Improved surgical procedures and implant developments for ligament or tendon repair require an in-depth understanding of tissue load-deformation and fatigue properties. Cyclic testing will provide crucial information on the behavior of these materials under reoccurring loads and on fatigue strength. Sparse data are available describing soft tissue behavior under cyclic loading. To examine fatigue strength, a new technology was trialed deploying 3D-printing to facilitate and standardize cyclic tests aiming to determine tendon fatigue behavior. Cadaveric flexor digitorum tendons were harvested and mounted for tensile testing with no tapering being made, using 3Dprinted clamps and holder arms, while ensuring a consistent testing length. Loads ranging between 200 to 510 N were applied at a frequency of 4 Hz, and cycles to failure ranged between 8 and >260,000. S–N curves (Woehler curves) were generated based on the peak stresses and cycles to failure. Power regression yielded a combined coefficient of determination of stress and cycles to failure of R 2 = 0.65, while the individual coefficients for tissues of single donors ranged between R 2 = 0.54 and R 2 = 0.88. The here-presented results demonstrate that S–N curves of human tendons can be obtained using a standardized setting deploying 3D-printing technology

The tumor microenvironment (TME) comprising immune cells and stromal components, such as fibroblasts and vessels, emerged as one of the most significant predictors of patient survival in a variety of solid tumors. With T cells representing the major cellular effector cells of the adaptive immune system and B cells orchestrating the humoral immune response, both cell types acquire crucial roles in the antitumor immune response. Thus, a high abundance of tumor-infiltrating CD8+ T cells and B cells has been generally associated with longer survival, while immunosuppressive subsets such as regulatory T cells (Treg) and M2-polarized macrophages are frequently linked to poor prognosis. Besides the frequency, also the spatial organization emerged as a clinically relevant parameter. Hence, the formation of T and B cells in tertiary lymphoid structures (TLS) was found to favor improved clinical outcome of patients. It was further reported that besides the prognostic value, the baseline immune architecture harbors the ability to predict the response to immunotherapies such as immune checkpoint inhibitor treatment and even chemotherapy. In turn, standard cytotoxic treatment regimens like radio- and chemotherapy, as well as novel immunotherapeutic or targeted approaches, exhibit distinct effects on various immune cells. Depending on the tumor entity, therapy, and immune cell subsets, differing modulation of infiltrating immune cells after therapy was observed. While previous studies mainly investigated an altered abundance of T and B cells, changes in functional orientation and composition of lymphocyte populations are gaining increasing relevance. In this thesis, the aim was to uncover the phenotype, frequency, composition, spatial distribution, clinical significance, and therapeutic modulation of the T cell compartment in soft tissue sarcoma (STS), and B cell populations in pancreatic ductal adenocarcinoma (PDAC). Due to the low incidence and heterogeneous nature of STS, detailed analyses of distinct CD8+ and CD4+ T cell subsets are lacking. To assess the effect of multimodal treatment, comprising radiotherapy and locoregional hyperthermia with or without chemotherapy, on the immune architecture, the patient cohort included matched pre- and post-therapy tissue samples. By assessing both the peritumoral and intratumoral region, additional information about the spatial distribution of STS-infiltrating T cells was gained. In PDAC, the T cell compartment and its therapeutic modulation has been explored in detail recently, but equivalent insight into the B cell landscape is missing. Going beyond the abundance of pan B cells, the aim was to identify proliferating B and T cells, germinal center (GC) B cells, plasmablasts, and plasma cells to investigate their modulation by neoadjuvant chemo(radio)therapy (NeoTx). Further insight into the spatial composition was gained by analyzing different regions (intratumoral and peritumoral) and tissue compartments (epithelial, stromal, TLS). To achieve this, three novel multiplex immunohistochemistry panels were established enabling simultaneous staining of six markers plus DAPI. For CD4+ T helper (Th) cells, the master transcription factors for Th1 (T-box expressed in T cells), Th2 (GATA-binding protein 3), Th17 (retinoic acid receptor-related orphan receptor T), and Treg (Forkhead box protein 3) were included in addition to CD3 and the proliferation marker Ki67. The CD8+ T cell panel comprised the phenotypic marker CD8, the immune checkpoint molecules programmed cell death protein 1 and lymphocyte-activation gene 3 as well as the activation-associated molecules granzyme B and 4-1BB, in addition to Ki67. It was thus found that post-treatment STS samples displayed moderately reduced frequencies of both CD8+ and CD3+ T cells in comparison to the pretreatment biopsy. The Th cell landscape was dominated by Th2 cells, whose density was significantly reduced upon multimodal therapy and a moderate redistribution favoring Th1 and Th17 cells was observed. While high frequencies of CD3+ and CD8+ T cells in the posttreatment tissues were associated with significantly longer disease-free survival, these populations held no prognostic value in the biopsy obtained prior to treatment, suggesting a reshaping of the TME upon therapy. Furthermore, the spatial distribution, reflected by the ratio of intra- to peritumoral CD8+ T cells, emerged as an independent prognostic factor for the risk of recurrence. In PDAC, B cell subsets were identified by staining for CD3, CD20, Ki67, the transcription factor B cell lymphoma 6, and the plasma cell markers CD38 and CD138. While CD3+ T cells were unaffected, significantly lower frequencies of proliferating B cells, GC B cells, plasmablasts, and plasma cells were observed in the NeoTx group compared to patients undergoing primary resection (PR). Furthermore, neoadjuvant-treated patients exhibited a significantly lower abundance of TLS, which was validated in an independent cohort. These results indicate that NeoTx differentially affects distinct immune cell subsets, and that B cellmediated antitumor immunity may be inhibited by chemo(radio)therapy. Spatial analysis further revealed that plasma cell accumulations frequently localized close to TLS, being accompanied by C-X-C motif chemokine ligand 12-expressing fibroblasts. Furthermore, patients with TLS exhibited significantly higher plasma cell frequencies, suggesting that TLS can foster the generation of plasma cells whose migration is then guided by fibroblastic tracks. Lastly, a prognostic value of pan T and B cells was observed only in the PR group, while these populations provided no clinical significance in neoadjuvant-treated patients. However, proliferating Ki67+CD20+ B cells emerged as an independent prognostic factor for a lower risk of death in the NeoTx group, suggesting a restorative post-treatment TME in these patients. Altogether, this thesis provided novel insights into the TME of STS and PDAC and its therapeutic alteration. Spatial analyses further enabled an improved understanding of the immune architecture and potential cell-cell interactions within the TME. In addition, strong associations with patient survival highlight the enormous significance of the TME and may guide future therapy development. Although the results do not encourage a concomitant application of cytotoxic therapy regimens and immunotherapy, patients may benefit from sequential combination treatments. An enhanced understanding of the immunomodulatory effects of NeoTx is pivotal for overcoming the immunosuppressive TME of STS and PDAC by refining existing treatment regimens and developing novel therapy approaches in order to improve the long-term outcome of patients.

Células mesenquimais indiferenciadas humanas foram obtidas por digestão enzimática e centrifugação do produto de lipoaspiração, expandidas in vitro, e implantadas no tecido subcutâneo de camundongos atímicos. No grupo I, cada animal recebeu o implante de uma membrana de 0,25cm2 de ácido glicólico e carbonato de trimetileno semeada com 1 x 106 destas células .No grupo II, cada um recebeu a injeção de 0,2ml de gel de ácido hialurônico reticulado contendo o mesmo número destas células. Com três semanas de implante, células humanas e vasos foram identificados nos dois carreadores. Entretanto, com oito semanas, somente no gel de ácido hialurônico as células humanas e os vasos estavam presentes / Human undifferentiated mesenchymal cells were obtained by enzymatic digestion and centrifugation of the product of liposuction. These cells were expanded, in vitro, and implanted subcutaneously in athymic mice. In group I, each animal received the implant of a 0,25cm2 membrane of glycolic acid and trimethylene carbonate, seeded with 1 x 106 of these cells. In group II, each one received 0,2 ml of cross-linked hyaluronic acid gel containing the same amount of these cells. With three weeks of implantation, human cells and vessels were identified in both carriers. However, with eight weeks of implantation, only in hyaluronic acid gel human cells and vessels were present

Synthetic vascular grafts are useful to bypass diseased arteries. The long-term failure of synthetic grafts is primarily due to intimal hyperplasia at the anastomotic sites. The accelerated intimal hyperplasia may stem from a compliance mismatch between the host artery and the graft since commercially available synthetic conduits are much stiffer than an artery. The objective of this thesis is to design a method for fabricating a vascular graft that mechanically matches the patients native artery over the expected physiologic range of pressures. The creation of an optimized mechanical graft will hopefully lead to an improvement in patency rates. The mechanical equivalency between the graft and the host artery is defined locally by several criteria including the diameter upon inflation, the elasticity at mean pressure, and axial force. A single parameter mathematical for a thin-walled tube is used to describe of the final mechanical behavior of a synthetic graft. For the general problem, the objective would be to fabricate a mechanics-matching vascular graft for each host artery. Typically, fabrication parameters are set initially and the properties of the fabricated graft are measured. However, by modeling the entire fabrication process and final mechanical properties, it is possible to invert the situation and let the typical output mechanical values be used to define the fabrication parameters. The resultant fabricated graft will then be mechanically matching. As a proof-of-concept, several prototype synthetic grafts were manufactured and characterized by a single Invariant to match a canine artery. The resultant graft equaled the diameter upon inflation, the elasticity at mean pressure, and axial force of the native canine artery within 6%. An alternative to making an individual graft for each artery is also presented. A surgeon may choose the best graft from a set of pre-manufactured grafts, using a computer program algorithm for best fit using two parameters in a neighborhood. The design optimization problem was solved for both canine carotid and human coronary arteries. In conclusion, the overall process of design, fabrication and selection of a mechanics matching synthetic vascular graft is shown to be reliable and robust.

Células mesenquimais indiferenciadas humanas foram obtidas por digestão enzimática e centrifugação do produto de lipoaspiração, expandidas in vitro, e implantadas no tecido subcutâneo de camundongos atímicos. No grupo I, cada animal recebeu o implante de uma membrana de 0,25cm2 de ácido glicólico e carbonato de trimetileno semeada com 1 x 106 destas células .No grupo II, cada um recebeu a injeção de 0,2ml de gel de ácido hialurônico reticulado contendo o mesmo número destas células. Com três semanas de implante, células humanas e vasos foram identificados nos dois carreadores. Entretanto, com oito semanas, somente no gel de ácido hialurônico as células humanas e os vasos estavam presentes / Human undifferentiated mesenchymal cells were obtained by enzymatic digestion and centrifugation of the product of liposuction. These cells were expanded, in vitro, and implanted subcutaneously in athymic mice. In group I, each animal received the implant of a 0,25cm2 membrane of glycolic acid and trimethylene carbonate, seeded with 1 x 106 of these cells. In group II, each one received 0,2 ml of cross-linked hyaluronic acid gel containing the same amount of these cells. With three weeks of implantation, human cells and vessels were identified in both carriers. However, with eight weeks of implantation, only in hyaluronic acid gel human cells and vessels were present

Diffuse optical tomography is a promising imaging modality that provides functional information of the soft biological tissues, with prime imaging applications including breast and brain tissue in-vivo. This modality uses near infrared light( 600nm-900nm) as the probing media, giving an advantage of being non-ionizing imaging modality. The image reconstruction problem in diffuse optical tomography is typically posed as a least-squares problem that minimizes the difference between experimental and modeled data with respect to optical properties. This problem is non-linear and ill-posed, due to multiple scattering of the near infrared light in the biological tissues, leading to infinitely many possible solutions. The traditional methods employ a regularization term to constrain the solution space as well as stabilize the solution, with Tikhonov type regularization being the most popular one. The choice of this regularization parameter, also known as hyper parameter, dictates the reconstructed optical image quality and is typically chosen empirically or based on prior experience. In this thesis, a simple back projection type image reconstruction algorithm is taken up, as they are known to provide computationally efficient solution compared to regularized solutions. In these algorithms, the hyper parameter becomes equivalent to filter factor and choice of which is typically dependent on the sampling interval used for acquiring data in each projection and the angle of projection. Determining these parameters for diffuse optical tomography is not so straightforward and requires usage of advanced computational models. In this thesis, a computationally efficient simplex Method based optimization scheme for automatically finding this filter factor is proposed and its performances is evaluated through numerical and experimental phantom data. As back projection type algorithms are approximations to traditional methods, the absolute quantitative accuracy of the reconstructed optical properties is poor .In scenarios, like dynamic imaging, where the emphasis is on recovering relative difference in the optical properties, these algorithms are effective in comparison to traditional methods, with an added advantage being highly computationally efficient. In the second part of this thesis, this hyper parameter choice for traditional Tikhonov type regularization is attempted with the help of Least-Squares QR-decompisition (LSQR) method. The established techniques that enable the automated choice of hyper parameters include Generalized Cross-Validation(GCV) and regularized Minimal Residual Method(MRM), where both of them come with higher over head of computation time, making it prohibitive to be used in the real-time. The proposed LSQR algorithm uses bidiagonalization of the system matrix to result in less computational cost. The proposed LSQR-based algorithm for automated choice of hyper parameter is compared with MRM methods and is proven to be computationally optimal technique through numerical and experimental phantom cases.

Three-dimensional (3D) printing has become broadly available and can be utilized to customize clamping mechanisms in biomechanical experiments. This report will describe our experience using 3D printed clamps to mount soft tissues from different anatomical regions. The feasibility and potential limitations of the technology will be discussed. Tissues were sourced in a fresh condition, including human skin, ligaments and tendons. Standardized clamps and fixtures were 3D printed and used to mount specimens. In quasi-static tensile tests combined with digital image correlation and fatigue trials we characterized the applicability of the clamping technique. Scanning electron microscopy was utilized to evaluate the specimens to assess the integrity of the extracellular matrix following the mechanical tests. 3D printed clamps showed no signs of clamping-related failure during the quasi-static tests, and intact extracellular matrix was found in the clamping area, at the transition clamping area and the central area from where the strain data was obtained. In the fatigue tests, material slippage was low, allowing for cyclic tests beyond 105 cycles. Comparison to other clamping techniques yields that 3D printed clamps ease and expedite specimen handling, are highly adaptable to specimen geometries and ideal for high-standardization and high-throughput experiments in soft tissue biomechanics.

Indiana University-Purdue University Indianapolis (IUPUI) / Instrument assisted soft tissue mobilization (IASTM) is a form of massage using rigid manufactured or cast devices. The delivered force, which is a critical parameter in massage during IASTM, has not been measured or standardized for most clinical practices. In addition to the force, the angle of treatment and frequency play an important role during IASTM. As a result, there is a strong need to characterize the delivered force to a patient, angle of treatment, and stroke frequency. This thesis proposes two novel mechatronic designs for a specific instrument from Graston Technique(Model GT3), which is a frequently used tool to clinically deliver localize pressure to the soft tissue. The first design is based on compression load cells, where 4-load cells are used to measure the force components in three-dimensional space. The second design uses a 3D load cell, which can measure all three force components force simultaneously. Both designs are implemented with IMUduino microcontroller chips which can also measure tool orientation angles and provide computed stroke frequency. Both designs, which were created using Creo CAD platform, were also analyzed thorough strength and integrity using the finite element analysis package ANSYS. Once the static analysis was completed, a dynamic model was created for the first design to simulate IASTM practice using the GT-3 tool. The deformation and stress on skin were measured after applying force with the GT-3 tool. Additionally, the relationship between skin stress and the load cell measurements has been investigated. The second design of the mechatronic IASTM tool was validated for force measurements using an electronic plate scale that provided the baseline force values to compare with the applied force values measured by the tool. The load cell measurements and the scale readings were found to be in agreement within the expected degree of accuracy. The stroke frequency was computed using the force data and determining the peaks during force application. The orientation angles were obtained from the built-in sensors in the microchip.

Objective: Soft tissue sarcomas (STS) and gastrointestinal stromal tumours (GIST) are a group of rare malignant tumours with a high and heterogenous disease burden. As evidence is scarce, we analysed the prevalence of increased emotional distress and identified distress‐associated factors in these patients. - Methods: The PROSa‐study (Burden and medical care of sarcoma) was conducted between 2017 and 2020 in 39 study centres. Cross‐sectional data from adult STS and GIST patients were analysed. Distress was measured with the Patient Health Questionnaire (PHQ‐4). The relation of socioeconomic and clinical factors with distress was explored in adjusted logistic regression models. - Results: Among 897 patients, 17% reported elevated anxiety and 19% reported depression. Unemployed patients (odds ratio [OR] 6.6; 95% CI 2.9–15.0), and those with a disability pension (OR 3.1; 95% CI 1.9–5.0) were more likely to experience distress compared to employed patients. Also, patients with a disability pass had higher odds of increased distress than those without (OR 1.8; 95% CI 1.2–2.7). Lowest distress was observed in patients 2 to <5 years and ≥5 years after diagnosis (comparison: <6 months) (OR 0.4; 95% CI 0.2–0.6) and (0.3; 95% CI 0.2–0.6). Patients with thoracic STS (vs. lower limbs) had twice the odds to experience distress(OR2.0;95%CI 1.1–3.6). Distress was seen almost twice as often in patients with progressive disease (vs. complete remission) (OR 1.7; 95% CI 1.1–2.8). - Conclusion: The prevalence of elevated distress in STS and GIST patients is high. In unemployed patients, in those with a disability pension and in newly diagnosed patients a noticeable increase was observed. Clinicians should be aware of these factors and consider the social aspects of the disease.

[EN] Nature is nonlinear. The linear description of physical phenomena is useful for explain observations with the simplest mathematical models, but they are only accurate for a limited range of input values. In the case of intense acoustics waves, linear models obviate a wide range of physical phenomena that are necessary for accurately describe such high-amplitude waves, indispensable for explain other exotic acoustic waves and mandatory for developing new applied techniques based on nonlinear processes. In this Thesis we study the interactions between nonlinearity and other basic wave phenomena such as non-classical attenuation, anisotropic dispersion and periodicity, and diffraction in specific configurations. First, we present intense strain waves in a chain of cations coupled by realistic interatomic potentials. Here, the nonlinear ionic interactions and lattice dispersion lead to the formation of supersonic kinks. These intrinsically-nonlinear localized dislocations travel long distances without changing its properties and explain the formation of dark traces in mica crystals. Then, we analyze nonlinear wave processes in a system composed of multilayered acoustic media. The rich nonlinear dynamics of this system is characterized by its strong dispersion. Here, harmonic generation processes and the relation with its band structure are presented, showing that the nonlinear processes can be enhanced, strongly minimized or simply modified by tuning the layer parameters. In this way, we show how the dynamics of intense monochromatic waves and acoustic solitons can be controlled by artificial layered materials. In a second part, we include diffraction and analyze four types of singular beams. First, we study nonlinear beams in two dimensional sonic crystals. In this system, the inclusion of anisotropic dispersion is tuned for obtain simultaneous self-collimation for fundamental and second harmonic beams. The conditions for optimal second harmonic generation are presented. Secondly, we present limited diffraction beam generation using equispaced axisymmetric diffraction gratings. The obtained beams are truncated version of zero-th order Bessel beams. Third, the grating spacing can be modified to achieve focusing, where the generated nonlinear beams presents high gain, around 30 dB, with a focal width which is between the diffraction limit and the sub-wavelength regime, but with its characteristic high amplitude side lobes strongly reduced. Finally, we observe that waves diffracted by spiral-shaped gratings generate high-order Bessel beams, conforming nonlinear acoustic vortex. The conditions to obtain arbitrary-order Bessel beams by these passive elements are presented. Finally, the interplay of nonlinearity and attenuation in biological media is studied in the context of medical ultrasound. First, a numerical method is developed. The method solves the constitutive relations for nonlinear acoustics and the frequency power law attenuation of biological media is modeled as a sum of relaxation processes. A new technique for reducing numerical dispersion based on artificial relaxation is included. Second, this method is used to study the harmonic balance as a function of the power law, showing the role of weak dispersion and its impact on the efficiency of the harmonic generation in soft-tissues. Finally, the study concerns the nonlinear behavior of acoustic radiation forces in frequency power law attenuation media. We present how the interplay between nonlinearity and the specific frequency power law of biological media can modify the value for acoustic radiation forces. The relation of the nonlinear acoustic radiation force with thermal effects are also discussed. The broad range of nonlinear processes analyzed in this Thesis contributes to understanding the behavior of intense acoustic waves traveling trough complex media, while its implications for enhancing existent applied acoustics techniques are presented. / [ES] La Naturaleza es no lineal. La descripción lineal de los fenómenos físicos es de gran utilidad para explicar nuestras observaciones con modelos matemáticos simples, pero éstos sólo son precisos en un limitado rango de validez. En el caso de onda acústica de alta intensidad, los modelos lineales obvian un amplio rango de fenómenos físicos que son necesarios para describir con precisión las ondas de gran amplitud, pero además son necesarios para explicar otros procesos más exóticos e indispensables para desarrollar nuevas aplicaciones basadas en propagación no lineal. En esta Tesis, estudiamos las interacciones entre no linealidad y otros procesos complejos como atenuación no-clásica, dispersión anisotrópica y periodicidad, y difracción en configuraciones específicas. En primer lugar, presentamos ondas de deformación en una cadena de cationes acoplados por potenciales realísticas. Aquí, las interacciones no lineales entre iones, producen la conformación de kinks supersónicos. Estas dislocaciones localizadas intrínsecamente no lineales viajan por la red largas distancias sin variar sus propiedades, y pueden explicar la formación de trazas en minerales como la mica. Aumentando la escala del problema, estudiamos los procesos acústicos no lineales en medios multicapa. La rica dinámica de estos medios está caracterizada por la fuerte dispersión debido a la periodicidad del sistema. Aquí, estudiamos los procesos de generación de harmónicos, mostrando como modificando la estructura podemos potenciar, minimizar, o simplemente modificar artificialmente la transferencia de energía entre las componentes espectrales, y de esta manera controlar la dinámica de las ondas y solitones en el interior de la estructura. En la segunda parte, incluimos difracción y analizamos cuatro tipos de haces singulares. En primer lugar, analizamos haces ultrasónicos no lineales en cristales de sonido bidimensionales. En este sistema, las propiedades de anisotropía del medio son ajustadas para obtener la auto-colimación simultánea del primer y segundo harmónico. Así, se obtiene la propagación no difractiva para las dos componentes. En segundo lugar, presentamos haces de difracción limitada empleando rejillas de difracción axisimétricas. Por último, demostramos la generación de haces de Bessel de orden superior mediante estructuras en espiral. En la última parte, estudiamos la competición entre no linealidad y la atenuación y dispersión observable en medios biológicos en el contexto de las aplicaciones de biomédicas de los ultrasonidos. En primer lugar desarrollamos un nuevo método computacional para la dependencia frecuencial en forma de ley de potencia de la absorción característica de los tejidos. Este método en dominio temporal es usado posteriormente para revisar los procesos básicos no lineales prestando especial interés en el paper de la dispersión del tejido. Por último, la resolución de las ecuaciones constitutivas nos permite abordar la descripción no lineal de la fuerza de radiación acústica producida en tejidos biológicos, y las implicaciones existentes con la deposición de energía y transferencia de momento para ondas ultrasónicas de alta intensidad. El amplio abanico de procesos no lineales analizados en esta tesis contribuye a una mejor comprensión de la dinámica de las ondas acústicas de alta intensidad en medios complejos, donde las implicaciones existentes en cuanto a la mejora de sus aplicaciones prácticas son puestas de manifiesto. / [CA] La Naturalesa és no lineal. La descripció lineal dels fenòmens físics és de gran utilitat per a explicar les nostres observacions amb models matemàtics simples, però aquests sol són precisos en un limitat rang de validesa. En el cas d'ona acústica d'alta intensitat, els models lineals obvien un ampli rang de fenòmens físics que són necessaris per a descriure amb precisió les ones de gran amplitud, però a més són necessaris per a explicar altres processos més exòtics i indispensables per a desenvolupar noves aplicacions basades en propagació no lineal. En aquesta Tesi, estudiem les interaccions entre no-linealitat i altres processos complexos com atenuació no-clàssica, dispersió anisotròpica i periodicitat, i difracció en configuracions específiques. En primer lloc, presentem ones de deformació en una cadena de cations acoblats per potencials realistes. Ací, les interaccions no lineals entre ions, produeixen la conformació de kinks supersònics. Aquestes dislocacions localitzades intrínsecament no lineals viatgen per la xarxa llargues distàncies sense variar les seues propietats, i poden explicar la formació de traces en minerals com la mica. Augmentant l'escala del problema, estudiem els processos acústics no lineals en mitjans multicapa. La rica dinàmica d'aquests mitjans es caracteritza per la forta dispersió a causa de la periodicitat del sistema. Ací, estudiem els processos de generació d'harmònics, mostrant com modificant l'estructura podem potenciar, minimitzar, o simplement modificar artificialment la transferència d'energia entre les components espectrals, i d'aquesta manera controlar la dinàmica de les ones i solitons a l'interior de l'estructura. En la segona part, incloem difracció i analitzem quatre tipus de feixos singulars. En primer lloc, analitzem feixos ultrasònics no lineals en cristalls de so bidimensionals. En aquest sistema, les propietats d'anisotropia del medi són ajustades per a obtenir l'acte-col·limació simultània del primer i segon harmònic. Així, s'obté la propagació no difractiva per a les dues components. En segon lloc, presentem feixos de difracció limitada emprant reixetes de difracció axisimètriques. Per últim, vam demostrar la generació de feixos de Bessel d'ordre superior mitjançant estructures en espiral. En l'última part, estudiem la competició entre no linealitat i l'atenuació i dispersió observable en medis biològics en el context de les aplicacions biomèdiques dels ultrasons. En primer lloc desenvolupem un nou mètode computacional per a la dependència freqüencial en forma de llei de potència de l'absorció característica dels teixits biològics. Aquest mètode en domini temporal és usat posteriorment per a revisar els processos bàsics no lineals prestant especial interés en el paper de la dispersió del teixit. Per últim, la resolució de les equacions constitutives ens permet abordar la descripció no lineal de la força de radiació acústica produïda en teixits biològics, i les implicacions existents amb la deposició d'energia i transferència de moment per a ones ultrasòniques d'alta intensitat. L'ampli ventall de processos no lineals analitzats en aquesta tesi contribueix a una millor comprensió de la dinàmica de les ones acústiques d'alta intensitat en medis complexos, on les implicacions existents quant a la millora de les seues aplicacions practiques són posades de manifest. / Jiménez González, N. (2015). Nonlinear Acoustic Waves in Complex Media [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/53237 / Premios Extraordinarios de tesis doctorales