Treatment Of Traumatic Brain Injury Research Articles

Median nerve electrical stimulation improves traumatic brain injury by reducing TACR1 to inhibit nuclear factor-κB and CCL7 activation in microglia.

The existing report elucidates that median nerve electrical stimulation (MNS) plays a role in treating traumatic brain injury (TBI). Herein, we explored the mechanism of MNS in TBI. A TBI-induced coma model (skull was hit by a cylindrical impact hammer) was established in adult Sprague-Dawley rats. Microglia were isolated from newborn Sprague-Dawley rats and was injured by lipopolysaccharide (LPS; 10 ng/mL). Consciousness was assessed by sensory and motor functions. Brain tissue morphology was detected using hematoxylin-eosin staining assay. Ionized calcium binding adapter molecule 1, NeuN and tachykinin receptor 1 (TACR1) level were detected by immunohistochemical assay. Levels of pro-inflammatory and anti-inflammatory factors were measured by enzyme linked immune sorbent assay (ELISA). Levels of TACR1, C-C motif chemokine 7 (CCL7), phosphorylation (p)-P65 and P65 were assessed by quantitative real time polymerase chain reaction (qRT-PCR) and western blot. M1 markers (inducible nitric oxide synthase and CD86) and M2 markers (arginase-1 (Arg1) and chitinase 3-like 3 (YM1)) of microglia as well as the transfection efficiency of short hairpin TACR1 (shTACR1) were assessed by qRT-PCR. Immunofluorescence and flow cytometry assay were used to detect microglia morphology and neuron apoptosis. MNS reduced neuron injury and microglia activation in the TBI-induced rat coma model. MNS reversed the effects of TBI on levels of inflammation-related factors, M1/M2 microglia markers, TACR1, p-P65/P65 and CCL7 in rats. shTACR1 reversed the effects of LPS on inflammation-related factors, M1/M2 microglia markers, microglia activation, neuron apoptosis, p-P65/P65 value and CCL7 level. Our results revealed that MNS improved TBI by reducing TACR1 to inhibit nuclear factor-κB (NF-κB) and CCL7 activation in microglia.

Neuroprotection or Sex Bias: A Protective Response to Traumatic Brain Injury in the Females

Traumatic brain injury (TBI) is a major healthcare problem and a common cause of mortality and morbidity. Clinical and preclinical research suggests sex-related differences in short- and long-term outcomes following TBI; however, males have been the main focus of TBI research. Females show a protective response against TBI. Female animals in preclinical studies and women in clinical trials have shown comparatively better outcomes against mild, moderate, or severe TBI. This reflects a favorable protective nature of the females compared to the males, primarily attributed to various protective mechanisms that provide better prognosis and recovery in the females after TBI. Understanding the sex difference in the TBI pathophysiology and the underlying mechanisms remains an elusive goal. In this review, we provide insights into various mechanisms related to the anatomical, physiological, hormonal, enzymatic, inflammatory, oxidative, genetic, or mitochondrial basis that support the protective nature of females compared to males. Furthermore, we sought to outline the evidence of multiple biomarkers that are highly potential in the investigation of TBI's prognosis, pathophysiology, and treatment and which can serve as objective measures and novel targets for individualized therapeutic interventions in TBI treatment. Implementations from this review are important for the understanding of the effect of sex on TBI outcomes and possible mechanisms behind the favorable response in females. It also emphasizes the critical need to include females as a biological variable and in sufficient numbers in future TBI studies.

Can transcranial photobiomodulation improve cognitive function in TBI patients? A systematic review

IntroductionTranscranial photobiomodulation (tPBM) is a non-invasive neuromodulation technology which has become a promising therapy for treating many brain diseases. Although it has been confirmed in studies targeting neurological diseases including Alzheimer’s and Parkinson’s that tPBM can improve cognitive function, the effectiveness of interventions targeting TBI patients remains to be determined. This systematic review examines the cognitive outcomes of clinical trials concerning tPBM in the treatment of traumatic brain injury (TBI).MethodsWe conducted a systematic literature review, following the PRISMA guidelines. The PubMed, Web of Science, Scopus, EMBASE, and Cochrane Library databases were searched before October 31, 2023.ResultsThe initial search retrieved 131 articles, and a total of 6 studies were finally included for full text-analysis after applying inclusion and exclusion criteria.ConclusionResults showed improvements in cognition for patients with chronic TBI after tPBM intervention. The mechanism may be that tPBM increases the volume of total cortical gray matter (GM), subcortical GM, and thalamic, improves cerebral blood flow (CBF), functional connectivity (FC), and cerebral oxygenation, improving brain function. However, due to the significant heterogeneity in application, we cannot summarize the optimal parameters for tPBM treatment of TBI. In addition, there is currently a lack of RCT studies in this field. Therefore, given this encouraging but uncertain finding, it is necessary to conduct randomized controlled clinical trials to further determine the role of tPBM in cognitive rehabilitation of TBI patients.

Investigating the Safety and Efficacy of Therapeutic Hypothermia in Pediatric Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Prior guidelines recommended maintaining normothermia following traumatic brain injury (TBI), but recent studies suggest therapeutic hypothermia as a viable option in pediatric cases. However, some others demonstrated a higher mortality rate. Hence, the impact of hypothermia on neurological symptoms and overall survival remains contentious. We conducted a systematic review and meta-analysis to evaluate the effects of hypothermia on neurological outcomes in pediatric TBI patients. The PubMed/Medline, Scopus, and Web of Science databases were searched until 1 January 2024 and data were analyzed using appropriate statistical methods. A total of eight studies, comprising nine reports, were included in this analysis. Our meta-analysis did not reveal significant differences in mortality (RR = 1.58; 95% CI = 0.89-2.82, p = 0.055), infection (RR = 0.95: 95% CI = 0.79-1.1, p = 0.6), arrhythmia (RR = 2.85: 95% CI = 0.88-9.2, p = 0.08), hypotension (RR = 1.54: 95% CI = 0.91-2.6, p = 0.10), intracranial pressure (SMD = 5.07: 95% CI = -4.6-14.8, p = 0.30), hospital length of stay (SMD = 0.10; 95% CI = -0.13-0.3, p = 0.39), pediatric intensive care unit length of stay (SMD = 0.04; 95% CI = -0.19-0.28, p = 0.71), hemorrhage (RR = 0.86; 95% CI = 0.34-2.13, p = 0.75), cerebral perfusion pressure (SMD = 0.158: 95% CI = 0.11-0.13, p = 0.172), prothrombin time (SMD = 0.425; 95% CI = -0.037-0.886, p = 0.07), and partial thromboplastin time (SMD = 0.386; 95% CI = -0.074-0.847, p = 0.10) between the hypothermic and non-hypothermic groups. However, the heart rate was significantly lower in the hypothermic group (-1.523 SMD = -1.523: 95% CI = -1.81--1.22 p < 0.001). Our findings challenge the effectiveness of therapeutic hypothermia in pediatric TBI cases. Despite expectations, it did not significantly improve key clinical outcomes. This prompts a critical re-evaluation of hypothermia's role as a standard intervention in pediatric TBI treatment.

Role of Hyperbaric Oxygen Therapy in Traumatic Brain Injury: A Systematic Review of Randomized Controlled Trials

Abstract Background Traumatic brain injury (TBI) is a significant public health concern. Standard care involves conservative management and pharmacological and surgical interventions. Hyperbaric oxygen therapy (HBOT) has emerged as a potential treatment for TBI, with varied findings in the literature. Our systematic review aims to comprehensively assess the efficacy and safety of HBOT in TBI management, addressing existing knowledge gaps and providing insights for clinical practice and future research. Methods A systematic literature search was performed in PubMed, SCOPUS, Central Cochrane Registry of Controlled Trials (The Cochrane Library), and ScienceDirect databases for the role of HBOT in TBI. We included studies involving randomized controlled trials (RCTs). Quasi-randomized controlled studies, prospective, retrospective observational studies, case series, case reports, letters, editorials, comments, animal studies, and studies from non-English literature were excluded. Results After identifying 306 articles, we narrowed it to 8 for qualitative synthesis. The studies were categorized into subgroups: those on patients with an acute history of cerebral injury and those with a history of mild TBI. The combined RCTs involved 651 patients (326 in the first subgroup, 325 in the second). Despite a uniform HBOT session duration of 60 minutes, variations in compression, decompression phases, and pressure used (1.5ATA to 2.5ATA) hindered meta-analysis comparability. Outcome measures differed, complicating comparisons. Overall, HBOT appears beneficial in the first group and less so in the second. Complications are primarily pulmonary, which include dyspnea, cyanosis, hyperoxic pneumonia, and increased fraction of inspired oxygen requirement. Conclusion Our study encountered challenges in reaching definitive conclusions due to outcome variability among the included studies. Despite mixed results, HBOT shows potential benefits for acute TBI patients. Conversely, our findings suggest the limited efficacy of HBOT for chronic traumatic brain injury patients. Further research is crucial, particularly exploring diverse HBOT treatment protocols to establish optimal pressure levels and the required number of sessions for effective outcomes

Elucidating the pivotal molecular mechanisms, therapeutic and neuroprotective effects of lithium in traumatic brain injury.

Traumatic brain injury (TBI) refers to damage to brain tissue by mechanical or blunt force via trauma. TBI is often associated with impaired cognitive abilities, like difficulties in memory, learning, attention, and other higher brain functions, that typically remain for years after the injury. Lithium is an elementary light metal that is only utilized in salt form due to its high intrinsic reactivity. This current review discusses the molecular mechanisms and therapeutic and neuroprotective effects of lithium in TBI. The "Boolean logic" was used to search for articles on the subject matter in PubMed and PubMed Central, as well as Google Scholar. Lithium's therapeutic action is extremely complex, involving multiple effects on gene secretion, neurotransmitter or receptor-mediated signaling, signal transduction processes, circadian modulation, as well as ion transport. Lithium is able to normalize multiple short- as well as long-term modifications in neuronal circuits that ultimately result in disparity in cortical excitation and inhibition activated by TBI. Also, lithium levels are more distinct in the hippocampus, thalamus, neo-cortex, olfactory bulb, amygdala as well as the gray matter of the cerebellum following treatment of TBI. Lithium attenuates neuroinflammation and neuronal toxicity as well as protects the brain from edema, hippocampal neurodegeneration, loss of hemispheric tissues, and enhanced memory as well as spatial learning after TBI.

Hydrogen mitigates brain injury by prompting NEDD4-CX43- mediated mitophagy in traumatic brain injury

BackgroundHydrogen (H2) has emerged as a potential therapeutic intervention for traumatic brain injury (TBI). However, the precise mechanism underlying H2's neuroprotective effects in TBI remain incompletely understood. MethodsTBI mouse model was induced using the controlled cortical impact (CCI) method, and a cell model was established by exposing astrocytes to lipopolysaccharide (LPS). Cell viability was detected by CCK-8 kits. Cell apoptosis was measured by flow cytometry. ELISA was used to detect cytokine quantification. Protein and gene expression was detected by western blot and RT-PCR analysis. Co-immunoprecipitation (CO-IP) were employed for protein-protein interactions. Morris water maze test and rotarod test were applied for TBI mice. ResultsH2 treatment effectively inhibited the LPS-induced cell injury and cell apoptosis in astrocytes. NEDD4 expression was increased following HRS treatment coupled with enhanced mitophagy in LPS-treated astrocytes. Overexpression of NEDD4 and down-regulation of connexin 43 (CX43) mirrored the protective effects of H2 treatment in LPS-exposed astrocytes. NEDD4 interacts CX43 to regulates the ubiquitinated degradation of CX43. While overexpression of CX43 reversed the protective effects of H2 treatment in LPS-exposed astrocytes. In addition, H2 treatment significantly alleviated brain injury in TBI mouse model. ConclusionH2 promoted NEDD4-CX43 mediated mitophagy to protect brain injury induced by TBI, highlighting a novel pathway underlying the therapeutic effects of H2 in TBI.

3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.

Ameliorative properties of quercetin in the treatment of traumatic brain injury: a mechanistic review based on underlying mechanisms.

Traumatic brain injury (TBI) is a leading cause of disability worldwide, with an estimated annual incidence of 27-69million. TBI is a severe condition that can lead to high mortality rates and long-term cognitive, behavioral, and physical impairments in young adults. It is a significant public health concern due to the lack of effective treatments available. Quercetin, a natural flavonoid found in various fruits and vegetables, has demonstrated therapeutic potential with anti-inflammatory, antioxidant, and neuroprotective properties. Recently, some evidence has accentuated the ameliorating effects of quercetin on TBI. This review discusses quercetin's ability to reduce TBI-related damage by regulating many cellular and molecular pathways. Quercetin in vitro and in vivo studies exhibit promise in reducing inflammation, oxidative stress, apoptosis, and enhancing cognitive function post-TBI. Further clinical investigation into quercetin's therapeutic potential as a readily available adjuvant in the treatment of TBI is warranted in light of these findings. This review adds to our knowledge of quercetin's potential in treating TBI by clarifying its mechanisms of action.

Safety evaluation of adenosine, lidocaine and magnesium (ALM) intranasal therapy toward human nasal epithelial cells in vitro.

Adenosine, lidocaine and Mg2+ (ALM) solution is an emerging therapy that reduces secondary injury after intravenous administration in experimental models of traumatic brain injury (TBI). Intranasal delivery of ALM may offer an alternative route for rapid, point-of-care management of TBI. As a preliminary safety screen, we evaluated whether ALM exerts cytotoxic or inflammatory effects on primary human nasal epithelial cells (pHNEC) in vitro. Submerged monolayers and air-liquid interface cultures of pHNEC were exposed to media only, normal saline only, therapeutic ALM or supratherapeutic ALM for 15 or 60 min. Safety was measured through viability, cytotoxicity, apoptosis, cellular and mitochondrial stress, and inflammatory mediator secretion assays. No differences were found in viability or cytotoxicity in cultures exposed to saline or ALM for up to 60 min, with no evidence of apoptosis after exposure to supratherapeutic ALM concentrations. Despite comparable inflammatory cytokine secretion profiles and mitochondrial activity, cellular stress responses were significantly lower in cultures exposed to ALM than saline. In summary, data show ALM therapy has neither adverse toxic nor inflammatory effects on human nasal epithelial cells, setting the stage for in vivo toxicity studies and possible clinical translation of intranasal ALM therapy for TBI treatment.

Viscoelastic cues to induce stem cell migration and neuronal differentiation in cell-free hydrogel-assisted TBI recovery

The concept of tissue-inducing biomaterials, such as osteoinductive biomaterials, has inspired the design of regenerative material with biomimetic cues to manipulate cell/tissue responses but has been little applied for neuroinduction in traumatic brain injury (TBI) treatment. Meanwhile, material design has typically focused on elasticity without viscoelasticity taken into consideration. Here, guided by the intrinsic viscoelasticity of brain tissue and the decisive role of viscoelasticity in cell-matrix interactions, we developed a family of brain-mimicking hydrogels, in which the viscoelasticity can be tuned over a wide range under the premise that hydrogels have a low modulus comparable to that of brain tissue. Then, we revealed the promoted migration of stem cells on the viscoelastic hydrogel resulted from the increased number of motor − clutch pairs and filopodia protrusions, as well as their enhanced neuronal differentiation. In a rat TBI model, the cell-free viscoelastic hydrogel successfully induced endogenous stem cells to migrate into lesions and differentiate into neurons, contributing to brain tissue regeneration and neurological function restoration. This study reveals the great promise of biomimetic viscoelastic matrices for TBI treatment, and simultaneously, provides intriguing insights for the design of tissue-inducing biomaterials.

An injectable refrigerated hydrogel for inducing local hypothermia and neuroprotection against traumatic brain injury in mice

BackgroundHypothermia is a promising therapy for traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI patients in clinical studies are inconsistent due to several severe side effects. Here, an injectable refrigerated hydrogel was designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. Hydrogel has four advantages: (1) It can be injected into injured sites after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) Hydrogels can biodegrade and be used for controlled drug release. (3) Released T1AM can induce hypothermia. (4) This hydrogel has increased medical value given its simple operation and ability to achieve timely treatment.MethodsPol/T hydrogels were prepared by a low-temperature mixing method and characterized. The effect of the Pol/T hydrogel on traumatic brain injury in mice was studied. The degradation of the hydrogel at the body level was observed with a small animal imager. Brain temperature and body temperature were measured by brain thermometer and body thermometer, respectively. The apoptosis of peripheral nerve cells was detected by immunohistochemical staining. The protective effect of the hydrogels on the blood–brain barrier (BBB) after TBI was evaluated by the Evans blue penetration test. The protective effect of hydrogel on brain edema after injury in mice was detected by Magnetic resonance (MR) in small animals. The enzyme linked immunosorbent assay (ELISA) method was used to measure the levels of inflammatory factors. The effects of behavioral tests on the learning ability and exercise ability of mice after injury were evaluated.ResultsThis hydrogel was able to cool the brain to hypothermia for 12 h while maintaining body temperature within the normal range after TBI in mice. More importantly, hypothermia induced by this hydrogel leads to the maintenance of BBB integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI in mice. This cooling method could be developed as a new approach for hypothermia treatment in TBI patients.ConclusionOur study showed that injectable and biodegradable frozen Pol/T hydrogels to induce local hypothermia in TBI mice can be used for the treatment of traumatic brain injury.Graphical

Edaravone Alleviates Traumatic Brain Injury by Inhibition of Ferroptosis via FSP1 Pathway.

Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.

Management of traumatic brain injury in India: A protocol for systematic review and meta-analysis

Abstract* Introduction This systematic review and meta-analysis protocol aims to evaluate the management of traumatic brain injury (TBI) in India, addressing a critical gap in the understanding and treatment of TBI in low- and middle-income countries (LMICs). Despite advancements in healthcare focusing primarily on communicable diseases, TBI remains a leading cause of death and disability worldwide, significantly affecting the quality of life of patients and their families. Recent interest has surged in platelet-rich plasma (PRP) as a novel treatment for TBI, necessitating a comprehensive review of its therapeutic benefits. Methodology The study will source articles from PubMed, EMBASE, SCOPUS, and the Cochrane Central Register of Controlled Trials, targeting a range of studies including randomized controlled trials (RCTs), observational studies, and cohort studies. The review will exclude case series, review articles, and studies not reported in English. The primary aim is to collate evidence-based data on TBI management, with particular focus on the Indian healthcare context, evaluating the efficacy of current treatments and the potential role of PRP in enhancing neurological function and recovery post-TBI. Data management will involve a rigorous selection process, with independent reviewers conducting initial screenings and resolving discrepancies through discussion or arbitration. A PRISMA flow diagram will illustrate the study selection procedure, and a standardized form will be used for data extraction, ensuring thoroughness and consistency. Conclusion By highlighting current knowledge gaps, this systematic review and meta-analysis will guide future research directions and clinical practice, potentially revolutionizing TBI management strategies in LMICs. This protocol underscores the necessity for high-quality, evidence-based approaches to TBI treatment, aiming to improve patient outcomes through enhanced management practices.

The Role of Nanotechnology in Understanding the Pathophysiology of Traumatic Brain Injury.

Recently, traumatic brain injury (TBI) has been a growing disorder due to frequent brain dysfunction. The Glasgow Coma Scale expresses TBI as classified as having mild, moderate, or severe brain effects, according to the effects on the brain. Brain receptors undergo various modifications in their pathology through chemical synaptic pathways, leading to depression, Alzheimer's, and Parkinson's disease. These brain disorders can be controlled using central receptors such as dopamine, glutamate, and γ-aminobutyric acid, which are clearly explained in this review. Furthermore, there are many complications in TBI's clinical trials and diagnostics, leading to insignificant treatment, causing permanent neuro-damage, physical disability, and even death. Bio-screening and conventional molecular-based therapies are inappropriate due to poor preclinical testing and delayed recovery. Hence, modern nanotechnology utilizing nanopulsed laser therapy and advanced nanoparticle insertion will be suitable for TBI's diagnostics and treatment. In recent days, nanotechnology has an important role in TBI control and provides a higher success rate than conventional therapies. This review highlights the pathophysiology of TBI by comprising the drawbacks of conventional techniques and supports suitable modern alternates for treating TBI.

Therapeutic efficacy of cinnamein, a component of balsam of Tolu/Peru, in controlled cortical impact mouse model of TBI

Traumatic brain injury (TBI) remains a major health concern which causes long-term neurological disability particularly in war veterans, athletes and young adults. In spite of intense clinical and research investigations, there is no effective therapy to cease the pathogenesis of the disease. It is believed that axonal injury during TBI is potentiated by neuroinflammation and demyelination and/or failure to remyelination. This study highlights the use of naturally available cinnamein, also chemically known as benzyl cinnamate, in inhibiting neuroinflammation, promoting remyelination and combating the disease process of controlled cortical impact (CCI)-induced TBI in mice. Oral delivery of cinnamein through gavage brought down the activation of microglia and astrocytes to decrease the expression of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in hippocampus and cortex of TBI mice. Cinnamein treatment also stimulated remyelination in TBI mice as revealed by PLP and A2B5 double-labeling, luxol fast blue (LFB) staining and axonal double-labeling for neurofilament and MBP. Furthermore, oral cinnamein reduced the size of lesion cavity in the brain, improved locomotor functions and restored memory and learning in TBI mice. These results suggest a new neuroprotective property of cinnamein that may be valuable in the treatment of TBI.

Effect of Daytime versus Nighttime on Prehospital Care and Outcomes after Severe Traumatic Brain Injury.

Background/Objectives: Severe traumatic brain injury (TBI) is a frequent cause of morbidity and mortality worldwide. In the Netherlands, suspected TBI is a criterion for the dispatch of the physician-staffed helicopter emergency medical services (HEMS) which are operational 24 h per day. It is unknown if patient outcome is influenced by the time of day during which the incident occurs. Therefore, we investigated the association between the time of day of the prehospital treatment of severe TBI and 30-day mortality. Methods: A retrospective analysis of prospectively collected data from the BRAIN-PROTECT study was performed. Patients with severe TBI treated by one of the four Dutch helicopter emergency medical services were included and followed up to one year. The association between prehospital treatment during day- versus nighttime, according to the universal daylight period, and 30-day mortality was analyzed with multivariable logistic regression. A planned subgroup analysis was performed in patients with TBI with or without any other injury. Results: A total of 1794 patients were included in the analysis, of which 1142 (63.7%) were categorized as daytime and 652 (36.3%) as nighttime. Univariable analysis showed a lower 30-day mortality in patients with severe TBI treated during nighttime (OR 0.74, 95% CI 0.60-0.91, p = 0.004); this association was no longer present in the multivariable model (OR 0.82, 95% CI 0.59-1.16, p = 0.262). In a subgroup analysis, no association was found between mortality rates and the time of prehospital treatment in patients with combined injuries (TBI and any other injury). Patients with isolated TBI had a lower mortality rate when treated during nighttime than when treated during daytime (OR 0.51, 95% CI 0.34-0.76, p = 0.001). Within the whole cohort, daytime versus nighttime treatments were not associated with differences in functional outcome defined by the Glasgow Outcome Scale. Conclusions: In the overall study population, no difference was found in 30-day mortality between patients with severe TBI treated during day or night in the multivariable model. Patients with isolated severe TBI had lower mortality rates at 30 days when treated at nighttime.

Injectable Hydrogels Based on Hyaluronic Acid and Gelatin Combined with Salvianolic Acid B and Vascular Endothelial Growth Factor for Treatment of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) leads to structural damage in the brain, and is one of the major causes of disability and death in the world. Herein, we developed a composite injectable hydrogel (HA/Gel) composed of hyaluronic acid (HA) and gelatin (Gel), loaded with vascular endothelial growth factor (VEGF) and salvianolic acid B (SAB) for treatment of TBI. The HA/Gel hydrogels were formed by the coupling of phenol-rich tyramine-modified HA (HA-TA) and tyramine-modified Gel (Gel-TA) catalyzed by horseradish peroxidase (HRP) in the presence of hydrogen peroxide (H2O2). SEM results showed that HA/Gel hydrogel had a porous structure. Rheological test results showed that the hydrogel possessed appropriate rheological properties, and UV spectrophotometry results showed that the hydrogel exhibited excellent SAB release performance. The results of LIVE/DEAD staining, CCK-8 and Phalloidin/DAPI fluorescence staining showed that the HA/Gel hydrogel possessed good cell biocompatibility. Moreover, the hydrogels loaded with SAB and VEGF (HA/Gel/SAB/VEGF) could effectively promote the proliferation of bone marrow mesenchymal stem cells (BMSCs). In addition, the results of H&E staining, CD31 and α-SMA immunofluorescence staining showed that the HA/Gel/SAB/VEGF hydrogel possessed good in vivo biocompatibility and pro-angiogenic ability. Furthermore, immunohistochemical results showed that the injection of HA/Gel/SAB/VEGF hydrogel to the injury site could effectively reduce the volume of defective tissues in traumatic brain injured mice. Our results suggest that the injection of HA/Gel hydrogel loaded with SAB and VEGF might provide a new approach for therapeutic brain tissue repair after traumatic brain injury.

Transcranial direct current stimulation promotes angiogenesis and improves neurological function via the OXA-TF-AKT/ERK signaling pathway in traumatic brain injury.

Traumatic brain injury (TBI) and its resulting complications pose a major challenge to global public health, resulting in increased rates of disability and mortality. Cerebrovascular dysfunction is nearly universal in TBI cases and is closely associated with secondary injury after TBI. Transcranial direct current stimulation (tDCS) shows great potential in the treatment of TBI; however, the exact mechanism remains elusive. In this study, we performed in vivo and in vitro experiments to explore the effects and mechanisms of tDCS in a controlled cortical impact (CCI) rat model simulating TBI. In vivo experiments show that tDCS can effectively reduce brain tissue damage, cerebral edema and neurological deficits. The potential mechanism may be that tDCS improves the neurological function of rats by increasing orexin A (OXA) secretion, upregulating the TF-AKT/ERK signaling pathway, and promoting angiogenesis at the injury site. Cellular experiments showed that OXA promoted HUVEC migration and angiogenesis, and these effects were counteracted by the ERK1/2 inhibitor LY3214996. The results of Matrigel experiment in vivo showed that TNF-a significantly reduced the ability of HUVEC to form blood vessels, but OXA could rescue the effect of TNF-a on the ability of HUVEC to form blood vessels. However, LY3214996 could inhibit the therapeutic effect of OXA. In summary, our preliminary study demonstrates that tDCS can induce angiogenesis through the OXA-TF-AKT/ERK signaling pathway, thereby improving neurological function in rats with TBI.

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.