Biohybrids for Neural Tracts Regeneration

[ES] Las lesiones del sistema nervioso que implican la interrupción de haces axonales son devastadoras para el individuo. La regeneración autónoma de los tractos axonales dañados o degenerados es poco frecuente, ya que intervienen una gran cantidad de factores que limitan esta recuperación. Hoy en día, la medicina convencional no cuenta con tratamientos efectivos y exitosos para estas lesiones, y el tratamiento de los síntomas suele ser la mejor solución. Para revertirlo y lograr la reconexión funcional de las neuronas, la ingeniería de tejidos actualmente opta por el uso de soportes tridimensionales biocompatibles, células y moléculas bioactivas. Específicamente, una de las estrategias propuestas han sido los conductos nerviosos guiados, no solo para lesiones de nervios periféricos sino también para tractos del sistema nervioso central. En esta Tesis Doctoral, se propone la combinación de un conducto tubular hueco de ácido hialurónico (HA) relleno con fibras de ácido poli-L-lactida (PLA) en su lumen, y con células de Schwann (SC) pre-cultivadas como células de soporte de la extension axonal para superar los obstáculos que limitan la regeneración de axones in vivo. Se ha demostrado que el conducto de HA y las fibras de PLA mantienen la proliferación de las SC, las cuales forman una estructura cilíndica denominada 'vaina de SC' en la pared interna del lumen del conducto y a su vez crecen de forma direccional en las fibras de PLA. El conjunto unidireccional paralelo formado por las fibras PLA y las SC recapitula las características direccionales de los tractos axonales en el sistema nervioso. Al sembrar un explante de ganglio de la raíz dorsal (DRG) en uno de los extremos del conducto, se ha conseguido el crecimiento de los axones del DRG y se ha estudiado las características de las SC, los axones crecidos y su asociación, comprobando que el biohíbrido es capaz de soportar el crecimiento axonal. Además, se propone un concepto multimodular para superar las limitaciones típicas de la regeneración axonal a larga distancia, con la combinación de haces de fibras de PLA en el lumen de varios conductos o módulos de HA individuales más cortos que se posicionan uno detrás del otro, diseñando conductos nerviosos guiados con la longitud deseada, junto con SC pre-cultivadas. El conducto multimodular demostró ser eficaz para promover el crecimiento dirigido de axones. Además, se ha desarrollado un constructo compuesto por la estructura formada por las fibras de PLA y las SC, denominado 'cordón neural', tras eliminar el conducto de HA, lo que abre la puerta a la generación de una estructura neural in vitro para su trasplante.[CA] Les lesions de el sistema nerviós que impliquen la interrupció de feixos axonals són devastadores per a l'individu. La regeneració autònoma dels tractes axonals danyats o degenerats és poc freqüent, ja que intervenen una gran quantitat de factors que limiten aquesta recuperació. Avui dia, la medicina convencional no compta amb tractaments efectius i reeixits per aquestes lesions, i el tractament dels símptomes sol ser la millor solució. Per revertir i aconseguir la reconnexió funcional de les neurones, l'enginyeria de teixits actualment opta per l'ús de suports tridimensionals biocompatibles, cèl·lules i molècules bioactives. Específicament, una de les estratègies proposades han estat els conductes nerviosos guiats, no només per lesions de nervis perifèrics sinó també per tractes de sistema nerviós central. En aquesta tesi doctoral, es proposa la combinació d'un conducte tubular buit d'àcid hialurònic (HA) farcit amb fibres d'àcid poli-L-lactida (PLA) en el seu lumen, i amb cèl·lules de Schwann (SC) pre-cultivades com a cèl·lules de suport de l'extension axonal per superar els obstacles que limiten la regeneració d'axons in vivo. S'ha demostrat que el conducte d'HA i les fibres de PLA mantenen la proliferació de les SC, les quals formen una estructura cilíndica anomenada 'beina de SC' a la paret interna de l'lumen de l'conducte i al seu torn creixen de manera direccional en les fibres de PLA. El conjunt unidireccional paral·lel format per les fibres PLA i les SC recapitula les característiques direccionals dels tractes axonals en el sistema nerviós. A l'sembrar un explantament de gangli de l'arrel dorsal (DRG) en un dels extrems de l'conducte, s'ha seguit el creixement dels axons de l'DRG i s'ha estudiat les característiques de les SC, els axons crescuts i la seva associació, comprovant que el biohíbrido és capaç de suportar el creixement axonal. A més, es proposa un concepte multimodular per superar les limitacions típiques de la regeneració axonal a llarga distància, amb la combinació de feixos de fibres de PLA en el lumen de diversos conductes o mòduls de HA individuals més curts que es posicionen un darrere l'l'altre, dissenyant conductes nerviosos guiats amb la longitud desitjada, juntament amb SC pre-cultivades. El conducte multimodular va demostrar ser eficaç per promoure el creixement dirigit d'axons. A més, s'ha desenvolupat un constructe format per l'estructura formada per les fibres de PLA i les SC, denominat 'cordó neural', després d'eliminar el conducte d'HA, el que obre la porta a la generació d'una estructura neural in vitro per al seu trasplantament.[EN] Injuries to the nervous system that involve the disruption of axonal bundles are devastating to the individual. Autonomous regeneration of damaged or degenerated axonal tracts is infrequent since a large number of factors are involved limiting this recovery. Nowadays, conventional medicine does not have effective and successful treatments for these injuries, and the treatment of symptoms is often the best solution. In order to reverse it and achieve the functional reconnection of neurons, tissue engineering currently opts for the use of biocompatible three-dimensional supports, cells, and bioactive molecules. Specifically, one of the proposed strategies has been nerve guidance conduits, not only for peripheral nerve injuries but also for tracts of the central nervous system. In this Doctoral Thesis, we propose the combination of hyaluronic acid (HA) single-channel tubular conduit filled with poly-L-lactide acid (PLA) fibres in its lumen, with pre-cultured Schwann cells (SC) as cells supportive of axon extension to overcome the obstacles limiting axon regeneration in vivo. We have proved that HA conduit and PLA fibres sustain the proliferation of SC, which form a cylindrical structure named 'SC sheath' on the inner wall of the lumen of the conduit and in turn grow directionally in the PLA fibres. The parallel unidirectional ensemble formed by PLA fibres and SC recapitulates the directional features of axonal pathways in the nervous system. Planting a dorsal root ganglion (DRG) explant on one of the conduit's ends, we have followed axon outgrowth from the DRG and studied the features of SC, the grown axons and their association, checking that the biohybrid is capable of supporting axonal growth. Furthermore, we propose a multimodular concept to overcome the typical limitations of long-distance axonal regeneration, with the combination of PLA fibres bundle in the lumen of several shorter individual HA conduits or modules which positioned themselves one behind the other, designing nerve guided conduits with the desired length, together with pre-cultured SC. The multimodular conduit proved effective in promoting directed axon growth. Moreover, we developed a construct consisting of the structure formed by the PLA fibres and the SC, named 'neural cord', after eliminating the HA conduit, that opens the door to the generation of a neural structure in vitro for transplantation.La presente tesis doctoral se ha realizado con la financiación del Ministerio de Economía y Competitividad a través de los proyectos MAT2015-66666-C3-1-R, DPI2015-72863-EXP, y AEI RTI2018-095872-B-C21-C22/ERDF. Agradezco también la beca FPU15/04975 al Ministerio de Educación Cultura y Deportes.Rodríguez Doblado, L. (2021). Biohybrids for Neural Tracts Regeneration [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/16519

Estudio mediante simulación de las heterogeneidades electrofisiológicas apico-basales en el ventrículo humano

[ES] Las enfermedades cardíacas representan hoy en día una de las principales causas de mortalidad en los países desarrollados, constituyendo en su conjunto un importante problema de salud pública. Tanto estas enfermedades, como aquellas que afectan de forma directa o indirecta a la actividad cardíaca (hipertiroidismo e hipercalcemia entre otras) pueden ser diagnosticadas y estudiadas mediante la señal del electrocardiograma (ECG). Por tanto, surge la necesidad de estudiar en profundidad la actividad cardíaca y la señal resultante de su actividad: el ECG. En la actualidad existen modelos computacionales que permiten simular la actividad del corazón y calcular el ECG. La onda T del ECG permite diagnosticar diversas enfermedades, y es importante que los modelos computacionales sean capaces de reproducirla con precisión. Estudios recientes relacionan la forma de onda T a la heterogeneidad apico-basal, lo cual se puede abordar con modelado y simulación. En efecto, el estudio de la actividad cardiaca mediante modelado y simulación supone en la actualidad un gran avance en la investigación clínica reduciendo la necesidad de estudios invasivos o experimentación animal, permitiendo anticipar comportamientos frente a fármacos y enfermedades.[EN] Nowadays, cardiac illnesses are the main cause of death in developped countries, being an important public health problem. These illnesses, as well as thoseaffecting cardiac activity directly or indirectly, can be diagnosed and studied using the signal of the electrocardiogram (ECG). Therefore, there is a need to study in depth the electrophysiological cardiac activity and the derived extracellular signal, the ECG. Cardiac electrical activity can be simulated using computational models and the derived ECG can be computed. The T wave of the ECG is analyzed and used to diagnose a variety of illnesses. The T waveform depend on apicobasal heterogeneities as has been related in recent studies. The study of cardiac activity through modeling and simulation would be a big step for clinical research reducing the need of invasive studies or animal experiments, which helps anticipate behaviounder drugs administration or in disease conditions.[CAT/VA] Les malalties cardíaques representen hui dia una de les principals causes de mortalitat als països desenvolupats, constituint en el seu conjunt un important problema de salut pública. Tant aquestes malalties, com aquelles que afecten de forma directa o indirecta a l'activitat cardíaca (hipertiroïdisme i hipercalcemia entre altres) poden ser diagnosticades i estudiades mitjançant el senyal de l'electrocardiograma (ECG). Per tant, sorgeix la necessitat d'estudiar en profunditat l'activitat cardíaca i el senyal resultant de la seua activitat: el ECG. En l'actualitat existeixen models computacionals que permeten simular l'activitat del cor i calcular el ECG. L'ona T del ECG permet diagnosticar diverses malalties, i és important que els models computacionals siguen capaços de reproduir-la amb precisió. Estudis recents relacionen la forma d'ona T a l'heterogeneïtat apico-basal, la qual cosa es pot abordar amb modelatge i simulació. En efecte, l'estudi de l'activitat cardíaca mitjançant modelatge i simulació suposa en l'actualitat un gran avanç en la investigació clínica reduint la necessitat d'estudis invasius o experimentació animal, permetent anticipar comportaments enfront de fàrmacs i malalties.González Doblado, L. (2019). Estudio mediante simulación de las heterogeneidades electrofisiológicas apico-basales en el ventrículo humano. http://hdl.handle.net/10251/129308TFG

Multimodular Bio-Inspired Organized Structures Guiding Long-Distance Axonal Regeneration

Axonal bundles or axonal tracts have an aligned and unidirectional architecture present in many neural structures with different lengths. When peripheral nerve injury (PNI), spinal cord injury (SCI), traumatic brain injury (TBI), or neurodegenerative disease occur, the intricate architecture undergoes alterations leading to growth inhibition and loss of guidance through large distance. In order to overcome the limitations of long-distance axonal regeneration, here we combine a poly-L-lactide acid (PLA) fiber bundle in the common lumen of a sequence of hyaluronic acid (HA) conduits or modules and pre-cultured Schwann cells (SC) as cells supportive of axon extension. This multimodular preseeded conduit is then used to induce axon growth from a dorsal root ganglion (DRG) explant placed at one of its ends and left for 21 days to follow axon outgrowth. The multimodular conduit proved effective in promoting directed axon growth, and the results may thus be of interest for the regeneration of long tissue defects in the nervous system. Furthermore, the hybrid structure grown within the HA modules consisting in the PLA fibers and the SC can be extracted from the conduit and cultured independently. This “neural cord” proved to be viable outside its scaffold and opens the door to the generation of ex vivo living nerve in vitro for transplantation.This research was funded by the Spanish Government’s State Research Agency (AEI) through projects DPI2015-72863-EXP and RTI2018-095872-B-C22/ERDF. Laura Rodríguez Doblado acknowledges scholarship FPU15/04975 of the Spanish Ministry of Education, Culture, and Sports

Análisis comparativo de sedimentos en el Canal de Panamá con el Río Checua

Visita técnica internacionalEste documento fue desarrollado, a partir de la visita técnica internacional realizada al Canal de Panamá en el año 2019, obteniendo por medio de ésta conocimientos y experiencias que permitieron la recolección de información y la comparación de los parametros hidrologicos y técnicas de control de sedimentos, entre las cuencas hidrográficas del canal de Panamá y el río Checua.INTRODUCCIÓN 1. GENERALIDADES 2. MARCO DE REFERENCIA 3. ALCANCES Y LIMITACIONES 4. METODOLOGIA 5. ANALISIS DE INFORMACION DE SEDIMENTOS Y SUS PROCESOS DE CONTROL EN LA CUENCA HIDROGRÁFICA DEL CANAL DE PANAMÁ Y CUENCA HIDROGRÁFICA DEL RÍO CHECUA. 6. ANÁLISIS COMPARATIVO DE SEDIMENTOS Y SUS PROCESOS DE CONTROL ENTRE CUENCA HIDROGRÁFICA RÍO CHECUA (CHRC) Y CUENCA HDRIGRÁFICA DEL CANAL DE PANAMÁ (CHCP) 7. TRANSFERENCIA TECNOLÓGICA 8. CONCLUSIONES 9. RECOMENDACIONES 10. BIBLIOGRAFIA 11. ANEXOSPregradoIngeniero Civi

Evaluación de las matemáticas emergentes de 0 a 3 años

A first exploration of the assessment of emergent mathematics, which refers to the first mathematics of an intuitive and informal nature developed by children under 3 years of age, is carried out. In order to obtain data, firstly, a semi-structured interview was conducted with a teacher at a nursery school and, secondly, an educational proposal implemented in a group of 12 children aged 1-2 years was documented and interpreted mathematically, based on the rubric "Acquisition of informal mathematical knowledge from 0 to 3 years" (ACMI 0-3). The results show: a) the lack of teacher education in strategies and resources for the assessment of emergent mathematics; b) the validity of the rubric used to document and mathematically interpret the children's actions, showing that most actions are associated with the recognition of sensory qualities and the relative position of objects. It is concluded that it is necessary to provide disciplinary and pedagogical knowledge, both in pre-service and in-service education, so that nursery school professionals can promote and assess emergent mathematics effectively.Se realiza una primera exploración de la evaluación de las matemáticas emergentes, que se refieren a las primeras matemáticas de naturaleza intuitiva e informal que desarrollan los niños menores de 3 años. Para la obtención de datos, en primer lugar, se ha realizado una entrevista semiestructurada a una maestra de una Escuela Infantil y, en segundo lugar, se ha documentado e interpretado matemáticamente una propuesta educativa implementada en un grupo de 12 niños de 1-2 años, a partir de la rúbrica “Adquisición de conocimientos matemáticos informales de 0 a 3 años” (ACMI 0-3). Los resultados muestran: a) la carencia de formación por parte de los docentes en cuanto a las estrategias y recursos para la evaluación de las matemáticas emergentes; b) la validez de la rúbrica utilizada para documentar e interpretar matemáticamente las acciones de los niños, evidenciándose que la mayoría de acciones se asocian al reconocimiento de las cualidades sensoriales y la posición relativa de los objetos. Se concluye que es necesario proporcionar conocimientos disciplinares y didácticos, tanto en la formación inicial como continua, para que las profesionales de la Escuela Infantil puedan promover y evaluar las matemáticas emergentes de manera eficaz

Engineered axon tracts within tubular biohybrid scaffolds

Injuries to the nervous system that involve the disruption of axonal pathways are devastating to the individual and require specific tissue engineering strategies. Here we analyse a cells-biomaterials strategy to overcome the obstacles limiting axon regenerationin vivo, based on the combination of a hyaluronic acid (HA) single-channel tubular conduit filled with poly-L-lactide acid (PLA) fibres in its lumen, with pre-cultured Schwann cells (SCs) as cells supportive of axon extension. The HA conduit and PLA fibres sustain the proliferation of SC, which enhance axon growth acting as a feeder layer and growth factor pumps. The parallel unidirectional ensemble formed by PLA fibres and SC tries to recapitulate the directional features of axonal pathways in the nervous system. A dorsal root ganglion (DRG) explant is planted on one of the conduit's ends to follow axon outgrowth from the DRG. After a 21 d co-culture of the DRG + SC-seeded conduit ensemble, we analyse the axonal extension throughout the conduit by scanning, transmission electronic and confocal microscopy, in order to study the features of SC and the grown axons and their association. The separate effects of SC and PLA fibres on the axon growth are also experimentally addressed. The biohybrid thus produced may be considered a synthetic axonal pathway, and the results could be of use in strategies for the regeneration of axonal tracts

Mitophagy in human diseases

Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post‐mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age‐related neurodegener-ative diseases, such as Parkinson’s and Alzheimer’s diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.This research was funded by the Spanish “Ministerio de Ciencia, Innovación y Universidades” (MICIU) and ERDF/FEDER funds, grant number RTI2018-093864-B-I00, and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 721236-TREATMENT to M.M

Según los Consumidores Argentinos: ¿el Color y el Nivel de Marmoreo son indicadores de la Calidad de la Carne?

Socializamos el resultado de una encuesta que analiza las preferencias de los consumidores argentinos en base al color y contenido de grasa de la carne bovina.Publishe

Biohybrids for spinal cord injury repair

This is the peer reviewed version of the following article: Martínez-Ramos, C, Doblado, LR, Mocholi, EL, et al. Biohybrids for spinal cord injury repair. J Tissue Eng Regen Med. 2019; 13: 509-521, which has been published in final form at https://doi.org/10.1002/term.2816. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Spinal cord injuries (SCIs) result in the loss of sensory and motor function with massive cell death and axon degeneration. We have previously shown that transplantation of spinal cord-derived ependymal progenitor cells (epSPC) significantly improves functional recovery after acute and chronic SCI in experimental models, via neuronal differentiation and trophic glial cell support. Here, we propose an improved procedure based on transplantation of epSPC in a tubular conduit of hyaluronic acid containing poly (lactic acid) fibres creating a biohybrid scaffold. In vitro analysis showed that the poly (lactic acid) fibres included in the conduit induce a preferential neuronal fate of the epSPC rather than glial differentiation, favouring elongation of cellular processes. The safety and efficacy of the biohybrid implantation was evaluated in a complete SCI rat model. The conduits allowed efficient epSPC transfer into the spinal cord, improving the preservation of the neuronal tissue by increasing the presence of neuronal fibres at the injury site and by reducing cavities and cyst formation. The biohybrid-implanted animals presented diminished astrocytic reactivity surrounding the scar area, an increased number of preserved neuronal fibres with a horizontal directional pattern, and enhanced coexpression of the growth cone marker GAP43. The biohybrids offer an improved method for cell transplantation with potential capabilities for neuronal tissue regeneration, opening a promising avenue for cell therapies and SCI treatment.Secretaria de Estado de Investigacion, Desarrollo e Innovacion, Grant/Award Number: MAT2015-66666-C3-1-R MINECO/FEDER MAT2015-66666-C3-2-R MINECO/FEDER; Spanish Ministry of Education, Culture and Sports through Laura Rodriguez Doblado, Grant/Award Number: FPU15/04975Martínez-Ramos, C.; Rodriguez Doblado, L.; López Mocholi, E.; Alastrue-Agudo, A.; Sánchez Petidier, M.; Giraldo-Reboloso, E.; Monleón Pradas, M.... (2019). Biohybrids for spinal cord injury repair. Journal of Tissue Engineering and Regenerative Medicine. 13(3):509-521. https://doi.org/10.1002/term.2816S509521133Ahuja, C. S., & Fehlings, M. (2016). Concise Review: Bridging the Gap: Novel Neuroregenerative and Neuroprotective Strategies in Spinal Cord Injury. STEM CELLS Translational Medicine, 5(7), 914-924. doi:10.5966/sctm.2015-0381Alastrue-Agudo, A., Erceg, S., Cases-Villar, M., Bisbal-Velasco, V., Griffeth, R. J., Rodriguez-Jiménez, F. J., & Moreno-Manzano, V. (2014). Experimental Cell Transplantation for Traumatic Spinal Cord Injury Regeneration: Intramedullar or Intrathecal Administration. Methods in Molecular Biology, 23-35. doi:10.1007/978-1-4939-1435-7_3Alastrue-Agudo, A., Rodriguez-Jimenez, F., Mocholi, E., De Giorgio, F., Erceg, S., & Moreno-Manzano, V. (2018). FM19G11 and Ependymal Progenitor/Stem Cell Combinatory Treatment Enhances Neuronal Preservation and Oligodendrogenesis after Severe Spinal Cord Injury. International Journal of Molecular Sciences, 19(1), 200. doi:10.3390/ijms19010200Alfaro-Cervello, C., Soriano-Navarro, M., Mirzadeh, Z., Alvarez-Buylla, A., & Garcia-Verdugo, J. M. (2012). Biciliated ependymal cell proliferation contributes to spinal cord growth. The Journal of Comparative Neurology, 520(15), 3528-3552. doi:10.1002/cne.23104Assunção-Silva, R. C., Gomes, E. D., Sousa, N., Silva, N. A., & Salgado, A. J. (2015). Hydrogels and Cell Based Therapies in Spinal Cord Injury Regeneration. Stem Cells International, 2015, 1-24. doi:10.1155/2015/948040BASSO, D. M., BEATTIE, M. S., & BRESNAHAN, J. C. (1995). A Sensitive and Reliable Locomotor Rating Scale for Open Field Testing in Rats. Journal of Neurotrauma, 12(1), 1-21. doi:10.1089/neu.1995.12.1Bonner, J. F., & Steward, O. (2015). Repair of spinal cord injury with neuronal relays: From fetal grafts to neural stem cells. Brain Research, 1619, 115-123. doi:10.1016/j.brainres.2015.01.006Collins, M. N., & Birkinshaw, C. (2013). Hyaluronic acid based scaffolds for tissue engineering—A review. Carbohydrate Polymers, 92(2), 1262-1279. doi:10.1016/j.carbpol.2012.10.028Donnelly, D. J., & Popovich, P. G. (2008). Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Experimental Neurology, 209(2), 378-388. doi:10.1016/j.expneurol.2007.06.009Erceg, S., Ronaghi, M., Oria, M., García Roselló, M., Aragó, M. A. P., Lopez, M. G., … Stojkovic, M. (2010). Transplanted Oligodendrocytes and Motoneuron Progenitors Generated from Human Embryonic Stem Cells Promote Locomotor Recovery After Spinal Cord Transection. STEM CELLS, 28(9), 1541-1549. doi:10.1002/stem.489Gómez-Villafuertes, R., Rodríguez-Jiménez, F. J., Alastrue-Agudo, A., Stojkovic, M., Miras-Portugal, M. T., & Moreno-Manzano, V. (2015). Purinergic Receptors in Spinal Cord-Derived Ependymal Stem/Progenitor Cells and Their Potential Role in Cell-Based Therapy for Spinal Cord Injury. Cell Transplantation, 24(8), 1493-1509. doi:10.3727/096368914x682828Hesp, Z. C., Goldstein, E. A., Miranda, C. J., Kaspar, B. K., & McTigue, D. M. (2015). Chronic Oligodendrogenesis and Remyelination after Spinal Cord Injury in Mice and Rats. Journal of Neuroscience, 35(3), 1274-1290. doi:10.1523/jneurosci.2568-14.2015Kjell, J., & Olson, L. (2016). Rat models of spinal cord injury: from pathology to potential therapies. Disease Models & Mechanisms, 9(10), 1125-1137. doi:10.1242/dmm.025833Kumar, P., Choonara, Y., Modi, G., Naidoo, D., & Pillay, V. (2015). Multifunctional Therapeutic Delivery Strategies for Effective Neuro-Regeneration Following Traumatic Spinal Cord Injury. Current Pharmaceutical Design, 21(12), 1517-1528. doi:10.2174/1381612821666150115152323Li, G., Che, M.-T., Zhang, K., Qin, L.-N., Zhang, Y.-T., Chen, R.-Q., … Zeng, Y.-S. (2016). Graft of the NT-3 persistent delivery gelatin sponge scaffold promotes axon regeneration, attenuates inflammation, and induces cell migration in rat and canine with spinal cord injury. Biomaterials, 83, 233-248. doi:10.1016/j.biomaterials.2015.11.059Li, X., & Dai, J. (2018). Bridging the gap with functional collagen scaffolds: tuning endogenous neural stem cells for severe spinal cord injury repair. Biomaterials Science, 6(2), 265-271. doi:10.1039/c7bm00974gLiang, Y., Walczak, P., & Bulte, J. W. M. (2013). The survival of engrafted neural stem cells within hyaluronic acid hydrogels. Biomaterials, 34(22), 5521-5529. doi:10.1016/j.biomaterials.2013.03.095Lim, S. H., Liu, X. Y., Song, H., Yarema, K. J., & Mao, H.-Q. (2010). The effect of nanofiber-guided cell alignment on the preferential differentiation of neural stem cells. Biomaterials, 31(34), 9031-9039. doi:10.1016/j.biomaterials.2010.08.021Liu, C., Huang, Y., Pang, M., Yang, Y., Li, S., Liu, L., … Liu, B. (2015). Tissue-Engineered Regeneration of Completely Transected Spinal Cord Using Induced Neural Stem Cells and Gelatin-Electrospun Poly (Lactide-Co-Glycolide)/Polyethylene Glycol Scaffolds. PLOS ONE, 10(3), e0117709. doi:10.1371/journal.pone.0117709Lu, P., Wang, Y., Graham, L., McHale, K., Gao, M., Wu, D., … Tuszynski, M. H. (2012). Long-Distance Growth and Connectivity of Neural Stem Cells after Severe Spinal Cord Injury. Cell, 150(6), 1264-1273. doi:10.1016/j.cell.2012.08.020Morita, S., & Miyata, S. (2012). Synaptic localization of growth-associated protein 43 in cultured hippocampal neurons during synaptogenesis. Cell Biochemistry and Function, 31(5), 400-411. doi:10.1002/cbf.2914Ortuño-Lizarán, I., Vilariño-Feltrer, G., Martínez-Ramos, C., Pradas, M. M., & Vallés-Lluch, A. (2016). Influence of synthesis parameters on hyaluronic acid hydrogels intended as nerve conduits. Biofabrication, 8(4), 045011. doi:10.1088/1758-5090/8/4/045011Raspa, A., Marchini, A., Pugliese, R., Mauri, M., Maleki, M., Vasita, R., & Gelain, F. (2016). A biocompatibility study of new nanofibrous scaffolds for nervous system regeneration. Nanoscale, 8(1), 253-265. doi:10.1039/c5nr03698dRequejo-Aguilar, R., Alastrue-Agudo, A., Cases-Villar, M., Lopez-Mocholi, E., England, R., Vicent, M. J., & Moreno-Manzano, V. (2017). Combined polymer-curcumin conjugate and ependymal progenitor/stem cell treatment enhances spinal cord injury functional recovery. Biomaterials, 113, 18-30. doi:10.1016/j.biomaterials.2016.10.032Rodriguez-Jimenez, F. J., Alastrue, A., Stojkovic, M., Erceg, S., & Moreno-Manzano, V. (2016). Connexin 50 modulates Sox2 expression in spinal-cord-derived ependymal stem/progenitor cells. Cell and Tissue Research, 365(2), 295-307. doi:10.1007/s00441-016-2421-ySimitzi, C., Ranella, A., & Stratakis, E. (2017). Controlling the morphology and outgrowth of nerve and neuroglial cells: The effect of surface topography. Acta Biomaterialia, 51, 21-52. doi:10.1016/j.actbio.2017.01.023Steward, O., Sharp, K. G., Yee, K. M., Hatch, M. N., & Bonner, J. F. (2014). Characterization of Ectopic Colonies That Form in Widespread Areas of the Nervous System with Neural Stem Cell Transplants into the Site of a Severe Spinal Cord Injury. Journal of Neuroscience, 34(42), 14013-14021. doi:10.1523/jneurosci.3066-14.2014Stokols, S., & Tuszynski, M. H. (2006). Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury. Biomaterials, 27(3), 443-451. doi:10.1016/j.biomaterials.2005.06.039Straley, K. S., Foo, C. W. P., & Heilshorn, S. C. (2010). Biomaterial Design Strategies for the Treatment of Spinal Cord Injuries. Journal of Neurotrauma, 27(1), 1-19. doi:10.1089/neu.2009.0948Theodore, N., Hlubek, R., Danielson, J., Neff, K., Vaickus, L., Ulich, T. R., & Ropper, A. E. (2016). First Human Implantation of a Bioresorbable Polymer Scaffold for Acute Traumatic Spinal Cord Injury. Neurosurgery, 79(2), E305-E312. doi:10.1227/neu.0000000000001283Tian, L., Prabhakaran, M. P., & Ramakrishna, S. (2015). Strategies for regeneration of components of nervous system: scaffolds, cells and biomolecules. Regenerative Biomaterials, 2(1), 31-45. doi:10.1093/rb/rbu017Vilariño-Feltrer, G., Martínez-Ramos, C., Monleón-de-la-Fuente, A., Vallés-Lluch, A., Moratal, D., Barcia Albacar, J. A., & Monleón Pradas, M. (2016). Schwann-cell cylinders grown inside hyaluronic-acid tubular scaffolds with gradient porosity. Acta Biomaterialia, 30, 199-211. doi:10.1016/j.actbio.2015.10.040Vismara, I., Papa, S., Rossi, F., Forloni, G., & Veglianese, P. (2017). Current Options for Cell Therapy in Spinal Cord Injury. Trends in Molecular Medicine, 23(9), 831-849. doi:10.1016/j.molmed.2017.07.005Wen, Y., Yu, S., Wu, Y., Ju, R., Wang, H., Liu, Y., … Xu, Q. (2015). Spinal cord injury repair by implantation of structured hyaluronic acid scaffold with PLGA microspheres in the rat. Cell and Tissue Research, 364(1), 17-28. doi:10.1007/s00441-015-2298-1Wilson, J. R., & Fehlings, M. G. (2011). Emerging Approaches to the Surgical Management of Acute Traumatic Spinal Cord Injury. Neurotherapeutics, 8(2), 187-194. doi:10.1007/s13311-011-0027-3Xie, J., Liu, W., MacEwan, M. R., Bridgman, P. C., & Xia, Y. (2014). Neurite Outgrowth on Electrospun Nanofibers with Uniaxial Alignment: The Effects of Fiber Density, Surface Coating, and Supporting Substrate. ACS Nano, 8(2), 1878-1885. doi:10.1021/nn406363

A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries

[EN] Tissue engineering, including cell transplantation and the application of biomaterials and bioactive molecules, represents a promising approach for regeneration following spinal cord injury (SCI). We designed a combinatorial tissue-engineered approach for the minimally invasive treatment of SCI¿a hyaluronic acid (HA)-based scaffold containing polypyrrole-coated fibers (PPY) combined with the RAD16-I self-assembling peptide hydrogel (Corning® PuraMatrix¿peptide hydrogel (PM)), human induced neural progenitor cells (iNPCs), and a nanoconjugated form of curcumin (CURC). In vitro cultures demonstrated that PM preserves iNPC viability and the addition of CURC reduces apoptosis and enhances the outgrowth of Nestin-positive neurites from iNPCs, compared to nonembedded iNPCs. The treatment of spinal cord organotypic cultures also demonstrated that CURC enhances cell migration and prompts a neuron-like morphology of embedded iNPCs implanted over the tissue slices. Following sub-acute SCI by traumatic contusion in rats, the implantation of PMembedded iNPCs and CURC with PPY fibers supported a significant increase in neuro-preservation (as measured by greater III-tubulin staining of neuronal fibers) and decrease in the injured area (as measured by the lack of GFAP staining). This combination therapy also restricted platelet-derived growth factor expression, indicating a reduction in fibrotic pericyte invasion. Overall, these findings support PM-embedded iNPCs with CURC placed within an HA demilune scaffold containing PPY fibers as a minimally invasive combination-based alternative to cell transplantation alone.This research was funded by the Science by Women program, Women for Africa Foundation to H.E. and the grants FEDER/Ministerio de Ciencia e Innovacion-Agencia Estatal de Investigacion [RTI2018-095872-B-C21 and -C22/ERDF]; Part of the equipment employed in this work was funded by Generalitat Valenciana and cofinanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020). RISEUP project FetOpen in H2020 Program: H2020-FETOPEN-2018-2019-2020-01.Elkhenany, H.; Bonilla, P.; Giraldo-Reboloso, E.; Alastrue Agudo, A.; Edel, MJ.; Vicent, MJ.; Gisbert-Roca, F.... (2021). A Hyaluronic Acid Demilune Scaffold and Polypyrrole-Coated Fibers Carrying Embedded Human Neural Precursor Cells and Curcumin for Surface Capping of Spinal Cord Injuries. Biomedicines. 9(12):1-19. https://doi.org/10.3390/biomedicines9121928S11991