Statistical anatomical modelling for efficient and personalised spine biomechanical models

Personalised medicine is redefining the present and future of healthcare by increasing treatment efficacy and predicting diseases before they actually manifest. This innovative approach takes into consideration patient’s unique genes, environment, and lifestyle. An essential component is physics-based simulations, which allows the outcome of a treatment or a disease to be replicated and visualised using a computer. The main requirement to perform this type of simulation is to build patient-specific models. These models require the extraction of realistic object geometries from images, as well as the detection of diseases or deformities to improve the estimation of the material properties of the studied object. The aim of this thesis was the design of a general framework for creating patient- specific models for biomechanical simulations using a framework based on statistical shape models. The proposed methodology was tested on the construction of spine models, including vertebrae and intervertebral discs (IVD). The proposed framework is divided into three well-defined components: The paramount and first step is the extraction of the organ or anatomical structure from medical images. In the case of the spine, IVDs and vertebrae were extracted from Magnetic Resonance images (MRI) and Computed Tomography (CT), respectively. The second step is the classification of objects according to different factors, for instance, bones by its type and grade of fracture or IVDs by its degree of degeneration. This process is essential to properly model material properties, which depends on the possible pathologies of the tissue. The last component of the framework is the creation of the patient-specific model itself by combining the information from previous steps. The behaviour of the developed algorithms was tested using different datasets of spine images from both computed tomography (CT) and Magnetic resonance (MR) images from different institutions, type of population and image resolution

Automatic segmentation of the spine by means of a probabilistic atlas with a special focus on ribs suppression

[EN] Purpose: The development of automatic and reliable algorithms for the detection and segmentation of the vertebrae are of great importance prior to any diagnostic task. However, an important problem found to accurately segment the vertebrae is the presence of the ribs in the thoracic region. To overcome this problem, a probabilistic atlas of the spine has been developed dealing with the proximity of other structures, with a special focus on ribs suppression. Methods: The data sets used consist of Computed Tomography images corresponding to 21 patients suffering from spinal metastases. Two methods have been combined to obtain the final result: firstly, an initial segmentation is performed using a fully automatic level-set method; secondly, to refine the initial segmentation, a 3D volume indicating the probability of each voxel of belonging to the spine has been developed. In this way, a probability map is generated and deformed to be adapted to each testing case. Results: To validate the improvement obtained after applying the atlas, the Dice coefficient (DSC), the Hausdorff distance (HD), and the mean surface-to-surface distance (MSD) were used. The results showed up an average of 10 mm of improvement accuracy in terms of HD, obtaining an overall final average of 15.51 2.74 mm. Also, a global value of 91.01 3.18% in terms of DSC and a MSD of 0.66 0.25 mm were obtained. The major improvement using the atlas was achieved in the thoracic region, as ribs were almost perfectly suppressed. Conclusion: The study demonstrated that the atlas is able to detect and appropriately eliminate the ribs while improving the segmentation accuracy.The authors thank the financial support of the Spanish Ministerio de Economia y Competitividad (MINECO) and FEDER funds under Grants TEC2012-33778 and BFU2015-64380-C2-2-R (D.M.) and DPI2013-4572-R (J.D., E.D.)Ruiz-España, S.; Domingo, J.; Díaz-Parra, A.; Dura, E.; D'ocon-Alcaniz, V.; Arana, E.; Moratal, D. (2017). 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A Generative Shape Compositional Framework to Synthesise Populations of Virtual Chimaeras

Generating virtual populations of anatomy that capture sufficient variability while remaining plausible is essential for conducting in-silico trials of medical devices. However, not all anatomical shapes of interest are always available for each individual in a population. Hence, missing/partially-overlapping anatomical information is often available across individuals in a population. We introduce a generative shape model for complex anatomical structures, learnable from datasets of unpaired datasets. The proposed generative model can synthesise complete whole complex shape assemblies coined virtual chimaeras, as opposed to natural human chimaeras. We applied this framework to build virtual chimaeras from databases of whole-heart shape assemblies that each contribute samples for heart substructures. Specifically, we propose a generative shape compositional framework which comprises two components - a part-aware generative shape model which captures the variability in shape observed for each structure of interest in the training population; and a spatial composition network which assembles/composes the structures synthesised by the former into multi-part shape assemblies (viz. virtual chimaeras). We also propose a novel self supervised learning scheme that enables the spatial composition network to be trained with partially overlapping data and weak labels. We trained and validated our approach using shapes of cardiac structures derived from cardiac magnetic resonance images available in the UK Biobank. Our approach significantly outperforms a PCA-based shape model (trained with complete data) in terms of generalisability and specificity. This demonstrates the superiority of the proposed approach as the synthesised cardiac virtual populations are more plausible and capture a greater degree of variability in shape than those generated by the PCA-based shape model

An End-to-End Deep Learning Generative Framework for Refinable Shape Matching and Generation

Generative modelling for shapes is a prerequisite for In-Silico Clinical Trials (ISCTs), which aim to cost-effectively validate medical device interventions using synthetic anatomical shapes, often represented as 3D surface meshes. However, constructing AI models to generate shapes closely resembling the real mesh samples is challenging due to variable vertex counts, connectivities, and the lack of dense vertex-wise correspondences across the training data. Employing graph representations for meshes, we develop a novel unsupervised geometric deep-learning model to establish refinable shape correspondences in a latent space, construct a population-derived atlas and generate realistic synthetic shapes. We additionally extend our proposed base model to a joint shape generative-clustering multi-atlas framework to incorporate further variability and preserve more details in the generated shapes. Experimental results using liver and left-ventricular models demonstrate the approach's applicability to computational medicine, highlighting its suitability for ISCTs through a comparative analysis

Automatic Segmentation of the Lumbar Spine from Medical Images

Segmentation of the lumbar spine in 3D is a necessary step in numerous medical applications, but remains a challenging problem for computational methods due to the complex and varied shape of the anatomy and the noise and other artefacts often present in the images. While manual annotation of anatomical objects such as vertebrae is often carried out with the aid of specialised software, obtaining even a single example can be extremely time-consuming. Automating the segmentation process is the only feasible way to obtain accurate and reliable segmentations on any large scale. This thesis describes an approach for automatic segmentation of the lumbar spine from medical images; specifically those acquired using magnetic resonance imaging (MRI) and computed tomography (CT). The segmentation problem is formulated as one of assigning class labels to local clustered regions of an image (called superpixels in 2D or supervoxels in 3D). Features are introduced in 2D and 3D which can be used to train a classifier for estimating the class labels of the superpixels or supervoxels. Spatial context is introduced by incorporating the class estimates into a conditional random field along with a learned pairwise metric. Inference over the resulting model can be carried out very efficiently, enabling an accurate pixel- or voxel-level segmentation to be recovered from the labelled regions. In contrast to most previous work in the literature, the approach does not rely on explicit prior shape information. It therefore avoids many of the problems associated with these methods, such as the need to construct a representative prior model of anatomical shape from training data and the approximate nature of the optimisation. The general-purpose nature of the proposed method means that it can be used to accurately segment both vertebrae and intervertebral discs from medical images without fundamental change to the model. Evaluation of the approach shows it to obtain accurate and robust performance in the presence of significant anatomical variation. The median average symmetric surface distances for 2D vertebra segmentation were 0.27mm on MRI data and 0.02mm on CT data. For 3D vertebra segmentation the median surface distances were 0.90mm on MRI data and 0.20mm on CT data. For 3D intervertebral disc segmentation a median surface distance of 0.54mm was obtained on MRI data

Segmentación automática de la columna vertebral mediante un atlas probabilístico con un enfoque especial en la supresión de costillas

[ES] Puesto que la metástasis ósea es una patología vertebral de gran importancia, una segmentación precisa de los cuerpos vertebrales es el paso previo al análisis biomecánico que permita predecir el riesgo de fractura en vértebras metastásicas. Además, la localización exacta del canal vertebral es esencial en el proceso de radioterapia para evitar daños de la médula espinal, y un paso importante para automatizar la segmentación. Este Trabajo Final de Grado tiene como objetivo desarrollar un método automático para la detección y segmentación de las vértebras a través del análisis de Tomografía Computarizada utilizando un grupo de 21 pacientes con metástasis en la columna vertebral. Conseguir una segmentación automática de los cuerpos vertebrales es una tarea compleja debido a la presencia de las costillas en la región torácica. Como solución se han combinado un método Level-Set capaz de segmentar las vértebras y un atlas probabilístico para suprimir las costillas y automatizar el proceso. Para evaluar la segmentación se ha utilizado la distancia Hausdorff (HD) y el coeficiente Dice (DSC). Tras aplicar el atlas, la HD disminuye 11 mm de media y el DSC mejora un 1.3%. Los resultados demuestran que el atlas es capaz de detectar y suprimir las costillas adecuadamente.[EN] Since bone metastases is a relevant vertebral pathology, an accurate segmentation of the vertebral bodies is the previous step to biomechanical analysis to predict the risk of fracture in metastatic vertebrae. In addition, a proper location of the spinal canal is an essential process in radiotherapy processes to prevent spinal cord damages and a relevant step to automate the segmentation process. Aided by the Computerized Tomography technique, the target of this Final Degree Project is to model an automated method for the detection and segmentation of the spine and test it in a group of 21 patients with spinal metastases. To achieve an automatic segmentation of the vertebral bodies is a complex task due to the presence of the ribs in the thoracic region. As a solution, a Level-Set method used in the vertebrae segmentation process and a probabilistic atlas to suppress the ribs and automate the process have been combined. Both, the DICE similarity coefficient (DSC) and the Hausdorff (HD) distance have been used to evaluate the segmentation process. On average, HD decreases 11 mm and DSC improves 1.3% after applying the atlas. The results show that the atlas is able to detect and suppress the ribs properly.D' Ocón Alcañiz, V. (2019). Segmentación automática de la columna vertebral mediante un atlas probabilístico con un enfoque especial en la supresión de costillas. Universitat Politècnica de València. http://hdl.handle.net/10251/128515TFG

Group-wise similarity registration of point sets using Student’s t-mixture model for statistical shape models

A probabilistic group-wise similarity registration technique based on Student’s t-mixture model (TMM) and a multi-resolution extension of the same (mr-TMM) are proposed in this study, to robustly align shapes and establish valid correspondences, for the purpose of training statistical shape models (SSMs). Shape analysis across large cohorts requires automatic generation of the requisite training sets. Automated segmentation and landmarking of medical images often result in shapes with varying proportions of outliers and consequently require a robust method of alignment and correspondence estimation. Both TMM and mrTMM are validated by comparison with state-of-the-art registration algorithms based on Gaussian mixture models (GMMs), using both synthetic and clinical data. Four clinical data sets are used for validation: (a) 2D femoral heads ( 1000 samples generated from DXA images of healthy subjects); (b) control-hippocampi ( 50 samples generated from T1-weighted magnetic resonance (MR) images of healthy subjects); (c) MCI-hippocampi ( 28 samples generated from MR images of patients diagnosed with mild cognitive impairment); and (d) heart shapes comprising left and right ventricular endocardium and epicardium ( 30 samples generated from short-axis MR images of: 10 healthy subjects, 10 patients diagnosed with pulmonary hypertension and 10 diagnosed with hypertrophic cardiomyopathy). The proposed methods significantly outperformed the state-of-the-art in terms of registration accuracy in the experiments involving synthetic data, with mrTMM offering significant improvement over TMM. With the clinical data, both methods performed comparably to the state-of-the-art for the hippocampi and heart data sets, which contained few outliers. They outperformed the state-of-the-art for the femur data set, containing large proportions of outliers, in terms of alignment accuracy, and the quality of SSMs trained, quantified in terms of generalization, compactness and specificity

CARACTERIZACIÓN CUANTITATIVA DE LA PATOLOGÍA DISCAL Y LUMBAR DEGENERATIVA MEDIANTE ANÁLISIS DE IMAGEN POR RESONANCIA MAGNÉTICA Y DETECCIÓN Y SEGMENTACIÓN DE LA COLUMNA VERTEBRAL EN PACIENTES ONCOLÓGICOS A PARTIR DEL ANÁLISIS DE IMAGEN EN TOMOGRAFÍA COMPUTARIZADA

[EN] Over the last 20 years health system has been revolutionized by imaging technology so diagnostic imaging has become the mainstay of the management of patients. Nowadays, degeneration of the intervertebral discs, herniation and spinal stenosis are very common entities that affect millions of people and cause back pain. The development of computer-aided diagnosis (CAD) methods for classifying and quantifying these pathologies has increased in the past decade as a way to assist radiologists in the diagnosis task. So, the main objective of the first part of this Doctoral Thesis is the development of a CAD software for the classification and quantification of spine disease by means of Magnetic Resonance image analysis. To this end, two different groups of patients have been used, one as training group (14 patients) and the other as testing group (53 patients). To classify disc degeneration according to the gold standard, Pfirrmann classification, a method mainly based on the measurement of disc signal intensity and structure has been developed. The method developed to detect disc herniations has been focused on disc segmentation and its approximation by an ellipse, in this way it is possible to extract disc shape features for detecting contour abnormalities. The method developed to detect spinal stenosis, based on signal intensity, has been developed to extract the spinal canal and, by applying different techniques, to detect spinal stenosis at every intervertebral disc level and quantify the severity of the pathology. The results have shown a segmentation inaccuracy below 1%. Regarding reproducibility, it has been obtained an almost perfect agreement (measured by the k and ICC statistics) for all the analysed pathologies. The results have shown that the developed methods can assist radiologists to perform their decision-making tasks, providing support for enhanced reproducibility of MRI reports and achieving greater objectivity. However, not only the intervertebral discs are susceptible to suffer several pathologies. The vertebral bodies are also subject to a wide variety of diseases because of different circumstances. So, prior to any diagnosis task, an accurate detection and segmentation of the vertebral bodies are the first crucial steps. Therefore, the main objective of the second part of this Doctoral Thesis is the development of an automatic method for the detection and segmentation of the spine in Computed Tomography imaging. Performing an automatic and robust segmentation is a very challenging task due to the difficulty discriminating between the ribs and the vertebral bodies. To overcome this problem, two different segmentation methods have been combined: the first method uses a Level-Set method to perform an initial segmentation; the second method uses a probabilistic atlas to refine the initial segmentation with a special focus on ribs suppression. So a 3D volume indicating the probability of each voxel of belonging to the spine has been developed, by means of a set of images, corresponding to 14 patients (training group), manually segmented by an expert. The generated probability map has been deformed and adapted to each testing case. To evaluate the segmentation results and the improvement obtained after applying the atlas to the initial segmentation, the Dice similarity coefficient (DSC) and the Hausdorff distance (HD) have been used. The results have shown up an average of 11 mm of improvement in segmentation accuracy in terms of HD, obtaining an overall final average of 14,98 ± 1,32 mm. A refinement of 1,3 % has been obtained in terms of DSC, with a global value of 91,75 ± 1,20 %. The study has demonstrated that the atlas is able to detect and appropriately eliminate the ribs while improving the segmentation accuracy.[ES] En los últimos 20 años el sistema sanitario se ha visto revolucionado por la tecnología de la imagen, por lo que el diagnóstico por imagen se ha convertido en un pilar fundamental en el manejo de los pacientes. Hoy en día la degeneración de los discos intervertebrales, la hernia discal y la estenosis del canal vertebral, son tres patologías que afectan a millones de personas y causan dolor de espalda. El desarrollo de sistemas CAD para clasificar y cuantificar estas patologías se ha incrementado en la última década como una forma de ayuda al radiólogo en el diagnóstico. Por tanto, la primera parte de esta Tesis Doctoral tiene como objetivo el desarrollo de un sistema CAD para la clasificación y cuantificación de la patología discal por medio del análisis de Imagen por Resonancia Magnética. Con este fin se han utilizado dos grupos de pacientes, uno como grupo de entrenamiento (14 pacientes) y el otro como grupo de prueba (53 pacientes). Para la clasificación de la degeneración discal se ha desarrollado un método basado en el cálculo de la estructura del disco y de su señal de intensidad. El método de detección de herniaciones se ha centrado en la segmentación del disco y su aproximación por una elipse, para extraer así información sobre la forma del disco. El método de detección de estenosis, basado en la señal de intensidad, ha sido desarrollado para extraer el canal vertebral y, con la aplicación de diferentes técnicas, detectar estrechamientos a la altura de los discos y cuantificar la gravedad de los mismos. Los resultados han demostrado una alta precisión en la segmentación, con un error inferior al 1 %. En cuanto a la reproducibilidad, se ha obtenido un acuerdo casi perfecto (medido con los coeficientes CCI y k) para todas las patologías analizadas. Los resultados obtenidos demuestran que los métodos desarrollados pueden servir de ayuda al radiólogo en el diagnóstico, mejorando la reproducibilidad y logrando una mayor objetividad. Sin embargo, no sólo los discos intervertebrales son susceptibles de sufrir alguna patología. Los cuerpos vertebrales también pueden sufrir lesiones por diversas circunstancias. No obstante, antes de realizar cualquier tarea de diagnóstico, llevar a cabo una detección y segmentación precisa de los cuerpos vertebrales es un primer paso crucial. Así pues, la segunda parte de esta Tesis Doctoral tiene como objetivo el desarrollo de un método automático para la detección y segmentación de la columna vertebral por medio del análisis de Tomografía Computarizada. Llevar a cabo una segmentación automática y precisa es una tarea complicada debido principalmente a la gran dificultad para distinguir entre los cuerpos vertebrales y las costillas. Para solucionar este problema se han combinado dos métodos de segmentación diferentes: el primero utiliza un método Level-Set para llevar a cabo una segmentación inicial; el segundo utiliza un atlas probabilístico, para refinar la segmentación inicial, con un enfoque especial en la supresión de las costillas. Por tanto, se ha obtenido un volumen 3D indicando la probabilidad de cada voxel de pertenecer o no a la columna vertebral, por medio de un conjunto de imágenes correspondientes a 14 pacientes segmentadas manualmente por un experto. El mapa de probabilidad generado ha sido deformado y adaptado a cada uno de los 7 pacientes del grupo de prueba. Para evaluar los resultados de la segmentación y la mejora obtenida después de aplicar el atlas a la segmentación inicial, se ha utilizado el coeficiente Dice (DSC) y la distancia Hausdorff (HD). Los resultados han demostrado una mejora en la precisión de la segmentación de 11 mm de media en términos de HD, con una media global de 14,98 ± 1,32 mm. En términos de DSC se ha obtenido una mejora de un 1,3 % , con una media global de 91,75 ± 1,20 %. El estudio ha demostrado que el atlas es capaz de detectar y eliminar apropiadamente las estructuras costales[CA] En els últims 20 anys el sistema sanitari s'ha vist revolucionat per la tecnologia de la imatge, per la qual cosa el diagnòstic per imatge s'ha convertit en un pilar fonamental en el maneig dels pacients. Hui en dia la degeneració dels discos intervertebrals, l'hèrnia discal i l'estenosi del canal vertebral, són tres patologies molt comunes que afecten milions de persones i causen dolor d'esquena. El desenvolupament de sistemes CAD per a classificar i quantificar estes patologies s'ha incrementat en l'última dècada com una forma d'ajuda al radiòleg en el diagnòstic. Per tant, la primera part d'aquesta Tesi Doctoral té com a objectiu el desenvolupament d'un sistema CAD per a la classificació i quantificació de la patologia discal per mitjà de l'anàlisi d'Imatge per Ressonància Magnètica. Amb aquest fi s'han utilitzat dos grups de pacients distints, un com a grup d'entrenament (14 pacients) i l'altre com a grup de prova (53 pacients). Per a la classificació de la degeneració discal, s'ha desenvolupat un mètode basat en el càlcul de l'estructura del disc i del seu senyal d'intensitat. El mètode de detecció d'herniacions s'ha centrat en la segmentació del disc i la seua aproximació per una el·lipse, per a extraure així informació sobre la forma del disc. El mètode de detecció d'estenosi, basat en el senyal d'intensitat, ha sigut desenvolupat per a extraure el canal vertebral i amb l'aplicació de diferents tècniques detectar estrenyiments a l'altura dels discos i quantificar la gravetat dels mateixos. Els resultats han demostrat una alta precisió en la segmentació, amb un error inferior a l'1 %. En quant a la reproduïbilitat, s'ha obtingut un acord quasi perfecte (mesurat amb els coeficients CCI i k) per a totes les patologies analitzades. Els resultats obtinguts demostren que els mètodes desenvolupats poden servir d'ajuda al radiòleg en el diagnòstic, millorant la reproduïbilitat i aconseguint una major objectivitat. No obstant això, no sols els discos intervertebrals són susceptibles de patir alguna patologia. Els cossos vertebrals també poden patir lesions per diverses circumstàncies. Per tant, abans de realitzar qualsevol tasca de diagnòstic, dur a terme una detecció i segmentació precisa dels cossos vertebrals és un primer pas crucial. Així, doncs, la segona part d'aquesta Tesi Doctoral té com a objectiu el desenvolupament d'un mètode automàtic per a la detecció i segmentació de la columna vertebral per mitjà de l'anàlisi de Tomografia Computada. Dur a terme una segmentació automàtica i precisa és una tasca complicada degut principalment a la gran dificultat per a distingir entre els cossos vertebrals i les costelles. Per a solucionar aquest problema s'han combinat dos mètodes de segmentació diferents: el primer utilitza un mètode Level-Set per a dur a terme una segmentació inicial; el segon utilitza un atles probabilístic, per a refinar la segmentació inicial amb un enfocament especial en la supressió de les costelles. Per tant, s'ha obtingut un volum 3D indicant la probabilitat de cada voxel de pertànyer o no a la columna vertebral, per mitjà d'un conjunt d'imatges corresponents a 14 pacients (grup d'entrenament) segmentades manualment per un expert. El mapa de probabilitat generat ha sigut deformat i adaptat a cadascun dels 7 pacients del grup de prova. Per a avaluar els resultats de la segmentació i la millora obtinguda després d'aplicar l'atles a la segmentació inicial, s'ha utilitzat el coeficient Dice (DSC) i la distància Hausdorff (HD). Els resultats han demostrat una millora en la precisió de la segmentació d'11 mm de mitja en termes de HD, amb una mitja global de 14,98 ± 1,32 mm. S'ha obtingut una millora d'un 1,3 % en termes de DSC, amb una mitja global de 91,75 ± 1,20 %. L'estudi ha demostrat que l'atles és capaç de detectar i eliminar apropiadament les estructures costals alhora que millora la precisió de la segmentació.Ruiz España, S. (2016). CARACTERIZACIÓN CUANTITATIVA DE LA PATOLOGÍA DISCAL Y LUMBAR DEGENERATIVA MEDIANTE ANÁLISIS DE IMAGEN POR RESONANCIA MAGNÉTICA Y DETECCIÓN Y SEGMENTACIÓN DE LA COLUMNA VERTEBRAL EN PACIENTES ONCOLÓGICOS A PARTIR DEL ANÁLISIS DE IMAGEN EN TOMOGRAFÍA COMPUTARIZADA [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/68485TESI

Morphogenesis and Protein Composition of Valve Silica Deposition Vesicles from Diatoms

The silica-based cell walls of diatoms are outstanding examples of nature’s capability to synthesize complex porous structures with genetically controlled patterns from the nanometer scale to the range of hundreds of micrometers. Formation of the cell wall building blocks (valves and girdle bands) occurs in membrane-bound compartments, termed silica deposition vesicles (SDVs), which are unique organelles in silica-forming protists. Isolation of the SDVs has not yet been achieved, which has severely hampered the efforts to understand the mechanisms of biological silica morphogenesis. The present thesis aimed to address this shortcoming. The foundation was the development of an improved cell cycle synchronization and a fluorescence labeling method for the model diatom Thalassiosira pseudonana that enabled rapid identification of valve SDVs in a cell lysate. Correlative fluorescence and electron microscopy allowed visualizing the development of valve silica with unprecedented spatio-temporal resolution. Elemental analysis and demineralization of immature valves provided the first direct chemical evidence that silica morphogenesis is an interplay of inorganic and organic molecules inside the valve SDVs. Cryo TEM imaging of valve SDVs indicated the formation of organic patterns that precede silica depostion. From these observations, an organic biomolecule dependent, liquid-liquid phase separation based model for pore formation in the diatom T. pseudonana was proposed. The second part of this thesis was focused on the enrichment of valve SDVs from T. pseudonana and the subsequent proteomics based identification of more than 40 potential valve SDV proteins. Among these, three diatom-specific proteins contained conserved protein protein interaction domains (ankyrin-repeats) and were surprisingly predicted to be located in the cytoplasm. The fluorescent tagging of the three proteins (termed dANK1-3) confirmed their association with the valve SDVs. When the respective dank genes were knocked out by CRISPR/Cas9, the valves displayed permanent anomalies in the quantity and the pattern of ~22 nm sized pores. Double knockout mutants lacking both dank1 and dank3 were almost completely devoid of pores. The analysis of valve morphogenesis in the single and double knockout mutants revealed phenotypic changes that were consistent with the liquid-liquid phase separation based model for pore pattern formation in diatom biosilica. The work of this thesis has provided for the first time direct access to valve SDVs, which has opened entirely new possibilities for studying the composition, properties, and working mechanism of an organelle that forms a complex shaped mineral