Biosimilar medicines in dermatology: key aspects

Article reproduced (or made available) with permission of Practical Dermatology®, www.practicaldermatology.com.En el artículo se recoge la aplicación de los medicamentos biosimilares biotecnológicos) en patologías dermatológicas

Risk Management Plan and Pharmacovigilance System. Biopharmaceuticals: Biosimilars

Editor literario del libro, Giancarlo Nota - All chapters are Open Access articles distributed under the Creative Commons Non Commercial-Share Alike-Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited

Simulating Extraocular Muscle Dynamics. A Comparison between Dynamic Implicit and Explicit Finite Element Methods

The finite element method has been widely used to investigate the mechanical behavior of biological tissues. When analyzing these particular materials subjected to dynamic requests, time integration algorithms should be considered to incorporate the inertial effects. These algorithms can be classified as implicit or explicit. Although both algorithms have been used in different scenarios, a comparative study of the outcomes of both methods is important to determine the performance of a model used to simulate the active contraction of the skeletal muscle tissue. In this work, dynamic implicit and dynamic explicit solutions are presented for the movement of the eye ball induced by the extraocular muscles. Aspects such as stability, computational time and the influence of mass-scaling for the explicit formulation were assessed using ABAQUS software. Both strategies produced similar results regarding range of movement of the eye ball, total deformation and kinetic energy. Using the implicit dynamic formulation, an important amount of computational time reduction is achieved. Although mass-scaling can reduce the simulation time, the dynamic contraction of the muscle is drastically altered

Sequential non-rigid structure from motion using physical priors

© 20xx IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.We propose a new approach to simultaneously recover camera pose and 3D shape of non-rigid and potentially extensible surfaces from a monocular image sequence. For this purpose, we make use of the Extended Kalman Filter based Simultaneous Localization And Mapping (EKF-SLAM) formulation, a Bayesian optimization framework traditionally used in mobile robotics for estimating camera pose and reconstructing rigid scenarios. In order to extend the problem to a deformable domain we represent the object's surface mechanics by means of Navier's equations, which are solved using a Finite Element Method (FEM). With these main ingredients, we can further model the material's stretching, allowing us to go a step further than most of current techniques, typically constrained to surfaces undergoing isometric deformations. We extensively validate our approach in both real and synthetic experiments, and demonstrate its advantages with respect to competing methods. More specifically, we show that besides simultaneously retrieving camera pose and non-rigid shape, our approach is adequate for both isometric and extensible surfaces, does not require neither batch processing all the frames nor tracking points over the whole sequence and runs at several frames per second.Peer ReviewedPostprint (author's final draft

Real-time 3D reconstruction of non-rigid shapes with a single moving camera

© . This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/This paper describes a real-time sequential method to simultaneously recover the camera motion and the 3D shape of deformable objects from a calibrated monocular video. For this purpose, we consider the Navier-Cauchy equations used in 3D linear elasticity and solved by finite elements, to model the time-varying shape per frame. These equations are embedded in an extended Kalman filter, resulting in sequential Bayesian estimation approach. We represent the shape, with unknown material properties, as a combination of elastic elements whose nodal points correspond to salient points in the image. The global rigidity of the shape is encoded by a stiffness matrix, computed after assembling each of these elements. With this piecewise model, we can linearly relate the 3D displacements with the 3D acting forces that cause the object deformation, assumed to be normally distributed. While standard finite-element-method techniques require imposing boundary conditions to solve the resulting linear system, in this work we eliminate this requirement by modeling the compliance matrix with a generalized pseudoinverse that enforces a pre-fixed rank. Our framework also ensures surface continuity without the need for a post-processing step to stitch all the piecewise reconstructions into a global smooth shape. We present experimental results using both synthetic and real videos for different scenarios ranging from isometric to elastic deformations. We also show the consistency of the estimation with respect to 3D ground truth data, include several experiments assessing robustness against artifacts and finally, provide an experimental validation of our performance in real time at frame rate for small mapsPeer ReviewedPostprint (author's final draft

A Numerical Exploration of the Crystalline Lens: from Presbyopia to Cataracts and Intraocular Lenses

Esta tesis aborda, de forma numérica, la resolución de tres problemas relacionados con el cristalino. En primer lugar, se ha construido un modelo de elementos finitos del cristalino humano para abordar la simulación de la acomodación, gracias a la incorporación de la contracción muscular del músculo ciliar. El modelo se ha validado con resultados experimentales comparando con Ramasubramanian & Glasser, 2015. Con el mismo modelo, se ha estudiado como afecta el cambio de las propiedades mecánicas de los tejidos del cristalino en la pérdida de amplitud de la acomodación con la edad para entender si la rigidización de los tejidos juega un papel importante en la presbicia. La conclusión principal del estudio numérico ha sido que las propiedades mecánicas y tensiones iniciales de la cápsula del cristalino proporciona la fuerza necesaria para acomodar, es decir, cambiar su curvatura para enfocar de cerca. Especificamente, el ratio de rígidez entre el núcleo y el cristalino gobierna cómo el cristalino cambia de forma. Con la edad, se produce una rigidización del núcleo, y el incremento de la relación entre ambas rigideces (núcleo y corteza) podría ser el principal responsable de la pérdida de la amplitud de acomodación con la edad. En segundo lugar, se ha estudiado la estabilidad biomecánica de diferentes diseños de lentes intraoculares (IOL). Las IOLs sustituyen las funciones del cristalino en pacientes con cataratas, es por ello necesario garantizar su estabilidad en el interior del saco para garantizar una visión adecuada. Entre los aspectos estudiados destaca la caracterización mecánica de los materiales acrílicos con los que se fabrican las lentes. Para ello, se han combinado ensayos uniaxiales con ensayos de indentación. Éstos últimos se han utilizado para caracterizar la respuesta visco-elástica del material. El definir la respuesta del material mediante modelos visco hiperelásticos es necesario para posteriormente analizar la estabilidad de la IOL mediante elementos finitos. Este análisis se ha defino a dos niveles, en un primer nivel se analiza la estabilidad de la IOL simulando el ensayo establecido en la norma ISO 11979-3:2012. Esta norma es de obligado cumplimiento para los fabricantes antes de introducir un nuevo diseño en el mercado. Se ha realizado un estudio estadístico para estudiar el efecto de la geometría de los hápticos tipo C-loop en la estabilidad mecánica de la IOL, obteniendo que el entronque, la unión entre el háptico y la lente, es el parámetro más influyente. Para validar la metodología numérica, se fabricaron varios diseños y se analizaron experimentalmente para comparar los resultados correspondientes con biomarcadores mecánicos (desplazamiento axial, rotación y la inclinación de la IOL) que están relacionados con la calidad visual resultante de la IOL. En un segundo nivel, se ha simulado la respuesta de la IOL en el interior del saco capsular, estudiando la influencia de diferentes parámetros del paciente, como geometría y propiedades mecánicas del saco. También se ha analizado la influencia de parámetros de la cirugía de la catarata, como es el diámetro y posición de la capsulorexis. En este último nivel, se ha estudiado tanto la respuesta instantánea, es decir, tras la cirugía, como a largo plazo, cuando sucede la huella de fusión (fusion footprint) entre la cápsula y la IOL. Para que los modelos computacionales sean de ayuda a los cirujanos o puedan servir en tiempo real, se ha planteado una metodología basada en inteligencia artificial. En este caso la base de datos de partida corresponde a modelos numéricos altamente fiables y con ellos, se genera datos con los que se entrena la red neuronal. En esta tesis, se estudia la estabilidad de la IOL en función del diámetro de compresión del paciente y la edad, que a su vez influye en las propiedades mecánicas del saco. Por último, se ha evaluado experimentalmente la influencia del material de la IOL (hidrófobo o hidrofílico) y su geometría durante la inyección de la IOL en el saco, registrando la fuerza de inyección que debe realizar el cirujano. De cara a evitar complicaciones (se dañe la IOL o el tejido corneal) durante la cirugía, es conveniente que la fuerza a ejercer sea baja. Se ha comprobado que su valor está fuertemente influenciado por el material de la lente.¿Por qué el cristalino es de vital importancia?El cristalino es el responsable tanto del cambio dinámico de la potencia refractiva del ojo a través del mecanismo de acomodación como de la corrección de las aberraciones de la córnea. El cambio óptico dinámico es consecuencia de un cambio geométrico del cristalino. Sin embargo, a medida que el cristalino envejece, disminuye este cambio óptico dinámico y se opacifica, lo que da lugar a las dos patologías comúnmente asociadas al envejecimiento como es, la presbicia y las cataratas. Por este motivo, en esta tesis doctoral se ha profundizado en el estudio mecánico del cristalino y tras su sustitución mediante una lente intraocular artificial durante la cirugía de catarata. La metodología establecida pueden ayudar en un futuro tanto al diseño de nuevos implantes como a los oftalmólogos a seleccionar la IOL adecuada a cada paciente para mejora su calidad visual.This thesis addresses three different case studies related to the crystalline lens. Firstly, the mechanical causes of the loss of accommodation amplitude with age, called presbyopia, were analysed through the finite element method. A high-fidelity simulation of the mechanism of accommodation including the contraction of the ciliary muscle was developed. This allowed us to analyse accommodation in depth, showing that although the lens capsule provides the force to accommodate, the stiffness ratio between the lens cortex and lens nucleus could have a higher effect on how the lens changes its shape. Secondly, the biomechanical stability of intraocular lenses (IOLs) was analysed. IOLs are essential for post-cataract patients as they substitute the functions of the crystalline lens. In this thesis, a wide variety of solutions were addressed: from the visco- and hyper-elasticity characterisation of IOL acrylic materials from depth sensing indentation and uniaxial tests to the simulation of the IOL biomechanical stability inside the capsular bag. We also performed a high-fidelity simulation of the IOL compression standards tests required by the IOLs to be commercialised and the results obtained were compared with clinical data. Lastly, we developed a patient-specific methodology to customise the IOL haptic design. Most of the numerical methology developed is intended to be used in the IOL pre-design phase to avoid costs and time. Thirdly, the IOL delivery during cataract surgery according to haptic and material design and injector characteristics was experimentally studied to avoid any possibility of IOL and eye damage. Apart from the injector size, the IOL material was the most influential parameter in the force exerted in IOL delivery. Why is the crystalline lens of vital importance? The crystalline lens is the responsible for both the dynamic change of the refractive power of the eye through the mechanism of accommodation and the correction of cornea aberrations. The dynamic optical change is consequence of change of the lens shape. However, as the lens ages over time, it decreases this dynamic optical change and becomes cloudy, what leads to the two most common lens-related pathologies, presbyopia and cataracts. Therefore, it is of utmost importance to study the lens mechanics and all issues related to the artificial intraocular lens that substitutes the lens during cataract surgery.<br /

Caracterización mecánica y modelado numérico de la pared abdominal : desarrollo de una metodología de ayuda al diseño de mallas sintéticas para la reparación herniaria.

La cirugía abdominal mediante la implantación de mallas sintéticas es la más utilizada para la reparación de hernias, pero estas mallas pueden causar varios problemas a los pacientes. Hoy en día, existe una gran variedad de mallas y no está científicamente demostrado cuál es la prótesis ideal ni cuáles son las pautas de orientación de las mismas en el cuerpo humano cuando se trata de mallas anisótropas. Las prótesis actuales han sufrido modicaciones en su estructura y su porosidad en los últimos tiempos con el objetivo de mejorar su adaptación al tejido. A pesar de estas mejoras, la "prótesis ideal" no ha sido obtenida, siendo común la reaparición de las hernias. Para entender el fenómeno es esencial que se caracterize mecánicamente la pared abdominal. Para entender dicho comportamiento es necesario distinguir entre las fibras de colágeno y las musculares, porque en el tejido del músculo, las fibras de colágeno son las responsables de la resistencia mecánica y rigidez y las fibras musculares de la contracción. La dirección de las fibras de colágeno determinan la dirección de anisotropía del material, propiedad a tener en cuenta posteriormente en la formulación del modelo constitutivo. Debido a la distinta orientación de las fibras en cada capa (fibras musculares y de colágeno), en este estudio se analiza la influencia del estudio de las capas separadas en comparación con el músculo en conjunto considerándolo como un material compuesto. Una vez que se ha entendido el comportamiento mecánico del músculo, se caracterizan tres mallas quirúrgicas utilizadas en la reparación herniaria. A su vez, se compara su comportamiento con el de la pared abdominal para estudiar qué malla es la que mejor reproduce el comportamiento de la pared abdominal. En el contexto del modelado matemático, se ha denido un modelo constitutivo 3D hiperelástico anisótropo cuasi-incompresible para el músculo abdominal y otro 2D para las mallas. Utilizando los datos experimentales y realizando un ajuste numérico se han obtenido un conjunto de parámetros, para la función densidad de energía planteada en cada caso, que son capaces de reproducir el comportamiento real del músculo abdominal y de cada una de las mallas mediante un modelo de elementos finitos (FE). En último lugar, con el objetivo de reproducir el comportamiento del abdomen sin dañar y el abdomen que ha sufrido una cirugía abdominal, se plantea un modelo simplificado de elementos finitos que simula el abdomen del animal de experimentación utilizado sometido a una presión abdominal interna. Con este modelo se trata de ver cómo se comporta el conjunto del abdomen bajo la presencia de las diferentes mallas estudiadas

Using Inverse Finite Element Analysis to Obtain Passive Mechanical Behavior of Abdominal Wall

In this work we develop a methodology to characterize in vivo the passive mechanical behavior of abdominal muscle, using for that finite element simulations combined with inverse analysis and optimization algorithms. The knowledge of the mechanical response of the muscle is needed to determine the features of the mesh in cases of hernia surgery

A validated finite element model to reproduce Helmholtz’s theory of accommodation: a powerful tool to investigate presbyopia

Purpose To reproduce human in vivo accommodation numerically. For that purpose, a finite element model specific for a 29-year-old subject was designed. Once the proposed numerical model was validated, the decrease in accommodative amplitude with age was simulated according to data available in the literature. Methods In contrast with previous studies, the non-accommodated eye condition was the reference configuration. Consequently, two aspects were specifically highlighted: contraction of the ciliary muscle, which was simulated by a continuum electro-mechanical model and incorporation of initial lens capsule stresses, which allowed the lens to become accommodated after releasing the resting zonular tension. Results The morphological changes and contraction of the ciliary muscle were calibrated accurately according to the experimental data from the literature. All dynamic optical and biometric lens measurements validated the model. With the proposed numerical model, presbyopia was successfully simulated. Conclusions The most widespread theory of accommodation, proposed by Helmholtz, was simulated accurately. Assuming the same initial stresses in the lens capsule over time, stiffening of the lens nucleus is the main cause of presbyopia

A 3D multi-scale skeletal muscle model to predict active and passive responses. Application to intra-abdominal pressure prediction

Computational models have been used extensively to study the behavior of skeletal muscle structures, however few of these models are able to evaluate their 3D active response using as input experimental measurements such as electromyography. Hence, improving the activation mechanisms in simulation models can provide interesting and useful achievements in this field. Therefore, the purpose of this paper was to develop a multi-scale chemo-mechanical material model to consider the active behavior of skeletal muscle in 3D geometries. The model was used to investigate the response of abdominal muscles which represent a challenging scenario due to their complex geometry and anatomical conditions. Realistic muscle geometries and other tissues of the human abdomen, including transverse abdominis (TA), internal oblique (IO), external oblique (EO), rectus abdominis (RA), rectus sheath (RSH), linea alba (LA) and aponeurosis (APO) were considered. Since the geometry of these tissues was obtained from magnetic resonance images, an iterative algorithm was implemented to find the initial stress state that achieve the equilibrium of them with the intra-abdominal pressure. In order to investigate the functionality of the proposed model, the increase of intra-abdominal pressure was calculated during cough in the supine position while the Ca2+ signal for activating the muscles was set in regard to experimentally recorded electrical activity from previous studies. The amount of intra-abdominal pressure calculated by the model is consistent with reported experimental results. This model can serve as a virtual laboratory to analyze the role of the abdominal wall components in different conditions, such as the performance of meshes used for repairing hernia defects