Funktionelle Herzklappen-Stent Designs für zukünftige autologe, transkatheter Klappenprothesen in pulmonaler Position

Background Transcatheter pulmonary valve replacement (TPVR) has asserted its position as a cornerstone in cardiology and become a nonsurgical alternative for patients with a dysfunctional right ventricular outflow tract (RVOT), demonstrating excellent early and late clinical outcomes. Short- and long-term complications of TPVR include stent fracture and migration, coronary compression, and valve regurgitation. Objective The purpose of this study is to describe methodology for developing Nitinol stents by conducting a computational design and finite element analysis in conjunction with 3D reconstruction of animal cardiac CT for TPVR. Methods 3D cardiac CT reconstruction was achieved using 3D Slicer, from which the RVOT + pulmonary artery (PA) was exported for blood flow simulation and hoop force acquisition with the stents. Functional stents were designed using Autodesk Fusion 360 and divided into three morphological geometries: group 1–straight tubular stents, group 2–corollaceous stents, and group 3–corollaceous stents with an elliptic geometry. Stent simulations for stent life and radial force, and the hoop force of the stent during expansion with the RVOT+PA model were obtained in Ansys. The blood flow simulation of RVOT+PA was performed using Ansys with the velocity-based coupled solver. Results 3D cardiac CT reconstructions were obtained in STL format, from which the right ventricle (RV) +PA model was performed for the blood flow simulation and the hoop force was obtained with the stents. Twelve functional stents were successfully designed and exported in SAT and STP formats for simulation. All stent life (Times)/radial force (N) were achieved: Group 1 comprised the stents DGS 3 (3219.2/1.88E+05), DGS 5 (16406/1.94E+05), DGS 7 (1.00E+06/1.89E+05), DGS 8B (0/3.74E+05), DGS-10B (8370.1/2.41E+05), DGS 12D (1.00E+06/2.41E+08); Group 2 comprised the stents DGS 8A (0/3.60E+05), DGS 9A (0/3.60E+05), DGS 10A (46093/2.28E+05), DGS 12C (2.50E+005/1.69E+05); Group 3 comprised the stents DGS 12A (1.00E+06/2.38E+08), DGS 12B (54509/2.20E+05). Hoop force (N) was obtained from the 12 stents: Group 1–DGS 5 (57802), DGS 7 (54647), DGS 8B (53248), DGS 10B (56650), DGS 12D (46297). Group 2–DGS 8A (50490), DGS 9A (60393), DGS 10A (23639), DGS 12C (29802). Group 3–DGS 12A (16368), DGS 12B (16368). The RV+PA blood flow simulation demonstrated that the anterior part of the PA wall had the largest shear force. Conclusions DGS 12C, DGS 12D, DGS 10A, DGS 10B, DGS 7, and DGS 5 can be subsequently tested in vitro. Autologous pulmonary valves could be sutured onto the functional stents to maintain their original geometry prior to implantation. Pre-implantation 3D CT reconstruction and stent simulation can be performed for better evaluation and visualization. The RV+PA blood flow simulation may serve as a significant input for the design of stents and pulmonary valve to determine the shear force throughout the cardiac cycle.Hintergrund Der katheterbasierte Pulmonalklappenersatz ist ein Eckpfeiler der Kardiologie und bietet zudem eine nicht-chirurgische Alternative für die Behandlung funktionsgestörter rechtsventrikulärer Ausflusstrakte oder bioprothetischer Klappen mit hervorragenden frühen und späten klinischen Ergebnissen. Kurz- und langfristige Komplikationen von TPVR umfassen Stentfraktur/-migration, Komprimierung der Koronararterien und Klappeninsuffizienz. Ziel Ziel dieser Studie ist es, die Methodik und das Konzept für Nitinol-Stents mithilfe rechnerischer Entwürfe und Finite-Elemente-Analysen anhand von 3D-Rekonstruktionen kardialer CT-Untersuchungen in Tieren für die Anwendung von TPVR zu beschreiben. Methoden Die 3D-Rekonstruktion der CT-Untersuchungen erfolgte mit der Software 3D Slicer, aus der die RVOT und Pulmonalarterie (PA) in Verbindung mit den Stents für die Blutflusssimulation und die Umfangsspannung exportiert wurde. Die funktionellen Stents wurden mit Fusion 360 entworfen und danach in die Formate SAT und STP exportiert. Simulationen für die Lebensdauer und Radialkraft sowie für die Umfangsspannung der Stents bei der Freisetzung mit dem RVOT+PA-Modell wurden in Ansys berechnet. Die Blutflusssimulation von RVOT+PA wurde in Ansys mit dem geschwindigkeitsbasierten gekoppelten Solver durchgeführt. Ergebnisse Zwölf funktionelle Stents wurden mithilfe von Fusion 360 generiert. SAT- und STP-Dateien wurden zur Simulation in Ansys exportiert. 3D Kardio-CT-Rekonstruktionen wurden mithilfe im STL-Format kreiert, aus dem das RVOT+PA-Modell des Prä-CT ausgewählt wurde, um die Blutflusssimulation durchzuführen und die Ringkraft der Stents zu erhalten. Die Lebensdauer (Anzahl) und Radialkraft (N) der Stents wurden wie folgt berechnet: DGS-3 (3219.2/1.88E+05), DGS-5 (16406/1.94E+05), DGS-7 (1.00E+06/1.89E+05), DGS-8A (0/3.60E+05), DGS-8B (0/3.74E+05), DGS-9A (0/3.60E+05), DGS-10A (46093/2.28E+05), DGS-10B (8370.1/2.41E+05), DGS-12A (1.00E+06/2.38E+08), DGS-12B (54509/2.20E+05), DGS-12D (1.00E+06/2.41E+08), DGS-12C (2.50E+005/1.69E+05). Die jeweilige Umspannungskraft (N) wurde wie folgt berechnet: DGS-5 (57802), DGS-7 (54647), DGS-8A (50490), DGS-8B (53248), DGS-9A (60393), DGS-10A (23639), DGS-10B (56650), DGS-12A (16368), DGS-12B (16368), DGS-12C (29802), DGS-12D (46297). Die RV+PA-Blutflusssimulation zeigte, dass der vordere Teil der PA-Wand die größte Scherkraft aufwies. Schlussfolgerungen DGS-12C, DGS-12D, DGS-10A, DGS-10B, DGS-7 und DGS-5 können nachfolgend in vitro getestet werden. Autologe Pulmonalklappen können zur Erhaltung der ursprünglichen Geometrie vor der Implantation auf funktionelle Stents aufgenäht werden. Vor der Implantation können Kardio-CT 3D-Rekonstruktion und Stentsimulationen zur besseren Bewertung und Visualisierung durchgeführt werden. Die Blutflusssimulation von RVOT+PA kann einen bedeutsamen Beitrag zur Gestaltung von Stents und Pulmonalklappen leisten, um die Scherkraft während des gesamten Herzzyklus zu erhalten

Developing DNS Tools to Study Channel Flow Over Realistic Plaque Morphology

In a normal coronary artery, the flow is laminar and the velocity is parabolic in nature. Over time, plaques deposit along the artery wall, narrowing the artery and creating an obstruction, a stenosis. As the stenosis grows, the characteristics of the flow change and transition occurs, resulting in turbulent flow distal to the stenosis. To date, direct numerical simulation (DNS) of turbulent flow has been performed in a number of studies to understand how stenosis modifies flow dynamics. However, the effect of the actual shape and size of the obstruction has been disregarded in these DNS studies. An ideal approach is to obtain geometrical information of the stenotic channel using medical imaging methods such as IVUS (Intravascular Ultrasound) and couple them with numerical solvers that simulate the flow in the stenotic channel. The purpose of the present thesis is to demonstrate the feasibility of coupling the IVUS geometry with DNS solver. This preliminary research will provide the necessary tools to achieve the long term goal of developing a framework for the morphological features of the stenosis on the flow modifications in a diseased coronary artery. In the present study, the geometrical information of the stenotic plaque has been provided by the medical imaging team at the Cleveland Clinic Foundation for 42 patients who underwent IVUS. The integration of the geometrical information of the stenotic plaque with the DNS was performed in 3 stages 1) fuzzy logic scheme was used to group the 42 patients into categories, 2) meshing algorithm was generated to interface with the DNS solver, and 3) the existing DNS for channel flow was modified to account for inhomogeneity in the streamwise direction. A plaque classification system was developed using statistical k-means clustering with fuzzy logic. Four distinct morphological categories were found in plaque measurements obtained from the 42 patients. Patients were then assigned a degree of membership to each category based on a fuzzy evaluation system. Flow simulations showed distinct turbulent flow characteristics when comparing the four categories, and similar characteristics within each category. An existing DNS solver that used the fourth-order velocity second-order vorticity formulation of the Navier-Stokes equations was modified to account for inhomogeneity in the streamwise direction. A multigrid method was implemented, using Green\u27s method to compute unknown boundary conditions at the walls in using an influence matrix approach. The inflow is the free stream laminar flow condition; the outflow is computed explicitly with a buffer domain and by parabolizing the Navier Stokes equation. The transitional flow solver was tested using blowing and suction disturbances at the wall to generate the Tollmien-Schlichting waves predicted by linear stability theory. The toolset developed as a part of this thesis demonstrates the feasibility of integrating realistic geometry with DNS. This tool can be used for patient-specific simulation of stenotic flow in coronary and carotid arteries. Additionally, within the field of fluid dynamics, this framework will contribute to the understanding of transition and turbulence in stenotic flows

Towards development of automatic path planning system in image-guided neurosurgery

With the advent of advanced computer technology, many computer-aided systems have evolved to assist in medical related work including treatment, diagnosis, and even surgery. In modern neurosurgery, Magnetic Resonance Image guided stereotactic surgery exactly complies with this trend. It is a minimally invasive operation being much safer than the traditional open-skull surgery, and offers higher precision and more effective operating procedures compared to conventional craniotomy. However, such operations still face significant challenges of planning the optimal neurosurgical path in order to reach the ideal position without damage to important internal structures. This research aims to address this major challenge. The work begins with an investigation of the problem of distortion induced by MR images. It then goes on to build a template of the Circle of Wills brain vessels, realized from a collection of Magnetic Resonance Angiography images, which is needed to maintain operating standards when, as in many cases, Magnetic Resonance Angiography images are not available for patients. Demographic data of brain tumours are also studied to obtain further understanding of diseased human brains through the development of an effect classifier. The developed system allows the internal brain structure to be ‘seen’ clearly before the surgery, giving surgeons a clear picture and thereby makes a significant contribution to the eventual development of a fully automatic path planning system

Handheld image acquisition with real-time vision for human-computer interaction on mobile applications

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica), Universidade de Lisboa, Faculdade de Ciências, 2019Várias patologias importantes manifestam-se na retina, sendo que estas podem ter origem na própria retina ou então provirem de doenças sistémicas. A retinopatia diabética, o glaucoma e a degeneração macular relacionada com a idade são algumas dessas patologias oculares, e também as maiores causas de cegueira nos países desenvolvidos. Graças à maior prevalência que se tem verificado, tem havido uma aposta cada vez maior na massificação do rastreio destas doenças, principalmente na população mais suscetível de as contrair. Visto que a retina é responsável pela formação de imagens, ou seja, pelo sentido da visão, os componentes oculares que estão localizados anteriormente têm de ser transparentes, permitindo assim a passagem da luz. Isto faz com que a retina e, por sua vez, o tecido cerebral, possam ser examinados de forma não-invasiva. Existem várias técnicas de imagiologia da retina, incluindo a angiografia fluoresceínica, a tomografia de coerência ótica e a retinografia. O protótipo EyeFundusScope (EFS) da Fraunhofer é um retinógrafo portátil, acoplado a um smartphone, que permite a obtenção de imagens do fundo do olho, sem que seja necessária a dilatação da pupila. Utiliza um algoritmo de aprendizagem automática para detetar lesões existentes na retina, que estão normalmente associadas a um quadro de retinopatia diabética. Para além disso, utiliza um sistema de suporte à decisão, que indica a ausência ou presença da referida retinopatia. A fiabilidade deste tipo de algoritmos e o correto diagnóstico por parte de oftalmologistas e neurologistas estão extremamente dependentes da qualidade das imagens adquiridas. A consistência da captura portátil, com este tipo de retinógrafos, está intimamente relacionada com uma interação apropriada com o utilizador. De forma a melhorar o contributo prestado pelo utilizador, durante o procedimento habitual da retinografia, foi desenvolvida uma nova interface gráfica de utilizador, na aplicação Android do EFS. A abordagem pretendida consiste em tornar o uso do EFS mais acessível, e encorajar técnicos não especializados a utilizarem esta técnica de imagem médica, tanto em ambiente clínico como fora deste. Composto por vários elementos de interação, que foram criados para atender às necessidades do protocolo de aquisição de imagem, a interface gráfica de utilizador deverá auxiliar todos os utilizadores no posicionamento e alinhamento do EFS com a pupila do doente. Para além disto, poderá existir um controlo personalizado do tempo despendido em aquisições do mesmo olho. Inicialmente, foram desenhadas várias versões dos elementos de interação rotacionais, sendo posteriormente as mesmas implementadas na aplicação Android. Estes elementos de interação utilizam os dados recolhidos dos sensores inerciais, já existentes no smartphone, para transmitir uma resposta em tempo real ao utilizador enquanto este move o EFS. Além dos elementos de interação rotacionais, também foram implementados um temporizador e um indicador do olho que está a ser examinado. Após a implementação de três configurações com as várias versões dos elementos de interação, procedeu-se à realização dos testes de usabilidade. No entanto, antes desta etapa se poder concretizar, foram realizados vários acertos e correções com a ajuda de um olho fantoma. Durante o planeamento dos testes de usabilidade foi estabelecido um protocolo para os diferentes cenários de uso e foi criado um tutorial com as principais cautelas que os utilizadores deveriam ter aquando das aquisições. Os resultados dos testes de usabilidade mostram que a nova interface gráfica teve um efeito bastante positivo na experiência dos utilizadores. A maioria adaptou-se rapidamente à nova interface, sendo que para muitos contribuiu para o sucesso da tarefa de aquisição de imagem. No futuro, espera-se que a combinação dos dados fornecidos pelos sensores inerciais, juntamente com a implementação de novos algoritmos de reconhecimento de imagem, sejam a base de uma nova e mais eficaz técnica de interação em prática clínica. Além disso, a nova interface gráfica poderá proporcionar ao EFS uma aplicação que sirva exclusivamente para efeitos de formação profissional.Many important diseases manifest themselves in the retina, both primary retinal conditions and systemic disorders. Diabetic retinopathy, glaucoma and age-related macular degeneration are some of the most frequent ocular disorders and the leading causes of blindness in developed countries. Since these disorders are becoming increasingly prevalent, there has been the need to encourage high coverage screening among the most susceptible population. As its function requires the retina to see the outside world, the involved optical components must be transparent for image formation. This makes the retinal tissue, and thereby brain tissue, accessible for imaging in a non-invasive manner. There are several approaches to visualize the retina including fluorescein angiography, optical coherence tomography and fundus photography. The Fraunhofer’s EyeFundusScope (EFS) prototype is a handheld smartphone-based fundus camera, that doesn’t require pupil dilation. It employs advanced machine learning algorithms to process the image in search of lesions that are often associated with diabetic retinopathy, making it a pre-diagnostic tool. The robustness of this computer vision algorithm, as well as the diagnose performance of ophthalmologists and neurologists, is strongly related with the quality of the images acquired. The consistency of handheld capture deeply depends on proper human interaction. In order to improve the user’s contribution to the retinal acquisition procedure, a new graphical user interface was designed and implemented in the EFS Acquisition App. The intended approach is to make the EFS easier to use by non-ophthalmic trained personnel, either in a non-clinical or in a clinical environment. Comprised of several interaction elements that were created to suit the needs of the acquisition procedure, the graphical user interface should help the user to position and align the EFS illumination beam with the patient’s pupil as well as keeping track of the time between acquisitions on the same eye. Initially, several versions of rotational interaction elements were designed and later implemented on the EFS Acquisition App. These used data from the smartphone’s inertial sensors to give real-time feedback to the user while moving the EFS. Besides the rotational interactional elements, a time-lapse and an eye indicator were also designed and implemented in the EFS. Usability tests took place, after three assemblies being successfully implemented and corrected with the help of a model eye ophthalmoscope trainer. Also, a protocol for the different use-case scenarios was elaborated, and a tutorial was created. Results from the usability tests, show that the new graphical user interface had a very positive outcome. The majority of users adapted very quickly to the new interface, and for many it contributed for a successful acquisition task. In the future, the grouping of inertial sensors data and image recognition may prove to be the foundations for a more efficient interaction technique performed in clinical practices. Furthermore, the new graphical user interface could provide the EFS with an application for educational purposes

Development of a novel in-vitro vascular model for determination of physiological and pathophysiological mechanobiology

Background/Aims The aim of the study was to develop a biological and technological method to investigate in-vitro the physiology and pathophysiology biomechanical phenomena of a vascular wall. In particular, cellular contraction and relaxation as a biomechanical response to vasoactive substances and different mechanical stimulation intervals were studied to provide data for basic research and pharmacological developments in cardiovascular diseases such as arterial hypertension. Methods: Methodologically, the study is based on CellDrum technology, which is a method to determine cellular stress changes of a few kilo Pascal(kPa). Especially for this study, a new approach was developed to characterize the cell stresses of monolayers and multilayer tissue equivalents in a standardized way. A monolayer model consisting of human aortic smooth muscle cells (haSMC) was primarily developed for CellDrum as a vascular in-vitro cell culture model. Also, a model of human aortic endothelial cells (haEC) was established, and an approach for a 3D co-culture model of both cell types was developed. Vasoactive substances with different mechanisms of action and concentrations were tested to represent the physiological properties of the model. For the first time, the biomechanical influence of blood sera was analyzed on the CellDrum models to test the potential possibility of a laboratory screening procedure. The PulSElect system was developed, which exposes the CellDrum models to a defined, cyclical, mechanical stress by stretching, to simulate the symptoms of mechanically induced hypertension. The influence of the mechanical stress was observed by cytoskeletal alignment quantification, transcriptome analysis, gene expression of mechanosensitive as well as biomechanically relevant genes and biomechanical stress evaluation to elucidate cellular stiffening and cellular stress management. Results The haSMC cell models showed significant physiological and biomechanical changes in cell tone after application of the vasoactive substances, sera and conditioned media (~-6-10% relative to initial tension). Mechanical stimulation of the cells allowed quantification of both mechanical and transcriptomic changes as well as morphological adaptation. Furthermore, it was possible to present the obtained results in a time-dependent manner. Also, mechanical stimulation has been shown to induce the development of the contractile phenotype of haSMC and improve its cellular integrity, resulting in increased basal tension and overall contractility. As an extension of a well-established haSMC CellDrum model, an approach for direct co-cultivation of human aortic smooth muscle cells and endothelial cells was elaborated. Conclusion Different CellDrum models have been established to replicate biomechanical processes of the vascular system. The study showed that the CellDrum technology is a suitable method to analyze biomechanical stress changes caused by different stimuli using haSMC. The analysis of blood sera using CellDrums allows for possible future use as a screening method for pharmacological and medical laboratory research. Since the CellDrum technology is not limited to the use of monolayers, it is possible to think about an extension of cell models with additional cell types and cell layers. Although we have already been able to show partial co-cultivation of smooth muscle cells and endothelial cells, further research is needed to establish this sufficiently. Increased expression levels of mechanosensitive genes have been shown to correlate with literature data on the pathogenesis of hypertension, using microarray analysis (Affymetrix) and qPCR. Nevertheless, it remains a speculative reflection of the cellular changes due to induced hypertension. The data and findings obtained to provide the promising potential supporting research and development of personalized medication, sports medicine, cell biology and stem cell research using CellDrum technology