Perspectives on the Novel Multifunctional Nerve Guidance Conduits: From Specific Regenerative Procedures to Motor Function Rebuilding.

Peripheral nerve injury potentially destroys the quality of life by inducing functional movement disorders and sensory capacity loss, which results in severe disability and substantial psychological, social, and financial burdens. Autologous nerve grafting has been commonly used as treatment in the clinic; however, its rare donor availability limits its application. A series of artificial nerve guidance conduits (NGCs) with advanced architectures are also proposed to promote injured peripheral nerve regeneration, which is a complicated process from axon sprouting to targeted muscle reinnervation. Therefore, exploring the interactions between sophisticated NGC complexes and versatile cells during each process including axon sprouting, Schwann cell dedifferentiation, nerve myelination, and muscle reinnervation is necessary. This review highlights the contribution of functional NGCs and the influence of microscale biomaterial architecture on biological processes of nerve repair. Progressive NGCs with chemical molecule induction, heterogenous topographical morphology, electroactive, anisotropic assembly microstructure, and self-powered electroactive and magnetic-sensitive NGCs are also collected, and they are expected to be pioneering features in future multifunctional and effective NGCs.

Osteopontin modulates microglial activation states and attenuates inflammatory responses after subarachnoid hemorrhage in rats.

AIMS: Osteopontin (OPN) has demonstrated neuroprotective effects in various stroke models. Its role in neuroinflammation after brain injury remains to be elucidated. This study aims to clarify the effect of OPN on neuroinflammation, particularly on the functional states of microglia after subarachnoid hemorrhage (SAH). METHODS: 77 rats were randomly divided into the following groups: Sham, SAH 24 h, SAH + rOPN, SAH + Vehicle (PBS), SAH + OPN siRNA, and SAH + Scr siRNA, SAH + rOPN+Fib-14 and SAH + rOPN+DMSO. Modified Garcia and beam balance tests were used to evaluate neurobehavioral outcomes. Semi-quantitative immunofluorescence staining was performed to measure expression of myeloperoxidase (MPO) and microglia activation state markers CD16, CD206 after SAH and recombinant OPN treatment. The quantification of microglia activation and functional markers CD16, CD206, TNF-α and IL-10 were further evaluated using Western-blotting. RESULTS: Nasal administration of rOPN improved neurological dysfunction, attenuated neutrophil infiltration, and decreased expression of phenotypic and functional markers of pro-inflammatory microglia CD16 and TNF-α. It also promoted an anti-inflammatory microglial state, as evidenced by increased expression of CD206 and IL-10. Furthermore, after blocking the phosphorylation of FAK signaling, the effects of rOPN on microglial activation states were partially reversed. The downstream pathways of STAT3 and NF-κB also exhibited consistent changes, suggesting the involvement of the STAT3 and NF-κB pathways in OPN's modulation of microglial activation via integrin-FAK signaling. CONCLUSION: OPN attenuates inflammatory responses after SAH by promoting an anti-inflammatory microglial state, potentially mediated through the integrin-FAK-STAT3 and NF-κB signaling pathways.

Dual drug-loaded PLGA fibrous scaffolds for effective treatment of breast cancer in situ.

Advanced metastatic breast cancer remains nearly an incurable disease. In situ therapy may help patients with worse prognoses have better clinical outcomes by significantly reducing systematic toxicity. Dural-drug fibrous scaffold was created and assessed using an in-situ therapeutic strategy, simulating the preferred regimens advised by the National Comprehensive Cancer Network. DOX, a once-used chemotherapy drug is embedded into scaffolds and produces a fast release for two cycles to kill tumor cells. PTX, a hydrophobic drug is continuously injected and produces a gradual release for up to two cycles to treat long cycles. Chosen drug loading system and the designated fabrication parameter controlled the releasing profile. Drug carrier system complied with the clinical regimen. It demonstrated both in vitro and in vivo anti-proliferative effects on the breast cancer model. The dosage of an intratumoral injection to drug capsules, the local tissue toxicity could be significantly reduced. To optimized intravenous injection with dual drugs, fewer side effects and a higher survival rate were seen even in the large tumor model (450-550 mm3). Drug delivery system makes the precise accumulation of the topical drug concentration possible, simulating clinically successful therapy and possibly offering better clinical treatment options for solid tumors.

Pre-Induced ICD Membrane-Coated Carrier-Free Nanoparticles for the Personalized Lung Cancer Immunotherapy.

Immunotherapy is a required adjuvant method in lung cancer therapy clinically. The single immune adjuvant failed to show the expected clinical therapeutic efficacy due to its rapid drug metabolism and inability to accumulate in the tumor site efficiently. Immunogenic cell death (ICD) is a new anti-tumor strategy combined with immune adjuvants. It can provide tumor-associated antigens, activate dendritic cells, and attract lymphoid T cells into the tumor microenvironment. Here doxorubicin-induced tumor membrane-coated iron (II)-cytosine-phosphate-guanine nanoparticles (DM@NPs) are shown for efficient co-delivery of tumor-associated antigens and adjuvant. Higher expression of ICD-related membrane proteins on the surface of the DM@NPs leads to the enhanced uptake of DM@NPs by dendritic cells (DCs), thereby promoting the DCs maturation and pro-inflammatory cytokines release. DM@NPs can remarkably increase the T cell infiltrations, remodel the tumor immune microenvironment and inhibit tumor progression in vivo. These findings reveal that pre-induced ICD tumor cell membrane-encapsulated nanoparticles can enhance immunotherapy responses and provide an effective biomimetic nanomaterial-based therapeutic strategy for lung cancer.

EGCG protects cardiomyocytes against hypoxia-reperfusion injury through inhibition of OMA1 activation.

Mitochondria are important for energy production and cardiomyocyte homeostasis. OMA1, a metalloendopeptidase, initiates the proteolytic process of the fusion-allowing protein OPA1, to deteriorate mitochondrial structure and function. In this study, mouse embryonic fibroblasts (MEFs) and neonatal mouse cardiomyocytes (NMCMs) subjected to hypoxia-reperfusion injury (HRI) and/or H2O2 were used to mimic oxidative stress in the heart following ischemia-reperfusion injury (IRI). In vitro experiments demonstrated that HRI or stimulation with H2O2 induced self-cleavage of OMA1 and the subsequent conversion of OPA1 from its long form to its short form, leading to mitochondrial fragmentation, cytochrome c release and apoptosis. By using Molecular Operating Environment (MOE) software to simulate the binding interaction of 2295 phytochemicals against OMA1, epigallocatechin gallate (EGCG) and betanin were selected as candidates of OMA1 inhibitor. We found that EGCG directly interacted with OMA1 and potently inhibited self-cleavage of OMA1, leading to attenuated OPA1 cleavage. This study, therefore, suggests to use OMA1 inhibition induced by EGCG to treat cardiac IRI.

Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario.

Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies.

Mesoporous nano-bioglass designed for the release of imatinib and in vitro inhibitory effects on cancer cells.

For treating bone cancer, controlled drug delivery is an important strategy. Bioactive scaffolds are widely used biomaterials due to their usefulness in localized drug delivery. The aim of this study was to develop mesoporous bioglass (MBG) with improved bioactivity and controllable drug delivery rate. By using pluronic 123 (P123) as a template, a facile sol-gel route was employed for the synthesis of MBG nanoparticles (NPs). The composition of the prepared sample was estimated by using energy dispersive X-ray spectroscopy (EDX). These nanoparticles demonstrated the specific surface area of 310m2/g and pore size of 13nm as measured by brunauer-emmett-teller (BET) and barrett-joyner-halenda (BJH) method, respectively. The spherical shape of NPs was confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Imatinib (IMT); an anti-cancer drug was loaded with the efficiency of 77.59%. The drug release kinetics were precisely controlled by changing the pH (4.4 to 10.4) as well as drug loading concentration (0.2-1.0mg/mL). The maximum cumulative drug release of 81% was observed over a time period of 250h at pH of 4.4. Importantly, significant inhibitory effects on the viability of the MG-63 osteocarcinoma cancer cells at 12.19µg/mL of IMT-MBG were observed. Furthermore, MBG demonstrated ionic dissolution with the release of Ca, K, Si, Na, and P ions upon immersion in simulated body fluid (SBF), which support the formation of hydroxycarbonate apatite (HCA), as confirmed by wide-angle X-ray diffraction (WAXD) pattern and fourier transform infrared (FTIR) spectroscopy. These features proved that IMT-MBG system is effective for bone tissue regeneration and bone cancer treatment.

Potassium-doped mesoporous bioactive glass: Synthesis, characterization and evaluation of biomedical properties.

A bifunctional mesoporous bioactive glass (MBG) with composition (49SiO2·20CaO·20Na2O·7K2O·4P2O5 mol%) was synthesized by a facile sol-gel method, using polyethylene glycol (PEG 6000) as a soft template. The structure, morphology (spherical with approximate size 1µm) and composition of MBG were determined by fourier transform infrared spectroscopy, the scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX), respectively. The surface area (189.53m2g-1 with the pore size of 21nm) of MBG was measured by Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH) analysis. The formation of hydroxyapatite (HAp) layer on the glass surface upon immersion in simulated body fluid (SBF) was monitored through X-ray diffraction (XRD) which indicates enhanced bioactivity as compared to previous studies. The animals study, protein adsorption ability, and cytotoxicity investigations show no tissue damage, good biomedical properties and no encumbrance with cell cycle (even at a concentration of 80µg/mL). Moreover, the cell proliferation analysis reveals the non-toxic property of MBG at a concentration of 20µg/mL. Notably, a cumulative drug (ciprofloxacin, an antibiotic) release of 75% was observed for first 48h and the further release of 90% was observed over a period of two weeks. The synthesized MBG also shows osteoblast activity and bone mineralization as revealed by alkaline phosphatase activity (ALP) and osteocalcin formation.