Valvulogenesis of a living, innervated pulmonary root induced by an acellular scaffold

Heart valve disease is a major cause of mortality and morbidity worldwide with no effective medical therapy and no ideal valve substitute emulating the extremely sophisticated functions of a living heart valve. These functions influence survival and quality of life. This has stimulated extensive attempts at tissue engineering “living” heart valves. These attempts utilised combinations of allogeneic/ autologous cells and biological scaffolds with practical, regulatory, and ethical issues. In situ regeneration depends on scaffolds that attract, house and instruct cells and promote connective tissue formation. We describe a surgical, tissue-engineered, anatomically precise, novel off-the-shelf, acellular, synthetic scaffold inducing a rapid process of morphogenesis involving relevant cell types, extracellular matrix, regulatory elements including nerves and humoral components. This process relies on specific material characteristics, design and “morphodynamism”.</p

Treatise on Hearing: The Temporal Auditory Imaging Theory Inspired by Optics and Communication

A new theory of mammalian hearing is presented, which accounts for the auditory image in the midbrain (inferior colliculus) of objects in the acoustical environment of the listener. It is shown that the ear is a temporal imaging system that comprises three transformations of the envelope functions: cochlear group-delay dispersion, cochlear time lensing, and neural group-delay dispersion. These elements are analogous to the optical transformations in vision of diffraction between the object and the eye, spatial lensing by the lens, and second diffraction between the lens and the retina. Unlike the eye, it is established that the human auditory system is naturally defocused, so that coherent stimuli do not react to the defocus, whereas completely incoherent stimuli are impacted by it and may be blurred by design. It is argued that the auditory system can use this differential focusing to enhance or degrade the images of real-world acoustical objects that are partially coherent. The theory is founded on coherence and temporal imaging theories that were adopted from optics. In addition to the imaging transformations, the corresponding inverse-domain modulation transfer functions are derived and interpreted with consideration to the nonuniform neural sampling operation of the auditory nerve. These ideas are used to rigorously initiate the concepts of sharpness and blur in auditory imaging, auditory aberrations, and auditory depth of field. In parallel, ideas from communication theory are used to show that the organ of Corti functions as a multichannel phase-locked loop (PLL) that constitutes the point of entry for auditory phase locking and hence conserves the signal coherence. It provides an anchor for a dual coherent and noncoherent auditory detection in the auditory brain that culminates in auditory accommodation. Implications on hearing impairments are discussed as well.Comment: 603 pages, 131 figures, 13 tables, 1570 reference

Some system considerations of neuron pools with feedback

This paper describes an approach to the analysis of the inputoutput relationships present in a neuron pool that receives a number of inputs. These inputs consist of primary inputs to the neuron pool and inputs resulting from feedback of information from the neuron pool as well. Multiple input-output relationships are obtained in terms of the synaptic weightings of the inputs, the membrane response characteristics of the neurons and the conduction delays on the feedback pathways. y=(I+MHD) -1 ·MFx is the explicit representation of the cell pool behavior assuming quasi-linear conditions, where y is the output vector of cell responses, I is the identity matrix, M is the response matrix of the cells, H is the feedback synaptic weighting matrix, D is the delay matrix, F is the input weighting matrix, and x is the input vector. It is shown that a solution to this formulation exists, is unique, is stable, and can be computed by specified algorithms. An insight gained from this formulation suggests that the output of each cell in the pool is related to virtually all of the inputs to the pool and the outputs of all cells in the pool.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47428/1/422_2004_Article_BF01259389.pd

Design and Implementation of a Passive Neurostimulator with Wireless Resonance-Coupled Power Delivery and Demonstration on Frog Sciatic Nerve and Gastrocnemius Muscle

The thesis presented has four goals: to perform a comprehensive literature review on current neurostimulator technology; to outline the current issues with the state-of-the-art; to provide a neurostimulator design that solves these issues, and to characterize the design and demonstrate its neurostimulation features. The literature review describes the physiology of a neuron, and then proceeds to outline neural interfaces and neurostimulators. The neurostimulator design process is then outlined and current requirements in the field are described. The novel neurostimulator circuit that implements a solution that has wireless capability, passive control, and small size is outlined and characterized. The circuit is demonstrated to operate wirelessly with a resonance-coupled multi-channel implementation, and is shown powering LEDs. The circuit was then fabricated in a miniature implementation which utilized a 10 x 20 x 3 mm&179 antenna, and occupied a volume approximating 1 cm&179. This miniature circuit is used to stimulate frog sciatic nerve and gastrocnemius muscle in vitro. These demonstrations and characterization show the device is capable of neurostimulation, can operate wirelessly, is controlled passively, and can be implemented in a small size, thus solving the aforementioned neurostimulator requirements. Further work in this area is focused on developing an extensive characterization of the device and the wireless power delivery system, optimizing the circuit design, and performing in vivo experiments with restoration of motor control in injured animals. This device shows promise to provide a comprehensive solution to many application-specific problems in neurostimulation, and be a modular addition to larger neural interface systems

Optics and Quantum Electronics

Contains table of contents on Section 3 and reports on nineteen research projects.Defense Advanced Research Projects Agency Grant F49620-96-0126Joint Services Electronics Program Grant DAAH04-95-1-0038National Science Foundation Grant ECS 94-23737U.S. Air Force - Office of Scientific Research Contract F49620-95-1-0221U.S. Navy - Office of Naval Research Grant N00014-95-1-0715Defense Advanced Research Projects Agency/National Center for Integrated Photonics TechnologyMultidisciplinary Research InitiativeU.S. Air Force - Office of Scientific ResearchNational Science Foundation/MRSECU.S. Navy - Office of Naval Research (MFEL) Contract N00014-91-J-1956National Institutes of Health Grant R01-EY11289U.S. Navy - Office of Naval Research (MFEL) Contract N00014-94-0717Defense Advanced Research Projects Agency Contract N66001-96-C-863

Effect of the relative position of electrode and stellate ganglion during thermal radiofrequency ablation: a simulation study

[EN] Purpose Stellate ganglion (SG) block by thermal radiofrequency ablation (RFA) is frequently conducted as a therapeutic intervention for sympathetic-maintained and neuropathic pain syndromes. RFA's partial lack of effectiveness could be partly due to the ablation zone (AZ) not completely covering the SG section and therefore preventing the 'cutting' of the afferent pathways. Our objective was to build a theoretical model to conduct computer simulations to assess the effect of the electrode position relative to the SG. Methods A three-dimensional model was built including the SG and adjacent tissues (vertebrae C7-T1-T2, trachea, carotid artery and vertebral artery). RFA (90-s, 80 degrees C) was simulated considering a 22 G-5 mm electrode. The AZ was computed using the 50 degrees C isotherm. Results An electrode displacement of 2 mm in any direction from the optimal position (centered on the SG) meant that the AZ did not fully cover the SG section. Likewise, SG size considerably affected the RFA effectiveness since the AZ fully covered the section of small but not large SGs. Conclusions The findings suggest that the currently used SG RFA settings (i.e., 22 G-5 mm electrode, 90-s, 80 degrees C) may not be appropriate due to their inability to achieve an AZ that fully covers the SG cross section under certain circumstances, such as a large SG and non-optimal positioning of the RF electrode with respect to the SG center.This work was supported by the Spanish Ministerio de Ciencia, Innovacion y Universidades under the 'Programa Estatal de I+D+i orientada a los retos de la Sociedad', Grant No 'RTI2018-094357-B-C21', the Universidad Nacional Arturo Jauretche - Argentina 'UNAJ Investiga' [80020170100019UJ], and by the 'Agencia Nacional de Promocion Cientifica y Tecnologica de Argentina' [PICT-2016-2303].Irastorza, RM.; Bovaira, M.; García-Vitoria, C.; Muñoz, V.; Berjano, E. (2021). Effect of the relative position of electrode and stellate ganglion during thermal radiofrequency ablation: a simulation study. International Journal of Hyperthermia. 38(1):1502-1511. https://doi.org/10.1080/02656736.2021.1974580S1502151138

EXPLORATION OF NOVEL METHODS FOR THE FABRICATION AND CHARACTERIZATION OF ORGANIC FIELD-EFFECT TRANSISTORS AND EXAMINATION OF FACTORS INFLUENCING OFET PERFORMANCE

This thesis explores novel methods for fabricating organic field effect transistors (OFETs) and characterizing OFET devices. Transfer printing is a promising process for fabricating organic thin-film devices. In this work, a transfer-printing process is developed for the polymer organic semiconductor P3HT. Pre-patterned P3HT is printed onto different dielectrics such as PMMA, polystyrene and polycarbonate. The P3HT layer is spun on a smooth silicon interface made hydrophobic by treatment with octyltrichlorosilane, which functions as a release layer. This method has distinct advantages over standard OFET fabrication methods in that 1) the active layer can be pre-patterned, 2) the solvent for the P3HT need not be compatible with the target substrate, and 3) the electrical contact formed mimics the properties of top contacts but with the spatial resolution of bottom contacts. Transparent, conducting films of carbon nanotubes (CNTs) are prepared by airbrushing, and characterized optically and electronically. OFETs with CNT films as source and drain electrodes are fabricated using various patterning techniques, and the organic/CNT contact resistance is characterized. CNT films make transparent, flexible electrodes with contact resistance comparable to that found for Au bottom-contacted P3HT transistors and comparable to CNT-film bottom-contacted pentacene transistors with CNTs deposited by other less flexible methods. A transparent OFET is demonstrated using transfer printing for the assembly of an organic semiconductor (pentacene), CNT film source, drain, and gate electrodes, and polymer gate dielectric and substrate. The dependence of the conductance and mobility in pentacene OFETs on temperature, gate voltage, and source-drain electric field is studied. The data are analyzed by extending a multiple trapping and release model to account for lowering of the energy required to excite carriers into the valence band (Poole-Frenkel effect). The temperature-dependent conductivity shows activated behavior, and the activation energy is lowered roughly linearly with the square-root of electric field, as expected for the Poole-Frenkel effect. The gate voltage dependence of the activation energy is used to extract the trap density of states, in good agreement with other measurements in the literature

Novel processing routes for neural interfaces

The thesis describes novel processing routes that have been developed to fabricate neural interfaces. A process has been investigated that uses microfabrication techniques to fabricate a multi-channel regenerative implant that can record nerve impulses in the peripheral nervous system (PNS), called the Spiral Peripheral Nerve Interface (SPNI). It is shown both theoretically and experimentally that the implant improves the ability to record signals in the PNS via micro-channels that act as axonal amplifiers. New processing routes are introduced to create robust interconnections from the SPNI to external electronics via ‘Microflex’ technology. To incorporate the new interconnection technology the SPNI had to be modified. During this modification the strain in the device was given specific consideration, for which a new bending model is presented. Modelling is used to show that electrochemical impedance spectroscopy can be used to assess the quality of the fabrication process. Electrochemical and mechanical tests show that the interconnection technology is suitable for a neural interfaces but the fabrication of perfectly sealed micro-channels was not evident. Thus, the SPNI was further improved by the introduction of a silicone sealing layer in the construction of the micro-channel array that was implemented using a novel adhesive bonding technique

Strategies for Guidance and Electrical and Biological Stimulation in a Neural Regeneration Device

Tesis por compendio[ES] Actualmente las lesiones del sistema nervioso periférico que conllevan una pérdida de continuidad de los haces axonales suelen implicar secuelas de tipo permanente. Es cierto que en el sistema nervioso periférico existe una cierta regeneración natural de los tractos axonales dañados, pero solamente cuando el espacio entre ambos extremos de la lesión es pequeño, como máximo de 5 mm. Si el espacio es mayor que esta distancia la regeneración no sucede de forma natural y se crea un neuroma traumático. Por tanto, estas lesiones largas requieren de una intervención quirúrgica para puentear la lesión, normalmente con un nervio autógrafo del propio paciente o un nervio alógrafo de un cadáver. No obstante, su uso presenta diversos inconvenientes, como la morbilidad del sitio donante donde puede ocurrir un neuroma, la necesidad de realizar una segunda cirugía, la diferencia de tamaño entre nervio receptor y donante o la necesidad de inmunosupresión en el caso de los nervios alógrafos. Por ello, la ingeniería de tejidos trabaja en el desarrollo de los conductos de guiado nervioso que incorporan estrategias para guiar topográficamente la regeneración, así como células y moléculas bioactivas. La presente tesis doctoral presenta un nuevo conducto de guiado nervioso con una aproximación multimodular para su aplicación en la regeneración de lesiones nerviosas largas (a partir de 15 mm) que hace uso de conductos tubulares huecos modulares de ácido hialurónico (HA) que contienen en su interior una estructura tubular de microfibras de ácido poliláctico (PLA). La estructura fibrilar aporta un guiado topográfico necesario para guiar el crecimiento axonal durante la regeneración a la vez que mantiene unidos los diferentes módulos de HA. Por su parte, los conductos de HA son un hidrogel que evita adherencias con el tejido circundante. A su vez, proporcionan un soporte sobre el que pueden crecer células presembradas. En concreto se ha optado por presembrar células de Schwann, las cuales son unas células gliales de soporte críticas para la regeneración del sistema nervioso periférico. Se ha observado que dichas células son capaces recubrir por completo las paredes internas de los conductos de HA formando una estructura tipo vaina, así como de recubrir las microfibras de PLA creciendo en dirección longitudinal. Los experimentos in vivo en modelo de nervio ciático de conejo han mostrado que la aproximación multimodular mejora significativamente la regeneración nerviosa gracias a proporcionar una mejor neovascularización. A su vez, gracias a las células de Schwann presembradas se ha logrado una mejora adicional de la regeneración nerviosa gracias a su efecto favorecedor del crecimiento axonal. Además, se han estudiado diferentes mejoras aplicables al conducto de guiado nervioso con el objetivo de mejorar los resultados obtenidos in vivo. Gracias a la incorporación de fibroína de seda a los conductos de HA se ha logrado mejorar sus propiedades mecánicas y biológicas. Asimismo, también se ha desarrollado un sustrato electroconductor de microfibras de PLA recubiertas con el polímero electroconductor Polipirrol gracias al cual se ha observado in vitro que es capaz de mejorar el crecimiento axonal al aplicar una estimulación eléctrica. Además, mediante un sistema de modificación génica de las células de Schwann por electrotransfección se ha logrado aumentar su secreción del factor neurotrófico derivado del cerebro (BDNF), gracias a lo cual se ha observado que se incrementa la velocidad de crecimiento axonal in vitro.[CA] Actualment les lesions del sistema nerviós perifèric que comporten una pèrdua de continuïtat dels feixos axonals solen implicar seqüeles de tipus permanent. És cert que al sistema nerviós perifèric hi ha una certa regeneració natural dels tractes axonals danyats, però només quan l'espai entre ambdós extrems de la lesió és petit, com a màxim de 5 mm. Si l'espai és més gran que aquesta distància la regeneració no succeeix de manera natural i es crea un neuroma traumàtic. Per tant, aquestes lesions llargues requereixen una intervenció quirúrgica per pontejar la lesió, normalment amb un nervi autògraf del pacient o un nervi al·lògraf d'un cadàver. No obstant això, el seu ús presenta diversos inconvenients, com la morbilitat del lloc donant on pot ocórrer un neuroma, la necessitat de fer una segona cirurgia, la diferència de mida entre nervi receptor i donant o la necessitat d'immunosupressió en el cas dels nervis al·lògrafs . Per això, l'enginyeria de teixits treballa en el desenvolupament dels conductes de guiatge nerviós que incorporen estratègies per guiar topogràficament la regeneració, així com cèl·lules i molècules bioactives. Aquesta tesi doctoral presenta un nou conducte de guiatge nerviós amb una aproximació multimodular per a la seva aplicació en la regeneració de lesions nervioses llargues (a partir de 15 mm) que fa ús de conductes tubulars buits modulars d'àcid hialurònic (HA) que contenen al seu interior una estructura tubular de microfibres d'àcid polilàctic (PLA). L'estructura fibril·lar aporta un guiatge topogràfic necessari per guiar el creixement axonal durant la regeneració alhora que manté units els diferents mòduls d'HA. Per part seva, els conductes d'HA són un hidrogel que evita adherències amb el teixit circumdant. Alhora, proporcionen un suport sobre el qual poden créixer cèl·lules presembrades. En concret s'ha optat per presembrar cèl·lules de Schwann, les quals són unes cèl·lules glials de suport crítiques per a la regeneració del sistema nerviós perifèric. S'ha observat que aquestes cèl·lules són capaces de recobrir completament les parets internes dels conductes d'HA formant una estructura tipus beina, així com de recobrir les microfibres de PLA creixent en direcció longitudinal. Els experiments in vivo en model de nervi ciàtic de conill han mostrat que l'aproximació multimodular millora significativament la regeneració nerviosa gràcies a proporcionar una millor neovascularització. Alhora, gràcies a les cèl·lules de Schwann presembrades s'ha aconseguit una millora addicional de la regeneració nerviosa gràcies al seu efecte afavoridor del creixement axonal. A més, s'han estudiat diferents millores aplicables al conducte de guiatge nerviós per tal de millorar els resultats obtinguts in vivo. Gràcies a la incorporació de fibroïna de seda als conductes d'HA s'ha aconseguit millorar les seues propietats mecàniques i biològiques. També s'ha desenvolupat un substrat electroconductor de microfibres de PLA recobertes amb el polímer electroconductor Polipirrol gràcies al qual s'ha observat in vitro que és capaç de millorar el creixement axonal quan s'aplica una estimulació elèctrica. A més, mitjançant un sistema de modificació gènica de les cèl·lules de Schwann per electrotransfecció s'ha aconseguit augmentar la secreció del factor neurotròfic derivat del cervell (BDNF), gràcies a la qual cosa s'ha observat que s'incrementa la velocitat de creixement axonal in vitro.[EN] Currently, lesions of the peripheral nervous system that lead to a loss of continuity of the axonal bundles usually involve permanent sequelae. It is true that in the peripheral nervous system there is some natural regeneration of damaged axonal tracts, but only when the space between the two ends of the lesion is small, at most 5 mm. If the gap is greater than this distance, regeneration does not occur naturally, and a traumatic neuroma is created. Therefore, these long injuries require surgical intervention to bridge the injury, usually with an autograph nerve from the patient or an allograph nerve from a cadaver. However, its use has various drawbacks, such as the morbidity of the donor site where a neuroma can occur, the need to perform a second surgery, the difference in size between the recipient and donor nerves, or the need for immunosuppression in the case of allograft nerves. For this reason, tissue engineering works on the development of nerve guidance conduits that incorporate strategies to topographically guide the regeneration, as well as cells and bioactive molecules. This doctoral thesis presents a new nerve guidance conduit with a multimodular approach for its application in the regeneration of long nerve lesions (from 15 mm) that makes use of modular hollow tubular conduits of hyaluronic acid (HA) that contain in their inside a tubular structure of microfibers of polylactic acid (PLA). The fibrillar structure provides the necessary topographic guidance to guide axonal growth during regeneration while keeping the different HA modules together. For their part, the HA conduits are a hydrogel that prevents adhesions with the surrounding tissue. In turn, they provide a support on which preseeded cells can grow. Specifically, it has been decided to pre-seed Schwann cells, which are glial support cells that are critical for the regeneration of the peripheral nervous system. It has been observed that these cells are capable of completely covering the inner walls of the HA conduits, forming a sheath-like structure, as well as covering the PLA microfibers by growing in a longitudinal direction. In vivo experiments in a rabbit sciatic nerve model have shown that the multimodular approach significantly improves nerve regeneration by providing better neovascularization. In turn, thanks to the pre-seeded Schwann cells, an additional improvement in nerve regeneration has been achieved thanks to its promoting effect on axonal growth. In addition, different improvements applicable to the nerve guidance conduit have been studied with the aim of improving the results obtained in vivo. Thanks to the incorporation of silk fibroin into HA conduits, their mechanical and biological properties have been improved. Likewise, an electroconductive substrate of PLA microfibers coated with the electroconductive polymer Polypyrrole has also been developed, thanks to which it has been observed in vitro that it is capable of improving axonal growth by applying electrical stimulation. In addition, by means of a gene modification system of Schwann cells by electrotransfection, it has been possible to increase their secretion of brain-derived neurotrophic factor (BDNF), thanks to which it has been observed that the speed of axonal growth is increased in vitro.Agradezco la ayuda de los diferentes proyectos del Ministerio de Economía y Competitividad del Gobierno de España que han hecho posible la financiación de esta tesis doctoral: MAT2015-66666-C3-1-R, DPI2015-72863-EXP, AEI RTI2018-095872-B-C21-C22/ERDF y FPU16/01833 del Ministerio de Universidades del Gobierno de España, sin la cual no hubiera podido realizar esta tesis doctoral.Gisbert Roca, F. (2022). Strategies for Guidance and Electrical and Biological Stimulation in a Neural Regeneration Device [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/189937Compendi