Repair Of Traumatic Brain Injury Research Articles

Strongly Adhesive, Self-Healing, Hemostatic Hydrogel for the Repair of Traumatic Brain Injury.

With wide clinical demands, therapies for traumatic brain injury (TBI) are a major problem in surgical procedures and after major trauma. Due to the difficulty in regeneration of neurons or axons after injury, as well as the inhibition of blood vessel growth by the formation of neural scars, existing treatment measures have limited effectiveness in repairing brain tissue. Herein, the biomultifunctional hydrogels are developed for TBI treatment based on the Schiff base reaction of calcium ion (Ca2+)-cross-linked oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS). The obtained COCS hydrogel exhibits excellent adhesion to wet tissues, self-repair capability, and antimicrobial properties. What's particularly interesting is that the addition of Ca2+ increases the hydrogel's extensibility, enhancing its hemostatic capabilities. Biological assessments indicate that the COCS hydrogel demonstrates excellent biocompatibility, hemostatic properties, and the ability to promote arterial vessel repair. Importantly, the COCS hydrogel promotes the growth of cerebral microvessels by upregulating CD31, accelerates the proliferation of astrocytes, enhances the expression of GFAP, and stimulates the expression of neuron-specific markers such as NEUN and β-tubulin. All of these findings highlight that the strongly adhesive, self-healing, hemostatic hydrogel shows great potential for the repair of traumatic brain injury and other tissue repair therapy.

Astrocyte-Derived Exosomal miR-148a-3p Suppresses Neuroinflammation and Restores Neurological Function in Traumatic Brain Injury by Regulating the Microglial Phenotype.

Interactions between astrocytes and microglia play an important role in the regeneration and repair of traumatic brain injury (TBI), and exosomes are involved in cell-cell interactions. A TBI model was constructed in rats. Brain extract (Ext) was isolated 1 d after TBI. Astrocyte-derived exosomes were obtained by coculturing Ext with primary astrocytes, and the morphology of exosomes was observed by electron microscopy. The isolated exosomes were cocultured with microglia to observe phenotypic changes in M1 and M2 markers. Aberrant RNA expression was detected in necrotic brain tissue and edematous brain tissue. The role of miR-148a-3p in regulating microglial phenotype was explored by knocking down or overexpressing miR-148a-3p. Finally, the effect of miR-148a-3p on TBI was studied in a rat TBI model. Astrocyte-derived exosomes stimulated by Ext promoted the transition of microglia from the M1 phenotype to the M2 phenotype. MiR-148a-3p was highly expressed in TBI. Transfecting miR-148a-3p promoted the transition of microglia from the M1 phenotype to the M2 phenotype and inhibited the lipopolysaccharide-induced inflammatory response in pre-microglia. In a rat TBI model, miR-148a-3p significantly improved the modified neurological severity score and attenuated brain injury, which promoted the transition of microglia from the M1 phenotype to the M2 phenotype. MiR-148a-3p alleviated TBI by inhibiting the nuclear factor κB pathway. Astrocyte-derived exosomal miR-148a-3p regulates the microglial phenotype, inhibits neuroinflammation, and restores neurological function in TBI. These results provide new potential targets for the treatment of TBI.

Low-temperature 3D-printed collagen/chitosan scaffolds loaded with exosomes derived from neural stem cells pretreated with insulin growth factor-1 enhance neural regeneration after traumatic brain injury.

There are various clinical treatments for traumatic brain injury, including surgery, drug therapy, and rehabilitation therapy; however, the therapeutic effects are limited. Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury. In this study, we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (3D-CC-INExos) to improve traumatic brain injury repair and functional recovery after traumatic brain injury in rats. Composite scaffolds comprising collagen, chitosan, and exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (INExos) continuously released exosomes for 2 weeks. Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model, as assessed by the Morris water maze test and modified neurological severity scores. In addition, immunofluorescence staining and transmission electron microscopy showed that 3D-CC-INExos implantation significantly improved the recovery of damaged nerve tissue in the injured area. In conclusion, this study suggests that transplanted 3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation.

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1.

FAM76B has been reported to be a nuclear speckle-localized protein with unknown function. In this study, FAM76B was first demonstrated to inhibit the NF-κB-mediated inflammatory pathway by affecting the translocation of hnRNPA2B1 in vitro. We further showed that FAM76B suppressed inflammation in vivo using a traumatic brain injury (TBI) mouse model. Lastly, FAM76B was shown to interact with hnRNPA2B1 in human tissues taken from patients with acute, organizing, and chronic TBI, and with different neurodegenerative diseases. The results suggested that FAM76B mediated neuroinflammation via influencing the translocation of hnRNPA2B1 in vivo during TBI repair and neurodegenerative diseases. In summary, we for the first time demonstrated the role of FAM76B in regulating inflammation and further showed that FAM76B could regulate the NF-κB-mediated inflammatory pathway by affecting hnRNPA2B1 translocation, which provides new information for studying the mechanism of inflammation regulation.

3D printing of injury-preconditioned secretome/collagen/heparan sulfate scaffolds for neurological recovery after traumatic brain injury in rats

BackgroundThe effects of traumatic brain injury (TBI) can include physical disability and even death. The development of effective therapies to promote neurological recovery is still a challenging problem. 3D-printed biomaterials are considered to have a promising future in TBI repair. The injury-preconditioned secretome derived from human umbilical cord blood mesenchymal stem cells showed better stability in neurological recovery after TBI. Therefore, it is reasonable to assume that a biological scaffold loaded with an injury-preconditioned secretome could facilitate neural network reconstruction after TBI.MethodsIn this study, we fabricated injury-preconditioned secretome/collagen/heparan sulfate scaffolds by 3D printing. The scaffold structure and porosity were examined by scanning electron microscopy and HE staining. The cytocompatibility of the scaffolds was characterized by MTT analysis, HE staining and electron microscopy. The modified Neurological Severity Score (mNSS), Morris water maze (MWM), and motor evoked potential (MEP) were used to examine the recovery of cognitive and locomotor function after TBI in rats. HE staining, silver staining, Nissl staining, immunofluorescence, and transmission electron microscopy were used to detect the reconstruction of neural structures and pathophysiological processes. The biocompatibility of the scaffolds in vivo was characterized by tolerance exposure and liver/kidney function assays.ResultsThe excellent mechanical and porosity characteristics of the composite scaffold allowed it to efficiently regulate the secretome release rate. MTT and cell adhesion assays demonstrated that the scaffold loaded with the injury-preconditioned secretome (3D-CH-IB-ST) had better cytocompatibility than that loaded with the normal secretome (3D-CH-ST). In the rat TBI model, cognitive and locomotor function including mNSS, MWM, and MEP clearly improved when the scaffold was transplanted into the damage site. There is a significant improvement in nerve tissue at the site of lesion. More abundant endogenous neurons with nerve fibers, synaptic structures, and myelin sheaths were observed in the 3D-CH-IB-ST group. Furthermore, the apoptotic response and neuroinflammation were significantly reduced and functional vessels were observed at the injury site. Good exposure tolerance in vivo demonstrated favorable biocompatibility of the scaffold.ConclusionsOur results demonstrated that injury-preconditioned secretome/collagen/heparan sulfate scaffolds fabricated by 3D printing promoted neurological recovery after TBI by reconstructing neural networks, suggesting that the implantation of the scaffolds could be a novel way to alleviate brain damage following TBI.Graphical abstract

Therapeutic Application of Stem Cells in the Repair of Traumatic Brain Injury

Traumatic brain injury is the main cause of injury-related deaths and disabilities throughout the world, which is characterized by a disruption of the normal physiology of the brain following trauma. It can potentially cause severe complications such as physical, cognitive, and emotional impairment. In addition to understanding traumatic brain injury pathophysiology, this review explains the therapeutic potential of stem cells following brain injury in two pathways: response of endogenous neurogenic cells and transplantation of exogenous stem cell therapy. After traumatic brain injuries, clinical evidence indicated that endogenous neural progenitor cells might play an important role in regenerative medicine to treat brain injury. This is due to an increased neurogenic regeneration ability of these cells following brain injury. Besides, exogenous stem cell transplantation has also accelerated immature neuronal development and increased endogenous cellular proliferation in the damaged brain region. Therefore, a better understanding of the endogenous neural stem cell’s regenerative ability and the effect of exogenous stem cells on proliferation and differentiation ability may help researchers to understand how to increase functional recovery and tissue repair following injury.

Methane-rich saline restores brain SOD activity and alleviates cognitive impairment in rats with traumatic brain injury

Clinically, methane is an anti-inflammatory gas used to treat organ damage. There is no extensive research on methane's repair of traumatic brain injury (TBI), so this study aims to investigate the role of methane and its potential mechanism. A rat TBI model was established by mechanical impact. SD rats were divided into four groups, including sham group, TBI group, 2 or 20 mL/kg methane-rich saline (MS) group. Morris water maze test revealed that MS improved cognitive function in TBI rats. HE and Nissl staining showed that MS reduced the blurring of brain tissues boundary, the number of necrotic plaques and neurons in TBI rats. In addition, ELISA revealed that MS restored the oxidative stress of TBI rats and reversed the inflammatory effect of TBI on brain cells, and TUNEL staining detected that MS inhibited cell apoptosis. Western blotting showed that MS downregulated Caspase-3 and Bax protein levels and upregulated Bcl-2 level. And MS inhibited phosphorylated expressions of Janus kinase 1 (JAK1), signal transducer and activator of the transcription (STAT1) and NF-κb-p65. In conclusion, MS improved cognitive function, reduced inflammatory response and oxidative stress and inhibited cell apoptosis to relieve rat TBI by blocking the activation of the JAK1/STAT1/NF-κb-p65 pathway.

An Integrated Transcriptome Analysis Reveals IGFBP7 Upregulation in Vasculature in Traumatic Brain Injury.

Vasculature plays critical roles in the pathogenesis and neurological repair of traumatic brain injury (TBI). However, how vascular endothelial cells respond to TBI at the molecular level has not been systematically reviewed. Here, by integrating three transcriptome datasets including whole cortex of mouse brain, FACS-sorted mouse brain endothelial cells, and single cell sequencing of mouse brain hippocampus, we revealed the key molecular alteration of endothelial cells characterized by increased Myc targets and Epithelial-Mesenchymal Transition signatures. In addition, immunofluorescence staining of patients’ samples confirmed that IGFBP7 was up-regulated in vasculature in response to TBI. TGFβ1, mainly derived from microglia and endothelial cells, sufficiently induces IGFBP7 expression in cultured endothelial cells, and is significantly upregulated in response to TBI. Our results identified IGFBP7 as a potential biomarker of vasculature in response to TBI, and indicate that TGFβ signaling may contribute to the upregulation of IGFBP7 in the vasculature.

3D printing collagen/heparin sulfate scaffolds boost neural network reconstruction and motor function recovery after traumatic brain injury in canine.

Tissue engineering is considered highly promising for the repair of traumatic brain injury (TBI), and accumulating evidence has proved the efficacy of biomaterials and 3D printing. Although collagen is famous for its natural properties, some defects still restrict its potential applications in tissue repair. In this experimental study, we fabricated a kind of scaffold with collagen and heparin sulfate via 3D printing, which possesses favorable physical properties and suitable degradation rate along with satisfactory cytocompatibility. After implantation, the results of motor evoked potentials (MEPs) showed that the latency and amplitude can both be improved in hemiplegic limbs, and the structural integrity of the cerebral cortex and corticospinal tract can be enhanced significantly under magnetic resonance imaging (MRI) evaluation. Additionally, the results of in situ hybridization (ISH) and immunofluorescence staining also revealed the facilitating role of 3D printing collagen/heparin sulfate scaffolds on vascular and neural regeneration. Moreover, the individuals implanted with this kind of scaffold present better gait characteristics and preferable electromyography and myodynamia. In general, 3D printed collagen/heparin sulfate scaffolds have superb performance in both structural repair and functional improvement and may offer a new strategy for the repair of TBI.

Role of Carbon Monoxide in Traumatic Brain Injury Repair

Role of Carbon Monoxide in Traumatic Brain Injury Repair

Effects of SDF-1/CXCR4 on the Repair of Traumatic Brain Injury in Rats by Mediating Bone Marrow Derived Mesenchymal Stem Cells.

Our study aims to investigate the effects of the SDF-1/CXCR4 axis on the repair of traumatic brain injury (TBI) in rats by mediating bone marrow derived from mesenchymal stem cells (BMSCs). Healthy male SD rats were collected, their tibiofibulars were removed, cultured, and BMSCs were collected. The expression of cell-surface molecular proteins was examined using flow cytometry. The mRNA and protein expression of CXCR4 in cells were tested using qRT-PCR and western blotting analysis. An electronic brain injury instrument was utilized to build TBI rat models and each rat was assigned into the experiment, positive control and control groups (10 rats in each group). The morris water maze was used to calculate the escape latency and number of times rats in each group crossed the platform. Neurological severity scores (NSS) was calculated to evaluate the recovery of neurological functioning. The distribution of neuronal nuclear antigens was detected using double-labeling immunohistochemistry. The morphological changes in the hippocampal neuronal and the number of BrdU-positive cells were observed through Nissl's staining and high magnification. The mRNA and protein expressions of CXCR4 were gradually increased as SDF-1 concentration increased. NGF and BDNF positive cells were expressed in each group. The distribution of neuronal nuclear antigens in the experiment group was elevated compared to the control and positive control groups. Among the three groups, the experimental group had the shortest escape latency and the highest number platform crossings. The difference in NSS among the three groups was significant. The experimental group had better cell morphology and a higher number of BrdU-positive cells than the other groups. The present study demonstrates that transplanting BMSCs with SDF-1-induced CXCR4 expression can promote the repair of TBI. This is expected to become a new treatment regimen for TBI.

[PREPARATION OF PERSONALIZED BRAIN CAVITY SCAFFOLD WITH THREE-DIMENSIONAL PRINTING TECHNOLOGY BASED ON MAGNETIC RESONANCE IMAGING].

To explore a method of three-dimensional (3D) printing technology for preparation of personalized rat brain tissue cavity scaffolds so as to lay the foundation for the repair of traumatic brain injury (TBI) with tissue engineered customized cavity scaffolds. Five male Sprague Dawley rats[weighing (300±10) g] were induced to TBI models by electric controlled cortical impactor. Mimics software was used to reconstruct the surface profile of the damaged cavity based on the MRI data, computer aided design to construct the internal structure. Then collagen-chitosan composite was prepared for 3D bioprinter of bionic brain cavity scaffold. MRI scans showed the changes of brain tissue injury in the injured side, and the position of the cavity was limited to the right side of the rat brain cortex. The 3D model of personalized cavity containing the internal structure was successfully constructed, and cavity scaffolds were prepared by 3D printing technology. The external contour of cavity scaffolds was similar to that of the injured zone in the rat TBI; the inner positive crossing structure arranged in order, and the pore connectivity was good. Combined with 3D reconstruction based on MRI data, the appearance of cavity scaffolds by 3D printing technology is similar to that of injured cavity of rat brain tissue, and internal positive cross structure can simulate the topological structure of the extracellular matrix, and printing materials are collagen-chitosan complexes having good biocompatibility, so it will provide a new method for customized cavity scaffolds to repair brain tissue cavity after TBI.

Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury.

In this reach, we specifically linked RGIDKRHWNSQ, a functional peptide derived from BDNF, to the C-terminal of RADARADARADARADA (RADA16) to structure a functional self-assembling peptide hydrogel scaffold, RADA16-BDNF (R-B-SPH scaffold) for the better transplantation of the double cell unit. Also, the novel scaffold was used as cell-carrier for transplantation double cell unit (hUC-MSCs/astrocyte) for treating traumatic brain injury. The results of this study showing that R-B-SPH scaffold was pliancy and flexibility to fit the brain lesion cavity and promotes the outgrowth of axons and dendrites of the neurons derived from hUC-MSCs in vitro and in vivo, indicating the 3D R-B-SPH scaffold provided a suitable microenvironment for hUC-MSC survival, proliferation and differentiation. Also, our results showing the double-cells transplantation system (hUC-MSCs/astrocyte) may be a novel cell-based therapeutic strategy for neuroregeneration after TBI with potential value for clinical application.

Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury.

Transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen (HBO) treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid (2.5-3.0 atm impact force). The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil-positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions.

神经节苷脂对脑外伤大鼠大脑皮质Nogo-A表达的影响

目的：观察神经节苷脂(GM1)对脑外伤大鼠大脑皮质中Nogo-A表达的影响，探讨GM1促进脑外伤神经修复的可能机制。方法：采用SPF级SD大鼠100只，随机分为空白对照组(n=10)、假手术组(n=20)、损伤后生理盐水组(n=35)和损伤后GM1组(n=35)。通过HE染色观察各组大鼠脑组织不同时间点病理情况；用免疫组化的方法观察Nogo-A阳性细胞数量。结果：通过免疫组化的方法观察损伤后生理盐水组：Nogo-A阳性细胞在造模24时即明显升高，至72h时仍呈升高的趋势；GMl组:Nogo-A的阳性细胞数早期逐渐升高，至24h时数量最多，之后开始减少，应用GMl后，Nogo-A的阳性细胞数量的增加较为延后。结论：Nogo-A在颅脑损伤后其阳性细胞数量显著增高，抑制中枢神经损伤后的再生，神经节苷脂GM1在脑损伤后可部分抑制Nogo-A的表达，机制可能通过稳定细胞膜、减轻细胞水肿，从而发挥对实验性脑外伤大鼠的神经保护作用。 Objective: To observe the effects of the ganglioside (GM1) on Nogo-A expression in cerebral cortex for the rats which have brain trauma, to explore the possible mechanisms of GMl promoting the nerve repair of traumatic brain injury. Methods: SPF SD rats of 100 were randomly divided into four groups: no operation group (n=10), sham operation group (n=20), saline model group (n=35), GMI group (n=35). ELISA was used to detect Nogo-A expression in parietal cerebral cortex at different time. Results: By immunohistochemical method we observed in model group: the number Nogo-A positive cells increased at 24 hours in the model, and still slightly increased till 72 hours; in group GM1: the number Nogo-A of positive cells increased gradually in the early time, and became largest at24 h, then started to decrease, the application of GM1, after brain trauma, the increase in the number of Nogo-A positive cells was more delayed. Conclusions: the number of Nogo-A positive cells increased significantly after brain trauma, and inhibited the CNS regeneration after injury. After brain trauma, the ganglioside GM1 partially inhibited Nogo-A expression, and the mechanism might be through the stability of cell membrane, which played its neuroprotection roles in experimental traumatic brain injury in rats.

Changes of the GPR17 receptor, a new target for neurorepair, in neurons and glial cells in patients with traumatic brain injury

Unveiling the mechanisms participating in the damage and repair of traumatic brain injury (TBI) is fundamental to develop new therapies. The P2Y-like GPR17 receptor has recently emerged as a sensor of damage and a key actor in lesion remodeling/repair in the rodent brain, but its role in humans is totally unknown. Here, we characterized GPR17 expression in brain specimens from seven intensive care unit TBI patients undergoing neurosurgery for contusion removal and from 28 autoptic TBI cases (and 10 control subjects of matched age and gender) of two university hospitals. In both neurosurgery and autoptic samples, GPR17 expression was strong inside the contused core and progressively declined distally according to a spatio-temporal gradient. Inside and around the core, GPR17 labeled dying neurons, reactive astrocytes, and activated microglia/macrophages. In peri-contused parenchyma, GPR17 decorated oligodendrocyte precursor cells (OPCs) some of which had proliferated, indicating re-myelination attempts. In autoptic cases, GPR17 expression positively correlated with death for intracranial complications and negatively correlated with patients' post-traumatic survival. Data indicate lesion-specific sequential involvement of GPR17 in the (a) death of irreversibly damaged neurons, (b) activation of microglia/macrophages remodeling the lesion, and (c) activation/proliferation of multipotent parenchymal progenitors (both reactive astrocytes and OPCs) starting repair processes. Data validate GPR17 as a target for neurorepair and are particularly relevant to setting up new therapies for TBI patients.