Salman Sohrabi

Characterization of Nanoparticle Dispersion in Red Blood Cell Suspension by the Lattice Boltzmann-Immersed Boundary Method

Nanodrug-carrier delivery in the blood stream is strongly influenced by nanoparticle (NP) dispersion. This paper presents a numerical study on NP transport and dispersion in red blood cell (RBC) suspensions under shear and channel flow conditions, utilizing an immersed boundary fluid-structure interaction model with a lattice Boltzmann fluid solver, an elastic cell membrane model and a particle motion model driven by both hydrodynamic loading and Brownian dynamics. The model can capture the multiphase features of the blood flow. Simulations were performed to obtain an empirical formula to predict NP dispersion rate for a range of shear rates and cell concentrations. NP dispersion rate predictions from the formula were then compared to observations from previous experimental and numerical studies. The proposed formula is shown to accurately predict the NP dispersion rate. The simulation results also confirm previous findings that the NP dispersion rate is strongly influenced by local disturbances in the flow due to RBC motion and deformation. The proposed formula provides an efficient method for estimating the NP dispersion rate in modeling NP transport in large-scale vascular networks without explicit RBC and NP models.

Numerical Simulation of Particle Transport and Deposition in the Pulmonary Vasculature

To quantify the transport and adhesion of drug particles in a complex vascular environment, computational fluid particle dynamics (CFPD) simulations of blood flow and drug particulate were conducted in three different geometries representing the human lung vasculature for steady and pulsatile flow conditions. A fully developed flow profile was assumed as the inlet velocity, and a lumped mathematical model was used for the calculation of the outlet pressure boundary condition. A receptor-ligand model was used to simulate the particle binding probability. The results indicate that bigger particles have lower deposition fraction due to less chance of successful binding. Realistic unsteady flow significantly accelerates the binding activity over a wide range of particle sizes and also improves the particle deposition fraction in bifurcation regions when comparing with steady flow condition. Furthermore, surface imperfections and geometrical complexity coupled with the pulsatility effect can enhance fluid mixing and accordingly particle binding efficiency. The particle binding density at bifurcation regions increases with generation order and drug carriers are washed away faster in steady flow. Thus, when studying drug delivery mechanism in vitro and in vivo, it is important to take into account blood flow pulsatility in realistic geometry. Moreover, tissues close to bifurcations are more susceptible to deterioration due to higher uptake.

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

The inflammatory response in endothelial cells (ECs) leads to an increase in vascular permeability through the formation of gaps. However, the dynamic nature of vascular permeability and external factors involved is still elusive. In this work, we use a biomimetic blood vessel (BBV) microfluidic model to measure in real-time the change in permeability of the EC layer under culture in physiologically relevant flow conditions. This platform studies the dynamics and characterizes vascular permeability when the EC layer is triggered with an inflammatory agent using tracer molecules of three different sizes, and the results are compared to a transwell insert study. We also apply an analytical model to compare the permeability data from the different tracer molecules to understand the physiological and bio-transport significance of endothelial permeability based on the molecule of interest. A computational model of the BBV model is also built to understand the factors influencing transport of molecules of different sizes under flow. The endothelial monolayer cultured under flow in the BBV model was treated with thrombin, a serine protease that induces a rapid and reversible increase in endothelium permeability. On analysis of permeability data, it is found that the transport characteristics for fluorescein isothiocyanate (FITC) dye and FITC Dextran 4k Da molecules are similar in both BBV and transwell models, but FITC Dextran 70k Da molecules show increased permeability in the BBV model as convection flow (Peclet number > 1) influences the molecule transport in the BBV model. We also calculated from permeability data the relative increase in intercellular gap area during thrombin treatment for ECs in the BBV and transwell insert models to be between 12% and 15%. This relative increase was found to be within range of what we quantified from F-actin stained EC layer images. The work highlights the importance of incorporating flow in in vitro vascular models, especially in studies involving transport of large size objects such as antibodies, proteins, nano/micro particles, and cells.

Shear induced alignment of short nanofibers in 3D printed polymer composites

3D printing of composite materials offers an opportunity to combine the desired properties of composite materials with the flexibility of additive manufacturing in geometric shape and complexity. In this paper, the shear-induced alignment of aluminum oxide nanowires during stereolithography printing was utilized to fabricate a nanowire reinforced polymer composite. To align the fibers, a lateral oscillation mechanism was implemented and combined with wall pattern printing technique to generate shear flow in both vertical and horizontal directions. A series of specimens were fabricated for testing the composite materials tensile strength. The results showed that mechanical properties of the composite were improved by reinforcement of nanofibers through shear induced alignment. The improvement of tensile strength was approximately ∼28% by aligning the nanowires at 5 wt% (∼1.5% volume fraction) loading of aluminum oxide nanowires.

Characterization of nanoparticle binding dynamics in microcirculation using an adhesion probability function

Quantitative understanding of nanoparticles transport and adhesion dynamic in microcirculation is very challenging due to complexity of fluid dynamics and imaging setup. In-vitro experiments within microfluidic channels showed the significant influence of shear rate, carrier size, particle-substrate chemistry and vessel geometry on particle deposition rate. However, there are few theoretical models that can accurately predict experimental results. We have developed a numerical model to predict nanoparticle transport and binding dynamics and verified with our previous in-vitro tests results. A binding probability function is used to simplify the carrier attachment and detachment processes. Our results showed that due to the complex dynamics of particle transport and adhesion mechanism, the correlation between binding probability and actual deposition rate is not linear. Using experimental data, it is shown that the binding probability of small particles changes slightly with shear rate whereas the chance of binding for big particles decreases exponentially with shear. Our particulate model also captured some phenomena that cannot be achieved by continuum approach such as accumulation of drug particles in close vicinity of vessel wall. In addition, the effects of channel geometry and antibody density on particle binding are discussed extensively. The results from our particulate approach agrees well with experimental data suggesting that it can be used as a simple, yet efficient predictive tool for studying drug carrier binding in microcirculation.

Numerical simulation of cell squeezing through a micropore by the immersed boundary method

The deformability of cells has been used as a biomarker to detect circulating tumor cells from patient blood sample using microfluidic devices with microscale pores. Successful separations of circulating tumor cells from a blood sample require careful design of the micropore size and applied pressure. This paper presented a parametric study of cell squeezing through micropores with different size and pressure. Different membrane compressibility modulus was used to characterize the deformability of varying cancer cells. Nucleus effect was also considered. It shows that the cell translocation time through the micropore increases with cell membrane compressibility modulus and nucleus stiffness. Particularly, it increases exponentially as the micropore diameter or pressure decreases. The simulation results such as the cell squeezing shape and translocation time agree well with experimental observations. The simulation results suggest that special care should be taken in applying Laplace–Young equation to microfluidic design due to the nonuniform stress distribution and membrane bending resistance.

Nanoparticle transport and delivery in a heterogeneous pulmonary vasculature.

Quantitative understanding of nanoparticles delivery in a complex vascular networks is very challenging because it involves interplay of transport, hydrodynamic force, and multivalent interactions across different scales. Heterogeneous pulmonary network includes up to 16 generations of vessels in its arterial tree. Modeling the complete pulmonary vascular system in 3D is computationally unrealistic. To save computational cost, a model reconstructed from MRI scanned images is cut into an arbitrary pathway consisting of the upper 4-generations. The remaining generations are represented by an artificially rebuilt pathway. Physiological data such as branch information and connectivity matrix are used for geometry reconstruction. A lumped model is used to model the flow resistance of the branches that are cut off from the truncated pathway. Moreover, since the nanoparticle binding process is stochastic in nature, a binding probability function is used to simplify the carrier attachment and detachment processes. The stitched realistic and artificial geometries coupled with the lumped model at the unresolved outlets are used to resolve the flow field within the truncated arterial tree. Then, the biodistribution of 200nm, 700nm and 2µm particles at different vessel generations is studied. At the end, 0.2-0.5% nanocarrier deposition is predicted during one time passage of drug carriers through pulmonary vascular tree. Our truncated approach enabled us to efficiently model hemodynamics and accordingly particle distribution in a complex 3D vasculature providing a simple, yet efficient predictive tool to study drug delivery at organ level.

Finite Element Analysis of the Implantation Process of Overlapping Stents

Overlapping stents are widely used in vascular stent surgeries. However, the rate of stent fractures (SF) and in-stent restenosis (ISR) after using overlapping stents is higher than that of single stent implantations. Published studies investigating the nature of overlapping stents rely primarily on medical images, which can only reveal the effect of the surgery without providing insights into how stent overlap influences the implantation process. In this paper, a finite element analysis of the overlapping stent implantation process was performed to study the interaction between overlapping stents. Four different cases, based on three typical stent overlap modes and two classical balloons, were investigated. The results showed that overlapping contact patterns among struts were edge-to-edge, edge-to-surface, and noncontact. These were mainly induced by the nonuniform deformation of the stent in the radial direction and stent tubular structures. Meanwhile, the results also revealed that the contact pressure was concentrated in the edge of overlapping struts. During the stent overlap process, the contact pattern was primarily edge-to-edge contact at the beginning and edge-to-surface contact as the contact pressure increased. The interactions between overlapping stents suggest that the failure of overlapping stents frequently occurs along stent edges, which agrees with the previous experimental research regarding the safety of overlapping stents. This paper also provides a fundamental understanding of the mechanical properties of overlapping stents.

Antibody-coated nanoparticles are promising molecular probes for microscopic analysis of cell behavior

Cells are complex systems that respond to local environment and interact with their neighbors through various receptors expressed on the surface. Because of the presence of artifacts associated with microscope images during the fixing process, microscopy assays of fixed and stained cells cannot provide enough information to characterize cellular behaviors and cell–cell interactions [1]. Therefore, development of novel technologies capable of monitoring cellular scale events in real time is of significant importance for providing valuable kinetic and spatial information of cells [2]. Highly sensitive fluorescence microscopy has been widely used for real-time investigation and monitoring of spatiotemporal cellular events such as cell adhesion, cell migration as well as cell–cell, viral–cell, protein–cell and protein–protein interactions [3–5]. For instance, genetically labeled cells with green fluorescent protein (GFP) are being used to visualize cancer cells and metastatic process in live tissue or in the intact animal by whole-body imaging. The development of functional fluorophores and the discovery of GFP-modified versions such as yellow fluorescent protein and cyan fluorescent protein have provided the platform to image several events simultaneously at the single-cell level [1]. One example would be usage of multicolor fluorescence microscopy to study the entry of nanoparticles (NPs) and viruses into living or fixed cells. Dualcolor fluorescent imaging technique is also utilized for subcellular real-time imaging of cancer cell trafficking. By labeling cancer cells with GFP in the nucleus and red fluorescent protein in the cytoplasm, cancer cell trafficking in lymphatic vessels of nude live mice are studied using whole-body imaging. Fluorescent microscopy has further been combined with other microscopy techniques such as atomic force microscopy or electron microscopy to help broaden the understanding of subtle biological interactions and processes [6]. However, the labeling procedures are usually complex and the chemical modification introduced by the fluorescent probe can affect normal cell behavior [7].