Transcranial Ultrasound Holograms for the Blood-Brain Barrier Opening

[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/10251/171373TESI

Transcranial focusing of ultrasonic vortices by acoustic holograms

[EN] Acoustic vortex beams have great potential for contactless particle manipulation and torque-based biomedical applications. However, when focusing acoustic waves through aberration layers such as the human skull at ultrasonic frequencies results in strong phase aberrations which prevent the generation of sharp acoustic images. In the case of a wavefront containing phase dislocations, skull aberrations inhibit the focusing of acoustic vortex beams inside the cranial cavity. In this work, we demonstrate that phase-conjugated acoustic holograms can encode time-reversed fields simultaneously allowing the compensation of the aberrations of the skull and the generation of a focused vortex inside an ex-vivo human skull. The method is applied for single-element geometrically focused sources and results in a very simple and compact ultrasonic system. This work will pave the road to design low-cost particle trapping applications, clot manipulation, torque exertion in the brain and acoustic-radiation-force based biomedical applications.This research was supported by the Spanish Ministry of Science, Innovation, and Universities through "Juan de la Cierva-Incorporacion" Grants No. IJC2018-037897-I and No. PID2019-111436RB-C22, by the Agencia Valenciana de la Innovacio through Grants No. INNVAL10/19/016, No. INNVA1/2020/92, and No. INNCON/2020/009, and by the Generalitat Valenciana through Grant No. ACIF/2017/045. The action was cofinanced by the European Union through the Programa Operativo del Fondo Europeo de Desarrollo Regional (FEDER) of the Comunitat Valenciana, Grant No. IDIFEDER/2018/022.Jiménez-Gambín, S.; Jimenez, N.; Camarena Femenia, F. (2020). Transcranial focusing of ultrasonic vortices by acoustic holograms. Physical Review Applied. 14(5):1-10. https://doi.org/10.1103/PhysRevApplied.14.054070S11014

Multifocal acoustic holograms for deep-brain neuromodulation and BBB opening

[EN] Single-element focused ultrasound devices have demonstrated its ability to non-invasively open the Blood Brain Barrier. However, skull irregularities and absorption produce strong aberrations in the ultrasound focus. Recently, 3D-printed acoustic holograms were used to compensate aberrations and to produce a sharp focus. In addition, using this technology the geometry of the ultrasonic focus can be matched to the shape of the brain structure of interest. In this work, we experimentally and numerically report 3D-printed acoustic holograms for bilateral focusing through an ex-vivo human skull. Using holograms, we target different cerebral nuclei and the ultrasonic focuses are adapted to the target volumes, minimizing the acoustic field outside. Simultaneously, skull aberrations are corrected using phased-conjugation methods. The holographic surfaces were manufactured for a 100-mm aperture and 140-mm focal focused transducer at 500 kHz to focus through an ex-vivo human skull. Numerical and experimental results agree targeting several deep-brain nuclei: left-and-right putamen, caudate nuclei, and hippocampi, showing the potential of this low-cost technology to optimize BBBO or neuromodulation treatments.This research has been supported by the Spanish Ministry of Science, Innovation and Universities through grant Juan de la Cierva - Incorporacion (IJC2018-037897-I) and PID2019-111436RBC22, by the Agencia Valenciana de la Innovacio through grants INNVAL10/19/016 and INNCON/2020/009. Action cofinanced by the European Union through the Programa Operativo del Fondo Europeo de Desarrollo Regional (FEDER) of the Comunitat Valenciana 2014-2020 (IDIFEDER/2018/022).Andrés, D.; Jiménez-Gambín, S.; Jimenez, N.; Camarena Femenia, F. (2020). Multifocal acoustic holograms for deep-brain neuromodulation and BBB opening. IEEE. 1-3. https://doi.org/10.1109/IUS46767.2020.9251769S1

Efecto del método de definición de las propiedades acústicas de cráneo humano en la propagación focalizada de ultrasonidos

[EN] Combination of focused ultrasound and microbubbles is a non-ionizing technique for neurodegenerative diseases treatment allowing the blood-brain barrier opening locally, transiently, non-invasively and safely. In this paper, we numerically study the effect in the propagation of ultrasound beams through a human skull which acoustical properties are obtained from a CT-scan using different methods. We use a single-element focused transducer working at 500 kHz. Aberrations through parietal bone are assessed, such us focus deviation and attenuation. The acoustic field distribution is also evaluated. Finally, the homogeneous model, which is the simplest one, generates higher focal attenuation, while the heterogeneous models offer a lower attenuation in the focal spot for the studied incidence skull area.[ES] La combinación de ultrasonidos focalizados y microburbujas es una técnica no ionizante para el tratamiento de enfermedades neurodegenerativas permitiendo la apertura de la barrera hematoencefálica de forma local, transitoria, no invasiva, y segura. En este trabajo, se estudia numéricamente el efecto en la propagación de ultrasonidos a través de un cráneo humano cuyas propiedades acústicas se han obtenido por CT-scan empleando diferentes métodos. Se emplea un transductor focalizado mono-elemento trabajando en 500 kHz. Se evalúan las aberraciones a través del hueso parietal. Finalmente, el método homogéneo, que es el más simple, genera mayor atenuación del foco, mientras que los modelos heterogéneos ofrecen una menor atenuación de la zona focal para la zona de incidencia del cráneo estudiada.Este trabajo ha sido financiado por la subvención predoctoral ACIF 2017 de la GVA.Jiménez-Gambín, S.; Jimenez, N.; Camarena Femenia, F. (2019). Efecto del método de definición de las propiedades acústicas de cráneo humano en la propagación focalizada de ultrasonidos. Revista de Acústica. 50(1-2):20-24. http://hdl.handle.net/10251/140248S2024501-

Transcranial acoustic holograms for arbitrary fields generation using focused ultrasound into the brain

[EN] We present 3D printed holographic lenses that correct the aberrations of the skull and, simultaneously, produce arbitrary ultrasonic fields with the geometry of brain structures. Using experimental techniques on a human skull phantom (HSP), a multiple-point focusing lens is designed to focus at both human hippocampi at once; a beam following an arbitrary curved trajectory, i.e., a self-bending beam; and a holographic plate producing a broad focus that overlaps with the left hippocampus (LH). Skull and LH geometries and acoustic properties are obtained from CT-scans and MRI, respectively. Time-reversal (TR) method is used to obtain the magnitude and phase of the back-propagated field from the target shape towards the lens surface. The holographic lenses are designed assuming each pixel of the lens vibrates as a Fabry-Pérot resonator. The resulting lenses are 3D printed using SLA techniques. The three studied cases show similar results in simulation and experiment with and without the HSP: for the bi-focal beam, the reconstructed field accurately matches the target foci; for the curved trajectory beam, the target acoustic image is reconstructed by the designed holographic lens; for the broad focus beam, results present the same qualitative performance providing a similar overall covering of the LH. The reported holographic lenses can be used to control the spatial features of ultrasonic beams inside the skull in an unprecedented manner using single-element ultrasonic sources.This work was supported by Generalitat Valenciana through grants APOSTD/2017/042, ACIF/2017/045 and GV/2018/11. FC acknowledges financial support from Agencia Valenciana de la Innovacio through grant INNCON00/18/9 and European Regional Development Fund (IDIFEDER/2018/022).Jiménez-Gambín, S.; Jimenez, N.; Benlloch Baviera, JM.; Camarena Femenia, F. (2019). Transcranial acoustic holograms for arbitrary fields generation using focused ultrasound into the brain. Acoustical Society of America. 1-6. https://doi.org/10.1121/2.0001195S1

Acoustic Holograms for Bilateral Blood-Brain Barrier Opening in a Mouse Model

[EN] Transcranial focused ultrasound (FUS) in conjunction with circulating microbubbles injection is the sole non-invasive technique that temporally and locally opens the blood-brain barrier (BBB), allowing targeted drug delivery into the central nervous system (CNS). However, single-element FUS technologies do not allow the simultaneous targeting of several brain structures with high-resolution, and multi-element devices are required to compensate the aberrations introduced by the skull. In this work, we present the first preclinical application of acoustic holograms to perform a bilateral BBB opening in two mirrored regions in mice. The system consisted of a single-element focused transducer working at 1.68 MHz, coupled to a 3D-printed acoustic hologram designed to produce two symmetric foci in anesthetized mice in vivo and, simultaneously, compensate the aberrations of the wavefront caused by the skull bones. T1-weighed MR images showed gadolinium extravasation at two symmetric quasi-spherical focal spots. By encoding time-reversed fields, holograms are capable of focusing acoustic energy with a resolution near the diffraction limit at multiple spots inside the skull of small preclinical animals. This work demonstrates the feasibility of hologram-assisted BBB opening for low-cost and highly-localized targeted drug delivery in the CNS in symmetric regions of separate hemispheres.This work was supported in part by the Spanish Ministry of Science, Innovation, and Universities (MICINN) through Grants "Juan de la Cierva -Incorporacion" IJC2018-037897-I, and PID2019-111436RB-C22, in part by the Agencia Valenciana de la Innovacio through Grants INNVAL10/19/016, INNCON/2021/8, and INNVA1/2020/92, in part by Generalitat Valenciana through Grants ACIF/2017/045, AICO/2020/268, and BEFPI/2019/075, and in part by the National Institutes of Health through Grants 5R01EB009041 and 5R01AG038961. Action co-financed by the European Union through the Programa Operativo del Fondo Europeo de Desarrollo Regional (FEDER) of the Comunitat Valenciana (IDIFEDER/2018/022 and IDIFEDER/2021/004)Jiménez-Gambín, S.; Jimenez, N.; Pouliopoulos, AN.; Benlloch Baviera, JM.; Konofagou, EE.; Camarena Femenia, F. (2022). Acoustic Holograms for Bilateral Blood-Brain Barrier Opening in a Mouse Model. IEEE Transactions on Biomedical Engineering. 69(4):1359-1368. https://doi.org/10.1109/TBME.2021.31155531359136869

First in-vivo Demonstration of Bilateral Blood-Brain Barrier Opening Using Acoustic Holograms in Mice

[EN] Focused ultrasound (FUS) with microbubbles allows for non-invasive targeted drug delivery into the central nervous system (CNS) by temporally and locally disrupting the bloodbrain barrier (BBB). However, current FUS technologies are not able to simultaneously target several brain structures. In this work, we open the BBB in two regions in a murine brain using a single-element transducer with a coupled 3D-printed holographic lens, which is designed to simultaneously create two symmetric foci in anesthetized mice in vivo. The proposed approach shows many advantages: (1) simple and low-cost; (2) correction of aberrations due to skull and water cone; and (3) multiple BBB opening (BBBO) locations with only one sonication, becoming a time- and cost-effective therapeutic system for neurological diseases. For the in-vivo experiment, contrast-enhanced, T1- weighted MRI scan was conducted following BBBO, showing gadolinium extravasation at two symmetric focal spots. The two BBBO regions were separated by 3.0 +- 0.7 mm (n=5 mice) compared to 5.3 mm in full-wave simulations. This work shows the capability of bifocal ultrasound generation in separate animals using a unique uCT scan. A bilateral BBBO was achieved with a single sonication using a holographic lens in mice, thus improving the efficiency and defining a new approach for several neurodegenerative diseases targeting symmetric brain structures, e.g. hippocampus, putamen or caudate. This study demonstrates the feasibility of hologram-assisted BBBO for targeted drug delivery in the CNS in symmetric regions in separate hemispheres.This research has been supported by the Spanish Ministry of Science, Innovation and Universities through grants Juan de la Cierva - Incorporacion (IJC2018-037897-I) and PID2019-111436RB-C22, by the Agencia Valenciana de la Innovación through grant INNVAL10/19/016, by Generalitat Valenciana through grants No. ACIF/2017/045 and BEFPI/2019/075, and by the National Institutes of Health through grants 5R01EB009041 and 5R01AG038961. Action co-financed 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.; Jimenez, N.; Benlloch Baviera, JM.; Camarena Femenia, F.; Pouliopoulos, AN.; Konofagou, EE. (2020). First in-vivo Demonstration of Bilateral Blood-Brain Barrier Opening Using Acoustic Holograms in Mice. IEEE. 1-4. https://doi.org/10.1109/IUS46767.2020.9251487S1

On the Evaluation of the Suitability of the Materials Used to 3D Print Holographic Acoustic Lenses to Correct Transcranial Focused Ultrasound Aberrations

[EN] The correction of transcranial focused ultrasound aberrations is a relevant topic for enhancing various non-invasive medical treatments. Presently, the most widely accepted method to improve focusing is the emission through multi-element phased arrays; however, a new disruptive technology, based on 3D printed holographic acoustic lenses, has recently been proposed, overcoming the spatial limitations of phased arrays due to the submillimetric precision of the latest generation of 3D printers. This work aims to optimize this recent solution. Particularly, the preferred acoustic properties of the polymers used for printing the lenses are systematically analyzed, paying special attention to the effect of p-wave speed and its relationship to the achievable voxel size of 3D printers. Results from simulations and experiments clearly show that, given a particular voxel size, there are optimal ranges for lens thickness and p-wave speed, fairly independent of the emitted frequency, the transducer aperture, or the transducer-target distance.This work was partially supported by the Spanish "Ministerio de Economia y Competitividad" under the projects RTI2018-096904-B-I00 and TEC2016-80976-R. N.J. and S.J. acknowledge financial support from Generalitat Valenciana through Grants No. APOSTD/2017/042, No. ACIF/2017/045, and No. GV/2018/11. F.C. acknowledges financial support from Agencia Valenciana de la Innovacio through Grants No. INNCON00/18/9 and INNVAL10/19/016 and Generalitat Valenciana and European Regional Development Fund (Grant No. IDIFEDER/2018/022).Ferri García, M.; Bravo Plana-Sala, JM.; Redondo, J.; Jiménez-Gambín, S.; Jimenez, N.; Camarena Femenia, F.; Sánchez-Pérez, JV. (2019). 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Estudios sobre la propagación transcraneal de ultrasonidos

Algunas enfermedades neurodegenerativas como el Alzheimer o el Parkinson se podrían tratar combinando los ultrasonidos focalizados con la técnica de inyección de microburbujas, permitiendo así la apertura de la BHE (Barrera HEmatoencefálica) para tener acceso a zonas concretas del cerebro y el suministro efectivo de fármacos. En este estudio se lleva a cabo la focalización de ultrasonidos sobre cualquiera de las partes del cerebro humano, pero teniendo en cuenta especialmente que la incidencia del haz sobre el cráneo sea normal, a modo de realizar un análisis de las aberraciones (atenuación, FWHM y desviación del foco) generadas por el cráneo dependiendo del ángulo de incidencia y de la distancia de separación entre transductor y cráneo, empleando un transductor focalizado trabajando a 500 kHz. El estudio se basa en la simulación numérica en dominio temporal mediante el método k-space considerando las ondas longitudinales sobre un dominio 3D, donde el modelado del cráneo humano se realiza mediante tomografía computarizada. Las aberraciones del foco están muy ligadas a las irregularidades del cráneo, observando en algunos casos ciertas tendencias de evolución en las propiedades del foco, mientras que en otros el comportamiento es más complejo. La zona occipital es la que genera menos desviación y variación del FWHM en el foco.Some neurodegenerative diseases as Alzheimer’s or Parkinson’s are supposed to be treated by using focused ultrasound therapy and microbubble injection, aiming the BBB (Blood Brain Barrier) opening to have access to concrete zones of brain and then to effectively deliver therapeutic drugs. This study addresses the transcranial targeting of whatever part of human brain, but specially taking into account normal skull surface incidence, in order to analyze the aberrations (attenuation, FWHM and deviation of beam focus) generated by skull depending on angle of incidence and separation distance between transducer and skull, employing a focused transducer working at 500 kHz. This work is based on the numerical simulation in time domain using the k-space method considering the longitudinal wave son a 3D domain, where the modeling of the human skull is performed by CT scan. Focus aberrations are closely linked to the irregularities of the skull, in some cases observing certain trends of evolution in the properties of the focus, while in others the behavior is more complex. The occipital region generates less deviation and variation of the FWHM in focusJiménez Gambín, S. (2016). Estudios sobre la propagación transcraneal de ultrasonidos. Universitat Politècnica de València. http://hdl.handle.net/10251/72594TFG