Modeling Extracellular Vesicles-Mediated Interactions of Cells in the Tumor Microenvironment.

Interactions of cells via extracellular vesicles (EVs) manipulate various actions, including cancer initiation and progression, inflammation, anti-tumor signaling and cell migration, proliferation and apoptosis in the tumor microenvironment. EVs as the external stimulus can activate or inhibit some receptor pathways in a way that amplify or attenuate a kind of particle release at target cells. This can also be carried out in a biological feedback-loop where the transmitter is affected by the induced release initiated by the target cell due to the EVs received from the donor cell, to create a bilateral process. In this paper, at first we derive the frequency response of internalization function in the framework of a unilateral communication link. This solution is adapted to a closed-loop system to find the frequency response of a bilateral system. The overall releases of the cells, given by the combination of the natural release and the induced release, are reported at the end of this paper and the results are compared in terms of distance between the cells and reaction rates of EVs at the cell membranes.

The End-to-End Molecular Communication Model of Extracellular Vesicle-Based Drug Delivery.

A closer look at nature has recently brought more interest in exploring and utilizing intra-body communication networks composed of cells as intrinsic, perfectly biocompatible infrastructures to deliver therapeutics. Naturally occurring cell-to-cell communication systems are being manipulated to release, navigate, and take-up soluble cell-derived messengers that are either therapeutic by nature or carry therapeutic molecular cargo. One example of such structures is extracellular vesicles (EVs) which have been recently proven to have pharmacokinetic properties, opening new avenues for developing the next generation biotherapeutics. In this paper, we study theoretical aspects of the EV transfer within heart tissue as a case study by utilizing an information and communication technology-like approach in analyzing molecular communication systems. Our modeling implies the abstraction of the EV releasing cells as transmitters, the extracellular matrix as the channel, and the EV receiving cells as receivers. Our results, derived from the developed analytical models, indicate that the release can be modulated using external forces such as electrical signals, and the transfer and reception can be affected by the extracellular matrix and plasma membrane properties, respectively.The presented modeling provides initial results for the EV biodistributions and contribute to avoiding unplanned administration, often resulting in side- and adverse effects.

On Mathematical Analysis of Active Drug Transport Coupled With Flow-Induced Diffusion in Blood Vessels.

Blood vessels are flow-induced diffusive molecular channels equipped with transport mechanisms across their walls for conveying substances between the organs in the body. Mathematical modeling of the blood vessel as a molecular transport channel can be used for the characterization of the underlying processes and higher-level functions in the circulatory system. Besides, the mathematical model can be utilized for designing and realizing nano-scale molecular communication systems for healthcare applications including drug delivery systems. In this paper, a continuous-time Markov chain framework is proposed to simply model active transport mechanisms e.g. transcytosis, across the single-layered endothelial cells building the inner vessel wall. Correspondingly, a general homogeneous boundary condition over the vessel wall is introduced. Coupled with the derived boundary condition, the flow-induced diffusion problem in an ideal vessel structure with a cylindrical shape is accurately formulated which takes into account variation in all three dimensions. The corresponding concentration Green's function is analytically derived in terms of a convergent infinite series. Particle-based simulation results confirm the proposed analysis. Also, the effects of system parameters on the concentration Green's function are examined.

Diffusive Molecular Communication in Biological Cylindrical Environment.

Diffusive molecular communication (DMC) is one of the most promising approaches for realizing nano-scale communications in biological environments for healthcare applications. In this paper, a DMC system in biological cylindrical environment is considered, inspired by blood vessel structures in the body. The internal surface of the cylinder boundary is assumed to be covered by the biological receptors which may irreversibly react with hitting molecules. Also, the information molecules diffusing in the fluid medium are subject to a degradation reaction and flow. The concentration Green's function of diffusion in this environment is analytically derived which takes into account asymmetry in all radial, axial, and azimuthal coordinates. Employing obtained Green's function, information channel between transmitter and transparent receiver of DMC is characterized. To evaluate the DMC system in the biological cylinder, a simple on-off keying modulation scheme is adopted and corresponding error probability is derived. The particle-based simulation results confirm the proposed analysis. Also, the effect of different system parameters on the concentration Green's function are examined. Our results reveal that the degradation reaction and the boundary covered by biological receptors may be utilized to mitigate intersymbol interference and outperform the corresponding error probability.