Multiphysics simulation of magnetoelectric micro core-shells for wireless cellular stimulation therapy via magnetic temporal interference.

This paper presents an innovative approach to wireless cellular stimulation therapy through the design of a magnetoelectric (ME) microdevice. Traditional electrophysiological stimulation techniques for neural and deep brain stimulation face limitations due to their reliance on electronics, electrode arrays, or the complexity of magnetic induction. In contrast, the proposed ME microdevice offers a self-contained, controllable, battery-free, and electronics-free alternative, holding promise for targeted precise stimulation of biological cells and tissues. The designed microdevice integrates core shell ME materials with remote coils which applies magnetic temporal interference (MTI) signals, leading to the generation of a bipolar local electric stimulation current operating at low frequencies which is suitable for precise stimulation. The nonlinear property of the magnetostrictive core enables the demodulation of remotely applied high-frequency electromagnetic fields, resulting in a localized, tunable, and manipulatable electric potential on the piezoelectric shell surface. This potential, triggers electrical spikes in neural cells, facilitating stimulation. Rigorous computational simulations support this concept, highlighting a significantly high ME coupling factor generation of 550 V/m·Oe. The high ME coupling is primarily attributed to the operation of the device in its mechanical resonance modes. This achievement is the result of a carefully designed core shell structure operating at the MTI resonance frequencies, coupled with an optimal magnetic bias, and predetermined piezo shell thickness. These findings underscore the potential of the engineered ME core shell as a candidate for wireless and minimally invasive cellular stimulation therapy, characterized by high resolution and precision. These results open new avenues for injectable material structures capable of delivering effective cellular stimulation therapy, carrying implications across neuroscience medical devices, and regenerative medicine.

Optimization of Extracellular Vesicle Release for Targeted Drug Delivery.

Targeted drug delivery is a promising approach for many serious diseases, such as glioblastoma multiforme, one of the most common and devastating brain tumor. In this context, this work addresses the optimization of the controlled release of drugs which are carried by extracellular vesicles. Towards this goal, we derive and numerically verify an analytical solution for the end-to-end system model. We then apply the analytical solution either to reduce the disease treatment time or to reduce the amount of required drugs. The latter is formulated as a bilevel optimization problem, whose quasiconvex/quasiconcave property is proved here. For solving the optimization problem, we propose and utilize a combination of bisection method and golden-section search. The numerical results demonstrate that the optimization can significantly reduce the treatment time and/or the required drugs carried by extracellular vesicles for a therapy compared to the steady state solution.

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.

Implants with Sensing Capabilities.

Because of the aging human population and increased numbers of surgical procedures being performed, there is a growing number of biomedical devices being implanted each year. Although the benefits of implants are significant, there are risks to having foreign materials in the body that may lead to complications that may remain undetectable until a time at which the damage done becomes irreversible. To address this challenge, advances in implantable sensors may enable early detection of even minor changes in the implants or the surrounding tissues and provide early cues for intervention. Therefore, integrating sensors with implants will enable real-time monitoring and lead to improvements in implant function. Sensor integration has been mostly applied to cardiovascular, neural, and orthopedic implants, and advances in combined implant-sensor devices have been significant, yet there are needs still to be addressed. Sensor-integrating implants are still in their infancy; however, some have already made it to the clinic. With an interdisciplinary approach, these sensor-integrating devices will become more efficient, providing clear paths to clinical translation in the future.

Targeted Drug Delivery for Cardiovascular Disease: Modeling of Modulated Extracellular Vesicle Release Rates.

Invasive and medical therapy has led to major improvements in cardiovascular disease management, but important challenges remain open. The discovery of a nano-sized system of extracellular vesicles (EVs) is opening new possibilities for reprogramming malfunctioning cells and indicates that EVs can be employed in therapeutic biomedical applications as engineered drug vehicles. Molecular communication (MC) has applications for treating cells with directed drug delivery, employing special targeting transmembrane proteins. In this paper, we propose a novel drug delivery system for cardiovascular diseases using an EV-mediated MC platform and exemplify the potential use in hypertrophic cardiomyopathy. We utilize intracellular calcium signaling as a natural mediator of EVs released from synthetic cells and model the release rate. We propose to use the cells as a therapeutic release system with a control signal input which modulates the EVs release rate as the output signal. We also study the frequency domain of the proposed model and estimate the transfer function of the therapeutic release system model numerically where the root-mean-square error for two separate estimated output signals are 0.0353 and 0.0124. The proposed EV-mediated targeted drug delivery system can make breakthroughs in future healthcare, in cardiovascular and other diseases where targeting is required.

Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models.

Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling.

Molecular Communications in Viral Infections Research: Modeling, Experimental Data, and Future Directions.

Hundreds of millions of people worldwide are affected by viral infections each year, and yet, several of them neither have vaccines nor effective treatment during and post-infection. This challenge has been highlighted by the COVID-19 pandemic, showing how viruses can quickly spread and impact society as a whole. Novel interdisciplinary techniques must emerge to provide forward-looking strategies to combat viral infections, as well as possible future pandemics. In the past decade, an interdisciplinary area involving bioengineering, nanotechnology and information and communication technology (ICT) has been developed, known as Molecular Communications. This new emerging area uses elements of classical communication systems to molecular signalling and communication found inside and outside biological systems, characterizing the signalling processes between cells and viruses. In this paper, we provide an extensive and detailed discussion on how molecular communications can be integrated into the viral infectious diseases research, and how possible treatment and vaccines can be developed considering molecules as information carriers. We provide a literature review on molecular communications models for viral infection (intra-body and extra-body), a deep analysis on their effects on immune response, how experimental can be used by the molecular communications community, as well as open issues and future directions.

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.

Modeling of Modulated Exosome Release From Differentiated Induced Neural Stem Cells for Targeted Drug Delivery.

A novel implantable and externally controllable stem-cell-based platform for the treatment of Glioblastoma brain cancer has been proposed to bring hope to patients who suffer from this devastating cancer type. Induced Neural Stem Cells (iNSCs), known to have potent therapeutic effects through exosomes-based molecular communication, play a pivotal role in this platform. Transplanted iNSCs demonstrate long-term survival and differentiation into neurons and glia which then fully functionally integrate with the existing neural network. Recent studies have shown that specific types of calcium channels in differentiated neurons and astrocytes are inhibited or activated upon cell depolarization leading to the increased intracellular calcium concentration levels which, in turn, interact with mobilization of multivesicular bodies and exosomal release. In order to provide a platform towards treating brain cancer with the optimum therapy dosage, we propose mathematical models to compute the therapeutic exosomal release rate that is modulated by cell stimulation patterns applied from the external wearable device. This study serves as an initial and required step in the evaluation of controlled exosomal secretion and release via induced stimulation with electromagnetic, optical and/or ultrasonic waves.

Theoretical Aspects of Resting-State Cardiomyocyte Communication for Multi-Nodal Nano-Actuator Pacemakers.

The heart consists of billions of cardiac muscle cells-cardiomyocytes-that work in a coordinated fashion to supply oxygen and nutrients to the body. Inter-connected specialized cardiomyocytes form signaling channels through which the electrical signals are propagated throughout the heart, controlling the heart's beat to beat function of the other cardiac cells. In this paper, we study to what extent it is possible to use ordinary cardiomyocytes as communication channels between components of a recently proposed multi-nodal leadless pacemaker, to transmit data encoded in subthreshold membrane potentials. We analyze signal propagation in the cardiac infrastructure considering noise in the communication channel by performing numerical simulations based on the Luo-Rudy computational model. The Luo-Rudy model is an action potential model but describes the potential changes with time including membrane potential and action potential stages, separated by the thresholding mechanism. Demonstrating system performance, we show that cardiomyocytes can be used to establish an artificial communication system where data are reliably transmitted between 10 s of cells. The proposed subthreshold cardiac communication lays the foundation for a new intra-cardiac communication technique.

Energy-efficiency of Cardiomyocyte Stimulation with Rectangular Pulses.

In cardiac pacemaker design, energy expenditure is an important issue. This work aims to explore whether varying stimulation pulse configuration is a viable optimization strategy for reducing energy consumption by the pacemaker. A single cardiomyocyte was used as an experimental model. Each cardiomyocyte was stimulated with different stimulation protocols using rectangular waveforms applied in varying number, in short succession. The amplitude, the width of each pulse, and the interval between consecutive pulses were modified. The application of multiple pulses in a short sequence led to a reduction of the threshold voltage required for stimulation when compared to a single pulse. However, none of the employed multi-pulse sequences reduced the overall energy expenditure of cell stimulation when compared to a single pulse stimulation. Among multiple pulse protocols, a combination of two short pulses (1 ms) separated with a short interval (0.5 ms) had the same energy requirements as a single short pulse (1 ms), but required the application of significantly less voltage. While increasing the number of consecutive pulses does not reduce the energy requirements of the pacemaker, the reduction in threshold voltage can be considered in practice if lower stimulation voltages are desired.