A benchtop brain injury model using resected donor tissue from patients with Chiari malformation.

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

Nanoparticle platforms for Neural cell transplantation therapy

Μία από τις σημαντικότερες προκλήσεις της σύγχρονης κλινικής πρακτικής είναι η θεραπεία των νευρολογικών διαταραχών. Η υψηλή εξειδίκευση και η μειωμένη ικανότητα αναγέννησης του νευρικού ιστού σε συνδυασμό με τη θέση των προσβεβλημένων περιοχών καθιστά τη διαχείριση των σχετικών διαταραχών δύσκολη ή και αδύνατη σύμφωνα με τα διαθέσιμα επιστημονικά δεδομένα. Οι ασθενείς υποφέρουν από τις συνέπειες μιας οξείας ή χρόνιας νευρολογικής πάθησης και οι γιατροί αδυνατούν να βοηθήσουν σε μεγάλο αριθμό παθολογιών που επηρεάζουν τον εγκέφαλο και το νωτιαίο μυελό. Η θεραπεία αυτών των ασθενειών έχει γίνει το «ιερό δισκοπότηρο» της σύγχρονης ιατρικής και υπάρχει αυξανόμενο ενδιαφέρον και έρευνα σε έναν τομέα που στοχεύει στη βελτίωση της ποιότητας ζωής και τελικά την έκβαση του ασθενούς. Η μεταμόσχευση νευρικών κυττάρων με δυνατότητα επιβίωσης, ενσωμάτωση στον νευρικό ιστό του ξενιστή και αποκατάσταση της φυσιολογικής λειτουργίας έχει δείξει πολλά υποσχόμενα αποτελέσματα τόσο σε κλινικές δοκιμές όσο και σε πειραματικές μελέτες. Ωστόσο, οι προκλήσεις για την επίτευξη του μέγιστου δυναμικού των μεταμοσχευθέντων κυττάρων όσον αφορά την ανατομική αναδόμηση και την ανάκτηση της φυσιολογικής λειτουργίας χρησιμοποιώντας συμβατικές τεχνολογίες και μεθόδους έχει προκαλέσει μια στασιμότητα στην πρόοδο της έρευνας. Η νανοτεχνολογία προσφέρει τα μέσα για να γεφυρώσει το χάσμα μεταξύ των νευρωνικών θεραπειών της τρέχουσας και της επόμενης γενιάς, αναπτύσσοντας μεθόδους λήψης, σήμανσης, παρακολούθησης, προστασίας και εμφύτευσης με ακρίβεια διαφορετικών τύπων μεταμοσχευμένων κυττάρων. Τα οργανικά και ανόργανα νανοσωματίδια μαζί με υβριδικές μορφές παρέχουν ευελιξία, φυσικά χαρακτηριστικά όπως αλληλεπίδραση με μαγνητικά πεδία, εκπομπή φωτεινής ακτινοβολίας και χρησιμεύουν ως φορείς βιοδραστικών αντιδραστηρίων ξεπερνώντας τους περιορισμούς από τα διάφορα βιολογικά εμπόδια στην επιτυχή μεταμόσχευση νευρικών κυττάρων. Οι τεχνικές της νανομηχανικής προσφέρουν την ενσωμάτωση γονιδίων που είναι σε θέση να εκφράσουν νευροτροφικές πρωτεΐνες που σταθεροποιούν το μικρο-περιβάλλον και κατά συνέπεια διευκολύνουν την επιβίωση των μεταμοσχευμένων κυττάρων και είναι πολύ υποσχόμενες για πιθανή μελλοντική έρευνα και κλινικές εφαρμογές.One of the major challenges of the recent clinical practice is the treatment of neurological disorders. The high specialization and decreased regeneration capacity of the neural tissue in combination with the location of the affected areas makes the management of the relevant disorders difficult or even impossible in terms of the recent scientific knowledge. Patients suffer the consequences of an acute or chronic neurological insult and the doctors are unable to help in a large number of pathologies affecting the brain and the spinal cord. The treatment of those diseases has become the “holy grail” of modern medicine and there is increasing interest and research in a field which aims to improve the quality of life and ultimately the patient’s outcome. The transplantation of nerve cells with the potential of survival, integration into the local host circuity and restoration of function has shown promising results in both clinical trials and experimental studies. However, the challenges of achieving the maximum potential of the grafted cells in terms of anatomical reconstruction and physiological recovery using conventional technologies and methods has caused a stagnation in the progress of the research. The nanotechnology offers the means of closing the gap between current and next generation neural treatments by developing the methods of harvesting, labelling, tracking, protecting and precisely delivering different types of transplant cells. Organic and inorganic nanoparticles along with hybrid forms provide versatility, physical characteristics such as interaction with magnetic fields, luminescent properties and serve as the carriers for bioactive reagents and overcome the limitations posed by different biological barriers on the successful transplantation of neural cells. The nanoengineering techniques offer the incorporation of genes which are able to express neurotrophic proteins stabilizing the micro-environment and consequently facilitating the survival of the transplanted cells with exciting possible future research and clinical applications

Extramedullary malignant melanotic schwannoma of the spine: Case report and an up to date systematic review of the literature.

Background Melanotic schwannoma is a rare variant of schwannoma. Extramedullary melanotic schwannoma originates in the vicinity of nerve roots mimicking other intervertebral disc disorders. Therefore, T1 and T2-weighted MRI sequences become an essential tool for diagnosis. Aside from case reports, no large studies exist to provide consensus on the signal intensities in T1 and T2-weighted MR imaging. Moreover, no clear evidence is available to delineate prognosis. Here, a case report is presented together with a subsequent systematic review of the literature regarding this rare entity. Case description A 45-year old female presented with a one-year history of insidious onset of neck pain and paraesthesia. Magnetic resonance imaging confirmed an extramedullary lesion along the C6 nerve root with T1-weighted hyperintensity and T2-weighted hypointensity. Despite two surgical decompressions and adjuvant immunotherapy, the patient unfortunately passed away due to metastatic progression. Discussion According to the systematic review conducted, in over half of the cases of extramedullary melanotic schwannoma, there is local reoccurrence and/or distal metastasis. Moreover, in 64.7% and 70.6% of the cases, the T1-weighted image of the lesion appears hyperintense and hypointense on a T2-weighted image, respectively. It is an aggressive variant of schwannoma, one of the most commonly observed extramedullary tumours presenting to neurosurgical practice. Conclusion Our results highlight that specific T1 and T2-weighted imaging findings can provide valuable information, enabling early suspicion, influencing the surgical aims and strategy and the timely commencement of relevant immunotherapy. Considering the poor prognosis, early adjuvant therapy with other modalities should be considered

Neurosurgical grade biomaterial, DuraGenTM, offers a promising matrix for protected delivery of neural stem cells in clinical cell therapies

AimsTransplantation of neural stem cells (NSCs) into sites of neurological injury is being investigated in clinical trials around the world. These important self-renewing and multipotent precursors can generate the major central nervous system cell types – neurons, astrocytes and oligodendrocytes, and have a major role in ‘restorative cell therapeutics’. However, high stem cell death in host tissue (>∼90%) following surgical delivery procedures is a critical barrier to clinical translation. Polymer-based encapsulating biomaterials offer protective matrices to improve stem cell survival but the majority of studies use laboratory based formulations unsuitable for human use. We have tested the potential of an FDA-approved, commercially manufactured neurosurgical material (DuraGenTM), used widely in neurosurgical procedures as a dural replacement material, as a matrix to support the delivery of NSC transplant populations.MethodsNSCs derived from the subventricular zone of postnatal mice were directly seeded into DuraGenTM sheets of optimised thickness. A range of key parameters underpinning the regenerative capacity of the stem cells were assessed up to 16 days using immuno-histochemical and 3D microscopy methods. These include NSC survival, expression of stem cell specific markers, NSC self-renewal / proliferative capacity and stem cell differentiation into the three daughter phenotypes.ResultsHigh NSC viability (>∼94%) was detected in the DuraGenTM matrix at all time points, with retention of stem cell marker expression. The matrix demonstrated the capacity to support growth of all three daughter phenotypes with cells generated in the expected proportions, indicating that stem cell fate is not altered by the material. Notably, there was clear evidence of ongoing cellular, maturation of neurons, astrocytes and oligodendrocytes (Fig 1) with evidence of simple neural network formation within the matrix.Fig 1.DOWNLOAD FIGUREOPEN IN NEW TABDOWNLOAD POWERPOINTFig 1.DuraGenTM promotes growth, proliferation and differentiation in neural stem cells and maturation of daughter cell types.A. Proliferating neural stem cells (arrows) reveal the proliferation-permissive profile of the DuraGenTM matrix. B. Clusters of cells derived from neural stem cells in the visible fibrous DuraGenTM matrix. C. Supportive astrocytes growing in the porous DuraGenTM matrix. D. Complex neuronal processes growing in the 3D DuraGenTM matrix.ConclusionOur findings support the concept that DuraGenTM is a highly promising biomaterial to support the protected delivery of NSC populations to sites of neurological pathology, with no adverse effects on the fate of the stem cell population. We consider our findings have important implications for the use of this material for delivery of a range of clinical transplant populations for human neural cell therapy. Our findings also raise the possibility that surgical delivery of pre-formed neural circuits may be feasible to replace multiple cell populations in injury foci.Conflict of interest statementThis project was funded by the Royal College of Physicians Wolfson Foundation intercalated degree award and the Association of Clinical Pathologists student research award

Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms.

Peer reviewed: TrueINTRODUCTION: Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates. METHODS AND ANALYSIS: The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study's aims. ETHICS AND DISSEMINATION: Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN17658526

Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms.

INTRODUCTION: Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates. METHODS AND ANALYSIS: The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study's aims. ETHICS AND DISSEMINATION: Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN17658526

Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms

Introduction Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates.Methods and analysis The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study’s aims.Ethics and dissemination Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals.Trial registration number ISRCTN17658526