The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation (cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this 'proof-of-concept' study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.

Space exploration is crucial for understanding our surroundings and establishing scientific concepts to explore, monitor, and save our planet's environment. However, the response of the human nervous system in the environment of space poses numerous challenges. Brain complexity explains the vulnerability and intrinsic difficulty of recalibration after disturbance. Over the millennia, the brain has evolved to function at 1-G. Studying the brain and its physiology in different environments may shed light on multiple conditions encountered on Earth that are yet to be solved and dictate collaboration at international levels. The nervous system is affected by several stressors due to microgravity, radiation, isolation, disruption of circadian rhythm, impaired sleep dynamics, and hypercapnia associated with space travel. In this article, we aim to review several aspects related to the nervous system in weightless conditions, as well as the development and future of the emerging field of "space neuroscience." Space neuroscience is a fascinating, embryonic field that requires significant development. The establishment of frameworks for the strategic development of space neuroscience is vital, as more research and collaboration are required to overcome these numerous and diverse challenges, minimize risks, and optimize crew performance during planetary operations.

Transient or permanent loss of tissue perfusion due to ischaemic stroke can lead to damage to the neurovasculature, and disrupt brain homeostasis, causing long-term motor and cognitive deficits. Despite promising pre-clinical studies, clinically approved neuroprotective therapies are lacking. Most studies have focused on neurons while ignoring the important roles of other cells of the neurovascular unit, such as astrocytes and pericytes. Astrocytes are important for the development and maintenance of the blood–brain barrier, brain homeostasis, structural support, control of cerebral blood flow and secretion of neuroprotective factors. Emerging data suggest that astrocyte activation exerts both beneficial and detrimental effects following ischaemic stroke. Activated astrocytes provide neuroprotection and contribute to neurorestoration, but also secrete inflammatory modulators, leading to aggravation of the ischaemic lesion. Astrocytes are more resistant than other cell types to stroke pathology, and exert a regulative effect in response to ischaemia. These roles of astrocytes following ischaemic stroke remain incompletely understood, though they represent an appealing target for neurovascular protection following stroke. In this review, we summarise the astrocytic contributions to neurovascular damage and repair following ischaemic stroke, and explore mechanisms of neuroprotection that promote revascularisation and neurorestoration, which may be targeted for developing novel therapies for ischaemic stroke.

T2* weighted MRI using GRE and SWI sequences can potentially prognosticate the recanalization rate and clinical outcomes in patients with acute ischaemic stroke, using susceptibility vessel sign (SVS) and prominent hypointense vessel sign (PHVS). A literature search on PubMed, EMBASE databases and other sources from inception up to 01 February 2020 was conducted. 15 studies which reported SVS and PHVS were included in qualitative synthesis. 9 studies on SVS were included in quantitative synthesis i.e. metaanalysis. Meta-analysis did not show any significant difference in the recanalization rate between SVS positive group and SVS negative group (RR = 0.95, 95% CI = 0.87 to 1.05, p = 0.33). Treatment subgroup analysis (intravenous thrombolysis, IVT or mechanical thrombectomy, MT only) does not show significant association between the SVS and IVT only (RR = 0.73, 95% CI = 0.51 to 1.05, P=0.09); or MT only groups (RR = 0.99, 95% CI = 0.90 to 1.09, P=0.90). No significant association between poor clinical outcome at 3 months and presence of SVS (RR = 1.42, 95% CI = 0.79 to 2.57, p = 0.24). Treatment subgroup analysis revealed significant association of the SVS and poor clinical outcome at 3 months in the MT only (RR = 0.67, 95% CI = 0.55 to 0.82, p = 0.0001) or no thrombolytic treatment (RR = 2.83, 95% CI = 1.69 to 4.75, p < 0.0001). In conclusion, there is a significant association between the presence of SVS and poor clinical outcome in patients who underwent MT or without treatment, and no definitive association between the presence of SVS and recanalization rate for acute ischemic stroke.

High transplant cell loss is a major barrier to translation of stem cell therapy for pathologies of the brain and spinal cord. Encapsulated delivery of stem cells in biomaterials for cell therapy is gaining popularity but experimental research has overwhelmingly used laboratory grade materials unsuitable for human clinical use - representing a further barrier to clinical translation. A potential solution is to use neurosurgical grade materials routinely used in clinical protocols which have an established human safety profile. Here, we tested the ability of Duragen Plus™ - a clinical biomaterial used widely in neurosurgical duraplasty procedures, to support the growth and differentiation of neural stem cells- a major transplant population being tested in clinical trials for neurological pathology. Genetic engineering of stem cells yields augmented therapeutic cells, so we further tested the ability of the Duragen Plus™ matrix to support stem cells engineered using magnetofection technology and minicircle DNA vectors- a promising cell engineering approach we previously reported (Journal of Controlled Release, 2016 a &b). The safety of the nano-engineering approach was analysed for the first time using sophisticated data-independent analysis by mass spectrometry-based proteomics. We prove that the Duragen Plus™ matrix is a promising biomaterial for delivery of stem cell transplant populations, with no adverse effects on key regenerative parameters. This advanced cellular construct based on a combinatorial nano-engineering and biomaterial encapsulation approach, could therefore offer key advantages for clinical translation.

Objectives Achieving neural regeneration after spinal cord injury (SCI) represents a significant challenge. Neural stem cell (NSC) therapy offers replacement of damaged cells and delivery of pro-regenerative factors, but >95% of cells die when transplanted to sites of neural injury. Biomaterial scaffolds provide cellular protective encapsulation to improve cell survival. However, current available scaffolds are overwhelmingly not approved for human use, presenting a major barrier to clinical translation. Surgical biomaterials offer the unique benefit of being FDA-approved for human implantation. Specifically, a neurosurgical grade material, DuraGen™, used predominantly for human duraplasty has many attractive features of an ideal biomaterial scaffold. Here, we have investigated the use of DuraGen™ as a 3D cell encapsulation device for potential use in combinatorial, regenerative therapies. Methods Primary NSCs were seeded into optimised sheets of DuraGen™. NSC growth and fate within DuraGen™ were assessed using 3D microscopic fluorescence imaging techniques. Results DuraGen™ supports the survival (ca 95% viability, 12 days) and 3D growth of NSCs. NSC phenotype, proliferative capacity and differentiation into astrocytes, neurons and oligodendrocytes were unaffected by DuraGen™. Conclusions A ‘combinatorial therapy’, consisting of NSCs protected within a DuraGen™ matrix, offers a potential clinically translatable approach for neural cell therapy.

with evidence of simple neural network formation within the matrix.

Corticosteroids (CSs) are widely used clinically, for example in pediatric respiratory distress syndrome, and immunosuppression to prevent rejection of stem cell transplant populations in neural cell therapy. However, such treatment can be associated with adverse effects such as impaired neurogenesis and myelination, and increased risk of cerebral palsy. There is increasing evidence that CSs can adversely influence key biological properties of neural stem cells (NSCs) but the molecular mechanisms underpinning such effects are largely unknown. This is an important issue to address given the key roles NSCs play during brain development and as transplant cells for regenerative neurology. Here, we describe the use of label-free quantitative proteomics in conjunction with histological analyses to study CS effects on NSCs at the cellular and molecular levels, following treatment with methylprednisolone (MPRED). Immunocytochemical staining showed that both parent NSCs and newly generated daughter cells expressed the glucocorticoid receptor, with nuclear localisation of the receptor induced by MPRED treatment. MPRED markedly decreased NSC proliferation and neuronal differentiation while accelerating the maturation of oligodendrocytes, without concomitant effects on cell viability and apoptosis. Parallel proteomic analysis revealed that MPRED induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. Our findings support the hypothesis that some neurological deficits associated with CS use may be mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects.

BACKGROUND:Malignant infarction of the middle cerebral artery (MCI) is life threatening. It is associated with a mortality as high as 80%, and survival often at the expense of serious disability. Limited success of medical therapies has resulted in decompressive craniectomy (DC) being increasingly used as a treatment for MCI, although evidence of its efficacy is inconclusive. In this study, the efficacy of DC in improving survival, or survival free of severe disability, was assessed. METHODS:A meta-analysis was performed to approximate the efficacy of DC for treating MCI, considering age and time to surgery. A systematic literature review was conducted on Medline, Embase, and Cochrane library databases to August 1, 2018. Death and severe disability at 3, 6, 12, and 36 months follow-up were assessed, comparing best medical therapy with DC. RESULTS:18 studies were eligible for inclusion and represented 987 individuals who received DC. Nine of these were randomized controlled trials (RCTs) (n = 374 DC). Early DC (<48 hours from onset of stroke) reduced mortality (odds ratio [OR] = 0.18, 95% confidence interval [CI] = 0.11, 0.29; P < 0.00001) but not unfavourable outcome (modified Rankin Scale [mRS] >4) (OR = 1.38, 95% CI = 0.47, 4.11; P = 0.56) at 12 months follow-up. This survival benefit was maintained regardless of age. CONCLUSION:Early DC reduces mortality but does not appear to improve favourable outcomes in patients younger or older than 60 years after MCI. RCTs incorporating quality of life assessments are warranted for MCI patients, in addition to defining the optimal timing and benefits of DC in older patients.

Olfactory ensheathing cells (OECs) promote axonal regeneration and improve locomotor function when transplanted into the injured spinal cord. A recent clinical trial demonstrated improved motor function in domestic dogs with spinal injury following autologous OEC transplantation. Their utility in canines offers promise for human translation, as dogs are comparable to humans in terms of clinical management and genetic/environmental variation. Moreover, the autologous, minimally invasive derivation of OECs makes them viable for human spinal injury investigation. Genetic engineering of transplant populations may augment their therapeutic potential, but relies heavily on viral methods which have several drawbacks for clinical translation. We present here the first proof that magnetic particles deployed with applied magnetic fields and advanced DNA minicircle vectors can safely bioengineer OECs to secrete a key neurotrophic factor, with an efficiency approaching that of viral vectors. We suggest that our alternative approach offers high translational potential for the delivery of augmented clinical cell therapies.

Cerebral vasospasm is a potentially incapacitating or lethal complication in patients with aneurysmal subarachnoid hemorrhage (SAH). The development of effective preventative and therapeutic interventions has been largely hindered by the fact that the underlying pathogenic mechanisms of cerebral vasospasm remain poorly understood. However, intensive research during the last 3 decades has identified certain mechanisms that possibly play a role in its development. Experimental data suggest that calcium‐dependent and ‐independent vasoconstriction is taking place during vasospasm. It appears that the breakdown products of blood in the subarachnoid space are involved, through direct and/or indirect pathways, in the development of vasospasm after SAH. Free radicals reactions, an imbalance between vasoconstrictor and vasodilator substances (endothelium derived substances, e.g., nitric oxide, endothelin; arachidonic acid metabolites, e.g., prostaglandins, prostacyclin), inflammatory processes, an upheaval of neuronal mechanisms that regulate vascular tone, endothelial proliferation, and apoptosis have all been put forward as causative and/or pathogenic factors. Translational research in the field of vasospasm has traditionally aimed to identify agents/interventions in order to block the cascades initiated after SAH. The combination of novel approaches such as cerebral microdialysis, magnetic resonance spectroscopy, proteomics, and lipidomics could serve a dual purpose: elucidating the complex pathobiochemistry of vasospasm and providing clinicians with tools for early detection of this feared complication. The purpose of this Mini‐Review is to provide an overview of the pathogenesis of cerebral vasospasm and of novel approaches used in basic and translational research. © 2008 Wiley‐Liss, Inc.

S100B is a calcium-binding protein found in Schwann cells in the peripheral nervous system, and in astrocytes in the central nervous system. It has multiple functions including the inhibition of protein phosphorylation through interacting with kinase substrates, regulating enzyme activity and interacting with cytoskeletal elements. It is also involved in calcium homeostasis, and is believed to have a role in cytosolic calcium buffering. In recent years it has been shown that S100B is elevated and released into the circulation in a wide variety of neuropathologic states. As such it has generated a great deal of interest as a surrogate biomarker for injury to the CNS. It has been shown to be raised in many organic brain disorders such as traumatic brain injury, subarachnoid haemorrhage, stroke, epilepsy, multiple sclerosis, Parkinson's disease and hydrocephalus. In addition to this there is now clinical and laboratory evidence that it is raised in neuropsychiatric disorders such as schizophrenia, depression, bipolar disorder, anxiety, post-traumatic stress disorder and neuropsychiatric systemic lupus erythematosus. S100B has great potential to become a specific neurological screening tool that is predictive of outcome and reactive to treatments.

In recent years there has been a proliferation of interest in the brain‐specific protein S100B, its many physiologic roles, and its behaviour in various neuropathologic conditions. Since the mid‐1960s, its wide variety of intracellular and extracellular activities has been elucidated, and it has also been implicated in an increasing number of central nervous system (CNS) disorders. S100B is part of a superfamily of proteins, some of which (including S100B) have been implicated as calcium‐dependent regulatory proteins that modulate the activity of effector proteins or cells. S100B is primarily an astrocytic protein. Within cells, it may have a role in signal transduction, and it is involved in calcium homeostasis. Information about the functional implication of S100B secretion by astrocytes into the extracellular space is scant but there is substantial evidence that secreted glial S100B exerts trophic or toxic effects depending on its concentration. This review summarises the historic development and current knowledge of S100B, including recent interesting findings relating S100B to a diversity of CNS pathologies such as traumatic brain injury, Alzheimer's disease, Down's syndrome, schizophrenia, and Tourette's syndrome. These broad implications have led some workers to describe S100B as ‘the CRP (C‐reactive protein) of the brain.’ This review also examines S100B's potential role as a neurologic screening tool, or biomarker of CNS injury, analogous to the role of CRP as a marker of systemic inflammation. © 2007 Wiley‐Liss, Inc.