[ES] El tratamiento de enfermedades neurológicas está muy limitado por la ineficiente penetración de los fármacos en el tejido cerebral dañado debido a la barrera hematoencefálica (BHE), lo que imposibilita mejorar la salud del paciente. La BHE es un mecanismo de protección natural para evitar la difusión de agentes potencialmente peligrosas para el sistema nervioso central. No obstante, la BHE se puede inhibir mediante ultrasonidos focalizados e inyección de microburbujas de forma segura, localizada y transitoria, una tecnología empleada mundialmente. La principal ventaja es su carácter no invasivo, siendo así muy atractiva y cómoda para el paciente. Normalmente, la zona cerebral enferma se trata en su parte central empleando un único foco. Sin embargo, enfermedades como el Alzheimer o el Parkinson requieren un tratamiento sobre estructuras de geometría compleja y tamaño elevado, situadas en ambos hemisferios cerebrales. Por tanto, la tecnología actual está muy limitada al no cumplir dichos requisitos. Esta tesis doctoral tiene como objetivo el desarrollo de una técnica novedosa, basada en hologramas acústicos, para resolver las limitaciones presentes en los tratamientos neurológicos empleando ultrasonidos. Se estudian las lentes acústicas holográficas impresas en 3D, que acopladas a un transductor mono-elemento, permiten el control preciso del frente de onda ultrasónico tanto para (1) compensar las distorsiones que sufre el haz hasta alcanzar el cerebro, como (2) focalizarlo simultáneamente en regiones múltiples y de geometría compleja o formando de vórtices acústicos, proporcionando así efectividad en tiempo y coste. Por ello, la investigación desarrollada en esta tesis abre un camino prometedor en el campo de la biomedicina que permitirá mejorar los tratamientos neurológicos, además de aplicaciones en neuroestimulación o ablación térmica del tejido. / [CA] El tractament de malalties neurològiques està molt limitat per la ineficient penetració del fàrmac en el teixit cerebral danyat a causa de la barrera hematoencefàlica (BHE), i així no és possible una millora de salut del pacient. La BHE és un mecanisme de protecció natural per a evitar la difusió d'agents potencialment perillosos per al Sistema Nervios Central. No obstant això, aquesta barrera es pot inhibir mitjancant una tecnologia emprada mundialment basada en ultrasons focalitzats i injeccio de microbombolles. El principal avantatge és el seu caràcter no invasiu, sent així molt atractiva i còmoda per al pacient, i permet obrir la BHE de manera segura, localitzada i transitòria. Normalment, la zona cerebral malalta es tracta en la seua part central, emprant un unic focus. No obstant això, malalties com l'Alzheimer o el Parkinson requereixen un tractament al llarg d'estructures de geometria complexa i grandària elevada, situades en tots dos hemisferis cerebrals. Per tant, la tecnologia actual està fortament limitada al no complir amb aquests requeriments. Aquesta tesi doctoral està enfocada a investigar i desenvolupar una tècnica nova, basada en hologrames acústics, per a solucionar les limitacions presents en els tractaments neurològics. Una lent acústica holograca de baix cost impresa en 3D acoblada a un transductor d'element simple permet el control precs del front d'ona ultrasònic punt per a (1) compensar les distorsions que pateix el feix en el seu camí cap al cervell, i (2) focalització simultània del feix en regions multiples i de geometria complexa, proporcionant aix un tractament efectiu en temps i cost. Per això, la investigació desenvolupada en aquesta tesi demostra la possibilitat de realitzar qualsevol tractament neurològic, a més d'aplicacions en la neuroestimulació o l'ablació tèrmica dins del camp biomèdic. / [EN] Treatments for neurological diseases are strongly limited by the inefficient penetration of therapeutic drugs into the diseased brain due to the blood-brain barrier (BBB), and therefore no health improvement can be achieved. In fact, the BBB is a protection mechanism of the human body to avoid the diffusion of potentially dangerous agents into the central nervous system. Nevertheless, this barrier can be successfully inhibited by using a worldwide spread technology based on microbubble-enhanced focused ultrasound. Its main advantage is its non-invasive nature, thus defining a patient-friendly clinical procedure that allows to disrupt the BBB in a safe, local and transient manner. Conventionally, the diseased brain structure has been targeted in its center, with a single focus. However, Alzheimer's or Parkinson's Diseases do require that ultrasound is delivered to entire, complex-geometry and large-volume structures located at both hemispheres of the brain. Therefore, current technology presents several limitations as it does not fulfill these requirements. This doctoral thesis aims to develop a novel technique based on using focused ultrasound acoustic holograms to solve the existing limitations to treat neurological diseases. In this dissertation, we study 3D-printed holographic acoustic lenses coupled to a single-element transducer that allow to accurately control the acoustic wavefront to both (1) compensate distortions suffered by the beam in its path to the brain, and (2) simultaneous focusing in multiple and complex-geometry structures or acoustic vortex generation, providing a time- and cost- efficient procedure. Therefore, the research carried out throughout this thesis opens a promising path in the biomedical field to improve the treatment for neurological diseases, neurostimulation or tissue ablation applications. / Acknowledgments to the Spanish institution Generalitat Valenciana, which funding grant allowed me to develop this doctoral thesis, and as well funded my research stay at Columbia University. The development of the entire thesis was supported through grant Nª. ACIF/2017/045. Particularly, the research carried out in Chapter 3 and Chapter 4 was possible thanks to and supported through grant BEFPI/2019/075. Action co-financied by the Agència Valenciana de la Innovació through grant INNVAL10/19/016 and by the European Union through the Programa Operativo del Fondo Europeo de Desarrollo Regional (FEDER) of the Comunitat Valenciana 2014-2020 (IDIFEDER/2018/022). / Jiménez Gambín, S. (2021). Transcranial Ultrasound Holograms for the Blood-Brain Barrier Opening [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/171373 / TESIS

Contactless ultrasonic power transfer (UPT), using piezoelectric transducers, is based on transferring energy using acoustic waves, in which the waves are generated by an acoustic source or transmitter and then transferred through an acoustic medium such as water or human tissue to a sensor or receiver. The receiver then converts the mechanical strain induced by the incident acoustic waves to electricity and delivers to an electrical load, in which the electrical power output of the system can be determined. The execution and efficiency of this technology can be significantly enhanced through patterning, focusing, and localization of the transmitted acoustic energy in space to simultaneously power pre-determined distributed sensors or devices. A passive 3D-printed acoustic hologram plate alongside a single transducer can generate arbitrary and pre-designed ultrasound fields in a particular distance from the hologram mounted on the transmitter, i.e., a target plane. This dissertation presents the use of these simple, cost-effective, and high-fidelity acoustic holograms in UPT systems to selectively enhance and pattern the electrical power output from the receivers. Different holograms are numerically designed to create single and multi-focal pressure patterns in a target plane where an array of receivers are placed. The incident sound wave from a transmitter, after passing through the hologram, is manipulated, hence, the output field is the desired pressure field, which excites the receivers located at the pre-determined focal points more significantly. Furthermore, multi-functional holograms are designed to generate multiple images at different target planes and driving frequencies, called, respectively, multi-image-plane and multi-frequency patterning holograms. The multiple desired pressure distributions are encoded on the single hologram plate and each is reconstructed by changing the axial distance and by switching the frequency. Several proof-of-concept experiments are performed to verify the functionality of the computationally designed holograms, which are fabricated using modern 3D-printers, i.e., the desired wavefronts are encoded in the hologram plates' thickness profile, being input to the 3D-printer. The experiments include measurement of output pressure fields in water using needle hydrophones and acquisition of receivers' voltage output in UPT systems. Another technique investigated in this dissertation is the implementation of acoustic impedance matching layers deposited on the front leading surface of the transmitter and receiver transducers. Current UPT systems suffer from significant acoustic losses through the transmission line from a piezoelectric transmitter to an acoustic medium and then to a piezoelectric receiver. This is due to the unfavorable acoustic impedance mismatch between the transducers and the medium, which causes a narrow transducer bandwidth and a considerable reflection of the acoustic pressure waves at the boundary layers. Using matching layers enhance the acoustic power transmission into the medium and then reinforce the input as an excitation into the receiver. Experiments are performed to identify the input acoustic pressure from a cylindrical transmitter to a receiver disk operating in the 33-mode of piezoelectricity. Significant enhancements are obtained in terms of the receiver's electrical power output when implementing a two-layer matching structure. A design platform is also developed that can facilitate the construction of high-fidelity acoustically matched transducers, that is, the material layers' selection and determination of their thicknesses. Furthermore, this dissertation presents a numerical analysis for the dynamical motions of a high-intensity focused ultrasound (HIFU)-excited microbubble or stable acoustic cavitation, which includes the effects of acoustic nonlinearity, diffraction, and absorption of the medium, and entails the problem of several biomedical ultrasound applications. Finally, the design and use of acoustic holograms in microfluidic channels are addressed which opens the door of acoustic patterning in particle and cell sorting for medical ultrasound systems. / Doctor of Philosophy / This dissertation presents several techniques to enhance the wireless transfer of ultrasonic energy in which the sound wave is generated by an acoustic source or transmitter, transferred through an acoustic medium such as water or human tissue to a sensor or receiver. The receiver transducer then converts the vibrational energy into electricity and delivers to an electrical load in which the electrical power output from the system can be determined. The first enhancement technique presented in this dissertation is using a pre-designed and simple structured plate called an acoustic hologram in conjunction with a transmitter transducer to arbitrarily pattern and shape ultrasound fields at a particular distance from the hologram mounted on the transmitter. The desired wavefront such as single or multi-focal pressure fields or an arbitrary image such as a VT image pattern can simply be encoded in the thickness profile of this hologram plate by removing some of the hologram material based on the desired shape. When the sound wave from the transmitter passes this structured plate, it is locally delayed in proportion to the hologram thickness due to the different speed of sound in the hologram material compared to water. In this dissertation, various hologram types are designed numerically to implement in the ultrasonic power transfer (UPT) systems for powering receivers located at the predetermined focal points more significantly and finally, their functionality and performances are verified in several experiments. Current UPT systems suffer from significant acoustic losses through the transmission from a transmitter to an acoustic medium and then to a receiver due to the different acoustic impedance (defined as the product of density and sound speed) between the medium and transducers material, which reflects most of the incident pressure wave at the boundary layers. The second enhancement technology addressed in this dissertation is using intermediate materials, called acoustic impedance matching layers, bonded to the front side of the transmitter and receiver face to alleviate the acoustic impedance mismatch. Experiments are performed to identify the input acoustic pressure from a transmitter to a receiver. Using a two-layer matching structure, significant enhancements are observed in terms of the receiver's electrical power output. A design platform is also developed that can facilitate the construction of high-fidelity acoustically matched transducers, that is, the material layers' selection and determination of their thicknesses. Furthermore, this dissertation presents a numerical analysis for the dynamical motions of a microbubble exposed to a high-intensity focused ultrasound (HIFU) field, which entails the problem of several biomedical ultrasound applications such as microbubble-mediated ultrasound therapy or targeted drug delivery. Finally, an enhancement technique involving the design and use of acoustic holograms in microfluidic channels is addressed which opens the door of acoustic patterning in particle and cell sorting for medical ultrasound systems.