating type H vessel formation.

Plant-Derived Polyphenol and LL-37 Peptide-Modified Nanofibrous Scaffolds for Promotion of Antibacterial Activity, Anti-Inflammation, and Type-H Vascularized Bone Regeneration.

The regeneration of oral tissues is a challenging clinical problem because of the complex microbial and biological stress environments. Electrospun fibrous scaffolds have attracted significant interest as effective barrier membranes for guided bone regeneration (GBR); however, no mature strategy yet exists for the surface modification of fibers to provide versatility to satisfy clinical requirements. This study demonstrated a practical biosafety strategy: the combined use of plant polyphenols and LL-37 peptides to modify the fiber surface to endow the fibrous scaffold with antimicrobial activity, immunoregulation, and vascularized bone regeneration. We confirmed that the LL-37 peptides interacted with tannic acid (TA) through noncovalent bonds through experiments and molecular docking simulation analysis. In vitro experiments showed that the TA coating imparted strong antibacterial properties to the fibrous scaffold, but it also caused cytotoxicity. The grafting of LL-37 peptide promoted the spreading, migration, and osteogenic differentiation of mesenchymal stem cells and was also conducive to the M2 polarization of RAW264.7 cells. In vivo experiments further verified that the LL-37 peptide-grafted fibrous scaffold significantly enhanced angiogenesis, anti-inflammatory effects, and type-H vascularized bone regeneration. Overall, the fibrous scaffold modified by the LL-37 peptide through TA grafting has significant potential for GBR applications.

Fish Collagen and Hydroxyapatite Reinforced Poly(lactide- co-glycolide) Fibrous Membrane for Guided Bone Regeneration.

The purpose of this study was to fabricate a low-immunogenicity fish collagen (FC) and bioactive nanohydroxyapatite (n-HA) enhanced poly(lactide- co-glycolide) (PLGA) nanofibrous membrane for guided bone regeneration (GBR) via electrospinning. The physicochemical properties and morphology study revealed that FC and n-HA particles were homogeneously dispersed in the PLGA fibrous matrix. Notably, the formation of enhanced polymeric chain network due to the interaction between FC and PLGA significantly improved the tensile strength of the PLGA membrane. The incorporation of FC altered the degradation behavior of fibers and accelerated the degradation rate of the PLGA-based membranes. Moreover, the membranes exhibited favorable cytocompatibility with bone mesenchymal stem cells (BMSCs) and human gingiva fibroblasts (HGF) cells. More importantly, the optimized membrane satisfied the requirements of the 'Biological evaluation of medical devices' during the incipient biosafety evaluation. All the results indicate that this composite fibrous membrane exhibits significant potential for guided bone or tissue regeneration.

Development of biomimetic trilayer fibrous membranes for guided bone regeneration.

in order to build fibrous bone tissue scaffolds for guided bone regeneration and to mimic the trilayer structure and the multifunctional properties of the natural periosteum, we fabricated two fibrous trilayer membranes by conjugate electrospinning technology, in which poly(ε-caprolactone) (PCL) fiber was designed as an outer layer, the mixed fibers of PCL and polyurethane (co-PUPCL) as the interlayer, and degradable polyurethane fibers with or without nano-hydroxyapatite (n-HA) as the inner layer (PUHA or PU). The microstructure and characteristics of the trilayer membranes were evaluated and different monolayer fibers were fabricated as the contrast samples. The tensile strength values of each layer increased from the inner layer to the outer layer in the designed structure, while the step-by-step electrospinning method produced good adhesion of different layers. Furthermore, the degradable properties and hydrophilicity of the layers changed with dissymmetric fibrous structures. Cell proliferation assay and cell morphology observation indicated that the PUHA inner fibrous layer exhibited better cell attachment and proliferation than PU. In addition, the osteogenicity of the PUHA fibrous layer has been attested through protein expression by the differentiation of rat mesenchymal stem cells (rMSCs) into the osteogenic lineage. Cell infiltration testing on the two sides of the trilayer membranes in vitro and in vivo showed that the inner layer had good cellular penetration deep into the scaffolds, whereas the cells were barred by the outer layer. We have developed a trilayer structured membrane with different polymer fibers to replicate the natural periosteum by improving functional outcomes, which is a promising fibrous scaffold for clinical use in the repair of destroyed bone.

Electrospun silver ion-loaded calcium phosphate/chitosan antibacterial composite fibrous membranes for guided bone regeneration.

PURPOSE: The purpose of this study is to construct a guided bone regeneration membrane that is similar to bone components and structurally resembles the native extracellular matrix with sufficient antibacterial properties. MATERIALS AND METHODS: A novel type of biomimetic and bioactive silver ion-loaded calcium phosphate/chitosan (Ag-CaP/CS) membrane with antibacterial ability was successfully developed by incorporation of silver ion-loaded CaP via a one-step electrospinning method and subsequently crosslinked with vanillin. RESULTS: Evaluation of the physicochemical properties revealed that the fabricated fibrous membranes mimicked the extracellular matrix structure and the addition of CaP significantly increased the mineralization ability of the membranes. Importantly, the Ag-CaP/CS membranes exhibited a sustainable release of Ag+, which in turn inhibited the adhesion and growth of Staphylococcus mutans. The results of cell adhesion and MTT assay revealed that the Ag-CaP/CS membranes were cytocompatible with bone marrow stromal cells. CONCLUSION: The fabricated electrospinning Ag-CaP/CS nanofiber membranes with excellent biocompatibility and strong antimicrobial properties have great potential to be used for guided bone regeneration.

High incidence of JC viruria in JC-seropositive older individuals.

The prevalence of the human JC virus (JCV) in the general population at various ages was investigated. Polymerase chain reaction was employed to detect viral DNA in the urine. The results showed that the incidence of JC viruria was low in the young population, but it was high in the elderly. Hemagglutination inhibition assay was performed for JCV seroprevalence study. The results showed that the seropositive rate of JCV was lower in children than that in adults. The ratio of viruria to seropositive for JCV increased with age and reached 79.7% for those older than 70 years. The results indicated that aging immunity may correlate with JCV reactivation.