Poly ß-Cyclodextrin/Quaternary Ammoniated Chitosan Cryogel with a Porous Structure for Effective Hemostasis.

Uncontrolled bleeding is one of the most important causes threatening human health, but quick hemostasis remains a challenge. We prepared porous cryogels with poly ß-cyclodextrin (Pß-CD) and quaternary ammoniated chitosan (QCs). Pß-CD acts as a "water-grabbing agent" to assist QCs' ability to absorb and concentrate blood rapidly. The rat-tail amputation model and liver injury model exhibited that cryogels had excellent hemostatic performance. Moreover, cryogels showed good antibacterial activity and biocompatibility. Therefore, these cryogels can be used as potential hemostatic materials.

Bioinspired Ultra Tear-Resistant Elastomer with a Slidable Double-Network Structure.

Tear resistance is of vital importance in the fabrication and application of synthetic soft materials. However, the paradox of simultaneously improving the tearing energy and elasticity remains a huge challenge for conventional approaches. Here, inspired by the skin, we successfully constructed an extraordinary tear-resistant, superelastic elastomer by the introduction of nanosized polycyclodextrin into the elastomer network to form a slidable interpenetrate double network structure. The tearing energy of the SDEP elastomer is up to 274 KJ/m2, which is comparable to metals and alloys and increased more than 100 times compared with the chemically cross-linked elastomer. The fracture strain exceeded 3300%, which is hardly achieved by other materials with high tearing energy. This comprehensive improvement of antitearing and super elasticity property was achieved by (i) a slide ring effect to dissipate energy and blunt a crack tip; (ii) straightening and reorientation of the slidable double network to deflect the advancing of a crack tip; (iii) a double network sharing the load. These results provide a novel strategy to fabricate elastic, tear-resistant soft material, which may contribute to the practical application as tear-resistant flexible electronics and irregular-shaped stretchable devices.

Exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation after traumatic brain injury.

Exosomes derived from bone marrow mesenchymal stem cells can inhibit neuroinflammation through regulating microglial phenotypes and promoting nerve injury repair. However, the underlying molecular mechanism remains unclear. In this study, we investigated the mechanism by which exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation. Our in vitro co-culture experiments showed that bone marrow mesenchymal stem cells and their exosomes promoted the polarization of activated BV2 microglia to their anti-inflammatory phenotype, inhibited the expression of proinflammatory cytokines, and increased the expression of anti-inflammatory cytokines. Our in vivo experiments showed that tail vein injection of exosomes reduced cell apoptosis in cortical tissue of mouse models of traumatic brain injury, inhibited neuroinflammation, and promoted the transformation of microglia to the anti-inflammatory phenotype. We screened some microRNAs related to neuroinflammation using microRNA sequencing and found that microRNA-181b seemed to be actively involved in the process. Finally, we regulated the expression of miR181b in the brain tissue of mouse models of traumatic brain injury using lentiviral transfection. We found that miR181b overexpression effectively reduced apoptosis and neuroinflamatory response after traumatic brain injury and promoted the transformation of microglia to the anti-inflammatory phenotype. The interleukin 10/STAT3 pathway was activated during this process. These findings suggest that the inhibitory effects of exosomes derived from bone marrow mesenchymal stem cells on neuroinflamation after traumatic brain injury may be realized by the action of miR181b on the interleukin 10/STAT3 pathway.

Green Synthesis of Indeno[1,2-b]quinoxalines Using ß-Cyclodextrin as Catalyst.

An efficient, mild, and green method was developed for the synthesis of indeno[1,2-b]quinoxaline derivatives via o-phenylenediamine (OPD) and 2-indanone derivatives utilizing ß-cyclodextrin (ß-CD) as the supramolecular catalyst. The reaction can be carried out in water and in a solid state at room temperature. ß-CD can also catalyze the reaction of indan-1,2-dione with OPD with a high degree of efficiency. Compared to the reported methods, this procedure is milder, simpler, and less toxic, making it an eco-friendly alternative. In addition, the ß-CD can be recovered and reused without the loss of activity.

Recent Advances of Porous Materials Based on Cyclodextrin.

Porous materials have attracted significant attention because of their rising applications in many fields. Cyclodextrins (CDs) are suitable building units in the fabrication of porous materials owing to their intrinsic nanoporous structure, easy modification, and biocompatibility, which may result in the formation of CD-based organic frameworks (including cyclodextrin metal-organic frameworks (CD-MOFs) and cyclodextrin covalent organic frameworks (CD-COFs)), and CD-based polymer hybrid porous materials. This review focuses on the recent progress in the fabrication and applications of CD-based porous materials with novel structures and functionalities.

Apolipoprotein E, low-density lipoprotein receptor, and immune cells control blood-brain barrier penetration by AAV-PHP.eB in mice.

Rationale: The blood-brain barrier (BBB) prevents the effective delivery of therapeutic molecules to the central nervous system (CNS). A recently generated adeno-associated virus (AAV)-based vector, AAV-PHP.eB, has been found to penetrate the BBB more efficiently than other vectors including AAV-PHP.B. However, little is known about the mechanisms. In this study, we investigated how AAV-PHP.eB penetrates the BBB in mice. Methods: We injected AAV-PHP.eB into the bloodstream of wild-type C57BL/6 and BALB/c mice as well as mouse strains carrying genetic mutation in apolipoprotein E gene (Apoe) or low-density lipoprotein receptor gene (Ldlr), or lacking various components of the immune system. Then, we evaluated AAV-PHP.eB transduction to the brain and spinal cord in these mice. Results: We found that the transduction to the CNS of intravenous AAV-PHP.eB was more efficient in C57BL/6 than BALB/c mice, and significantly reduced in Apoe or Ldlr knockout C57BL/6 mice compared to wild-type C57BL/6 mice. Moreover, poor CNS transduction in BALB/c mice was dramatically increased by B-cell or natural killer-cell depletion. Conclusions: Our findings demonstrate that the ApoE-LDLR pathway underlies the CNS tropism of AAV-PHP.eB and that the immune system contributes to the strain specificity of AAV-PHP.eB.

Intracranial Pressure during External Ventricular Drainage Weaning Is an Outcome Predictor of Traumatic Brain Injury.

External ventricular drainage (EVD) is widely used in patients with a traumatic brain injury (TBI). However, the EVD weaning trial protocol varies and insufficient studies focus on the intracranial pressure (ICP) during the weaning trial. We aimed to establish the relationship between ICP during an EVD weaning trial and the outcomes of TBI. We enrolled 37 patients with a TBI with an EVD from July 2018 to September 2019. Among them, 26 were allocated to the favorable outcome group and 11 to the unfavorable outcome group (death, post-traumatic hydrocephalus, persistent vegetative state, and severe disability). Groups were well matched for sex, pupil reactivity, admission Glasgow Coma Scale score, Marshall computed tomography score, modified Fisher score, intraventricular hemorrhage, EVD days, cerebrospinal fluid output before the weaning trial, and the complications. Before and during the weaning trial, we recorded the ICP at 1-hour intervals to calculate the mean ICP, delta ICP, and ICP burden, which was defined as the area under the ICP curve. There were significant between-group differences in the age, surgery types, and intensive care unit days (p = 0.045, p = 0.028, and p = 0.004, respectively). During the weaning trial, 28 (75.7%) patients had an increased ICP. Although there was no significant difference in the mean ICP before and during the weaning trial, the delta ICP was higher in the unfavorable outcome group (p = 0.001). Moreover, patients who experienced death and hydrocephalus had a higher ICP burden, which was above 20 mmHg (p = 0.016). Receiver operating characteristic analyses demonstrated the predictive ability of these variables (area under the curve [AUC] = 0.818 [p = 0.002] for delta ICP and AUC = 0.758 [p = 0.038] for ICP burden > 20 mmHg). ICP elevation is common during EVD weaning trials in patients with TBI. ICP-related parameters, including delta ICP and ICP burden, are significant outcome predictors. There is a need for larger prospective studies to further explore the relationship between ICP during EVD weaning trials and TBI outcomes.

Super-fast degradation of high concentration methyl orange over bifunctional catalyst Fe/Fe3C@C with microwave irradiation.

Bifunctional catalyst Fe/Fe3C@C with magnetism was successfully prepared by sol-gel method and proved to degrade methyl orange with high efficiency under microwave irradiation. The Fe/Fe3C@C catalysts calcined at 500 °C, 600 °C, 700 °C were intensively characterized and compared in their crystalline structure, porosity, morphology and dielectric property. The results imply a phase and structure transformation in the materials as the calcination temperature increased. Fe/Fe3C@C-700 exhibited a core-shell structure and an apparent Fe3C phase. In addition, Fe/Fe3C@C-700 demonstrated excellent dielectric property as a microwave absorber than Fe/Fe3C@C-500 and Fe/Fe3C@C-600. At the same time, it gave a 100 % removal rate in 30 s for the degradation of methyl orange under microwave irradiation, outperformed the Fe/Fe3C@C-500 and Fe/Fe3C@C-600 and most other reported catalysts in similar studies. The possible mechanism of the methyl orange degradation should be ascribed to the in situ generation of •OH and O2•- active species over the Fe/Fe3C@C catalyst. The excellent microwave absorbing property of Fe/Fe3C@C-700 could also boost its catalytic activity and play a critical role during the super-fast microwave-assisted degradation process. The findings in this study could be informative for the development of a continuous process of dye wastewater treatment for industrial implementation.

Tough Self-Healing Elastomers Based on the Host-Guest Interaction of Polycyclodextrin.

Inspired by animal muscles, we developed a kind of tough elastomers combining high strength and high stretchability with autonomous self-healing capability. A key structural feature is the construction of a double network (DN) connected by the hydrogen bond and host-guest interactions. The first network is the classic elastomer polyacrylate matrix cross-linked by strong hydrogen bonding. The second network is formed through the host-guest interactions between polycyclodextrin and the adamantane (Ad) groups on the side of the polyacrylate chain. Supramolecular interactions between two networks make them miscible and interpenetrate in the molecular level and then can share the load as the sample was stretched. The host-guest interactions act not only as sacrificial bonds for energy dissipation but also as self-healing driving forces. The tensile strength of the DN elastomer reaches about 6.7 MPa and the strain is as high as about 950%. The DN elastomer can be easy to repair by touching the damaged surface together at ambient conditions when broken or cut. The recovered tensile strength can reach over 4.5 MPa, which is better than the most pristine strength of existing spontaneous self-healing elastomers.

Traumatic brain injury in China.

China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100 000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.

Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice.

AIMS: Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. METHODS: After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro-Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin-1(fer-1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long-term outcomes. RESULTS: TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis-related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid-reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer-1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long-term motor and cognitive function. CONCLUSION: This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

Effects of Brain Temperature on the Outcome of Patients with Traumatic Brain Injury: A Prospective Observational Study.

A prospective observational study collected temperature data from 51 patients in 11 neurosurgical centers and follow-up outcome information at 6 months in 49 patients. Brain temperature (Tbr) was measured directly by an intraventricular temperature sensor. Axillary temperature (Tax) and rectal temperature (Tre) were measured by electric thermometers. Tbr was 0.4 to 1.5°C higher than body temperature. Tre correlated well with the Tbr (coefficient: 0.7378; p < 0.05). Among all patients, Glasgow Coma Scale (GCS) scores on admission were significantly lower in the patients with post-operatively extreme peak temperature (Tpeak, < 37°C or >39°C in first 24 h) and major temperature variation (Tvari > 1°C in first 12 h; p < 0.05, p < 0.01, respectively). Among the patients with no temperature intervention, the extreme Tpeak group showed a lower Glasgow Outcome Scale-Extended (GOS-E) score at 6 months (p < 0.05) with lower GCS scores on admission (p < 0.01), compared with the moderate Tpeak group. Remarkably, the major Tvari group showed significantly lower GOS-E scores (p < 0.05) with the same GCS scores as the minor Tvari group. Thus, Tre is the better candidate to estimate Tbr. Spontaneously extreme Tpeak in TBI represents both more serious injury on admission and worse prognosis, and Tvari might be used as a novel prognostic parameter in TBI. Brain temperature is therefore one of the critical indicators evaluating injury severity, prognostication, and monitoring in the management of TBI. This prospective observational study has been registered in ClinicalTrials.gov ( https://clinicaltrials.gov ), and the registration number is NCT03068143.

Facile stabilization of a cyclodextrin metal-organic framework under humid environment via hydrogen sulfide treatment.

Increasing resistance to humid environments is a major challenge for the application of γ-CD-K-MOF (a green MOF) in real-world utilisation. γ-CD-K-MOF-H2S with enhanced moisture tolerance was obtained by simply treating MOF with H2S gas. XPS, Raman and TGA characterizations indicated that the H2S molecules coordinated with the metal centers in the framework. H2S acting as a newly available water adsorption potential well near the potassium centers protects the metal-ligand coordination bond from attack by water molecules and thus improves the moisture stability of MOF. After 7 days exposure in 60% relative humidity, γ-CD-K-MOF-H2S retained its crystal structure and morphology, while γ-CD-K-MOF had nearly collapsed. In addition, the formaldehyde uptake tests indicated that γ-CD-K-MOF retain their permanent porosity after interaction with H2S. This simple and facile one-step strategy would open a new avenue for preparation of moisture stable MOFs for practical applications.

Leeches-Inspired Hydrogel-Elastomer Integration Materials.

Inspired by the functions of leeches, for the first time homogeneous materials integrating hydrogels and elastomers were achieved by free radical polymerization. 2-Methoxyethyl acrylate (MEA) was used as elastomer monomer and Pluronics functionalized with vinyl groups acted as cross-linkers to impart the hydrogel property to the materials. The resulting Pluronic/PMEA gels possess a swelling ratio of about 210% and good water-retaining ability. Compression tests of Pluronic/PMEA gels at swelling equilibrium state show a stress up to 1.6 MPa under 85% strain. The gels act as elastomer after dehydration. Uniaxial tensile fracture stress and the elongation reached 1200 kPa and 500%, respectively, and compression stress was above 22 MPa. Furthermore, the Pluronic/PMEA gels also show self-healing properties. Owing to the excellent mechanical performance in both wet and dry conditions, this hydrogel-elastomer integrated material may have potential applications in tissue engineering, soft robotics, and biomedical devices.

Circular RNA Expression Profiles Alter Significantly after Traumatic Brain Injury in Rats.

Circular RNAs (circRNAs) are involved in a variety of diseases. However, the roles of circRNAs in traumatic brain injury (TBI) remain unknown. In this study, circRNA microarray was used to profile the altered circRNAs in the rat hippocampus following TBI. A total of 192 circRNAs were observed to be differentially expressed (fold change [FC] ≥1.5 and p < 0.05) after TBI, including 98 upregulated and 94 downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that many messenger RNAs (mRNAs) transcribed from the host genes of altered circRNAs were implicated in brain damage and neural regeneration. CircRNA/microRNA (miRNA) interaction was predicted using Arraystar's homemade miRNA target prediction software based on TargetScan and miRanda. Thus, our studies have demonstrated altered circRNA expression pattern in the rat hippocampus after TBI, which may play important roles in post-TBI physiological and pathological processes. These findings may provide not only a new direction for studying the molecular mechanisms underlying TBI but also a new possibility for the treatment of TBI by modulating circRNAs.

Electrical Guidance of Human Stem Cells in the Rat Brain.

Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies.

Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis.

Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to 'drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.

Alteration in Long Non-Coding RNA Expression after Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) causes a primary insult and initiates a secondary injury cascade. The mechanisms underlying the secondary injury are multifactorial and may include the aberrant expression of long non-coding RNA (lncRNA) post-TBI. Here, lncRNA microarray analysis was performed to profile the altered lncRNAs in the rat hippocampus after TBI. A total of 271 lncRNA probe sets and 1046 messenger RNA (mRNA) probe sets were differentially expressed after TBI. Gene ontology analysis showed that the main components of the most significantly changed categories were inflammation, DNA transcription, apoptosis, and necroptosis. Additionally, the pathway analysis and the pathway relation network revealed correlated pathways mainly involving inflammation, cell cycle, and apoptosis. A co-expression network of these aberrantly expressed lncRNAs and mRNAs was further constructed to predict the potential function of individual lncRNAs. Sub-co-expression networks were formed for the top three lncRNAs: NR_002704, ENSRNOT00000062543, and Zfas1. Thus, our study demonstrated differential expression of a series of lncRNAs in the rat hippocampus after TBI, which may be correlated with post-TBI physiological and pathological processes. The findings also may provide novel targets for further investigation of both the molecular mechanisms underlying TBI and potential therapeutic interventions.

Mild Hypothermia Promotes Pericontusion Neuronal Sprouting via Suppressing Suppressor of Cytokine Signaling 3 Expression after Moderate Traumatic Brain Injury.

Mild therapeutic hypothermia is a candidate for the treatment of traumatic brain injury (TBI). However, the role of mild hypothermia in neuronal sprouting after TBI remains obscure. We used a fluid percussion injury (FPI) model to assess the effect of mild hypothermia on pericontusion neuronal sprouting after TBI in rats. Male Sprague-Dawley rats underwent FPI or sham surgery, followed by mild hypothermia treatment (33°C) or normothermia treatment (37°C) for 3 h. All the rats were euthanized at 7 days after FPI. Neuronal sprouting that was confirmed by an increase in growth associated protein-43 (GAP-43) expression was evaluated using immunofluorescence and Western blot assays. The expression levels of several intrinsic and extrinsic sprouting-associated genes such as neurite outgrowth inhibitor A (NogoA), phosphatase and tensin homolog (PTEN), and suppressor of cytokine signaling 3 (SOCS3) were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). Our results revealed that mild hypothermia significantly increased the expression level of GAP-43 and dramatically suppressed the expression level of interleukin-6 (IL-6) and SOCS3 at 7 days after FPI in the ipsilateral cortex compared with that of the normothermia TBI group. These data suggest that post-traumatic mild hypothermia promotes pericontusion neuronal sprouting after TBI. Moreover, the mechanism of hypothermia-induced neuronal sprouting might be partially associated with decreased levels of SOCS3.