Spherical multi-layered structures are prevalent in numerous biological systems and engineered applications, including tumor spheroids, layered tissues, and multi-shell nanoparticles for targeted drug delivery. Despite their widespread occurrence, there remains a gap in modeling particle propagation through these complex structures from a molecular communication (MC) perspective. This paper introduces a generalized analytical framework for modeling diffusion-based molecular communication in multi-layered spherical environments. The framework is capable of supporting an arbitrary number of layers and flexible transmitter-receiver positioning. As an example, the detailed formulation is presented for the three-layer sphere, which is particularly relevant for different biological models such as tumor spheroids. The analytical results are validated using particle-based simulation (PBS) in scenarios that have short interlayer distances. The findings reveal that the characteristics of each layer significantly impact molecule propagation throughout the entire structure, making their consideration crucial for designing targeted therapies and optimizing drug delivery systems.

Realistic models of the components and processes are required for molecular communication (MC) systems. In this paper, a spheroidal receiver structure is proposed for MC that is inspired by the 3D cell cultures known as spheroids being widely used in organ-on-chip systems. A simple diffusive MC system is considered where the spheroidal receiver and a point source transmitter are in an unbounded fluid environment. The spheroidal receiver is modeled as a porous medium for diffusive signaling molecules, then its boundary conditions and effective diffusion coefficient are characterized. It is revealed that the spheroid amplifies the diffusion signal, but also disperses the signal which reduces the information communication rate. Furthermore, we analytically formulate and derive the concentration Green's function inside and outside the spheroid in terms of infinite series-forms that are confirmed by a particle-based simulator (PBS).

This paper proposes a novel imperfect transmitter (TX) model, namely the membrane fusion (MF)-based TX, that adopts MF between a vesicle and the TX membrane to release molecules encapsulated within the vesicle. For the MF-based TX, the molecule release probability and the fraction of molecules released from the TX membrane are derived. Incorporating molecular degradation and a fully-absorbing receiver (RX), the channel impulse response (CIR) is derived for two scenarios: 1) Both TX and RX are static, and 2) both TX and RX are diffusion-based mobile. Moreover, a sequence of bits transmitted from the TX to the RX is considered. The average bit error rate (BER) is obtained for both scenarios, wherein the probability mass function (PMF) of the number of molecules absorbed in the mobile scenario is derived. Furthermore, a simulation framework is proposed for the MF-based TX, based on which the derived analytical expressions are validated. Simulation results show that a low MF probability or low vesicle mobility slows the release of molecules and reduces the molecule hitting probability at the RX. Simulation results also indicate the difference between the MF-based TX and an ideal point TX in terms of the inter-symbol interference (ISI).

This paper proposes a novel imperfect spherical transmitter (TX) model, namely the membrane fusion (MF)-based TX, that adopts MF between a vesicle and the TX membrane to release molecules encapsulated within the vesicle. For the MF-based TX, the molecule release probability and the fraction of molecules released from the TX membrane are derived. Incorporating molecular degradation and a fully-absorbing receiver (RX), the end-to-end molecule hitting probability at the RX is also derived. A simulation framework for the MF-based TX is proposed, where the released point on the TX membrane and the released time of each molecule are determined. Aided by the simulation framework, the derived analytical expressions are validated. Simulation results verify that a low MF probability or low vesicle mobility slows the release of molecules from the TX, extends time required to reach the peak release probability, and reduces the end-to-end molecule hitting probability at the RX.

In quorum sensing (QS), bacteria exchange molecular signals to work together. An analytically-tractable model is presented for characterizing QS signal propagation within a population of bacteria and the number of responsive cooperative bacteria (i.e., cooperators) in a two-dimensional (2D) environment. Unlike prior works with a deterministic topology and a simplified molecular propagation channel, this work considers continuous emission, diffusion, degradation, and reception among randomly-distributed bacteria. Using stochastic geometry, the 2D channel response and the corresponding probability of cooperation at a bacterium are derived. Based on this probability, new expressions are derived for the moment generating function and different orders of moments of the number of cooperators. The analytical results agree with the simulation results obtained by a particle-based method. In addition, the Poisson and Gaussian distributions are compared to approximate the distribution of the number of cooperators and the Poisson distribution provides the best overall approximation. The derived channel response can be generally applied to any molecular communication model where single or multiple transmitters continuously release molecules into a 2D environment. The derived statistics of the number of cooperators can be used to predict and control the QS process, e.g., predicting and decreasing the likelihood of biofilm formation.

This paper investigates the estimation of different parameters, e.g., propagation distance and flow velocity, by utilizing two fully-absorbing receivers (RXs) in a one-dimensional (1D) environment. The time-varying number of absorbed molecules at each RX and the number of absorbed molecules in a time interval as time approaches infinity are derived. Noisy molecules in this environment, that are released by sources in addition to the transmitter, are also considered. A novel estimation method, namely difference estimation (DE), is proposed to eliminate the effect of noise by using the difference of received signals at the two RXs. For DE, the Cramer-Rao lower bound (CRLB) on the variance of estimation is derived. Independent maximum likelihood estimation is also considered at each RX as a benchmark to show the performance advantage of DE. Aided by particle-based simulation, the derived analytical results are verified. Furthermore, numerical results show that DE attains the CRLB and is less sensitive to the change of noise than independent estimation at each RX.

The exchange of small molecular signals within microbial populations is generally referred to as quorum sensing (QS). QS is ubiquitous in nature and enables microorganisms to respond to fluctuations in living environments by working together. In this study, a QS- based molecular communication system within a microbial population in a two-dimensional (2D) environment is analytically modeled. Microorganisms are randomly distributed on a 2D circle where each one releases molecules at random times. The number of molecules observed at each randomly-distributed bacterium is first derived by characterizing the diffusion and degradation of molecules within the population. Using the derived result and some approximation, the expected density of cooperative bacteria is derived. Our model captures the basic features of QS. The analytical results for noisy signal propagation agree with simulation results where the Brownian motion of molecules is simulated by a particle- based method. Therefore, we anticipate that our model can be used to predict the density of cooperators in a variety of QS-coordinated activities, e.g., biofilm formation and antibiotic resistance.

Molecular communication (MC) is a new communication engineering paradigm where molecules are employed as information carriers. MC systems are expected to enable new revolutionary applications, such as sensing of target substances in biotechnology, smart drug delivery in medicine, and monitoring of oil pipelines or chemical reactors in industrial settings. As for any other kind of communication, simple yet sufficiently accurate channel models are needed for the design, analysis, and efficient operation of MC systems. In this paper, we provide a tutorial review on mathematical channel modeling for diffusive MC systems. The considered end-to-end MC channel models incorporate the effects of the release mechanism, the MC environment, and the reception mechanism on the observed information molecules. Thereby, the various existing models for the different components of an MC system are presented under a common framework and the underlying biological, chemical, and physical phenomena are discussed. Deterministic models characterizing the expected number of molecules observed at the receiver and statistical models characterizing the actual number of observed molecules are developed. In addition, we provide the channel models for time-varying MC systems with moving transmitters and receivers, which are relevant for advanced applications such as smart drug delivery with mobile nanomachines. For complex scenarios, where simple MC channel models cannot be obtained from first principles, we investigate the simulation- and experiment-driven channel models. Finally, we provide a detailed discussion of potential challenges, open research problems, and future directions in channel modeling for diffusive MC systems.

Diffusive molecular communication (DMC) is envisioned as a promising approach to help realize healthcare applications within bounded biological environments. In this paper, a DMC system within a biological spherical environment (BSE) is considered, inspired by bounded biological sphere-like structures throughout the body. As a biological environment, it is assumed that the inner surface of the sphere's boundary is fully covered by biological receptors that may irreversibly react with hitting molecules. Moreover, information molecules diffusing in the sphere may undergo a degradation reaction and be transformed to another molecule type. Concentration Green's function (CGF) of diffusion inside this environment is analytically obtained in terms of a convergent infinite series. By employing the obtained CGF, the information channel between transmitter and transparent receiver of DMC in this environment is characterized. Interestingly, it is revealed that the information channel is reciprocal, i.e., interchanging the position of receiver and transmitter does not change the information channel. Results indicate that the conventional simplifying assumption that the environment is unbounded may lead to an inaccurate characterization in such biological environments.

In this paper, symbol-by-symbol maximum likelihood (ML) detection is proposed for a cooperative diffusion-based molecular communication (MC) system. In this system, the transmitter (TX) sends a common information symbol to multiple receivers (RXs) and a fusion center (FC) chooses the TX symbol that is more likely, given the likelihood of its observations from all RXs. The transmission of a sequence of binary symbols and the resultant intersymbol interference are considered in the cooperative MC system. Three ML detection variants are proposed according to different RX behaviors and different knowledge at the FC. The system error probabilities for two ML detector variants are derived, one of which is in closed form. The optimal molecule allocation among RXs to minimize the system error probability of one variant is determined by solving a joint optimization problem. Also for this variant, the equal distribution of molecules among two symmetric RXs is analytically shown to achieve the local minimal error probability. Numerical and simulation results show that the ML detection variants provide lower bounds on the error performance of simpler, non-ML cooperative variants and demonstrate that these simpler cooperative variants have error performance comparable to ML detectors.

Active transport such as fluid flow is sought in molecular communication to extend coverage, improve reliability, and mitigate interference. Flow models are often over-simplified, assuming one-dimensional diffusion with constant drift. However, diffusion and flow are usually encountered in three-dimensional bounded environments where the flow is highly non-uniform such as in blood vessels or microfluidic channels. For a qualitative understanding of the relevant physical effects inherent to these channels, based on the Péclet number and the transmitter-receiver distance, we study when simplified models of uniform flow and advection-only transport are applicable. For these two regimes, analytical expressions for the channel impulse response are derived and validated by particle-based simulation. Furthermore, as advection-only transport is typically overlooked and hence not analyzed in the molecular communication literature, we evaluate the symbol error rate for exemplary on-off keying as performance metric.

To estimate the molecular communication (MC) parameters (e.g., diffusion coefficient, reaction rate, and absorption rate) via observations at the transmitter and the receiver, we present an analytical framework for a diffusive MC system with a partially absorbing receiver and a general first-order chemical reaction during propagation, in both spherically asymmetric and spherically symmetric scenarios. The time-varying spatial distributions and the expected numbers of messenger molecules and their first-order reaction products inside the transmitter, as well as at the surface of the partially absorbing receiver, are derived in both scenarios, which can be simplified in the special cases of a fully absorbing receiver. Importantly, our analytical expressions are verified by particle-based simulations, which showcase the effect of the reaction rate on the transmitter and the receiver observations. The analytical results of channel impulse responses at the absorbing receiver as well as that inside the transmitter are first treated and solved for spherically asymmetric scenario in this work.

In this paper, symbol-by-symbol maximum likelihood (ML) detection is proposed for a cooperative diffusion-based molecular communication (MC) system. In this system, a fusion center (FC) chooses the transmitter's symbol that is more likely, given the likelihood of the observations from multiple receivers (RXs). We propose three different ML detection variants according to different constraints on the information available to the FC, which enables us to demonstrate trade- offs in their performance versus the information available. The system error probability for one variant is derived in closed form. Numerical and simulation results show that the ML detection variants provide lower bounds on the error performance of the simpler cooperative variants and demonstrate that majority rule detection has performance comparable to ML detection when the reporting is noisy.

This paper predicts the ability to externally control the firing times of a cortical neuron whose behavior follows the Izhikevich neuron model. The Izhikevich neuron model provides an efficient and biologically plausible method to track a cortical neuron's membrane potential and its firing times. The external control is a simple optogenetic model represented by a constant current source that can be turned on or off. This paper considers a firing frequency that is sufficiently low for the membrane potential to return to its resting potential after it fires. The time required for the neuron to charge and for the neuron to recover to the resting potential are fitted to functions of the Izhikevich neuron model parameters. Results show that linear functions of the model parameters can be used to predict the charging times with some accuracy and are sufficient to estimate the highest firing frequency achievable without interspike interference.

Optogenetics is an emerging field of neuroscience where neurons are genetically modified to express light-sensitive receptors that enable external control over when the neurons fire. Given the prominence of neuronal signaling within the brain and throughout the body, optogenetics has significant potential to improve the understanding of the nervous system and to develop treatments for neurological diseases. This paper uses a simple optogenetic model to compare the timing distortion between a randomly-generated target spike sequence and an externally-stimulated neuron spike sequence. The distortion is measured by filtering each sequence and finding the root mean square error between the two filter outputs. The expected distortion is derived in closed form when the target sequence generation rate is sufficiently low. Derivations are verified via simulations.

Molecular communication requires low-complexity symbol detection algorithms to deal with the many sources of uncertainty that are inherent in these channels.This paper proposes two variants of a high-performance asynchronous peak detection algorithm for a receiver that makes independent observations.The first variant has low complexity and measures the largest observation within a sampling interval.The second variant adds decision feedback to mitigate inter-symbol interference.Although the algorithm does not require synchronization between the transmitter and receiver, results demonstrate that the bit error performance of symbol-by-symbol detection using the first variant is better than using a single sample whose sampling time is chosen a priori.The second variant is shown to have performance comparable to that of an energy detector.Both variants of the algorithm demonstrate better resilience to timing offsets than that of existing detectors.

Diffusion-based molecular communication (MC) systems experience significant reliability losses. To boost the reliability, a MC scheme where multiple receivers (RXs) work cooperatively to decide the signal of a transmitter (TX) by sending the same type of molecules to a fusion center (FC) is proposed in this paper. The FC observes the total number of molecules received and compares this number with a threshold to determine the TX's signal. The proposed scheme is more bio-realistic and requires relatively low computational complexity compared to existing cooperative schemes where the RXs send and the FC recognizes different types of molecules. Asymmetric and symmetric topologies are considered, and closed-form expressions are derived for the global error probability for both topologies. Results show that the trade-off for simplified computations leads to a slight reduction in error performance, compared to the existing cooperative schemes.

Bacteria populations rely on mechanisms such as quorum sensing to coordinate complex tasks that cannot be achieved by a single bacterium. Quorum sensing is used to measure the local bacteria population density, and it controls cooperation by ensuring that a bacterium only commits the resources for cooperation when it expects its neighbors to reciprocate. This paper proposes a simple model for sharing a resource in a bacterial environment, where knowledge of the population influences each bacterium's behavior. Game theory is used to model the behavioral dynamics, where the net payoff (i.e., utility) for each bacterium is a function of its current behavior and that of the other bacteria. The game is first evaluated with perfect knowledge of the population. Then, the unreliability of diffusion introduces uncertainty in the local population estimate and changes the perceived payoffs. The results demonstrate the sensitivity to the system parameters and how population uncertainty can overcome a lack of explicit coordination.

Information delivery using chemical molecules is an integral part of biology at multiple distance scales and has attracted recent interest in bioengineering and communication. The collective signal strength at the receiver (i.e., the expected number of observed molecules inside the receiver), resulting from a large number of transmitters at random distances (e.g., due to mobility), can have a major impact on the reliability and efficiency of the molecular communication system. Modeling the collective signal from multiple diffusion sources can be computationally and analytically challenging. In this paper, we present the first tractable analytical model for the collective signal strength due to randomly-placed transmitters, whose positions are modelled as a homogeneous Poisson point process in three-dimensional (3D) space. By applying stochastic geometry, we derive analytical expressions for the expected number of observed molecules at a fully absorbing receiver and a passive receiver. Our results reveal that the collective signal strength at both types of receivers increases proportionally with increasing transmitter density. The proposed framework dramatically simplifies the analysis of large-scale molecular systems in both communication and biological applications.

In this paper, a cooperative diffusion-based molecular communication system is considered where distributed receivers collaboratively determine a transmitter's signal. In this system, the receivers first make local hard decisions about the current transmitted bit and then report these decisions to a fusion center (FC). The FC combines the local hard decisions to make a global decision using an N-out-of-K fusion rule. Asymmetric and symmetric topologies are considered and for each topology, two reporting scenarios, namely, perfect reporting and noisy reporting, are addressed. Closed-form analytical expressions for the expected global error probability are derived for all considered topologies and scenarios. Numerical and simulation results show that system reliability can be greatly improved by combining the detection information of distributed receivers.

This paper presents an analytical comparison of active and passive receiver models in diffusive molecular communication. In the active model, molecules are absorbed when they collide with the receiver surface. In the passive model, the receiver is a virtual boundary that does not affect molecule behavior. Two approaches are presented to derive transforms between the receiver signals. As an example, two models for an unbounded diffusion-only molecular communication system with a spherical receiver are unified. As time increases in the three-dimensional system, the transform functions have constant scaling factors, such that the receiver models are effectively equivalent. Methods are presented to enable the transformation of stochastic simulations, which are used to verify the transforms and demonstrate that transforming the simulation of a passive receiver can be more efficient and more accurate than the direct simulation of an absorbing receiver.

In this paper, we present an analytical model for a diffusive molecular communication (MC) system with a reversible adsorption receiver in a fluid environment. The time-varying spatial distribution of the information molecules under the reversible adsorption and desorption reaction at the surface of a bio-receiver is analytically characterized. Based on the spatial distribution, we derive the number of newly-adsorbed information molecules expected in any time duration. Importantly, we present a simulation framework for the proposed model that accounts for the diffusion and reversible reaction. Simulation results show the accuracy of our derived expressions, and demonstrate the positive effect of the adsorption rate and the negative effect of the desorption rate on the net number of newly-adsorbed information molecules expected. Moreover, our analytical results simplify to the special case of an absorbing receiver.

This paper studies a three-node network in which an intermediate nano-transceiver, acting as a relay, is placed between a nano-transmitter and a nano-receiver to improve the range of diffusion- based molecular communication. Motivated by the relaying protocols used in traditional wireless communication systems, we study amplify-and- forward (AF) relaying with fixed and variable amplification factor for use in molecular communication systems. To this end, we derive a closed-form expression for the expected end-to-end error probability. Furthermore, we derive a closed-form expression for the optimal amplification factor at the relay node for minimization of an approximation of the expected error probability of the network. Our analytical and simulation results show the potential of AF relaying to improve the overall performance of nano-networks.

Recently, hybrid models have emerged that combine microscopic and mesoscopic regimes in a single stochastic reaction-diffusion simulation. Microscopic simulations track every individual molecule and are generally more accurate. Mesoscopic simulations partition the environment into subvolumes, track when molecules move between adjacent subvolumes, and are generally more computationally efficient. In this paper, we present the foundation of a multi-scale stochastic simulator from the perspective of molecular communication, for both mesoscopic and hybrid models, where we emphasize simulation accuracy at the receiver and efficiency in regions that are far from the communication link. Our multi-scale models use subvolumes of different sizes, between which we derive the diffusion event transition rate. Simulation results compare the accuracy and efficiency of traditional approaches with that of a regular hybrid method and with those of our proposed multi-scale methods.

In this paper, we consider a two-hop molecular communication network consisting of one nanotransmitter, one nanoreceiver, and one nanotransceiver acting as a relay. We consider two different schemes for relaying to improve the range of diffusion-based molecular communication. In the first scheme, two different types of messenger molecules are utilized at the relay node for transmission and detection. In the second scheme, we assume that there is only one type of molecule available to be used as an information carrier. We identify self-interference as the performance-limiting effect for the second relaying scheme. Self-interference occurs when the relay must detect the same type of molecule that it also emits. Furthermore, we consider two relaying modes analogous to those used in wireless communication systems, i.e., full-duplex and half-duplex. In particular, while our main focus is on full-duplex relaying, half-duplex relaying is employed as a means to mitigate self-interference. In addition, we propose the adaptation of the decision threshold as an effective mechanism to mitigate self-interference at the relay for full-duplex transmission. We derive closed-form expressions for the expected error probability of the network for both considered relaying schemes.

This paper studies distance estimation for diffusive molecular communication. The strength of the channel impulse response generally decreases with distance, so it is measured to estimate the distance. The Cramer-Rao lower bound on the variance of the distance estimation error is derived. The lower bound is derived for a physically unbounded environment with molecule degradation and steady uniform flow. The maximum likelihood distance estimator is derived and its accuracy is shown via simulation to perform very close to the Cramer-Rao lower bound. An existing protocol is shown to be equivalent to the maximum likelihood distance estimator if only one observation is made. Simulation results also show the accuracy of existing protocols with respect to the Cramer-Rao lower bound.

In this paper, we study the performance of detectors in a diffusive molecular communication environment where steady uniform flow is present. We derive the expected number of information molecules to be observed in a passive spherical receiver, and determine the impact of flow on the assumption that the concentration of molecules throughout the receiver is uniform. Simulation results show the impact of advection on detector performance as a function of the flow's magnitude and direction. We highlight that there are disruptive flows, i.e., flows that are not in the direction of information transmission, that lead to an improvement in detector performance as long as the disruptive flow does not dominate diffusion and sufficient samples are taken.

This paper considers the impact of external noise sources, including interfering transmitters, on a diffusive molecular communication system, where the impact is measured as the number of noise molecules expected to be observed at a passive receiver. A unifying model for noise, multiuser interference, and intersymbol interference is presented, where, under certain circumstances, interference can be approximated as a noise source that is emitting continuously. The model includes the presence of advection and molecule degradation. The time-varying and asymptotic impact is derived for a series of special cases, some of which facilitate closed-form solutions. Simulation results show the accuracy of the expressions derived for the impact of a continuously-emitting noise source, and show how approximating old intersymbol interference as a noise source can simplify the calculation of the expected bit error probability of a weighted sum detector.

We consider the cooperative spectrum sensing problem in cognitive radio with energy detection. Secondary users with non-identical sensing channels make 1-bit sensing decisions that are reported to the secondary base station over non-identical noisy fading channels. The base station has reporting channel knowledge and combines the decisions with an M-out-of-K rule. We allow the secondary users to trade sensing time samples for additional reporting time slots to increase the reporting signal-to-noise ratios. We derive the false alarm and missed detection probabilities as functions of the secondary sensor decision thresholds and the durations for sensing and reporting. Furthermore, we bound these probabilities and impose practical constraints that enable convex optimization to minimize the false alarm probability for a target missed detection probability. We compare knowing the instantaneous reporting channels for optimization with knowing the average channels. Allowing secondary users to trade sensing time samples for additional reporting time slots is shown to significantly improve sensing performance, even with poor sensing and reporting channels and a small number of secondary users.

We consider the cooperative spectrum sensing problem in cognitive radio with energy detection. Secondary users with non-identical, independent sensing channels make 1-bit sensing decisions and report their decisions to the secondary base station over orthogonal fading channels. The base station acts as a fusion center by combining the decisions with OR-rule. We allow the secondary users to trade sensing time slots for additional reporting time slots. We derive the corresponding false alarm and missed detection probabilities, which are functions of the secondary sensor decision thresholds and the durations for sensing and reporting. Furthermore, we bound these probabilities and impose a practical convex region that enables convex optimization to minimize the false alarm probability for a target missed detection probability. Allowing secondary users to trade sensing time slots for additional reporting time slots is shown to significantly improve sensing performance, even with poor sensing channels and a small number of secondary users.