Numerical and experimental haemodynamic studies of stenotic coronary arteries

Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Biomateriais, Reabilitação e Biomecânica)Cardiovascular diseases remain the most frequent cause of mortality worldwide and constitute a major healthcare challenge. Among them, coronary artery disease causes nearly half of the deaths and, thus it is of great interest to better understand its development and effects. This disease is characterized by the narrowing (stenosis) of coronary arteries due to plaque deposition at the arterial wall, a pathological process known as atherosclerosis. This dissertation aimed to study the hemodynamics in stenotic coronary arteries, in order to get a deeper understanding of the effects of this pathology on the blood flow behavior. For this purpose, both numerical and experimental studies were conducted using idealized models. The numerical research was carried out using Ansys® software by means of computational fluid dynamics which applies the finite volume method. The experimental approach was performed using a high-speed video microscopy system, to visualize and investigate the blood flow in the in vitro stenotic biomodels. Initially, the influence of roughness in flow visualizations was studied, and the best biomodel was the one printed with the lowest resolution having been, therefore, the selected to perform the hemodynamic studies. To compare those results with numerical data, the flow was set to be laminar and stationary and the fluid was considered Newtonian. In general, the numerical and experimental results were in good agreement, not only in the prediction of the flow behavior with the appearance of recirculation zones in the post-stenotic section, but also in the velocity profiles. In a posterior phase, a pulsatile inlet condition was applied to compare the use of laminar and turbulent assumptions, using the SST k- model. The results obtained allowed to conclude that the second one is more appropriate to simulate the blood flow. Subsequently, the main differences in hemodynamics were examined considering blood as a Newtonian and non-Newtonian fluid (Carreau model). For these models, the differences were very slight in terms of velocity fields, but more significant for the wall shear stress measurements, with the Newtonian model predicting lower values. The remaining simulations were performed using the Carreau model and a transient inlet flow, having observed an increase in the velocities and wall shear stress values with the degree of stenosis, which is associated with a greater risk of thrombosis.As doenças cardiovasculares continuam a ser a causa mais frequente de mortalidade em todo o mundo e constituem um grande desafio para a saúde. Entre elas, a doença arterial coronariana causa quase metade das mortes e, portanto, é de enorme interesse entender melhor o seu desenvolvimento e efeitos. Esta doença é caracterizada pelo estreitamento (estenose) das artérias coronárias devido à deposição de placas na parede arterial, um processo patológico conhecido como aterosclerose. Esta dissertação teve como objetivo estudar a hemodinâmica nas artérias coronárias estenóticas, a fim de obter uma compreensão mais profunda dos efeitos desta patologia no comportamento do fluxo sanguíneo. Para tal, foram realizados estudos numéricos e experimentais, utilizando modelos idealizados. A investigação numérica foi realizada no software Ansys®, através da dinâmica computacional dos fluidos, que aplica o método dos volumes finitos. A abordagem experimental foi realizada utilizando um sistema de microscopia de vídeo de alta velocidade, para visualizar e investigar o fluxo sanguíneo nos biomodelos estenóticos in vitro. Inicialmente, estudou-se a influência da rugosidade nas visualizações do escoamento, e o melhor biomodelo foi o impresso com menor resolução tendo sido, portanto, o selecionado para a realização dos estudos hemodinâmicos. Para comparar esses resultados com dados numéricos, o escoamento foi definido como laminar e estacionário e o fluído foi considerado Newtoniano. Em geral, os resultados numéricos e experimentais foram concordantes, não só na previsão do comportamento do fluxo com aparecimento de zonas de recirculação na zona pós-estenótica, mas também nos perfis de velocidade. Numa fase posterior, foi aplicada uma condição de entrada pulsátil para comparar o uso de simulações de natureza laminar e turbulenta, usando o modelo SST k-. Os resultados obtidos permitiram concluir que a segunda é mais apropriado para simular o fluxo sanguíneo. Posteriormente, foram examinadas as principais diferenças hemodinâmicas, considerando o sangue como fluído Newtoniano e não-Newtoniano (modelo de Carreau). Para estes modelos, as diferenças foram muito pequenas nos perfis de velocidade, mas mais significativas nas tensões de corte na parede medidas, com o modelo Newtoniano a prever valores mais baixos. As restantes simulações foram realizadas usando o modelo de Carreau e um escoamento de entrada transiente, tendo-se observado um aumento dos valores das velocidades e da tensão de corte na parede com o grau de estenose, o que está associado a um maior risco de trombose

Editorial for the special issue on micro/nanofluidic and lab-on-a-chip devices for biomedical applications

Micro/Nanofluidic and lab-on-a-chip devices have been increasingly used in biomedical research [...

Microneedles in advanced microfluidic systems: a systematic review throughout lab and organ-on-a-chip applications

Microneedles (MNs) have been widely used in biomedical applications for drug delivery and biomarker detection purposes. Furthermore, MNs can also be used as a stand-alone tool to be combined with microfluidic devices. For that purpose, lab- or organ-on-a-chip are being developed. This systematic review aims to summarize the most recent progress in these emerging systems, to identify their advantages and limitations, and discuss promising potential applications of MNs in microfluidics. Therefore, three databases were used to search papers of interest, and their selection was made following the guidelines for systematic reviews proposed by PRISMA. In the selected studies, the MNs type, fabrication strategy, materials, and function/application were evaluated. The literature reviewed showed that although the use of MNs for lab-on-a-chip has been more explored than for organ-on-a-chip, some recent studies have explored this applicability with great potential for the monitoring of organ models. Overall, it is shown that the presence of MNs in advanced microfluidic devices can simplify drug delivery and microinjection, as well as fluid extraction for biomarker detection by using integrated biosensors, which is a promising tool to precisely monitor, in real-time, different kinds of biomarkers in lab- and organ-on-a-chip platforms.This work was supported by the project EXPL/EMD-EMD/0650/2021, and partially supported by the project PTDC/EEI-EEE/2846/2021, through national funds (OE), within the scope of the Scientific Research and Technological Development Projects (IC&DT) program in all scientific domains (PTDC), through the Foundation for Science and Technology, I.P. (FCT, I.P). This project also received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 101032481. V.C. is grateful for her Ph.D. grant from Fundação para a Ciência e Tecnologia (FCT) with reference UI/BD/151028/2021 and Fulbright Grant for Research with the support of FCT, AY2022/2023. R.O.R. thanks FCT for her contract funding provided through 2020.03975.CEECIND. The authors also acknowledge the partial financial support within the R&D Unit Project Scope: UIDB/04436/2020, UIDB/04077/2020, UIDB/00532/2020, LA/P/0045/2020

Blood flow modeling in coronary arteries: a review

Atherosclerosis is one of the main causes of cardiovascular events, namely, myocardium infarction and cerebral stroke, responsible for a great number of deaths every year worldwide. This pathology is caused by the progressive accumulation of low-density lipoproteins, cholesterol, and other substances on the arterial wall, narrowing its lumen. To date, many hemodynamic studies have been conducted experimentally and/or numerically; however, this disease is not yet fully understood. For this reason, the research of this pathology is still ongoing, mainly, resorting to computational methods. These have been increasingly used in biomedical research of atherosclerosis because of their high-performance hardware and software. Taking into account the attempts that have been made in computational techniques to simulate realistic conditions of blood flow in both diseased and healthy arteries, the present review aims to give an overview of the most recent numerical studies focused on coronary arteries, by addressing the blood viscosity models, and applied physiological flow conditions. In general, regardless of the boundary conditions, numerical studies have been contributed to a better understanding of the development of this disease, its diagnosis, and its treatment.This work was supported through the R&D Units Project Scope: UIDB/00319/2020, UIDB/04077/2020, NORTE-01-0145-FEDER-030171, and NORTE-01-0145-FEDER-029394, funded by COMPETE2020, NORTE 2020, PORTUGAL 2020, and FEDER

Visualization and measurements of blood cells flowing in microfluidic systems and blood rheology: a personalized medicine perspective

Hemorheological alterations in the majority of metabolic diseases are always connected with blood rheology disturbances, such as the increase of blood and plasma viscosity, cell aggregation enhancement, and reduction of the red blood cells (RBCs) deformability. Thus, the visualizations and measurements of blood cells deformability flowing in microfluidic devices (point-of-care devices) can provide vital information to diagnose early symptoms of blood diseases and consequently to be used as a fast clinical tool for early detection of biomarkers. For instance, RBCs rigidity has been correlated with myocardial infarction, diabetes mellitus, hypertension, among other blood diseases. In order to better understand the blood cells behavior in microfluidic devices, rheological properties analysis is gaining interest by the biomedical committee, since it is strongly dependent on the interactions and mechanical cells proprieties. In addition, the development of blood analogue fluids capable of reproducing the rheological properties of blood and mimic the RBCs behavior at in vitro conditions is crucial for the design, performance and optimization of the microfluidic devices frequently used for personalized medicine. By combining the unique features of the hemorheology and microfluidic technology for single-cell analysis, valuable advances in personalized medicine for new treatments and diagnosis approach can be achieved.This project has been funded by Portuguese national funds of FCT/MCTES (PIDDAC) through the base funding from the following research unit: UIDB/04077/2020, UIDB/00319/2020 and UIDB/00532/2020. The authors are also grateful for the partial funding of FCT through the projects NORTE-01-0145-FEDER-029394, NORTE-01-0145-FEDER-030171, funded by COMPETE2020, NORTE2020, PORTUGAL2020, and FEDER.Diana Pinho acknowledges the PhD scholarship SFRH/BD/89077/2012 attributed by FCT

Numerical study of the unsteady flow in simplified and realistic iliac bifurcation models

Cardiovascular diseases are a major cause of death and disability worldwide and they are commonly associated with the occurrence of atherosclerotic plaque deposition in the vessel walls, a process denoted as atherosclerosis. This is a chronic and progressive inflammatory disease of large-/medium-sized blood vessels that affects blood flow profiles, with the abdominal aorta and its branches being one of the locations prone to the development of this pathology, due to their curvatures and bifurcations. In this regard, the effect of flow patterns was studied and compared for both a simplified three-dimensional model of aorta bifurcation on the iliac arteries and a realistic model of iliac bifurcation, which was constructed from a computational tomography medical image. The flow patterns were analyzed in terms of velocity and wall shear stress distribution, but a special focus was given to the size and location of the recirculation zone. The simulations were performed using the Computational Fluid Dynamics software, FLUENT, taking into account the cardiac cycle profile at the infrarenal aorta. The shear stress and the velocity distribution observed for both models indicated that higher shear stress occurred along the flow divider wall (inner wall) and low shear stress occurred along the outer walls. In addition, the results demonstrated that the wall shear stress profiles were deeply affected by the transient profile of the cardiac cycle, with the deceleration phase being the most critical phase to the occurrence of backflow.This work was supported by FCT—Fundação para a Ciência e Tecnologia through the R&D Units Project Scope: UIDB/00319/2020, UIDB/04077/2020, and NORTE-01-0145-FEDER-030171, funded by COMPETE2020, NORTE 2020, PORTUGAL 2020, and FEDER

Manual and automatic image analysis segmentation methods for blood flow studies in microchannels

In blood flow studies, image analysis plays an extremely important role to examine raw data obtained by high-speed video microscopy systems. This work shows different ways to process the images which contain various blood phenomena happening in microfluidic devices and in microcirculation. For this purpose, the current methods used for tracking red blood cells (RBCs) flowing through a glass capillary and techniques to measure the cell-free layer thickness in different kinds of microchannels will be presented. Most of the past blood flow experimental data have been collected and analyzed by means of manual methods, that can be extremely reliable, but they are highly time-consuming, user-intensive, repetitive, and the results can be subjective to user-induced errors. For this reason, it is crucial to develop image analysis methods able to obtain the data automatically. Concerning automatic image analysis methods for individual RBCs tracking and to measure the well known microfluidic phenomena cell-free layer, two developed methods are presented and discussed in order to demonstrate their feasibility to obtain accurate data acquisition in such studies. Additionally, a comparison analysis between manual and automatic methods was performed.This project has been funded by Portuguese national funds of FCT/MCTES (PIDDAC) through the base funding from the following research units: UIDB/00532/2020 (Transport Phenomena Research Center—CEFT), UIDB/04077/2020 (Mechanical Engineering and Resource Sustainability Center—MEtRICs), UIDB/00690/2020 (CIMO). The authors are also grateful for the partial funding of FCT through the projects, NORTE-01-0145-FEDER-029394 (PTDC/EMD-EMD/29394/2017) and NORTE-01-0145-FEDER-030171 (PTDC/EMD-EMD/30171/2017) funded by COMPETE2020, NORTE2020, PORTUGAL2020 and FEDER. D. Bento acknowledges the PhD scholarship SFRH/BD/ 91192/2012 granted by FCT

Organ-on-a-chip platforms for drug screening and delivery in tumor cells: a systematic review

The development of cancer models that rectify the simplicity of monolayer or static cell cultures physiologic microenvironment and, at the same time, replicate the human system more accurately than animal models has been a challenge in biomedical research. Organ-on-a-chip (OoC) devices are a solution that has been explored over the last decade. The combination of microfluidics and cell culture allows the design of a dynamic microenvironment suitable for the evaluation of treatments’ efficacy and effects, closer to the response observed in patients. This systematic review sums the studies from the last decade, where OoC with cancer cell cultures were used for drug screening assays. The studies were selected from three databases and analyzed following the research guidelines for systematic reviews proposed by PRISMA. In the selected studies, several types of cancer cells were evaluated, and the majority of treatments tested were standard chemotherapeutic drugs. Some studies reported higher drug resistance of the cultures on the OoC devices than on 2D cultures, which indicates the better resemblance to in vivo conditions of the former. Several studies also included the replication of the microvasculature or the combination of different cell cultures. The presence of vasculature can influence positively or negatively the drug efficacy since it contributes to a greater diffusion of the drug and also oxygen and nutrients. Co-cultures with liver cells contributed to the evaluation of the systemic toxicity of some drugs metabolites. Nevertheless, few studies used patient cells for the drug screening assays.This work has been supported by the projects NORTE-01-0145-FEDER-030171 (project reference PTDC/EME-SIS/30171/2017), NORTE-01-0145-FEDER-029394 (project reference PTDC/EMDEMD/29394/2017), through the COMPETE2020, the Lisb@2020, the Programa Operacional Regional do Norte–Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement through the European Regional Development Fund (FEDER) and by Fundação para a Ciência e Tecnologia (FCT), and through FEDER and FCT, project references EXPL/EMD-EMD/0650/2021 and PTDC/EEI-EEE/2846/2021. The authors also acknowledge the partial financial support within the R&D Units Project Scope: UIDB/00319/2020, UIDB/04077/2020, UIDB/00690/2020, UIDB/04436/2020. This work was also funded by AMED-CREST Grant Number JP20gm1310001h0002. Raquel O. Rodrigues (R.O.R.) thanks FCT for her contract funding provided through 2020.03975.CEECIND

Diagnosis methods for COVID-19: A systematic review

At the end of 2019, the coronavirus appeared and spread extremely rapidly, causing millions of infections and deaths worldwide, and becoming a global pandemic. For this reason, it became urgent and essential to find adequate tests for an accurate and fast diagnosis of this disease. In the present study, a systematic review was performed in order to provide an overview of the COVID-19 diagnosis methods and tests already available, as well as their evolution in recent months. For this purpose, the Science Direct, PubMed, and Scopus databases were used to collect the data and three authors independently screened the references, extracted the main information, and assessed the quality of the included studies. After the analysis of the collected data, 34 studies reporting new methods to diagnose COVID-19 were selected. Although RT-PCR is the gold-standard method for COVID-19 diagnosis, it cannot fulfill all the requirements of this pandemic, being limited by the need for highly specialized equipment and personnel to perform the assays, as well as the long time to get the test results. To fulfill the limitations of this method, other alternatives, including biological and imaging analysis methods, also became commonly reported. The comparison of the different diagnosis tests allowed to understand the importance and potential of combining different techniques, not only to improve diagnosis but also for a further understanding of the virus, the disease, and their implications in humans

3D printing techniques and their applications to organ-on-a-chip platforms: a systematic review

Three-dimensional (3D) in vitro models, such as organ-on-a-chip platforms, are an emerging and effective technology that allows the replication of the function of tissues and organs, bridging the gap amid the conventional models based on planar cell cultures or animals and the complex human system. Hence, they have been increasingly used for biomedical research, such as drug discovery and personalized healthcare. A promising strategy for their fabrication is 3D printing, a layer-by-layer fabrication process that allows the construction of complex 3D structures. In contrast, 3D bioprinting, an evolving biofabrication method, focuses on the accurate deposition of hydrogel bioinks loaded with cells to construct tissue-engineered structures. The purpose of the present work is to conduct a systematic review (SR) of the published literature, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, providing a source of information on the evolution of organ-on-a-chip platforms obtained resorting to 3D printing and bioprinting techniques. In the literature search, PubMed, Scopus, and ScienceDirect databases were used, and two authors independently performed the search, study selection, and data extraction. The goal of this SR is to highlight the importance and advantages of using 3D printing techniques in obtaining organ-on-a-chip platforms, and also to identify potential gaps and future perspectives in this research field. Additionally, challenges in integrating sensors in organs-on-chip platforms are briefly investigated and discussed.The authors are grateful for the funding of FCT through the projects NORTE-01-0145- FEDER-029394, NORTE-01-0145-FEDER-030171 funded by COMPETE2020, NORTE2020, PORTUGAL2020, and FEDER. This work was also supported by Fundação para a Ciência e a Tecnologia (FCT) under the strategic grants UIDB/04077/2020, UIDB/00319/2020, UIDB/04436/2020 and UIDB/00532/2020. This work was also funded by AMED-CREST Grant Number JP20gm1310001h0002.Violeta Carvalho acknowledges the PhD scholarship UI/BD/151028/2021 attributed by FCT. Inês Gonçalves acknowledges the PhD scholarship BD/08646/2020 attributed by FCT