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- Blood flow in a bifurcation and confluence microchannel: effect of the cell-free layer in velocity profilesPublication . Pinho, Diana; Bento, David; Rodrigues, Raquel Oliveira; Fernandes, Carla S.; Garcia, Valdemar; Lima, Rui A.A few detailed studies have been performed in complex in vitro microvascular networks composed by bifurcations and confluences. The main purpose of the present work is to numerically simulate the flow of two distinct fluids through bifurcation and confluence geometries, i. e red blood cells (RBCs)suspended in Dextran40 with about 14% of heamatocrit and pure water. The simulations of pure water and RBCs flows were performed resorting to the commercial finite volume software package FLUENT. A well known hemodynamic phenomenon, known as Fahraeus-Lindqvist effect, observed in both in vivo and in vitro studies, results in the formation of a marginal cell-free layer (CFL) at regions adjacent to the wall. Recently, studies have shown that the formation of the CFL is affected by the geometry of the microchannel and for the case of the confluences a CFL tend to appear in the middle of the microchannel after the apex of the confluence. By using the CFL experimental data, the main objective of this work is to implement a CFL in the numerical simulations in order to obtain a better understanding of the effect of this layer on the velocity profiles.
- Cell-free layer (CFL) measurements in complex geometries: contractions and bifurcationsPublication . Novais, Susana; Pinho, Diana; Bento, David; Pinto, Elmano; Yaginuma, Tomoko; Fernandes, Carla S.; Garcia, Valdemar; Pereira, Ana I.; Lima, José; Mujika, Maite; Oliveira, Mónica S.N.; Dias, Ricardo P.; Arana, Sergio; Lima, Rui A.In this chapter we discuss the cell-free layer (CFL) developed adjacent to the wall of microgeometries containing complex features representative of the microcirculation, such as contractions, expansions, bifurcations and confluences. The microchannels with the different geometries were made of polydimethylsiloxane (PDMS) and we use optical techniques to evaluate the cell-free layer for red blood cells (RBC) suspensions with different hematocrit (Hct). The images are captured using a high-speed video microscopy system and the thickness of the cell free layer was measured using both manual and automatic image analysis techniques. The results show that in in vitro microcirculation, the hematocrit and the geometrical configuration have a major impact on the CFL thickness. In particular, the thickness of the cell-free layer increases as the fluid flows through a contraction-expansion sequence and that this increase is enhanced for lower hematocrit. In contrast, the flow rates tested in this studies did not show a clear influence on the CFL thickness.
- Técnicas de separação biomimética em microfluídicaPublication . Faustino, Vera; Pinho, Diana; Rodriques, Raquel; Garcia, Valdemar; Lima, Rui A.A separação e a identificação de células são essenciais em várias aplicações biomédicas, incluindo a biologia celular e os métodos de diagnóstico e terapêuticos. O sangue é um fluido não-Newtoniano contendo inúmeras informações preciosas sobre o estado fisiológico e patológico do corpo humano. No entanto, devido à sua complexidade, existem actualmente poucos métodos de análise precisos. A maioria das técnicas convencionais usadas na separação e contagem de células são dispendiosas e normalmente é necessário usar agentes externos adicionais para identificar as células. As técnicas biomiméticas de separação em microfluídica usam fenómenos microfluídicos, que ocorrem à microescala, para realizar a separação de determinadas células sanguíneas. Estes fenómenos incluem a separação do plasma, a camada livre de células (CLC), a migração dos glóbulos brancos (GBs), também designados por leucócitos, e a lei da bifurcação. Recentemente, vários investigadores têm replicado estes efeitos, que acontecem em ambientes in vivo, em sistemas microfluídicos, ou seja, em ambientes in vitro. Nos microcanais, os glóbulos vermelhos (GVs), devido à sua deformabilidade e ao gradiente de velocidades (às forças de sustentação), tendem a concentrar-se na zona central dos microcanais, enquanto os GBs e os GVs rígidos (tal como, os GVs infectados com malária) tendem a migrar para a CLC que se forma nas zonas próximas das paredes. A lei da bifurcação estabelece, relativamente ao comportamento dos GVs, que em microcanais com bifurcações eles tendem a escolher o microcanal de secção maior.
- A rapid and low-cost nonlithographic method to fabricate biomedical microdevices for blood flow analysisPublication . Pinto, Elmano; Faustino, Vera; Rodrigues, Raquel Oliveira; Pinho, Diana; Garcia, Valdemar; Miranda, João Mário; Lima, Rui A.Microfluidic devices are electrical/mechanical systems that offer the ability to work with minimal sample volumes, short reactions times, and have the possibility to perform massive parallel operations. An important application of microfluidics is blood rheology in microdevices, which has played a key role in recent developments of lab-on-chip devices for blood sampling and analysis. The most popular and traditional method to fabricate these types of devices is the polydimethylsiloxane (PDMS) soft lithography technique, which requires molds, usually produced by photolithography. Although the research results are extremely encouraging, the high costs and time involved in the production of molds by photolithography is currently slowing down the development cycle of these types of devices. Here we present a simple, rapid, and low-cost nonlithographic technique to create microfluidic systems for biomedical applications. The results demonstrate the ability of the proposed method to perform cell free layer (CFL) measurements and the formation of microbubbles in continuous blood flow.
- In vitro blood flow and cell-free layer in hyperbolic microchannels: visualizations and measurmentsPublication . Rodrigues, Raquel Oliveira; Lopes, Raquel; Pinho, Diana; Pereira, Ana I.; Garcia, Valdemar; Gassmann, Stefan; Sousa, Patrícia C.; Lima, Rui A.Red blood cells (RBCs) in microchannels has tendency to undergo axial migration due to the parabolic velocity profile, which results in a high shear stress around wall that forces the RBC to move towards the centre induced by the tank treading motion of the RBC membrane. As a result there is a formation of a cell free layer (CFL) with extremely low concentration of cells. Based on this phenomenon, several works have proposed microfluidic designs to separate the suspending physiological fluid from whole in vitro blood. This study aims to characterize the CFL in hyperbolic-shaped microchannels to separate RBCs from plasma. For this purpose, we have investigated the effect of hyperbolic contractions on the CFL by using not only different Hencky strains but also varying the series of contractions. The results show that the hyperbolic contractions with a Hencky strain of 3 and higher, substantially increase the CFL downstream of the contraction region in contrast with the microchannels with a Hencky strain of 2, where the effect is insignificant. Although, the highest CFL thickness occur at microchannels with a Hencky strain of 3.6 and 4.2 the experiments have also shown that cells blockage are more likely to occur at this kind of microchannels. Hence, the most appropriate hyperbolic-shaped microchannels to separate RBCs from plasma is the one with a Hencky strain of 3.
- Fabricação de microcanais utilizando o método de xurografia: visualização da camada livre de célulasPublication . Pinto, Elmano; Pinho, Diana; Bento, David; Correia, Teresa Montenegro; Garcia, Valdemar; Dias, Ricardo P.; Miranda, João MárioNo presente estudo, pretendeu-se desenvolver/melhorar uma metodologia de microfabricação de baixo custo, conhecida por xurografia e efectuar a visualização e quantificação da camada livre de células para diferentes escoamentos sanguíneos em microcanais.
- Visualization and measurement of red blood cells flowing in microfluidic devicesPublication . Rodrigues, Raquel Oliveira; Pinho, Diana; Faustino, Vera; Yaginuma, Tomoko; Bento, David; Fernandes, Carla S.; Garcia, Valdemar; Lima, Rui A.Several experimental techniques were performed in the past years using in vitro environments, in an attempt to not only understand the blood flow behaviour in microcirculation but also develop microfluidic devices as an alternative clinical methodology to detect blood diseases. Hence, the visualization and measurement of red blood cells (RBCs) flowing in a microfluidic device are important to provide not only essential information about hydrodynamic characteristics of the blood but also vital information to diagnose the initial symptoms of diseases during clinical investigations. For instance, RBC rigidity has been correlated with myocardial infarction, diabetes mellitus, hypertension, and also other haematological disorders and diseases that affect RBC deformation more directly, such as, hereditary spherocytosis, sickle cell anaemia and malaria. Regarding a better understanding of the RBCs deformation and motion, we present in this paper a compilation of studies made in our research group, using several microfluidic devices with different microchannel geometries and fabrication techniques (i.e., soft-lithography, xurography and hybrids) that focus in the shear and extensional flow behaviour, either in healthy or chemically stiffed RBCs.
- Blood flow visualization and measurements in microfluidic devices fabricated by a micromilling techniquePublication . Singhal, Jaron; Pinho, Diana; Lopes, Raquel; Sousa, Patrícia C.; Garcia, Valdemar; Schütte, Helmut; Lima, Rui A.; Gassmann, StefanThe most common and used technique to produce microfluidic devices for biomedical applications is the soft-lithography. However, this is a high cost and time-consuming technique. Recently, manufacturers were able to produce milling tools smaller than 100 μm and consequently have promoted the ability of the micromilling machines to fabricate microfluidic devices capable of performing cell separation. In this work, we show the ability of a micromilling machine to manufacture microchannels down to 30 μm and also the ability of a microfluidic device to perform partial separation of red blood cells from plasma. Flow visualization and measurements were performed by using a high-speed video microscopy system. Advantages and limitations of the micromilling fabrication process are also presented.
- Flow focusing technique to produce PDMS microparticles for blood analogue fluidsPublication . Silva, S.F.; Vega, E.J.; Pinho, Diana; Garcia, Valdemar; Lima, Rui A.; Montanero, J.M.The study of the blood flow behaviour through microchannels is crucial to improve our understanding about blood flow phenomena happening in the human microcirculatory system. However, the difficulties associated with the use of in vitro blood, such as coagulation and sample storage, have promoted the increasing interest to develop fluids with rheological properties similar to real blood [1]. Polydimethysiloxane (PDMS), due its remarkable properties such as good optical transparency, biocompatibility and permeability to gases, is widely used to fabricate microfluidic devices for in vitro blood experiments [2]. Recently, this inert elastomer has been used to produce monodisperse PDMS microbeads through a microfluidic approach [3]. Jiang et. al. have proposed a flow-focusing technique where a PDMS precursor was dispersed into microdroplets within an aqueous continuous phase [3]. By using this method they were able to produce PDMS microbeads with an average dimension of 80 microns. However, to develop blood analogue fluids it is essential to have PDMS microparticles with dimensions more close to the blood cells, i. e., the microparticles should have dimensions smaller than 20 microns. Hence, in this study a novel flow focusing technique was used to produce PDMS microparticles with dimensions more close to real blood cells. This technique was recently proposed to produce jets, droplets, and emulsions with sizes ranging from tens of microns down to the submicrometer scale [4]. This procedure is also based on the flow focusing principle which the above mentioned method relies on. Nevertheless, our technique makes use of the breakage of a steady jet to form the microparticles, which can lead to much higher production rates. In our technique, liquid is injected at a constant flow rate through a hypodermic needle to form a film over the needle’s outer surface. This film flows toward the needle tip until a liquid ligament is steadily ejected. Both the film motion and the liquid ejection are driven by the viscous and pressure forces exerted by a coflowing fluid stream. The outcome is a capillary jet which breaks up into droplets.
- Deformation of red blood cells, air bubbles and droplets in microfluidic devices: flow visualizations and measurementsPublication . Bento, David; Rodrigues, Raquel Oliveira; Faustino, Vera; Pinho, Diana; Fernandes, Carla S.; Pereira, Ana I.; Garcia, Valdemar; Miranda, João Mário; Lima, Rui A.Techniques, such as micropipette aspiration and optical tweezers, are widely used to measure cell mechanical properties, but are generally labor-intensive and time-consuming, typically involving a difficult process of manipulation. In the past two decades, a large number of microfluidic devices have been developed due to the advantages they offer over other techniques, including transparency for direct optical access,lower cost, reduced space and labor, precise control, and easy manipulation of a small volume of blood samples. This review presents recent advances in the development of microfluidic devices to evaluate the mechanical response of individual red blood cells (RBCs) and microbubbles flowing in constriction microchannels.Visualizations and measurements of the deformation of RBCs flowing through hyperbolic,smooth,and sudden-contraction microchannels were evaluated and compared. In particular, we show the potential of using hyperbolic-shaped microchannels to precisely control and assess small changes in RBC deformability in both physiological and pathological situations. Moreover, deformations of air microbubbles and droplets flowing through a microfluidic constriction were also compared with RBCs deformability.