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Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, los autores pertenecientes a la UAM y el nombre del grupo de colaboración, si lo hubiere, We present the design, fabrication, and characterization of an implantable neural interface based on anisotropic magnetoresistive (AMR) magnetic-field sensors that combine reduced size and high performance at body temperature. The sensors are based on La0.67Sr0.33MnO3 (LSMO) as a ferromagnetic material, whose epitaxial growth has been suitably engineered to get uniaxial anisotropy and large AMR output together with low noise even at low frequencies. The performance of LSMO sensors of different film thickness and at different temperatures close to 37 °C has to be explored to find an optimum sensitivity of ∼400%/T (with typical detectivity values of 2 nT·Hz-1/2 at a frequency of 1 Hz and 0.3 nT·Hz-1/2 at 1 kHz), fitted for the detection of low magnetic signals coming from neural activity. Biocompatibility tests of devices consisting of submillimeter-size LSMO sensors coated by a thin poly(dimethyl siloxane) polymeric layer, both in vitro and in vivo, support their high suitability as implantable detectors of low-frequency biological magnetic signals emerging from heterogeneous electrically active tissues

No information is available regarding priorities for pediatric-onset spinal cord injury (SCI). This study described the Health and Life (HL) domain priorities of youth with pediatric-onset SCI and their parents/caregivers living in Spain.A cross-sectional survey.Two SCI rehabilitation centers.Sixty participants, youth with pediatric-onset SCI (n = 26) and parents/caregivers (n = 34).Not applicable.Median overall priorities calculated on the basis of importance, unhappiness, and research measured with a new survey of pediatric HL domains and rated using a 5-point Likert Scale.A total of 60 surveys were received providing information on 35 individuals with SCI: 2-7-year-olds (25.7%), 8-12-year-olds (22.9%), 13-17-year-olds (31.4%), and 18-25-year-olds (20.0%). The top three overall HL priorities reported by parents/caregivers of 2-12-year-olds were "parenthood expectations" (84%), "leg/foot movement" (83%), and "bladder" function (83%), compared to "dressing/undressing" (78%), "walking/ability to move" (77%) and "bladder" function (77%) rated for 13-25-year-olds. "Sit-to-stand" (79%), "leg/foot movement" (78%) and "arm/hand movement" (77%) were reported as priorities by 13-25-year-olds. The 13-25-year-olds highlighted "sit-to-stand" (100%), "eating/drinking" (54%), and "physical function" (94%) as their top unhappiness, importance, and research priorities, respectively. Significant differences between tetraplegia and paraplegia were found in "mobility in the community" (unhappiness item) for 13-25-years-old.Health domains were considered the top overall HL priorities by parents/caregivers of 13-25-year-olds, compared to life domains reported for their 2-12-year-olds. This survey will aid rehabilitation professionals to engage stakeholders to implement a comprehensive SCI management program for the pediatric population.

Background: The Box and Block clinical test is a validated and standardized scale for use in the clinical environment that allows the assessment of rough manipulative dexterity. Proposing virtual methods to carry out these assessments is an attempt to eliminate some of the subjectivity that the test may entail depending on the observer and the way in which the patient gives instructions. Applied to the assessment of skills after neurological pathologies, previous experiences in stroke patients have been found. So, this work was centered on the Spinal Cord Injury. Objective: To present the virtual application of the Box and Block scale, as well as details about its design and development for its manipulation based on Leap Motion Controller. Methodology: The relationship between the results obtained in the actual test and in the virtual application in healthy subjects and, mostly, patients with cervical spinal cord injury is analyzed, obtaining a high correlation index between both tests’ performance. Results: A high correlation index was obtained between both tests performance, the real and virtual version of the Box and Block Test. Conclusion: This virtual test can serve as an element to evaluate in the future the effectiveness of the RehabHand prototype based on virtual reality applications with a therapeutic and a rehabilitative sense that, manipulated from Leap Motion Controller, allow the improvement of the manipulative dexterity in patients with neurological diseases such as spinal cord injury.

BACKGROUND: There is a growing interest in the use of technology in the field of neurorehabilitation in order to quantify and generate knowledge about sensorimotor disorders after neurological diseases, understanding that the technology has a high potential for its use as therapeutic tools. Taking into account that the rehabilitative process of motor disorders should extend beyond the inpatient condition, it’s necessary to involve low-cost technology, in order to have technological solutions that can approach the outpatient period at home. OBJECTIVE: to present the virtual applications-based RehabHand prototype for the rehabilitation of manipulative skills of the upper limbs in patients with neurological conditions and to determine the target population with respect to spinal cord injured patients. METHODS: Seven virtual reality applications have been designed and developed with a therapeutic sense, manipulated by means of Leap Motion Controller. The target population was determined from a sample of 40 people, healthy and patients, analyzing hand movements and gestures. RESULTS: The hand movements and gestures were estimated with a fitting rate between the range 0.607–0.953, determining the target population by cervical levels and upper extremity motor score. CONCLUSIONS: Leap Motion is suitable for a determined sample of cervical patients with a rehabilitation purpose.

Spinal cord injury (SCI) is characterized by the disruption of neuronal axons and the creation of an inhibitory environment for spinal tissue regeneration. For decades, researchers and clinicians have been devoting a great effort to develop novel therapeutic approaches which include the fabrication of biocompatible implants that could guide neural tissue repair in the lesion site in an attempt to recover the functionality of the nervous tissue. In this context, although fiberlike structures have been hypothesized to serve as a topographical guidance for axonal regrowth, work on the exploration of this type of materials is still limited for SCI. Aiming to develop such guidance platforms, we recently designed and explored in vitro reduced graphene oxide materials in the shape of microfibers (rGO-MFs). After preliminary studies to assess the feasibility of their implantation at the injured spinal cord in vivo, no evident signs of subacute local toxicity were noticed (10 days of implantation). In this work, we specifically examine for the first time the regenerative potential of these scaffolds, slightly modified in their fabrication for improved reproducibility, when chronically interfaced with a cervical spinal cord injury. After extensive characterization of their physicochemical properties and in vitro experiments with neural progenitor cells, their neural regenerative capacity in vivo is investigated in a rat experimental model of SCI after 4 months of implantation (chronic state). Behavioral tests involving the use of forelimbs are performed. Immunofluorescence studies evidence that rGO-MFs scaffolds foster the presence of neuronal structures along with blood vessels both within the epicenter and in the surroundings of the lesion area. Moreover, the inflammatory response does not worsen by the presence of this material. These findings outline the potential of rGO-MF-based scaffolds to promote regenerative features at the injured spinal cord such as axonal and vascular growth. Further studies including biological functionalization might improve their therapeutic potential by a synergistic effect of topographical and chemical cues, thus boosting neural repair after SCI.

Progress in the clinical application of recording and stimulation devices for neural diseases is still limited, mainly because of suboptimal material engineering and unfavorable interactions with biological entities. Nanotechnology is providing upgraded designs of materials to better mimic the native extracellular environment and attain more intimate contacts with individual neurons, besides allowing for the miniaturization of the electrodes. However, little progress has been done to date on the understanding of the biological impact that such neural interfaces have on neural network maturation and functionality. In this work, we elucidate the effect of a gold (Au) highly ordered nanostructure on the morphological and functional interactions with neural cells and tissues. Alumina-templated Au nanostructured electrodes composed of parallel nanowires of 160 nm in diameter and 1.2 μm in length (Au-NWs), with 320 nm of pitch, are designed and characterized. Equivalent non-structured Au electrodes (Au-Flat) are used for comparison. By using diverse techniques in in vitro cell cultures including live calcium imaging, we found that Au-NWs interfaced with primary neural cortical cells for up to 14 days allow neural networks growth and increase spontaneous activity and ability of neuronal synchronization, thus indicating that nanostructured features favor neuronal network. The enhancement in the number of glial cells found is hypothesized to be behind these beneficial functional effects. The in vivo effect of the implantation of these nanostructured electrodes and its potential relevance for future clinical applicability has been explored in an experimental model of rat spinal cord injury. Subacute responses to implanted Au-NWs show no overt reactive or toxic biological reactions besides those triggered by the injury itself. These results highlight the translational potential of Au-NWs electrodes for in vivo applications as neural interfaces in contact with central nervous tissues including the injured spinal cord.

Understanding neural physiopathology requires advances in nanotechnology-based interfaces, engineered to monitor the functional state of mammalian nervous cells. Such interfaces typically contain nanometer-size features for stimulation and recording as in cell-non-invasive extracellular microelectrode arrays. In such devices, it turns crucial to understand specific interactions of neural cells with physicochemical features of electrodes, which could be designed to optimize performance. Herein, versatile flexible nanostructured electrodes covered by arrays of metallic nanowires are fabricated and used to investigate the role of chemical composition and nanotopography on rat brain cells in vitro. By using Au and Ni as exemplary materials, nanostructure and chemical composition are demonstrated to play major roles in the interaction of neural cells with electrodes. Nanostructured devices are interfaced to rat embryonic cortical cells and postnatal hippocampal neurons forming synaptic circuits. It is shown that Au-based electrodes behave similarly to controls. Contrarily, Ni-based nanostructured electrodes increase cell survival, boost neuronal differentiation, and reduce glial cells with respect to flat counterparts. Nonetheless, Au-based electrodes perform superiorly compared to Ni-based ones. Under electrical stimulation, Au-based nanostructured substrates evoke intracellular calcium dynamics compatible with neural networks activation. These studies highlight the opportunity for these electrodes to excite a silent neural network by direct neuronal membranes depolarization.

Study designCohort study of patients with spinal cord injury (SCI)ObjectivesTo describe the clinical and analytical features of a Covid-19 infected cohort with SCI to contribute new knowledge for a more accurate diagnosis and to outline prevention measures.SettingThis study was conducted at the National Hospital for Paraplegics (Toledo, Spain).MethodsA cohort analysis of seven patients with SCI infected by Covid-19 was carried out. Diagnosis was confirmed with reverse transcriptase polymerase chain reaction (RT-PCR) of nasal exudate or sputum samples. Clinical, analytical and radiographic findings were registered.ResultsRT-PCR detected COVID-19 infection in all patients, affecting males and people with a cervical level of injury more often (5 out 7). The average delay for diagnostic confirmation was 4 days (interquartile range, 1-10). Fever was the most frequent symptom (6 out of 7). The second most common symptom was asthenia (4 out of 7), followed by dyspnea, cough and expectoration (3 out of 7 for each symptom). The MEWS score for Covid-19 severity rating was classified as severe in 5 out of 7. All but one patient showed radiological alterations evident in chest X-Rays at the time of diagnosis. All patients recovered gradually.ConclusionOur patients with SCI and Covid-19 infection exhibited fewer symptoms than the general population. Furthermore, they presented similar or greater clinical severity. The clinical evolution was not as pronounced as had been expected. This study recommends close supervision of the SCI population to detect early compatible signs and symptoms of Covid-19 infection.

Neural tissue engineering approaches show increasing promise for the treatment of neural diseases including spinal cord injury, for which an efficient therapy is still missing. Encouraged by both positive findings on the interaction of carbon nanomaterials such as graphene with neural components and the necessity of more efficient guidance structures for neural repair, we herein study the potential of reduced graphene oxide (rGO) microfibers as substrates for neural growth in the injured central neural tissue. Compact, bendable, and conductive fibers are obtained. When coated with neural adhesive molecules (poly-L-lysine and N-cadherin), these microfibers behave as supportive substrates of highly interconnected cultures composed of neurons and glial cells for up to 21 days. Synaptic contacts close to rGO are identified. Interestingly, the colonization by meningeal fibroblasts is dramatically hindered by N-cadherin coating. Finally, in vivo studies reveal the feasible implantation of these rGO microfibers as a guidance platform in the injured rat spinal cord, without evident signs of subacute local toxicity. These positive findings boost further investigation at longer implantation times to prove the utility of these substrates as components of advanced therapies for enhancing repair in the damaged central neural tissue including the injured spinal cord., This work was supported by the Instituto de Salud Carlos III-MINECO-FEDER (CP13/00060), the Ministerio de Economía y Competitividad, and the Fondo Europeo de Desarrollo Regional (MAT2016-78857-R and MAT2015-68639-R, MINECO/FEDER, UE). It was also partially funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 737116.

The COVID-19 pandemic represents an unprecedented global challenge in this century. COVID-19 is a viral respiratory infection, yet the clinical characteristics of this infection differ in spinal cord injury patients from those observed in the general population. Cough and asthenia are the most frequent symptoms in this population. Moreover, infected spinal cord injury patients rarely present complications that require admission to an Intensive Care Unit, in contrast to the general population. Thus, there is a clear need to understand how COVID-19 affects spinal cord injury patients from a molecular perspective. Here, we employed an -omics strategy in order to identify variations in protein abundance in spinal cord injury patients with and without COVID-19. After a quantitative differential analysis using isobaric tags and mass spectrometry and a verification phase, we have found differences mainly related to coagulation and platelet activation. Our results suggest a key role of heparin in the response of spinal cord injury patients to COVID-19 infection, showing a significant correlation between these proteins and heparin dose. Although the number of patients is limited, these data may shed light on new therapeutic options to improve the management these patients and, possibly, those of the general population as well., This research was funded by the Consejo Superior de InvestigacionesCientíficas (CSIC) through the project PIE 202020E108, the Instituto de Salud Carlos III through the project PI18/00995 (co-funded by European Regional Development Fund/European Social Fund - “Investing in your future”) and Grant PRB3 (IPT17/0019—ISCIII-SGEFI/ERDF). The MCNU (PGC2018-097019-B-I00) and La Caixa (HR17-00247).

[ES] En los pacientes con lesión medular cervical (LMC) se ve comprometida en mayor o menor medida la fuerza de las extremidades superiores, lo que se traduce en dependencia para las AVDs. Si la lesión es incompleta, puede preservarse la capacidad de marcha. En este contexto, resulta difícil realizar un diagnóstico clínico correcto y los equipos de fotogrametría constituyen una herramienta de gran valor para objetivar las secuelas motoras. El objetivo es presentar la metodología biomecánica de miembros superiores e inferiores aplicada a un caso de estudio. Se trata de un paciente varón de 61 años que padeció una LMC incompleta de etiología traumática que, previamente, había sufrido un TCE. Mediante fotogrametría se analizaron los recorridos articulares de la cadera, rodilla y tobillo durante los ciclos de la marcha y del hombro, codo y muñeca, así como una serie de índices cinemáticos descriptores del movimiento del miembro superior. Se obtuvo un patrón de marcha muy simétrico en ambos miembros inferiores. Sin embargo, la funcionalidad global y los índices de destreza en ambos miembros superiores presentaron una marcada asimetría entre ellos. Las herramientas biomecánicas evidencian aspectos del control motor no fácilmente visibles con los tests clínicos y que perfeccionan el diagnóstico de los casos complejos., [EN] In cervical spinal cord injured (SCI) patients, upper limbs strength is affected to a greater or lesser extent, producing dependence on the execution of ADLs. If the lesion is incomplete, the gait ability can be preserved. In this context, it is difficult to make a correct clinical diagnosis and the photogrammetry equipments constitute a tool of great value to determine with objectivity motor sequelae. The objective is to present the biomechanics methodology of upper and lower limbs applied to a case study. It is a 61- year-old male patient who suffered an incomplete SCI of traumatic etiology that had previously suffered a traumatic brain injury. Through photogrammetry, the range of motion of the hip, knee and ankle joints were analyzed during the cycles of the gait and the shoulder, elbow and wrist joints, as well as a series of kinematic indices describing the ability and dexterity of the upper limb movement. A very symmetrical gait pattern was obtained in both lower limbs. However, overall functionality and skill indices in both upper limbs present a high asymmetry between them. Biomechanical tools demonstrate aspects of motor control not easily visible with clinical tests and perfect diagnosis of complex cases

Neural diseases at the central nervous system including spinal cord injury (SCI) remain therapeutic challenges. Graphene materials are being delineated as alternative tools for neural repair. Herein, the regenerative ability of reduced graphene oxide (rGO) scaffolds to support pivotal features of neural repair at 4 months after SCI is assessed by an interdisciplinary approach. 3D randomly porous foams have been prepared in mechanical compliance with neural cells and tissues (Young's modulus of 1.3 ± 1.0 kPa) as demonstrated by atomic force microscopy techniques applied ex vivo. After implantation, the significant increase in Young's modulus caused by massive cell/protein infiltration does not alter the mechanical performance of the contralateral spinal cord but provides mechanical stability to the lesion. These aerogels appear fully vascularized and populated with neurites, some of them being myelinated excitatory axons. Clinically-inspired magnetic resonance imaging studies demonstrate that the scaffolds significantly reduce perilesional damage with respect to rats without implants and cause no compressive damage in the contralateral hemicord and rostral/caudal regions. The rGO implants do not either alter the rat spontaneous behaviour or induce toxicity in major organs. Finally, preliminary data suggest hints of rGO sheets dissociation and eventual degradation at the injured spinal cord for the first time. In summary, these 3D porous rGO scaffolds are able to induce, without any further biological functionalization, a compilation of positive effects that have been rarely described before, if ever, for any other material implanted in the injured spinal cord to date., This work was supported by the Ministerio de Economía y Competitividad and the Fondo Europeo de Desarrollo Regional (MAT2016-78857-R, MAT2016-76507-R and MAT2016-80394-R, MINECO/FEDER, UE) and the European Research Council ERC-AdG-340177 (3DNanoMech).

Incomplete cervical lesion is the most common type of human spinal cord injury (SCI) and causes permanent paresis of arm muscles, a phenomenon still incompletely understood in physiopathological and neuroanatomical terms. We performed spinal cord hemisection in adult rats at the caudal part of the segment C6, just rostral to the bulk of triceps brachii motoneurons, and analyzed the forces and kinematics of locomotion up to 4 months postlesion to determine the nature of motor function loss and recovery. A dramatic (50%), immediate and permanent loss of extensor force occurred in the forelimb but not in the hind limb of the injured side, accompanied by elbow and wrist kinematic impairments and early adaptations of whole-body movements that initially compensated the balance but changed continuously over the follow-up period to allow effective locomotion. Overuse of both contralateral legs and ipsilateral hind leg was evidenced since 5 days postlesion. Ipsilateral foreleg deficits resulted mainly from interruption of axons that innervate the spinal cord segments caudal to the lesion, because chronic loss (about 35%) of synapses was detected at C7 while only 14% of triceps braquii motoneurons died, as assessed by synaptophysin immunohistochemistry and retrograde neural tracing, respectively. We also found a large pool of propriospinal neurons projecting from C2-C5 to C7 in normal rats, with topographical features similar to the propriospinal premotoneuronal system of cats and primates. Thus, concurrent axotomy at C6 of brain descending axons and cervical propriospinal axons likely hampered spontaneous recovery of the focal neurological impairments.

Attractive physic-chemical features of graphene oxide (GO) and promising results in vitro with neural cells encourage its exploration for biomedical applications including neural regeneration. Fueled by previous findings at the subacute state, we herein investigate for the first time chronic tissue responses (at 30 days) to 3D scaffolds composed of partially reduced GO (rGO) when implanted in the injured rat spinal cord. These studies aim to define fibrotic, inflammatory and angiogenic changes at the lesion site induced by the chronic implantation of these porous structures. Injured animals receiving no scaffolds show badly structured lesion zones and more cavities than those carrying rGO materials, thus pointing out a significant role of the scaffolds in injury stabilization and sealing. Notably, GFAP cells and pro-regenerative macrophages are evident at their interface. Moreover, rGO scaffolds support angiogenesis around and, more importantly, inside their structure, with abundant and functional new blood vessels in whose proximities inside the scaffolds some regenerated neuronal axons are found. On the contrary, lesion areas without rGO scaffolds show a diminished quantity of blood vessels and no axons at all. These findings provide a foundation for the usefulness of graphene-based materials in the design of novel biomaterials for spinal cord repair and encourage further investigation for the understanding of neural tissue responses to this kind of materials in vivo., This work was supported by the Instituto de Salud Carlos III and the Ministerio de Economía y Competitividad (Grant CP13/00060), co-financed by FEDER. AGM and MCS acknowledge ISCIII-MINECO-FEDER for respective contracts.

The increasing prevalence and high sanitary costs of lesions affecting the central nervous system (CNS) at the spinal cord are encouraging experts in different fields to explore new avenues for neural repair. In this context, graphene and its derivatives are attracting significant attention, although their toxicity and performance in the CNS in vivo remains unclear. Here, the subacute tissue response to 3D flexible and porous scaffolds composed of partially reduced graphene oxide is investigated when implanted in the injured rat spinal cord. The interest of these structures as potentially useful platforms for CNS regeneration mainly relies on their mechanical compliance with neural tissues, adequate biocompatibility with neural cells in vitro and versatility to carry topographical and biological guidance cues. Early tissue responses are thoroughly investigated locally (spinal cord at C6 level) and in the major organs (i.e., kidney, liver, lung, and spleen). The absence of local and systemic toxic responses, along with the positive signs found at the lesion site (e.g., filler effect, soft interface for no additional scaring, preservation of cell populations at the perilesional area, presence of M2 macrophages), encourages further investigation of these materials as promising components of more efficient material-based platforms for CNS repair., This work was supported by the Instituto de Salud Carlos III (ISCIII) and Ministerio de Economía y Competitividad (MINECO) (Grant CP13/00060), co‐financed by FEDER funding, and MINECO (Grants MAT2011‐25329 and MAT2013‐43229‐R). AGM and MCS acknowledge ISCIII‐MINECO for respective contracts associated to project CP13/00060.

Incomplete cervical lesion is the most common type of human spinal cord injury (SCI) and causes permanent paresis of arm muscles, a phenomenon still incompletely understood in physiopathological and neuroanatomical terms. We performed spinal cord hemisections in adult rats at the caudal part of the segment C6, and analysed the forces and kinematics of locomotion up to four months post-injury to determine the nature of motor function loss and recovery. A severe (50 %), immediate and permanent loss of extensor force occurred in the forelimb but not in the hindlimb of the injured side, accompanied by elbow and wrist kinematic impairments and early adaptations of whole-body movements that initially compensated the balance but changed continuously over the follow-up period to allow effective locomotion.

The rat is widely used for modeling human spinal cord injury (SCI) and paraplegia. However, quadruped animals adapt trunk, forelimb and hindlimb movements to compensate for deficits, improving their behavioral scores and complicating the interpretation of spontaneous and treatment-induced function recovery. The kinematics of locomotion was studied in rats, both normal and after SCI (T9 contusion), and variables indicative of hindlimb function were related to brain-spinal cord connections (BSCC) spared during lesioning. Normal animals showed forward velocities characteristic of fast walking. The hind paw was placed approximately three centimeters in front of the hip at the initial contact. Hip height decreased during the first third of hindlimb stance and increased later. Mild and moderate spinal cord contusions destroyed the gray matter and adjacent axons but spared the ventrolateral tracts to various degrees. Injured animals placed the hindpaw in a more caudal position than normal and showed reduced forward velocity and hip height. Knee extension was also impaired, and both hindlimb and forelimb steps were adapted to compensate for the deficits. BSCC was estimated by averaging the transverse area of white matter at the lesion epicenter and the percentage of brain neurons labeled after peroxidase injection into L2 and L3. Recovery of hindlimb motor function was proportional to the amount of BSCC. On average, injured animals retained 18% of BSSC and recovered 23% of hindlimb function. These findings show that kinematic analysis is a reliable tool for assessing locomotor deficits and compensations and suggest limited spontaneous motor plasticity after SCI.