scholarly journals 518 New In Vitro Model of Traumatic Brain Injury to Assess Biomaterial Based Regenerative Strategies

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
R H Basit ◽  
S I Jenkins ◽  
D M Chari
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
High Throughput ◽  
Early Stage ◽  
Mixed Glial Culture ◽  
Vitro Model ◽  
Regenerative Therapies ◽  
Penetrating Traumatic Brain Injury

Abstract Introduction Penetrating traumatic brain injury (pTBI) management is largely supportive, with no clinically established regenerative therapies. Neurocompatible biomaterials offer a high potential to promote regenerative mechanisms but facile, high throughput, pathomimetic in vitro pTBI models for the developmental testing of neuro-materials is lacking. Method A mouse mixed glial culture system was utilised within which penetrating injuries could be induced. DuraGen PlusTM – an FDA approved neurosurgical grade biomaterial could be implanted into lesions to assess cell-biomaterial responses. Reactive gliosis (astrocytic morphological responses/GFAP expression) and microglial infiltration (Iba1 expression) were assessed/quantified. Results Key pathological features of pTBI were observed in the model, with the ability to (i) introduce reproducible lesions (diameter 949 ± 26 μm) and (ii) for DuraGen PlusTM to be implanted into lesions. Peri-lesional astrocytes displayed hypertrophic palisading morphologies and GFAP upregulation, analogous to gliosis in vivo. Significant microglial numbers infiltrated the DuraGen PlusTM implant at 7 days post-lesion (132.41 ± 15.83 cells/mm2) versus lesion only (82.04 ± 5.11 cells/mm2), p < 0.05). Conclusions We have developed a novel, neuropathomimetic pTBI model, wherein biomaterial implantation enables investigation of neural cell-biomaterial responses. This model can facilitate early-stage evaluation of novel biomaterials as high throughput, inexpensive and facile screening tool.

scholarly journals Hydrogen exerts neuroprotection by activation of the miR‐21/PI3K/AKT/GSK‐3β pathway in an in vitro model of traumatic brain injury

2020 ◽  
Vol 24 (7) ◽  
pp. 4061-4071 ◽  
Author(s):  
Lu Wang ◽  
Zhenyu Yin ◽  
Feng Wang ◽  
Zhaoli Han ◽  
Yifeng Wang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
In Vitro Model ◽  
Vitro Model ◽  
Gsk 3Β

scholarly journals The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway

2011 ◽  
Vol 29 (4) ◽  
pp. 630-636 ◽  
Author(s):  
TAO CHEN ◽  
LEI ZHANG ◽  
YAN QU ◽  
KAI HUO ◽  
XIAOFAN JIANG ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Akt Pathway

scholarly journals Embedded axonal fiber tracts improve finite element model predictions of traumatic brain injury

2019 ◽  
Vol 19 (3) ◽  
pp. 1109-1130 ◽  
Author(s):  
Marzieh Hajiaghamemar ◽  
Taotao Wu ◽  
Matthew B. Panzer ◽  
Susan S. Margulies
Keyword(s):  
Traumatic Brain Injury ◽  
Finite Element ◽  
Brain Injury ◽  
Strain Rate ◽  
Brain Tissue ◽  
Brain Injuries ◽  
Characteristic Curve ◽  
Strain And Strain Rate

AbstractWith the growing rate of traumatic brain injury (TBI), there is an increasing interest in validated tools to predict and prevent brain injuries. Finite element models (FEM) are valuable tools to estimate tissue responses, predict probability of TBI, and guide the development of safety equipment. In this study, we developed and validated an anisotropic pig brain multi-scale FEM by explicitly embedding the axonal tract structures and utilized the model to simulate experimental TBI in piglets undergoing dynamic head rotations. Binary logistic regression, survival analysis with Weibull distribution, and receiver operating characteristic curve analysis, coupled with repeated k-fold cross-validation technique, were used to examine 12 FEM-derived metrics related to axonal/brain tissue strain and strain rate for predicting the presence or absence of traumatic axonal injury (TAI). All 12 metrics performed well in predicting of TAI with prediction accuracy rate of 73–90%. The axonal-based metrics outperformed their rival brain tissue-based metrics in predicting TAI. The best predictors of TAI were maximum axonal strain times strain rate (MASxSR) and its corresponding optimal fraction-based metric (AF-MASxSR7.5) that represents the fraction of axonal fibers exceeding MASxSR of 7.5 s−1. The thresholds compare favorably with tissue tolerances found in in–vitro/in–vivo measurements in the literature. In addition, the damaged volume fractions (DVF) predicted using the axonal-based metrics, especially MASxSR (DVF = 0.05–4.5%), were closer to the actual DVF obtained from histopathology (AIV = 0.02–1.65%) in comparison with the DVF predicted using the brain-related metrics (DVF = 0.11–41.2%). The methods and the results from this study can be used to improve model prediction of TBI in humans.

scholarly journals Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury

2020 ◽  
Author(s):  
xiaobing long ◽  
Xiaolong Yao ◽  
Qian Jiang ◽  
Yiping Yang ◽  
Xuejun He ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mouse Model ◽  
Vital Role ◽  
Neurological Deficits ◽  
Inflammatory Factors ◽  
Protective Mechanism ◽  
Vitro Model ◽  
Phenotype Transformation

Abstract Background: The interaction between astrocytes and microglia plays a vital role in the damage and repair of brain lesions due to traumatic brain injury (TBI). Recent studies have shown that exosomes act as potent mediators involved in intercellular communication. Methods: In the current study, the expression of inflammatory factors and miR-873a-5p in the lesion area and edema area was evaluated in 15 patients with traumatic brain injury. Exosomes secreted by astrocytes were detected by immunofluorescence, Western blot, and electron microscopy. A mouse model of TBI and an in vitro model of lps-induced primary microglia were established to study the protective mechanism of exosomes from miR-873a-5p-overexpressing in TBI-induced nerve injury.Results: We discovered that exosomes derived from activated astrocytes promote microglial M2 phenotype transformation following TBI. More than 100 miRNAs were detected in these astrocyte-derived exosomes. miR-873a-5p is a major component that was highly expressed in human traumatic brain tissue. Moreover, miR-873a-5p significantly inhibited LPS-induced microglial M1 phenotype transformation and the subsequent inflammation through decreased phosphorylation of ERK and NF-κB p65. This effect also greatly improved the mNSS score and attenuated brain injury in a strictly controlled cortical impact mouse model. Conclusions: Taken together, our research indicates that miRNAs in the exosomes derived from activated astrocytes play a key role in the astrocyte-microglia interaction. miR-873a-5p, as one of the main components of these astrocyte-derived exosomes, attenuated microglia-mediated neuroinflammation and improved neurological deficits following TBI by inhibiting the NF-kB signalling pathway. These findings suggest a potential role for miR-873a-5p in treating traumatic brain injury.

scholarly journals Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

2018 ◽  
Author(s):  
Jenny B. Koenig ◽  
David Cantu ◽  
Cho Low ◽  
Farzad Noubary ◽  
Danielle Croker ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Epileptiform Activity ◽  
Synaptic Activity ◽  
Network Function ◽  
Cortical Hyperexcitability ◽  
Glycolytic Inhibitor ◽  
Cortical Slices

AbstractTraumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro glycolytic inhibition decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3-5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated loss of parvalbumin-positive inhibitory interneurons. In summary, inhibition of glycolysis with 2-DG may have therapeutic potential to restore network function following TBI.One Sentence SummaryFollowing traumatic brain injury in mice, in vivo treatment with the glycolytic inhibitor 2-deoxyglucose prevented cortical network pathology including cortical hyperexcitability, changes in synaptic activity, and loss of parvalbumin-expressing GABAergic interneurons.

scholarly journals The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Fangxia Guan ◽  
Tuanjie Huang ◽  
Xinxin Wang ◽  
Qu Xing ◽  
Kristyn Gumpper ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
Therapeutic Efficacy ◽  
Brain Dysfunction ◽  
Vital Role ◽  
Neurological Deficits ◽  
Human Umbilical Cord

Abstract Background Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. Methods In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. Results We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3β signaling. Conclusion MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

scholarly journals Hyaluronidase reduced edema after experimental traumatic brain injury

2019 ◽  
Vol 40 (10) ◽  
pp. 2026-2037 ◽  
Author(s):  
Patricia M Washington ◽  
Changhee Lee ◽  
Mary Kate R Dwyer ◽  
Elisa E Konofagou ◽  
Steven G Kernie ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Magnetic Resonance ◽  
Charge Density ◽  
Fixed Charge ◽  
Resonance Imaging ◽  
Fixed Charge Density

Cerebral edema and the subsequent increased intracranial pressure are associated with mortality and poor outcome following traumatic brain injury. Previous in vitro studies have shown that the Gibbs-Donnan effect, which describes the tendency of a porous, negatively charged matrix to attract positive ions and water, applies to brain tissue and that enzymatic reduction of the fixed charge density can prevent tissue swelling. We tested whether hyaluronidase, an enzyme that degrades the large, negatively charged glycosaminoglycan hyaluronan, could reduce brain edema after traumatic brain injury. In vivo, intracerebroventricular injection of hyaluronidase after controlled cortical impact in mice reduced edema in the ipsilateral hippocampus at 24 h by both the wet-weight/dry-weight method (78.15 ± 0.65% vs. 80.4 ± 0.46%; p < 0.01) and T2-weighted magnetic resonance imaging (13.88 ± 3.09% vs. 29.23 ± 6.14%; p < 0.01). Hyaluronidase did not adversely affect blood–brain-barrier-integrity measured by dynamic contrast-enhanced magnetic resonance imaging, nor did hyaluronidase negatively affect functional recovery after controlled cortical impact measured with the rotarod or Morris water maze tasks. Reduction of fixed charge density by hyaluronidase was confirmed in cortical explants in vitro (5.46 ± 1.15 µg/mg vs. 7.76 ± 1.87 µg/mg; p < 0.05). These data demonstrate that targeting the fixed charge density with hyaluronidase reduced edema in an in vivo mouse model of traumatic brain injury.

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