In this study, we show the importance of extensional rheology, in addition to the shear rheology, in the choice of blood analog solutions intended to be used in vitro for mimicking the microcirculatory system. For this purpose, we compare the flow of a Newtonian fluid and two well-established viscoelastic blood analog polymer solutions through microfluidic channels containing both hyperbolic and abrupt contractions/expansions. The hyperbolic shape was selected in order to impose a nearly constant strain rate at the centerline of the microchannels and achieve a quasihomogeneous and strong extensional flow often found in features of the human microcirculatory system such as stenoses. The two blood analog fluids used are aqueous solutions of a polyacrylamide ͑125 ppm w/w͒ and of a xanthan gum ͑500 ppm w/w͒, which were characterized rheologically in steady-shear flow using a rotational rheometer and in extension using a capillary breakup extensional rheometer ͑CaBER͒. Both blood analogs exhibit a shear-thinning behavior similar to that of whole human blood, but their relaxation times, obtained from CaBER experiments, are substantially different ͑by one order of magnitude͒. Visualizations of the flow patterns using streak photography, measurements of the velocity field using microparticle image velocimetry, and pressure-drop measurements were carried out experimentally for a wide range of flow rates. The experimental results were also compared with the numerical simulations of the flow of a Newtonian fluid and a generalized Newtonian fluid with shear-thinning behavior. Our results show that the flow patterns of the two blood analog solutions are considerably different, despite their similar shear rheology. Furthermore, we demonstrate that the elastic properties of the fluid have a major impact on the flow characteristics, with the polyacrylamide solution exhibiting a much stronger elastic character. As such, these properties must be taken into account in the choice or development of analog fluids that are adequate to replicate blood behavior at the microscale.

Nanomedicine has emerged in the last few decades as a field that can significantly impact the diagnose and therapy of human diseases. [1,2] Based on the outstanding properties that materials acquired at the nanoscale, such as high surface-to-volume ratio, high physicochemical stability, high charge carrier mobility and biocompatibility, a variety of nanoformulations have been developed to be applied in medicine by tailoring their size, shape, charge, and surface functional groups. [2,3] Based on those properties, the design of multifunctional nanoparticles (NPs) for nanomedicine is one of the most promising and exciting research areas that is expected to revolutionize the medical field in the next few decades. [4] Some of these multifunctional NPs have the potentiality to combine both diagnosis and therapy, the so-called theranostics, which is one of the ultimate goals of this field to achieve personalized and precise medical care (Figure 1). Among the therapeutic techniques, nanomaterials developed for drug delivery purpose have been widely investigated as smart drug nanocarriers capable to target tumor cells, protect drugs from degradation, enhance drug solubility, improve biodistribution, extend drug life cycle, and prevent lethal side-effects to healthy tissues and organs. [2,3] The design of these smart drug delivery systems can be engineered to target a specific location by taking advantages of the host environment, using for instance antibodies, aptamers or peptides; and then react autonomously as stimuli-responsive drug release agents, triggered by endogeneous chemical reactions (e.g., enzymes, pH, hydrolysis) or exogeneous stimulisensitive mechanisms (e.g., near infrared light, temperature raise induced by an alternating magnetic field, among others). [5] Comprehensive reviews on the topic of smart nano-based drug delivery systems can be found elsewhere. [5,6] Further complex functionality is represented by smart theranostics, which hold high promise for the nanomedicine of the future. Next, recent representative examples from the research arena are described. Cai et al. [7] make use of enzyme-responsiveness to design a cathepsin B-sensitive theranostic agent. They synthesized a biodegradable conjugate composed of a Gd chelate (Gd-DOTA) as a T1-magnetic resonance imaging (MRI) contrast agent, Despite the progress achieved in nanomedicine during the last decade, the translation of new nanotechnology-based therapeutic systems into clinical applications has been slow, especially due to the lack of robust preclinical tissue culture platforms able to mimic the in vivo conditions found in the human body and to predict the performance and biotoxicity of the developed nanomaterials. Organ-on-a-chip (OoC) platforms are novel microfluidic tools that mimic complex human organ functions at the microscale level. These integrated microfluidic networks, with 3D tissue engineered models, have been shown high potential to reduce the discrepancies between the results derived from preclinical and clinical trials. However, ...

We investigate the stability of steady planar stagnation flows of a dilute polyethylene oxide (PEO) solution using T-shaped microchannels. The precise flow rate control and well-defined geometries achievable with microfluidic fabrication technologies enable us to make detailed observations of the onset of elastically-driven flow asymmetries in steady flows with strong planar elongational characteristics. We consider two different stagnation flow geometries; corresponding to T-shaped microchannels with, and without, a recirculating cavity region. In the former case, the stagnation point is located on a free streamline, whereas in the absence of a recirculating cavity the stagnation point at the separating streamline is pinned at the confining wall of the microchannel. The kinematic differences in these two configurations affect the resulting polymeric stress fields and control the critical conditions and spatiotemporal dynamics of the resulting viscoelastic flow instability. In the free stagnation point flow, a strand of highly-oriented polymeric material is formed in the region of strong planar extensional flow. This leads to a symmetry-breaking bifurcation at moderate Weissenberg numbers followed by the onset of three-dimensional flow at high Weissenberg numbers, which can be visualized using streak-imaging and microparticle image velocimetry. When the stagnation point is pinned at the wall this symmetry-breaking transition is suppressed and the flow transitions directly to a threedimensional time-dependent flow at an intermediate flow rate. The spatial characteristics of these purely elastic flow transitions are compared quantitatively to the predictions of two-dimensional viscoelastic numerical simulations using a single-mode simplified PhanThien-Tanner (SPTT) model.

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Strong extensional flows of viscoelastic fluids generate purely-elastic instabilities and elastic turbulence at high Weissenberg numbers.

We present an experimental investigation of viscoelastic fluid flow in a cross-slot microgeometry under low Reynolds number flow conditions. By using several viscoelastic fluids, we investigate the effects of the microchannel bounding walls and the polymer solution concentration on the flow patterns. We demonstrate that for concentrated polymer solutions, the flow undergoes a bifurcation above a critical Weissenberg number (Wi) at which the flow becomes asymmetric but remains steady. The appearance of this elastic instability depends on the channel aspect ratio, defined as the ratio between the depth and the width of the channels. At high aspect ratios, when bounding wall effects are reduced, two types of elastic instabilities were observed, one in which the flow becomes asymmetric and steady, followed by a second instability at higher Wi, in which the flow becomes time-dependent. When the aspect ratio decreases, the bounding walls have a stabilizing effect, preventing the occurrence of steady asymmetric flow and postponing the transition to unsteady flow to higher Wi. For less concentrated solutions, the first elastic instability to steady asymmetric flow is absent and only the time-dependent flow instability is observed.

The characterization of the extensional rheology of polymeric solutions is important in several applications and industrial processes. Filament stretching and capillary breakup rheometers have been developed to characterize the extensional properties of polymeric solutions, mostly for high-viscosity fluids. However, for low concentration polymer solutions, the measurements are difficult using available devices, in terms of the minimum viscosity and relaxation times that can be measured accurately. In addition, when the slow retraction method is used, solvent evaporation can affect the measurements for volatile solvents. In this work, a new setup was tested for filament breakup experiments using the slow retraction method, high-speed imaging techniques, and an immiscible oil bath to reduce solvent evaporation and facilitate particle tracking in the thinning filament. Extensional relaxation times above around 100 μs were measured with the device for dilute and semi-dilute polymer solutions. Particle tracking velocimetry was also used to measure the velocity in the filament and the corresponding elongation rate, and to compare with the values obtained from the measured exponential decay of the filament diameter.

Significant progress has been made over the years on the topic of hemorheology, not only in terms of the development of more accurate and sophisticated techniques, but also in terms of understanding the phenomena associated with blood components, their interactions and impact upon blood properties. The rheological properties of blood are strongly dependent on the interactions and mechanical properties of red blood cells, and a variation of these properties can bring further insight into the human health state and can be an important parameter in clinical diagnosis. In this article, we provide both a reference for hemorheological research and a resource regarding the fundamental concepts in hemorheology. This review is aimed at those starting in the field of hemodynamics, where blood rheology plays a significant role, but also at those in search of the most up-to-date findings (both qualitative and quantitative) in hemorheological measurements and novel techniques used in this context, including technical advances under more extreme conditions such as in large amplitude oscillatory shear flow or under extensional flow, which impose large deformations comparable to those found in the microcirculatory system and in diseased vessels. Given the impressive rate of increase in the available knowledge on blood flow, this review is also intended to identify areas where current knowledge is still incomplete, and which have the potential for new, exciting and useful research. We also discuss the most important parameters that can lead to an alteration of blood rheology, and which as a consequence can have a significant impact on the normal physiological behavior of blood.