Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Chemotactic bacteria such as Escherichia coli can detect and respond to extremely low concentrations of attractants, concentrations of less than 5 nM in the case of aspartate1. They also sense gradients of attractants extending over five orders of magnitude in concentration (up to 1 mM aspartate)2,3. Here we consider the possibility that this combination of sensitivity and range of response depends on the clustering of chemotactic receptors on the surface of the bacterium4. We examine what will happen if ligand binding changes the activity of a receptor, propagating this change in activity to neighbouring receptors in a cluster5,6. Calculations based on these assumptions show that sensitivity to extracellular ligands increases with the extent of spread of activity through an array of receptors, but that the range of concentrations over which the array works is severely diminished. However, a combination of low threshold of response and wide dynamic range can be attained if the cell has both clusters and single receptors on its surface, particularly if the extent of activity spread can adapt to external conditions. A mechanism of this kind can account quantitatively for the sensitivity and response range of E. coli to aspartate. <s> BIB001 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Nanonetworks are networks of devices inherently working and communicating at a scale ranging between one and hundreds of nanometers. The motivation behind these nanonetworks is to enhance the complexity and range of operation of the system, as the nanomachines that will be part of these networks have significant limitations in terms of size and power consumption. Neither classical communication schemes nor protocols used in conventional networks are valid in this new scenario. For instance, synchronization between nodes is a feature commonly required to build a network architecture. In this paper, we propose Quorum Sensing as a valid tool to achieve synchronization in a cluster of nodes of a nanonetwork by means of molecular communication, and in a distributed manner. Quorum Sensing is a mechanism by which bacteria coordinate their behavior, based on the emission and reception of molecules called autoinducers. The authors present the communication aspects of this natural phenomenon, as well as some simulation results that show the performance of Quorum Sensing-enabled entities. As a conclusion, some possible applications are outlined. <s> BIB002 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> In this work, we describe the first modular, and programmable platform capable of transmitting a text message using chemical signalling - a method also known as molecular communication. This form of communication is attractive for applications where conventional wireless systems perform poorly, from nanotechnology to urban health monitoring. Using examples, we demonstrate the use of our platform as a testbed for molecular communication, and illustrate the features of these communication systems using experiments. By providing a simple and inexpensive means of performing experiments, our system fills an important gap in the molecular communication literature, where much current work is done in simulation with simplified system models. A key finding in this paper is that these systems are often nonlinear in practice, whereas current simulations and analysis often assume that the system is linear. However, as we show in this work, despite the nonlinearity, reliable communication is still possible. Furthermore, this work motivates future studies on more realistic modelling, analysis, and design of theoretical models and algorithms for these systems. <s> BIB003 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Synchronization is an essential feature of any communication system. Due to the very low throughput of molecular communications systems, blind synchronization is preferred in order to reduce communications overhead. In this paper, we present the first blind synchronization algorithm for the diffusion-based molecular communication channel. Considering a diffusion-based physical channel model, we use the non-decision directed maximum likelihood criterion for estimating the channel delay. We then derive the Cramer-Rao lower bound and evaluate the performance of the proposed synchronization algorithm by investigating its mean square error. <s> BIB004 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Spatial heterogeneity is a hallmark of living systems, even at the molecular scale in individual cells. A key example is the partitioning of membrane-bound proteins via lipid domain formation or cytoskeleton-induced corralling. Yet the impact of this spatial heterogeneity on biochemical signaling processes is poorly understood. Here we demonstrate that partitioning improves the reliability of biochemical signaling. We exactly solve a stochastic model describing a ubiquitous motif in membrane signaling. The solution reveals that partitioning improves signaling reliability via two effects: it moderates the non-linearity of the switching response, and it reduces noise in the response by suppressing correlations between molecules. An optimal partition size arises from a trade-off between minimizing the number of proteins per partition to improve signaling reliability and ensuring sufficient proteins per partition to maintain signal propagation. The predicted optimal partition size agrees quantitatively with experimentally observed systems. These results persist in spatial simulations with explicit diffusion barriers. Our findings suggest that molecular partitioning is not merely a consequence of the complexity of cellular substructures, but also plays an important functional role in cell signaling. <s> BIB005 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> The role of diffusion in the kinetics of reversible ligand binding to receptors on a cell surface or to a macromolecule with multiple binding sites is considered. A formalism is developed that is based on a Markovian master equation for the distribution function of the number of occupied receptors containing rate constants that depend on the ligand diffusivity. The formalism is used to derive (1) a nonlinear rate equation for the mean number of occupied receptors and (2) an analytical expression for the relaxation time that characterizes the decay of equilibrium fluctuations of the occupancy of the receptors. The relaxation time is shown to depend on the ligand diffusivity and concentration, the number of receptors, the cell radius, and intrinsic association/dissociation rate constants. This result is then used to estimate the accuracy of the ligand concentration measurements by the cell, which, according to the Berg-Purcell model, is related to fluctuations in the receptor occupancy, averaged over a finite interval of time. Specifically, a simple expression (which is exact in the framework of our formalism) is derived for the variance in the measured ligand concentration in the limit of long averaging times. <s> BIB006 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Recently, a tabletop molecular communication platform has been developed for transmitting short text messages across a room. The end-to-end system impulse response for this platform does not follow previously published theoretical works because of imperfect receiver, transmitter, and turbulent flows. Moreover, it is observed that this platform resembles a nonlinear system, which makes the rich body of theoretical work that has been developed by communication engineers not applicable to this platform. In this work, we first introduce corrections to the previous theoretical models of the end-to-end system impulse response based on the observed data from experimentation. Using the corrected impulse response models, we then formulate the nonlinearity of the system as noise and show that through simplifying assumptions it can be represented as Gaussian noise. Through formulating the system's nonlinearity as the output a linear system corrupted by noise, the rich toolbox of mathematical models of communication systems, most of which are based on linearity assumption, can be applied to this platform. <s> BIB007 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> The design and analysis of diffusive molecular communication systems generally requires knowledge of the environment's physical and chemical properties. Furthermore, prospective applications might rely on the timely detection of changes in the local system parameters. This paper studies the local estimation of channel parameters for diffusive molecular communication when a transmitter releases molecules that are observed by a receiver. The Fisher information matrix of the joint parameter estimation problem is derived so that the Cramer–Rao lower bound on the variance of locally unbiased estimation can be found. The joint estimation problem can be reduced to the estimation of any subset of the channel parameters. Maximum likelihood estimation leads to closed-form solutions for some single-parameter estimation problems and can otherwise be determined numerically. Peak-based estimators are proposed for low-complexity estimation of a single unknown parameter. <s> BIB008 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Biological systems often have to measure extremely low concentrations of chemicals with high precision. When dealing with such small numbers of molecules, the inevitable randomness of physical transport processes and binding reactions will limit the precision with which measurements can be made. An important question is what the lower bound on the noise would be in such measurements. Using the theory of diffusion-influenced reactions, we derive an analytical expression for the precision of concentration estimates that are obtained by monitoring the state of a receptor to which a diffusing ligand can bind. The variance in the estimate consists of two terms, one resulting from the intrinsic binding kinetics and the other from the diffusive arrival of ligand at the receptor. The latter term is identical to the fundamental limit derived by Berg and Purcell (Biophys. J., 1977), but disagrees with a more recent expression by Bialek and Setayeshgar. Comparing the theoretical predictions against results from particle-based simulations confirms the accuracy of the resulting expression and reaffirms the fundamental limit established by Berg and Purcell. <s> BIB009 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> To adapt their behaviour in changing environments, cells sense concentrations by binding external ligands to their receptors. However, incorrect ligands may bind nonspecifically to receptors, and when their concentration is large, this binding activity may interfere with the sensing of the ligand of interest. Here, I derive analytically the physical limit to the accuracy of concentration sensing amid a large number of interfering ligands. A scaling transition is found when the mean bound time of correct ligands is twice that of incorrect ligands. I discuss how the physical bound can be approached by a cascade of receptor states generalizing kinetic proof-reading schemes. <s> BIB010 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Variability in the chemical composition of the extracellular environment can significantly degrade the ability of cells to detect rare cognate ligands. Using concepts from statistical detection theory, we formalize the generic problem of detection of small concentrations of ligands in a fluctuating background of biochemically similar ligands binding to the same receptors. We discover that in contrast with expectations arising from considerations of signal amplification, inhibitory interactions between receptors can improve detection performance in the presence of substantial environmental variability, providing an adaptive interpretation to the phenomenon of ligand antagonism. Our results suggest that the structure of signaling pathways responsible for chemodetection in fluctuating and heterogeneous environments might be optimized with respect to the statistics and dynamics of environmental composition. The developed formalism stresses the importance of characterizing nonspecific interactions to understand function in signaling pathways. <s> BIB011 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Some cells have to take decision based on the quality of surroundings ligands, almost irrespective of their quantity, a problem we name "absolute discrimination". An example of absolute discrimination is recognition of not-self by immune T Cells. We show how the problem of absolute discrimination can be solved by a process called "adaptive sorting". We review several implementations of adaptive sorting, as well as its generic properties such as antagonism. We show how kinetic proofreading with negative feedback implements an approximate version of adaptive sorting in the immune context. Finally, we revisit the decision problem at the cell population level, showing how phenotypic variability and feedbacks between population and single cells are crucial for proper decision. <s> BIB012 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> The recent advancements in nanotechnology, electronic technology, and biology enable bio-inspired nanosensors. Bionanosensor networks, which are composed of nanoscale devices, are envisioned to apply to a great number of potential applications. Clock synchronization is essential to establish a distributed cooperation among the bionanosensors. This paper investigates the clock synchronization issue among the bionanosensors in the presence of Gaussian propagation delay for their molecular communication mechanism. A two-way message exchange mechanism is proposed. The closed-form expressions of maximum-likelihood estimators for the clock offset and the clock skew are derived. The convergence and the Cramer-Rao lower bound of the estimators are analytically analyzed. Simulation results further demonstrate the effectiveness of the proposed estimators. This paper lays a foundation for the complex cooperation of nanomachines in the bionanosensor networks. <s> BIB013 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Unlike normal diffusion, in anomalous diffusion, the movement of a molecule is described by the correlated random walk model where the mean square displacement of a molecule depends on the power law of time. In molecular communication (MC), there are many scenarios when the propagation of molecules cannot be described by normal diffusion process, where anomalous diffusion is a better fit. In this paper, the effects of anomalous subdiffusion on concentration-encoded molecular communication (CEMC) are investigated. Although classical (i.e., normal) diffusion is a widely-used model of diffusion in molecular communication (MC) research, anomalous subdiffusion is quite common in biological media involving bio-nanomachines, yet inadequately addressed as a research issue so far. Using the fractional diffusion approach, the molecular propagation effects in the case of pure subdiffusion occurring in an unbounded three-dimensional propagation medium have been shown in detail in terms of temporal dispersion parameters of the impulse response of the subdiffusive channel. Correspondingly, the bit error rate (BER) performance of a CEMC system is investigated with sampling-based (SD) and strength (i.e., energy)-based (ED) signal detection methods. It is found that anomalous subdiffusion has distinctive time-dispersive properties that play a vital role in accurately designing a subdiffusive CEMC system. Unlike normal diffusion, to detect information symbols in subdiffusive CEMC, a receiver requires larger memory size to operate correctly and hence a more complex structure. An in-depth analysis has been made on the performances of SD and ED optimum receiver models under diffusion noise and intersymbol interference (ISI) scenarios when communication range, transmission data rate, and memory size vary. In subdiffusive CEMC, the SD method <s> BIB014 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> In molecular communication (MC) systems, the expected number of molecules observed at the receiver over time after the instantaneous release of molecules by the transmitter is referred to as the channel impulse response (CIR). Knowledge of the CIR is needed for the design of detection and equalization schemes. In this paper, we present a training-based CIR estimation framework for MC systems, which aims at estimating the CIR based on the observed number of molecules at the receiver due to emission of a sequence of known numbers of molecules by the transmitter. Thereby, we distinguish two scenarios depending on whether or not statistical channel knowledge is available. In particular, we derive maximum likelihood and least sum of square errors estimators, which do not require any knowledge of the channel statistics. For the case, when statistical channel knowledge is available, the corresponding maximum a posteriori and linear minimum mean square error estimators are provided. As performance bound, we derive the classical Cramer Rao (CR) lower bound, valid for any unbiased estimator, which does not exploit statistical channel knowledge, and the Bayesian CR lower bound, valid for any unbiased estimator, which exploits statistical channel knowledge. Finally, we propose the optimal and suboptimal training sequence designs for the considered MC system. Simulation results confirm the analysis and compare the performance of the proposed estimation techniques with the respective CR lower bounds. <s> BIB015 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Nanoscale molecular communication is a viable way of exchanging information between nanomachines. In this investigation, a low-complexity and noncoherent signal detection technique is proposed to mitigate the inter-symbol-interference (ISI) and additive noise. In contrast to existing coherent detection methods of high complexity, the proposed noncoherent signal detector is more practical when the channel conditions are hard to acquire accurately or hidden from the receiver. The proposed scheme employs the molecular concentration difference to detect the ISI corrupted signals and we demonstrate that it can suppress the ISI effectively. The difference in molecular concentration is a stable characteristic, irrespective of the diffusion channel conditions. In terms of complexity, by excluding matrix operations or likelihood calculations, the new detection scheme is particularly suitable for nanoscale molecular communication systems with a small energy budget or limited computation resource. <s> BIB016 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Molecular communications via diffusion (MCvD) represents a relatively new area of wireless data transfer with especially attractive characteristics for nanoscale applications. Due to the nature of diffusive propagation, one of the key challenges is to mitigate inter-symbol interference (ISI) that results from the long tail of channel response. Traditional coherent detectors rely on accurate channel estimations and incur a high computational complexity. Both of these constraints make coherent detection unrealistic for MCvD systems. In this paper, we propose a low-complexity and noncoherent signal detector, which exploits essentially the local convexity of the diffusive channel response. A threshold estimation mechanism is proposed to detect signals blindly, which can also adapt to channel variations. Compared to other noncoherent detectors, the proposed algorithm is capable of operating at high data rates and suppressing ISI from a large number of previous symbols. Numerical results demonstrate that not only is the ISI effectively suppressed, but the complexity is also reduced by only requiring summation operations. As a result, the proposed noncoherent scheme will provide the necessary potential to low-complexity molecular communications, especially for nanoscale applications with a limited computation and energy budget. <s> BIB017 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Symbol synchronization refers to the estimation of the start of a symbol interval and is needed for reliable detection. In this paper, we develop a symbol synchronization framework for molecular communication (MC) systems where we consider some practical challenges which have not been addressed in the literature yet. In particular, we take into account that in MC systems, the transmitter may not be equipped with an internal clock and may not be able to emit molecules with a fixed release frequency. Such restrictions hold for practical nanotransmitters, e.g. modified cells, where the lengths of the symbol intervals may vary due to the inherent randomness in the availability of food and energy for molecule generation, the process for molecule production, and the release process. To address this issue, we propose to employ two types of molecules, one for synchronization and one for data transmission. We derive the optimal maximum likelihood (ML) symbol synchronization scheme as a performance upper bound. Since ML synchronization entails high complexity, we also propose two low-complexity synchronization schemes, namely a peak observation-based scheme and a threshold-trigger scheme, which are suitable for MC systems with limited computational capabilities. Our simulation results reveal the effectiveness of the proposed synchronization~schemes and suggest that the end-to-end performance of MC systems significantly depends on the accuracy of symbol synchronization. <s> BIB018 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> 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. <s> BIB019 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Diffusion-based molecular communication (DBMC) has emerged as a promising communication option, particularly for biomedical and healthcare applications. Although, numerous studies have been conducted to evaluate and analyse DBMC system, investigation on DBMC through multilayer channels has had less attention. In this paper, a closed-form expression is derived for the mean molecular concentration over an n-layer channel. An averaged diffusion coefficient for thin, dissimilar and multilayer propagation channels is determined through the addition of a diffusion resistance for each medium analogously to the sum of series resistors in circuit theory. The channel characteristics such as impulse response, time delay and attenuation are analytically obtained using amplitude detection technique. The effects of layer thickness and the distance between a transmitter nanomachine and a receiver nanomachine on the channel time delay and channel attenuation under the pulse modulation scheme are evaluated and discussed. The results show that increasing the diffusion coefficient leads to time delay decrements; however, the channel attenuation remains unchanged. Moreover, lengthening the transmission distance increases the time delay and decreases the channel attenuation. Copyright © 2015 John Wiley & Sons, Ltd. <s> BIB020 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> The use of maximum likelihood (ML) to estimate molecule concentration has been investigated theoretically. The key contribution of this paper is to show how the theoretical ML estimator can be implemented as a chemical reaction network (CRN). The proposed CRN can be implemented by DNA strand displacement reactions and therefore leads to a biochemical implementation of the theoretical ML estimator. <s> BIB021 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> © 2018 Kuscu, Akan. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. We consider a microfluidic molecular communication (MC) system, where the concentration-encoded molecular messages are transported via fluid flow-induced convection and diffusion, and detected by a surface-based MC receiver with ligand receptors placed at the bottom of the microfluidic channel. The overall system is a convection-diffusion-reaction system that can only be solved by numerical methods, e.g., finite element analysis (FEA). However, analytical models are key for the information and communication technology (ICT), as they enable an optimisation framework to develop advanced communication techniques, such as optimum detection methods and reliable transmission schemes. In this direction, we develop an analytical model to approximate the expected time course of bound receptor concentration, i.e., the received signal used to decode the transmitted messages. The model obviates the need for computationally expensive numerical methods by capturing the nonlinearities caused by laminar flow resulting in parabolic velocity profile, and finite number of ligand receptors leading to receiver saturation. The model also captures the effects of reactive surface depletion layer resulting from the mass transport limitations and moving reaction boundary originated from the passage of finite-duration molecular concentration pulse over the receiver surface. Based on the proposed model, we derive closed form analytical expressions that approximate the received pulse width, pulse delay and pulse amplitude, which can be used to optimize the system from an ICT perspective. We evaluate the accuracy of the proposed model by comparing model-based analytical results to the numerical results obtained by solving the exact system model with COMSOL Multiphysics. <s> BIB022 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> We study non-coherent detection schemes for molecular communication (MC) systems with negligible inter-symbol interference that do not require knowledge of the channel state information (CSI). In particular, we first derive the optimal maximum likelihood (ML) multiple-symbol (MS) detector for MC systems. As a special case of the optimal MS detector, we show that the optimal ML symbol-by-symbol (SS) detector can be equivalently written in the form of a threshold-based detector, where the optimal decision threshold is constant and depends only on the statistics of the MC channel. The main challenge of the MS detector is the complexity associated with the calculation of the optimal detection metric. To overcome this issue, we propose an approximate MS detection metric that can be expressed in closed form. In addition, we develop a non-coherent decision-feedback detector, which introduces a lower detection delay compared with the optimal MS detector, and a suboptimal blind detector, which has a significantly lower complexity than the optimal MS detector. Finally, we derive analytical expressions for the bit error rate (BER) of the optimal SS detector, as well as upper and lower bounds for the BER of the optimal MS detector. Simulation results confirm the analysis and reveal the effectiveness of the proposed optimal and suboptimal detection schemes compared with the benchmark scheme that assumes perfect CSI knowledge, particularly, when the number of observations used for detection is sufficiently large. Simulation results are also presented that show the performance of the proposed detectors, when inter-symbol interference is non-negligible. <s> BIB023 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Synthetic biology, through genetic circuit engineering in biological cells, is paving the way toward the realization of programmable man-made living devices, able to naturally operate within normally less accessible domains, i.e. , the biological and the nanoscale. The control of the information processing and exchange between these engineered-cell devices, based on molecules and biochemical reactions, i.e. , molecular communication (MC), will be enabling technologies for the emerging paradigm of the Internet of Bio-Nano Things, with applications ranging from tissue engineering to bioremediation. In this paper, the design of genetic circuits to enable MC links between engineered cells is proposed by stemming from techniques for information coding and inspired by recent studies favoring the efficiency of analog computation over digital in biological cells. In particular, the design of a joint encoder-modulator for the transmission of binary-modulated molecule concentration is coupled with a decoder that computes the a-posteriori log-likelihood ratio of the information bits from the propagated concentration. These functionalities are implemented entirely in the biochemical domain through activation and repression of genes, and biochemical reactions, rather than classical electrical circuits. Biochemical simulations are used to evaluate the proposed design against a theoretical encoder/decoder implementation taking into account impairments introduced by diffusion noise. <s> BIB024 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> This paper builds on our earlier work on designing demodulators for diffusion-based molecular communication using a Markovian approach. The demodulation filters take the form of an ordinary differential equation which computes log-posteriori probability of observing a transmission symbol given the continuous history of receptor activities. This work considers the realisation of these demodulation filters using molecular circuits, i.e. a set of chemical reactions. There are two key issues to overcome. First, these filters require the computation of a derivative. Second, these filters require a model of the expected signal and one needs to derive a method to encode this expected signal. In this paper, we use time-scale separation to handle the derivative computation. For the case where the transmitter uses rectangular pulses as its transmitting symbols, we show how the expected signal can be encoded. We show that the output of the derived molecular circuit is approximately equal to the log-posteriori probability calculated by the demodulation filter if the log-posteriori probability is positive. <s> BIB025 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Molecular Communication (MC) is a bio-inspired communication technique that uses molecules as a method of information transfer among nanoscale devices. MC receiver is an essential component having profound impact on the communication system performance. However, the interaction of the receiver with information bearing molecules has been usually oversimplified in modeling the reception process and developing signal detection techniques. In this paper, we focus on the signal detection problem of MC receivers employing receptor molecules to infer the transmitted messages encoded into the concentration of molecules, i.e., ligands. Exploiting the observable characteristics of ligand-receptor binding reaction, we first introduce a Maximum Likelihood (ML) detection method based on instantaneous receptor occupation ratio, as aligned with the current MC literature. Then, we propose a novel ML detection technique, which exploits the amount of time the receptors stay unbound in an observation time window. A comprehensive analysis is carried out to compare the performance of the detectors in terms of bit error probability. In evaluating the detection performance, emphasis is given to the receptor saturation problem resulting from the accumulation of messenger molecules at the receiver as a consequence of intersymbol interference. The results reveal that detection based on receptor unbound time is quite reliable even in saturation, whereas the reliability of detection based on receptor occupation ratio substantially decreases as the receiver gets saturated. Finally, we also discuss the potential methods of implementing the detectors. <s> BIB026 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> E. Challenges for Developing MC Detection Techniques <s> Molecular Communications (MC) is a bio-inspired wireless communication technique that uses molecules as a means of information transfer among bio-nano devices. In this paper, we focus on the signal detection problem of MC receivers employing receptor molecules to infer the transmitted messages encoded into the concentration of molecules, i.e., ligands. We particularly consider a very common scenario in physiological conditions, where there is non-negligible concentration of interferer molecules in the channel, which have similar binding characteristics with the ligands, and thus, can bind to the receptors, causing substantial interference with the MC signal. We investigate three different maximum likelihood (ML) detection methods based on different observable parameters of the ligand-receptor binding mechanism, which are the instantaneous number of bound receptors and the amount of time the receptors stay unbound or bound within an observation time window. We carry out a comparative analysis to numerically evaluate the performance of the detection methods under different system settings. <s> BIB027
As reviewed in Section III-D, the MC detection problem has been widely addressed from several aspects for different channel and receiver configurations. However, the proposed solutions are still far from being feasible for envisioned MC devices. The main reason behind this discrepancy between the theoretical solutions and the real practice, which is also revealed by the preliminary experimental airborne MC studies performed with macroscale off-the-shelf components BIB003 , BIB007 , is that there is no micro/nanoscale MC testbed that can be used as a validation framework to optimize the devised methods. In parallel to this general problem regarding MC technologies, major challenges for MC detection can be further detailed as follows: • Synchronization: The majority of the proposed detection techniques assume a perfect synchronization between the transmitter and the receiver. In fact, synchronization is essential for the proper operation of the proposed solutions. There are many studies proposing different synchronization methods, e.g., using quorum sensing to globally synchronize the actions of nanomachines in a nanonetwork BIB002 , blind synchronization and clock synchronization based on the ML estimation of the channel delay BIB004 , BIB013 , peak observation-time-based and threshold-triggerbased symbol synchronization schemes employing a different type of molecule for the purpose of synchronization BIB018 . However, these methods are either too complex for the limited capabilities for the nanomachines, or they rely on stable CSI, which is not the case for timevarying MC channels. Moreover, the effect of these nonideal synchronization techniques on the performance of the proposed detection methods has not been revealed. Another potential solution to the synchronization problem could be to develop asynchronous detection techniques that obviate the need for synchronization. As reviewed in Section III-D1, there are a few promising solutions for asynchronous MC detection, e.g., peak-detection and threshold-based detection methods BIB019 . However, they are mostly built on simplifying assumptions for receiver and channel geometry and properties, which may result in unexpected performance in real applications. • Physical Properties of the Receiver: Although there is little physical correspondence for passive and absorbing receivers, many of the detection schemes are built on these assumptions, as they enable a mathematically tractable analysis. As reviewed in Section III-D2, although they consider the effect of receptor reactions, the initial studies on reactive receivers also follow similar assumptions on the device architecture and geometry to simplify the analyses. However, for practical systems, the physical properties of the realistic receiver architectures and their impact on the molecular propagation in the MC channel should be taken into consideration to the most possible extent. Finite element simulations on microfluidic MC channel with bioFET receivers and macroscale MC experiments with alcohol sensors clearly reveal the effect of the coupling between the MC receiver and the channel BIB022 , BIB007 . The coupling is highly nonlinear, and in most of the cases, it is not analytically tractable; therefore, beyond the available analytical tools, researchers may need to focus on stochastic simulations and experiments to validate the performance of the proposed detection techniques in realistic scenarios. • Physical Properties of the Channel: Most of the MC detection studies assume free diffusion, or diffusion plus uniform flow, for molecular propagation in an unbounded 3D environment. However, in practice MC channel will be bounded with varying boundary conditions, and can include nonuniform and disruptive flows, obstacles, temperature fluctuations, and charged molecules affecting the diffusion coefficient, and particles leading to channel crowding. Some of these aspects have recently started to be addressed through channel modeling studies, e.g., subdiffusive MC channel due to molecular crowding BIB014 , diffusion-based MC in multilayered biological media BIB020 . However, these simplified models are not able to provide enough insight into the detection problem in realistic channels. The highly time-varying properties of the MC channel have also been addressed by researchers through channel estimation techniques BIB015 , BIB008 and noncoherent detection techniques BIB016 BIB017 BIB023 , which are reviewed in Section III-D1. These studies are built on simplifying assumptions on channel and receiver architecture. • Reactive Receivers: Although reactive receiver concept provides a more realistic approach to the detection problem, the research in this direction is still at its infancy, and the developed received signal models are not complex enough to reflect many intricacies. For example, most of the previous studies assume independent receptors being exposed to the same ligand concentration; however, this is not always the case, as the binding of one receptor can affect the binding of neighboring ones  , and receptors can form cooperative clusters to control sensitivity by exploiting spatial heterogeneity BIB001 , BIB005 . The interplay between diffusion and reaction is also often neglected in these studies by assuming the timescales of both processes are separated sufficiently. However, in most practical cases, reaction and diffusion rates are close to each other, and reactions are correlated with the transport process, which depends on the channel properties BIB006 , BIB009 . These problems are crucial to analyze the spatio-temporal correlations among the receptors and the coupling between the diffusion channel and reactive receiver. Moreover, except for a few recent studies BIB024 , BIB025 , BIB021 , the design of intracellular reaction networks to implement the proposed detectors are usually neglected. The additional noise and delay stemming from these reaction networks should be taken into account while evaluating the performance of the overall detection. Furthermore, a proper analysis of the trade-off between energy, detection accuracy and detection speed is required to develop an optimization framework for the detector design in reactive receivers. • Receiver Saturation: Another challenge associated with reactive receivers is the saturation of receptors in the case of strong ISI or external interference, which can severely limit the receiver dynamic range, and hamper the ability of the receiver to discriminate different signal levels. The saturation problem has been recently addressed in BIB026 through steady-state assumption for the ligand-receptor binding reactions; however, in general it is neglected assuming an infinite number of receptors on the receiver. The problem can also be alleviated by adaptive threshold detection techniques and adaptive transmission schemes as in detection with passive/absorbing receivers. • Receiver Selectivity: Receiver selectivity is also a major issue for MC detection, and it has just started to be addressed from MC perspective. The physiologically relevant environments usually include many similar types of molecules, and the receptor-ligand coupling is not typically ideal, such that many different types of ligands present in the channel can bind the same receptors as the messenger ligands, causing molecular interference. Even if there are different types of receptor molecules for each ligand type in an MC system with MoSK, the cross-talk between receptors is unavoidable because of the nonideal coupling between receptor and ligands. Therefore, there is a need for selective detection methods exploiting the properties of ligand-receptor binding reaction. The amount of time a receptor stays bound is informative of the ligand unbinding rate, which is directly linked with the affinity between a particular type of ligand-receptor pair. The bound time intervals are exploited in BIB027 to detect the MC messages based on the ML estimation of the ratio of correct ligands to the interferers. However, this technique requires the receiver to know the type and probability distribution of the interferer molecules, and it is developed only for one type of interferer. To implement selective detection methods in engineered bacteria-based MC devices, the kinetic proofreading and adaptive sorting techniques implemented by reaction networks of the T cells in the immune system can be exploited BIB010 , BIB011 , BIB012 . Additionally, MC spectrum sensing methods can be developed based on the information inferred from the receptor bound time intervals to apply cognitive radio techniques in crowded MC nanonetworks where many nanomachines communicate using same type of molecules. V. CONCLUSION MC has attracted significant research attention over the last decade. Although ICT aspects of MC, i.e., information theoretical models of MC channels, modulation and detection techniques for MC and system-theoretical modeling of MC applications, are well-studied, these research efforts mostly rely on unrealistic assumptions isolating the MC channel from the physical processes regarding transmitting and receiving operations. The reason being that although there are some proposals for MC-Tx/Rx based on synthetic biology and nanomaterials, there is no implementation of any artificial micro/nanoscale MC system to date. As a result, feasibility and performance of ICT techniques proposed for MC could not be validated. In this paper, we provide a comprehensive survey on the recent proposals for the physical design of MC-Tx/Rx and the state-of-the-art in the theoretical MC research covering modulation, coding and detection techniques. We first investigate the fundamental requirements for the physical design of micro/nanoscale MC-Tx/Rx in terms of energy and molecule consumption, and operating conditions. In light of these requirements, the state-of-the-art design approaches as well as novel MC-Tx/Rx architectures, i.e., artificial Tx/Rx designs enabled by the nanomaterials, e.g., graphene, and biological Tx/Rx designs enabled by synthetic biology, are covered. In addition, we highlight the opportunities and challenges regarding the implementation of Tx/Rx and corresponding ICT techniques which are to be built on these devices. The guidelines on the physical design of MC-Tx/Rxs that are provided in this paper will help the researchers to design experimental MC setups and develop realistic channel models considering the transceiving processes. In this way, the longstanding discrepancy between theory and practice in MC can be overcome towards unleashing the huge societal and economic impact of MC by paving the way for ICT-based early diagnosis and treatment of diseases, such as IoNT-based continuous health monitoring, smart drug delivery, artificial organs, and lab-on-a-chips.