On the adhesion of particles to a cell layer under flow

The non-specific adhesion of spherical particles to a cell substrate is analyzed in a parallel plate flow chamber, addressing the effect of the particle size. Differently from other experiments, the total volume of the injected particles has been fixed, rather than the total number of particles, as the diameter d of the particles is changed from 500 nm up to 10 $\mu$m. From the analysis of the experimental data, simple and instructive scaling adhesion laws have been derived showing that (i) the number of particles adherent to the cell layer per unit surface decreases with the size of the particle as d^(-1.7) ; and consequently (ii) the volume of the particles adherent per unit surface increases with the size of the particles as d^(+1.3). These results are of importance in the "rational design" of nanoparticles for drug delivery and biomedical imaging.Comment: Submitted on behalf of TIMA Editions (http://irevues.inist.fr/tima-editions

Kinematic and dynamic forcing strategies for predicting the transport of inertial capsules via a combined lattice Boltzmann-Immersed Boundary method

Modeling the transport of deformable capsules under different flow regimens is crucial in a variety of fields, including oil rheology, blood flow and the dispersion of pollutants. The aim of this study is twofold. Firstly, a combined Lattice Boltzmann-Immersed Boundary (LBM-IB) approach is developed for predicting the transport of inertial deformable capsules. A Moving Least Squares (MLS) scheme has been implemented to correlate the pressure, velocity and force fields of the fluid domain with the capsule dynamics. This computational strategy has been named LBM Dynamic IB. Secondly, this strategy is directly compared with a more conventional approach, named LBM Kinematic IB, where capsules move with the same velocity of the surrounding fluid. Multiple test cases have been considered for assessing the accuracy and efficiency of the Dynamic over Kinematic IB scheme, including the stretching of circular capsules in shear flow, the transport in a plane Poiseuille flow of circular and biconcave capsules, with and without inertia. By monitoring the capsule geometry over time, the two schemes have been documented to be in excellent agreement, especially for low Capillary numbers (Ca $\leq$ 0.01), in the case of non-inertial capsules. Despite a moderate increase in computational burden, the presented LBM Dynamic IB scheme is the sole capable of predicting the dynamics of both non-inertial and inertial deformable capsules. The proposed approach can be efficiently employed for studying the transport of blood cells, cancer cells and nano/micro capsules within a capillary flow

The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows

The margination dynamics of microparticles with different shapes has been analyzed within a laminar flow mimicking the hydrodynamic conditions in the microcirculation. Silica spherical particles, quasi-hemispherical and discoidal silicon particles have been perfused in a parallel plate flow chamber. The effect of the shape and density on their margination propensity has been investigated at different physiologically relevant shear rates S. Simple scaling laws have been derived showing that the number n of marginating particles scales as S(-0.63) for the spheres; S(-0.85) for discoidal and S(-1) for quasi-hemispherical particles, regardless of their density and size. Within the range considered for the shear rate, discoidal particles marginate in a larger number compared to quasi-hemispherical and spherical particles. These results may be of interest in drug delivery and bio-imaging applications, where particles are expected to drift towards and interact with the walls of the blood vessels

Elucidating the role of matrix porosity and rigidity in glioblastoma type IV progression

The highly infiltrating nature of glioma cells is the major cause for the poor prognosis of brain malignancies. Motility, proliferation, and gene expression of cells in natural and synthetic gels have been analyzed by several authors, yet quantitative studies elucidating the role of matrix porosity and rigidity in the development of whole malignant masses are missing. Here, an experimental\u2010computational framework is introduced to analyze the behavior of U87\u2010MG cells and spheroids in compact hyaluronic acid gels (HA), replicating the brain parenchyma; and fibrous collagen gels (COL), resembling the organized structures of the brain. Experimentally it was observed that individual U87\u2010MG cells in COL assumed an elongated morphology within a few hours post inclusion (p.i.) and travelled longer distances than in HA. As spheroids, U87\u2010MG cells rapidly dispersed into COL resulting in infiltrating regions as large as tumor cores ( 48600 \u3bcm, at 8 days p.i.). Conversely, cells in HA originated smaller and denser infiltrating regions ( 48300 \u3bcm, at 8 days p.i.). Notably, COL tumor core size was only 20% larger than in HA, at longer time points. Computationally, by introducing for the first time the effects of matrix heterogeneity in our numerical simulations, the results confirmed that matrix porosity and its spatial organization are key factors in priming the infiltrating potential of these malignant cells. The experimental\u2010numerical synergy can be used to predict the behavior of neoplastic masses under diverse conditions and the efficacy of combination therapies simultaneously aiming at killing cancer cells and modulating the tumor microenvironment

Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles

Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nano-delivery system for therapeutic nucleic acids. The great effort put in the development of ionizable lipids with increased in vivo potency brought LNPs from the laboratory benches to the FDA approval of patisiran in 2018 and the ongoing clinical trials for mRNA-based vaccines against SARS-CoV-2. Despite these success stories, several challenges remain in RNA delivery, including what is known as “endosomal escape.” Reaching the cytosol is mandatory for unleashing the therapeutic activity of RNA molecules, as their accumulation in other intracellular compartments would simply result in efficacy loss. In LNPs, the ability of ionizable lipids to form destabilizing non-bilayer structures at acidic pH is recognized as the key for endosomal escape and RNA cytosolic delivery. This is motivating a surge in studies aiming at designing novel ionizable lipids with improved biodegradation and safety profiles. In this work, we describe the journey of RNA-loaded LNPs across multiple intracellular barriers, from the extracellular space to the cytosol. In silico molecular dynamics modeling, in vitro high-resolution microscopy analyses, and in vivo imaging data are systematically reviewed to distill out the regulating mechanisms underlying the endosomal escape of RNA. Finally, a comparison with strategies employed by enveloped viruses to deliver their genetic material into cells is also presented. The combination of a multidisciplinary analytical toolkit for endosomal escape quantification and a nature-inspired design could foster the development of future LNPs with improved cytosolic delivery of nucleic acids

Flow chamber analysis of size effects in the adhesion of spherical particles

The non-specific adhesion of spherical micro- and nano-particles to a cell substrate is investigated in a parallel plate flow chamber. Differently from prior in-vitro analyses, the total volume of the particles injected into the flow chamber is kept fixed whilst the particle diameter is changed in the range 0.5–10 μm. It is shown that: (i) the absolute number of particles adherent to the cell layer per unit surface decreases with the size of the particle as d−1.7; (ii) the volume of the particles adherent per unit surface increases with the size of the particles as d+1.3. From these results and considering solely non-specific particles, the following hypothesis are generated (i) use the smallest possible particles in biomedical imaging and (ii) use the largest possible particles in drug delivery

A parametric study of a multiphase porous media model for tumor spheroids and environment interactions

Computational models for tumor growth provide an effective in silico tool to investigate the different stages of cancer growth. Recently, a series of computational models based on porous media theory has been proposed to predict tumor evolution and its interactions with the host tissue. In addition, a specialization of the original models, adapted for tumor spheroids, has been proposed and validated experimentally. However, due to the complexity of the modeling framework, a systematic understanding of the role of the parameters governing the equations is still lacking. In this work, we perform a parametric analysis on a set of fundamental parameters appearing in the model equations. We investigate the effects of a variation of these coefficients on the spheroid growth curves and, in particular, on the final radii reached by the cell aggregates in the growth saturation stage. Finally, we provide a discussion of the results and give a brief summary of our findings