Recent developments in the Internet of Bio-Nano Things (IoBNT) are laying the groundwork for innovative applications across the healthcare sector. Nanodevices designed to operate within the body, managed remotely via the internet, are envisioned to promptly detect and actuate on potential diseases. In this vision, an inherent challenge arises due to the limited capabilities of individual nanosensors; specifically, nanosensors must communicate with one another to collaborate as a cluster. Aiming to research the boundaries of the clustering capabilities, this survey emphasizes data-driven communication strategies in molecular communication (MC) channels as a means of linking nanosensors. Relying on the flexibility and robustness of machine learning (ML) methods to tackle the dynamic nature of MC channels, the MC research community frequently refers to neural network (NN) architectures. This interdisciplinary research field encompasses various aspects, including the use of NNs to facilitate communication in MC environments, their implementation at the nanoscale, explainable approaches for NNs, and dataset generation for training. Within this survey, we provide a comprehensive analysis of fundamental perspectives on recent trends in NN architectures for MC, the feasibility of their implementation at the nanoscale, applied explainable artificial intelligence (XAI) techniques, and the accessibility of datasets along with best practices for their generation. Additionally, we offer open-source code repositories that illustrate NN-based methods to support reproducible research for key MC scenarios. Finally, we identify emerging research challenges, such as robust NN architectures, biologically integrated NN modules, and scalable training strategies.

This paper presents a novel optically controllable molecular communication (MC) transmitter (TX) design based on vesicular nanodevices (NDs), functionalized for controlled signaling molecule release via transmembrane proteins. All system components are chemically realizable, bridging the gap between MC theory and practical implementation. The NDs enable optical-to-chemical signal conversion, making them suitable as externally controllable TXs in various MC systems. The proposed design comprises two cooperating modules, namely an energizing and a release module, allowing the release of different signaling molecules depending on the module configuration. We introduce a general system model and provide a detailed mathematical analysis of a specific TX realization, deriving both exact and approximate analytical expressions for the released signaling molecule concentration, which are validated via numerical methods. The proposed model also accounts for the impact of buffering media commonly present in experimental or in-body environments. We further incorporate the impact of multiple NDs and parameter randomness inherent to vesicle synthesis into our model. The proposed models for single and multiple ND scenarios enable system parameter optimization, aiding the future experimental realization of the proposed MC TXs.

Superparamagnetic iron-oxide nanoparticles (SPI-ONs) have emerged as promising information carriers in the field of molecular communication (MC). However, a critical discrepancy exists between theoretical models and experimental realities: while theoretical frameworks typically assume neutral buoyancy and neglect gravitational forces, practical implementations exhibit significant gravity-induced sedimentation. This oversight leads to substantial prediction errors and system unreliability. To address this, we developed an experimental testbed featuring a vertically oriented bifurcated channel, specifically designed to isolate and quantify the impact of gravity on signal propagation. Our experimental results empirically demonstrate that sedimentation causes significant deviations in channel impulse response (CIR), contradicting the simplifying assumptions found in existing literature. Furthermore, we elucidate the physical mechanism of sedimentation based on hydrodynamic instability to clarify the factors driving this settling behavior. This work highlights the necessity of incorporating gravitational effects into system modelling to ensure accurate performance assessment in realistic MC environments.

Recently, bacterial nanocellulose (BNC), a biological material produced by non-pathogenic bacteria that possesses excellent material properties for various medical applications, has received increased interest as a carrier system for drug delivery. However, the vast majority of existing studies on drug release from BNC are feasibility studies with modeling and design aspects remaining largely unexplored. To narrow this research gap, this paper proposes a novel model for the drug release from BNC. Specifically, the drug delivery system considered in this paper consists of a BNC fleece coated with a polymer. The polymer coating is used as an additional diffusion barrier, enabling the controlled release of an active pharmaceutical ingredient. The proposed physics-based model reflects the geometry of the BNC and incorporates the impact of the polymer coating on the drug release. Hence, it can be useful for designing BNC-based drug delivery systems in the future. The accuracy of the model is validated with experimental data obtained in wet lab experiments.

Synthetic molecular communication (MC) in the cardiovascular system (CVS) is a key enabler for many envisioned medical applications in the human body, such as targeted drug delivery, early cancer detection, and continuous health monitoring. The design of MC systems for such applications requires suitable models for the signaling molecule propagation through complex vessel networks (VNs). Existing theoretical models offer limited analytical tractability and lack closed-form solutions, making the analysis of large-scale VNs either infeasible or not insightful. To overcome these limitations, in this paper, we propose a novel closed-form physical model, termed MIGHT, for advection-diffusion-driven transport of signaling molecules through complex VNs. The model represents the received molecule flux as a weighted sum of inverse Gaussian (IG) distributions, parameterized by physical properties of the network. The proposed model is validated by comparison with an existing convolution-based model and finite-element simulations. Further, we show that the model can be applied for the reduction of large VNs to simplified representations preserving the essential transport dynamics and for estimating representative VNs based on received signals from unknown VNs.

Molecular communication (MC) enables information exchange through the transmission of signaling molecules (SMs) and holds promise for many innovative applications. However, most existing MC studies rely on simplified transmitter (TX) models that do not account for the physical and biochemical limitations of realistic biological hardware. This work extends previous efforts toward developing models for practical MC systems by proposing a more realistic TX model that incorporates the delay in SM release and TX noise introduced by biological components. Building on this more realistic, functionalized vesicle-based TX model, we propose two novel modulation schemes specifically designed for this TX to mitigate TX-induced memory effects that arise from delayed and imperfectly controllable SM release. The proposed modulation schemes enable low-complexity receiver designs by mitigating memory effects directly at the TX. Numerical evaluations demonstrate that the proposed schemes improve communication reliability under realistic biochemical constraints, offering an important step toward physically realizable MC systems.

Synthetic molecular communication (MC) in the cardiovascular system is a key enabler for many envisioned medical applications inside the human body, such as targeted drug delivery, early disease detection, and continuous health monitoring. The design of synthetic MC systems for such applications requires suitable models for the signaling molecule propagation through complex vessel networks (VNs). Existing theoretical models offer limited analytical tractability and lack closed-form solutions, making the analysis of realistic large-scale VNs either infeasible or not insightful. To overcome these limitations, in this paper, we propose a novel closed-form physical model, termed mixture of inverse Gaussians for hemodynamic transport (MIGHT), for the advection-diffusion-driven transport of signaling molecules through complex VNs. The model represents the received molecule flux as a weighted sum of inverse Gaussian distributions, parameterized by the physical properties of the underlying VN. We show that MIGHT is capable of accurately representing the transport dynamics of signaling molecules in large-scale VNs ranging from simple single-input single-output (SISO) to complex multiple-input multiple-output (MIMO) network topologies. The accuracy of the proposed model is validated by comparison to the results from an existing convolution-based model and numerical finite-element simulations, with all finite-element simulation data available on Zenodo. Furthermore, we investigate three applications of the model, namely the reduction of SISO-VNs to obtain simplified representations preserving the essential transport dynamics, the identification and analysis of network regions that are most important for molecule transport in MIMO-VNs comprising multiple transmitters and multiple receivers, and the estimation of representative SISO-VNs that can reproduce the received signal of an unknown SISO-VN.

Motivated by classical communications engineering, early works in molecular communication (MC) largely adopted established modeling and signal processing concepts from wireless electromagnetic communication systems. In the context of the human cardiovascular system (CVS), MC channel models evolved from simple unbounded and single-duct environments mimicking individual blood vessels to complex vessel network (VN) topologies, generally at the expense of analytical tractability. Up until now, this has largely prohibited rigorous communication-theoretic analysis of large-scale VNs. In this work, we leverage a recently established closed-form analytical channel model for VNs, named mixture of inverse Gaussians for hemodynamic transport (MIGHT), to conduct the first systematic communication-theoretic study of MC in complex, large-scale VNs. Based on MIGHT, we derive a Poisson channel noise model and unveil structural analogies between multipath wireless communications (MWC) and advective-diffusive MC in VNs. In particular, we establish classical MWC metrics, namely the root mean squared (RMS) delay spread, the mean excess delay, and the coherence bandwidth, for MC in VNs and derive closed-form expressions for the channel frequency response and power delay profile (PDP). Building on this characterization, we propose a VN-adapted, coherent decision-feedback (DF) detector and show how the derived multipath metrics can inform the choice of critical system parameters like the symbol duration, the sampling time, and the memory length. Additionally, we evaluate the detector's performance in different VNs exhibiting inter-symbol interference (ISI). Together, these contributions open the door to a systematic, MWC-inspired MC system design for large-scale VNs.

We present a fluid-based experimental molecular communication (MC) testbed which uses media modulation. Motivated by the natural human cardiovascular system, the testbed operates in a closed-loop tube system. The proposed system is designed to be resource-efficient and controllable from outside the tube. As signaling molecule, the testbed employs the biocompatible green fluorescent protein variant "Dreiklang" (GFPD). GFPDs can be reversibly switched via light of different wavelengths between a bright fluorescent state and a less fluorescent state. GFPDs in solution are filled into the testbed prior to the start of information transmission and remain there for an entire experiment. For information transmission, an optical transmitter (TX) and an optical eraser (EX), which are located outside the tube, are used to write and erase the information encoded in the state of the GFPDs, respectively. At the receiver (RX), the state of the GFPDs is read out by fluorescence detection. In our testbed, due to the closed-loop setup and the long experiment durations of up to 125 hours, we observe new forms of inter-symbol interferences (ISI), which do not occur in short experiments and open-loop systems. In particular, up to four different forms of ISI, namely channel ISI, inter-loop ISI, offset ISI, and permanent ISI, occur in the considered system. For the testbed, we developed a communication scheme, which includes blind transmission start detection, symbol-by-symbol synchronization, and adaptive threshold detection, that supports higher order modulation. We comprehensively analyze our MC experiments using the absolute mean Euclidean distance (AMED), eye diagram, and bit error rate (BER) as performance metrics. Furthermore, we experimentally demonstrate the error-free transmission of 5,370 bit at a data rate of 36 bitmin-1 using 8-ary modulation and the error-free binary transmission of around 90,000 bit at a data rate of 12 bitmin-1. For the latter experiment, data was transmitted continuously for a period of more than five days (125 hours) during which no signaling molecules were injected into or removed from the system. All signals recorded during the experiments, representing more than 250 kbit of data transmitted via MC, and parts of the evaluation code are publicly available on Zenodo and Github, respectively.

The notion of synthetic molecular communication (MC) refers to the transmission of information via signaling molecules and is foreseen to enable innovative medical applications in the human cardiovascular system (CVS). Crucially, the design of such applications requires accurate and experimentally validated channel models that characterize the propagation of signaling molecules, not just in individual blood vessels, but in complex vessel networks (VNs), as prevalent in the CVS. However, experimentally validated models for MC in VNs remain scarce. To address this gap, we propose a novel channel model for MC in complex VN topologies, which captures molecular transport via advection, molecular and turbulent diffusion, as well as adsorption and desorption at the vessel walls. We specialize this model for superparamagnetic iron-oxide nanoparticles (SPIONs) as signaling molecules by introducing a new receiver (RX) model for planar coil inductive sensors, enabling end-to-end experimental validation with a dedicated SPION testbed. Validation covers a range of channel topologies, from single-vessel topologies to branched VNs with multiple paths between transmitter (TX) and RX. Additionally, to quantify how the VN topology impacts signal quality, and inspired by multi-path propagation models in conventional wireless communications, we introduce two metrics, namely molecule delay and multi-path spread. We show that these metrics link the VN structure to molecule dispersion induced by the VN and mediately to the resulting signal-to-noise ratio (SNR) at the RX. The proposed VN structure-SNR link is validated experimentally, demonstrating that the proposed framework can support tasks such as optimal sensor placement in the CVS or the identification of suitable testbed topologies for specific SNR requirements. All experimental data are openly available on Zenodo.

Air-based molecular communication (MC) has the potential to be one of the first MC systems to be deployed in real-world applications, enabled by commercially available sensors. However, these sensors usually exhibit non-linear and cross-reactive behavior, contrary to the idealizing assumption of linear and perfectly molecule type-specific sensing often made in the MC literature. To address this mismatch, we propose several detectors and transmission schemes for a molecule mixture communication system where the receiver (RX) employs non-linear, cross-reactive sensors. All proposed schemes are based on the first- and second-order moments of the symbol likelihoods that are fed through the non-linear RX using the Unscented Transform. In particular, we propose an approximate maximum likelihood (AML) symbol-by-symbol detector for inter-symbol-interference (ISI)-free transmission scenarios and a complementary mixture alphabet design algorithm which accounts for the RX characteristics. When significant ISI is present at high data rates, the AML detector can be adapted to exploit statistical ISI knowledge. Additionally, we propose a sequence detector which combines information from multiple symbol intervals. For settings where sequence detection is not possible due to extremely limited computational power at the RX, we propose an adaptive transmission scheme which can be combined with symbol-by-symbol detection. Using computer simulations, we validate all proposed detectors and algorithms based on the responses of commercially available sensors as well as artificially generated sensor data incorporating the characteristics of metal-oxide semiconductor sensors. By employing a general system model that accounts for transmitter noise, ISI, and general non-linear, cross-reactive RX arrays, this work enables reliable communication for a large class of MC systems.

The notion of synthetic molecular communication (MC) refers to the transmission of information via molecules and is largely foreseen for use within the human body, where traditional electromagnetic wave (EM)-based communication is impractical. MC is anticipated to enable innovative medical applications, such as early-stage tumor detection, targeted drug delivery, and holistic approaches like the Internet of Bio-Nano Things (IoBNT). Many of these applications involve parts of the human cardiovascular system (CVS), here referred to as networks, posing challenges for MC due to their complex, highly branched vessel structures. To gain a better understanding of how the topology of such branched vessel networks affects the reception of a molecular signal at a target location, e.g., the network outlet, we present a generic analytical end-to-end model that characterizes molecule propagation and reception in linear branched vessel networks (LBVNs). We specialize this generic model to any MC system employing superparamagnetic iron-oxide nanoparticles (SPIONs) as signaling molecules and a planar coil as receiver (RX). By considering components that have been previously established in testbeds, we effectively isolate the impact of the network topology and validate our theoretical model with testbed data. Additionally, we propose two metrics, namely the molecule delay and the multi-path spread, that relate the LBVN topology to the molecule dispersion induced by the network, thereby linking the network structure to the signal-to-noise ratio (SNR) at the target location. This allows the characterization of the SNR at any point in the network solely based on the network topology. Consequently, our framework can, e.g., be exploited for optimal sensor placement in the CVS or identification of suitable testbed topologies for given SNR requirements.

This paper presents a novel physics-based model for signal propagation in closed-loop molecular communication (MC) systems, which are particularly relevant for many envisioned biomedical applications, such as health monitoring or drug delivery within the closed-loop human cardiovascular system (CVS). Compared to open-loop systems, which are mostly considered in MC, closed-loop systems exhibit different characteristic effects influencing signaling molecule (SM) propagation. One key phenomenon are the periodic SM arrivals at the receiver (RX), leading to various types of inter-symbol interference (ISI) inherent to closed-loop system. To capture these characteristic effects, we propose an analytical model for the SM propagation inside closed-loop systems. The model accounts for arbitrary spatio-temporal SM release patterns at the transmitter (TX), and incorporates several environmental effects such as fluid flow, SM diffusion, and SM degradation. Moreover, to capture a wide range of practically relevant degradation and clearance mechanisms, the model includes both local removal (e.g., due to SM absorption into organs) and global removal (e.g., due to chemical degradation) of SMs. The accuracy of the proposed model is validated with three-dimensional (3-D) particle-based simulations (PBSs). Moreover, we utilize the proposed model to develop a rigorous characterization of the various types of ISI encountered in closed-loop MC systems.

This paper studies the codebook-based configuration of a reconfigurable intelligent surface (RIS) that extends the coverage of a base station (BS) while utilizing energy harvesting to facilitate selfsustainable operation. For a given coverage area, we design a RIS codebook and propose a mathematical framework for analyzing the efficiency of three common energy harvesting schemes: power splitting (PS), element splitting (ES), and time splitting (TS). Thereby, we use a tile-based architecture at the RIS to exploit the advantages of both radio-frequency (RF) combining and direct-current (DC) combining. Moreover, we account for deterministic and random transmit signals for beam training and data transmission, respectively, and show their impact on the RF-DC conversion efficiencies at the rectifiers. Our main objective is to minimize the average transmit power at the BS by jointly optimizing the splitting ratio for the incident signal at the RIS and the power allocated to each RIS codeword. While the optimal power allocation is derived analytically, we show that the optimal splitting ratio can be determined by performing a grid search over a single optimization variable. Our performance evaluation reveals that the efficiency of the optimized splitting schemes depends on the adopted power consumption model and the number of tiles at the RIS. In particular, our results show that depending on the system parameters a different splitting scheme will achieve the lowest transmit power at the BS.

Synthetic molecular communication (SMC) is a key enabler for future healthcare systems in which Internet of Bio-Nano-Things (IoBNT) devices facilitate the continuous monitoring of a patient's biochemical signals. To close the loop between sensing and actuation, both the detection and the generation of in-body molecular communication (MC) signals is key. However, generating signals inside the human body, e.g., via synthetic nanodevices, poses a challenge in SMC, due to technological obstacles as well as legal, safety, and ethical issues. Hence, this paper considers an SMC system in which signals are generated indirectly via the modulation of a natural in-body MC system, namely the gut-brain axis (GBA). Therapeutic GBA modulation is already established as treatment for neurological diseases, e.g., drug refractory epilepsy (DRE), and performed via the administration of nutritional supplements or specific diets. However, the molecular signaling pathways that mediate the effect of such treatments are mostly unknown. Consequently, existing treatments are standardized or designed heuristically and able to help only some patients while failing to help others. In this paper, we propose to leverage personal health data, e.g., gathered by in-body IoBNT devices, to design more versatile and robust GBA modulation-based treatments as compared to the existing ones. To show the feasibility of our approach, we define a catalog of theoretical requirements for therapeutic GBA modulation. Then, we propose a machine learning model to verify these requirements for practical scenarios when only limited data on the GBA modulation exists. By evaluating the proposed model on several datasets, we confirm its excellent accuracy in identifying different modulators of the GBA. Finally, we utilize the proposed model to identify specific modulatory pathways that play an important role for therapeutic GBA modulation.

Air-based molecular communication (MC) has the potential to be one of the first MC systems to be deployed in real-world applications, enabled by existing sensor technologies such as metal-oxide semi-conductor (MOS) sensors. However, commercially available sensors usually exhibit non-linear and cross-reactive behavior, contrary to the idealizing assumptions about linear and perfectly molecule type-specific sensing often made in the MC literature. To address this gap, we propose a detector for molecule mixture communication with a general non-linear, cross-reactive receiver (RX) array that performs approximate maximum likelihood detection on the sensor outputs. Additionally, we introduce an algorithm for the design of mixture alphabets that accounts for the RX characteristics. We evaluate our detector and alphabet design algorithm through simulations that are based on measurements reported for two commercial MOS sensors. Our simulations demonstrate that the proposed detector achieves similar symbol error rates as data-driven methods without requiring large numbers of training samples and that the alphabet design algorithm outperforms methods that do not account for the RX characteristics. Since the proposed detector and alphabet design algorithm are also applicable to other chemical sensors, they pave the way for reliable air-based MC.

Molecular communication (MC) research is increasingly focused on applications within the human body, such as health monitoring and drug delivery, which require testing in realistic and living environments. Thus, elevating experimental MC research to the next level requires developing realistic in vivo experimental testbeds. In this paper, we introduce the chorioallantoic membrane (CAM) model as the first versatile 3D in vivo MC testbed. The CAM itself is a highly vascularized membrane formed in fertilized chicken eggs and the CAM model has gained significance in various research fields, including bioengineering, cancer research, and drug development. Its versatility, reproducibility, and realistic biological properties make it perfectly suited for next-generation MC testbeds, facilitating the transition from proof-of-concept systems to practical applications. In this paper, we provide a comprehensive introduction to the CAM model, its properties, and its applications in experimental research. Additionally, we present a characterization of the CAM model as an MC system. As an experimental study, we investigate the distribution of fluorescent molecules in the closed-loop vascular system of the CAM model. We derive an analytical model based on the wrapped normal distribution to describe the propagation of particles in dispersive closed-loop systems, where the propagation of particles is mainly influenced by diffusion and flow. Based on this analytical model, we propose parametric models to approximate the particle propagation dynamics inside the CAM model. The model parameters are estimated via curve fitting to experimental results using a nonlinear least squares method. We provide a dataset containing experimental results for 69 regions in 25 eggs, on which we evaluate the proposed parametric models. Moreover, we discuss the estimated parameters, their relationships, and plausibility. Furthermore, we investigate and develop a parametric model for the long-term behavior of particles in the CAM model and their accumulation in the chick embryo's liver.

Large intelligent reflecting surfaces (IRSs) possess a large near-field (NF) range, which makes their configuration challenging. To reduce the potentially significant overhead associated with configuring these large IRSs, phase shift codebooks are a promising approach. However, most existing IRS codebooks focus on maximizing the beamforming gain of the IRS, rather than optimizing the signal-to-noise ratio (SNR) at the receiver, which is more critical to the quality of service (QoS). In this paper, we introduce an IRS codebook design that maximizes the minimum SNR within a target receiver volume by optimizing the IRS phase shifts. We observe that, in the considered NF range, maximizing the IRS reflection gain for the farthest surface of the target receiving volume is equivalent to maximizing the SNR within the entire volume. Based on this observation, we derive an analytical phase shift design, where each unit cell (UC) of the IRS focuses on a specific point. Next, we formulate a nonconvex optimization problem, for a second, improved codebook design, and find a local optimum for the minimum SNR based on sucessive convex approximation (SCA). The optimized design reveals a trade-off between the minimum SNR and the codebook size, while achieving excellent performance across the entire considered NF. Numerical evaluations show that both proposed designs outperform several baseline schemes from the literature.

In the context of the Internet of Bio-Nano Things (IoBNT), nano-devices are envisioned to perform complex tasks collaboratively, i.e., by communicating with each other. One candidate for the implementation of such devices are engineered cells due to their inherent biocompatibility. However, because each engineered cell has only little computational capabilities, transmitter and receiver (RX) functionalities can afford only limited complexity. In this paper, we propose a simple, yet modular, architecture for a cellular RX that is capable of processing a stream of observed symbols using chemical reaction networks. Furthermore, we propose two specific detector implementations for the RX. The first detector is based on a machine learning model that is trained offline, i.e., before the cellular RX is deployed. The second detector utilizes pilot symbol-based training and is therefore able to continuously adapt to changing channel conditions online, i.e., after deployment. To coordinate the different chemical processing steps involved in symbol detection, the proposed cellular RX leverages an internal chemical timer. Furthermore, the RX is synchronized with the transmitter via external, i.e., extracellular, signals. Finally, the proposed architecture is validated using theoretical analysis and stochastic simulations. The presented results confirm the feasibility of both proposed implementations and reveal that the proposed online learning-based RX is able to perform reliable detection even in initially unknown or slowly changing channels. By its modular design and exclusively chemical implementation, the proposed RX contributes towards the realization of versatile and biocompatible nano-scale communication networks for IoBNT applications narrowing the existing implementation gap in cellular molecular communication (MC).

Although visionary applications of molecular communication (MC), such as long-term continuous health monitoring by cooperative in-body nanomachines, have been proposed, MC is still in its infancy when it comes to practical implementation. In particular, long-term experiments and applications face issues such as depletion of signaling molecules (SMs) at the transmitter (TX) and inter-symbol interference (ISI) at the receiver (RX). To overcome these practical challenges, a new class of SMs with switchable states seems to be promising for future MC applications. In this work, we provide an overview of existing switchable SMs, and classify them according to their properties. Furthermore, we highlight how switchable SMs can be utilized as information carriers for media modulation. In addition, we present theoretical and experimental results for an end-to-end MC system employing the green fluorescent protein variant "Dreiklang" (GFPD) as switchable SM. Our experimental results show, for the first time, successful information transmission in a closed-loop pipe system using media modulation. Finally, we discuss media modulation specific challenges and opportunities.