Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> We demonstrate a new protein detection methodology based upon frequency domain electrical measurement using silicon nanowire field-effect transistor (SiNW FET) biosensors. The power spectral density of voltage from a current-biased SiNW FET shows 1/f-dependence in frequency domain for measurements of antibody functionalized SiNW devices in buffer solution or in the presence of protein not specific to the antibody receptor. In the presence of protein (antigen) recognized specifically by the antibody-functionalized SiNW FET, the frequency spectrum exhibits a Lorentzian shape with a characteristic frequency of several kilohertz. Frequency and conventional time domain measurements carried out with the same device as a function of antigen concentration show more than 10-fold increase in detection sensitivity in the frequency domain data. These concentration-dependent results together with studies of antibody receptor density effect further address possible origins of the Lorentzian frequency spectrum. Our resu... <s> BIB001 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Molecular communication (MC) will enable the exchange of information among nanoscale devices. In this novel bio-inspired communication paradigm, molecules are employed to encode, transmit and receive information. In the most general case, these molecules are propagated in the medium by means of free diffusion. An information theoretical analysis of diffusion-based MC is required to better understand the potential of this novel communication mechanism. The study and the modeling of the noise sources is of utmost importance for this analysis. The objective of this paper is to provide a mathematical study of the noise at the reception of the molecular information in a diffusion-based MC system when the ligand-binding reception is employed. The reference diffusion-based MC system for this analysis is the physical end-to-end model introduced in a previous work by the same authors, where the reception process is realized through ligand-binding chemical receptors. The reception noise is modeled in this paper by following two different approaches, namely, through the ligand-receptor kinetics and through the stochastic chemical kinetics. The ligand-receptor kinetics allows to simulate the random perturbations in the chemical processes of the reception, while the stochastic chemical kinetics provides the tools to derive a closed-form solution to the modeling of the reception noise. The ligand-receptor kinetics model is expressed through a block scheme, while the stochastic chemical kinetics results in the characterization of the reception noise using stochastic differential equations. Numerical results are provided to demonstrate that the analytical formulation of the reception noise in terms of stochastic chemical kinetics is compliant with the reception noise behavior resulting from the ligand-receptor kinetics simulations. <s> BIB002 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Nanotechnology is enabling the development of devices in a scale ranging from one to a few one hundred nanometers. Nanonetworks, i.e., the interconnection of nano-scale devices, are expected to expand the capabilities of single nano-machines by allowing them to cooperate and share information. Traditional communication technologies are not directly suitable for nanonetworks mainly due to the size and power consumption of existing transmitters, receivers and additional processing components. All these define a new communication paradigm that demands novel solutions such as nano-transceivers, channel models for the nano-scale, and protocols and architectures for nanonetworks. In this talk, first the state-of-the-art in nano-machines, including architectural aspects, expected features of future nano-machines, and current developments are presented for a better understanding of the nanonetwork scenarios. Moreover, nanonetworks features and components are explained and compared with traditional communication networks. Novel nano-antennas based on nano-materials as well as the terahertz band are investigated for electromagnetic communication in nanonetworks. Furthermore, molecular communication mechanisms are presented for short-range networking based on ion signaling and molecular motors, for medium-range networking based on flagellated bacteria and nanorods, as well as for long-range networking based on pheromones and capillaries. Finally, open research challenges such as the development of network components, molecular communication theory, and new architectures and protocols, which need to be solved in order to pave the way for the development and deployment of nanonetworks within the next couple of decades are presented. <s> BIB003 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Nanosensors based on the unique electronic properties of nanotubes and nanowires offer high sensitivity and have the potential to revolutionize the field of Point-of- Care (POC) medical diagnosis. The direct current (dc) detection of a wide array of organic and inorganic molecules has been demonstrated on these devices. However, sensing mechanism based on measuring changes in dc conductance fails at high background salt concentrations, where the sensitivity of the devices suffers from the ionic screening due to mobile ions present in the solution. Here, we successfully demonstrate that the fundamental ionic screening effect can be mitigated by operating single-walled carbon nanotube field effect transistor as a high-frequency biosensor. The nonlinear mixing between the alternating current excitation field and the molecular dipole field can generate mixing current sensitive to the surface-bound biomolecules. Electrical detection of monolayer streptavidin binding to biotin in 100 mM buffer solution is achieved at a frequency beyond 1 MHz. Theoretical modeling confirms improved sensitivity at high frequency through mitigation of the ionic screening effect. The results should promise a new biosensing platform for POC detection, where biosensors functioning directly in physiologically relevant condition are desired. <s> BIB004 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> In the Molecular Communication (MC), molecules are utilized to encode, transmit, and receive information. Transmission of the information is achieved by means of diffusion of molecules and the information is recovered based on the molecule concentration variations at the receiver location. The MC is very prone to intersymbol interference (ISI) due to residual molecules emitted previously. Furthermore, the stochastic nature of the molecule movements adds noise to the MC. For the first time, we propose four methods for a receiver in the MC to recover the transmitted information distorted by both ISI and noise. We introduce sequence detection methods based on maximum a posteriori (MAP) and maximum likelihood (ML) criterions, a linear equalizer based on minimum mean-square error (MMSE) criterion, and a decision-feedback equalizer (DFE) which is a nonlinear equalizer. We present a channel estimator to estimate time varying MC channel at the receiver. The performances of the proposed methods based on bit error rates are evaluated. The sequence detection methods reveal the best performance at the expense of computational complexity. However, the MMSE equalizer has the lowest performance with the lowest computational complexity. The results show that using these methods significantly increases the information transmission rate in the MC. <s> BIB005 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> In this paper, we perform receiver design for a diffusive molecular communication environment. Our model includes flow in any direction, sources of information molecules in addition to the transmitter, and enzymes in the propagation environment to mitigate intersymbol interference. We characterize the mutual information between receiver observations to show how often independent observations can be made. We derive the maximum likelihood sequence detector to provide a lower bound on the bit error probability. We propose the family of weighted sum detectors for more practical implementation and derive their expected bit error probability. Under certain conditions, the performance of the optimal weighted sum detector is shown to be equivalent to a matched filter. Receiver simulation results show the tradeoff in detector complexity versus achievable bit error probability, and that a slow flow in any direction can improve the performance of a weighted sum detector. <s> BIB006 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <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> BIB007 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Field-effect transistor-based biosensors (bioFETs) have shown great promise in the field of fast, ultra-sensitive, label-free detection of biomolecules. Reliability and accuracy, when trying to measure small concentrations, is of paramount importance for the translation of these research devices into the clinical setting. Our knowledge and experience with these sensors has reached a stage where we are able to identify three main aspects of bioFET sensing that currently limit their applications. By considering the intrinsic device noise as a limitation to the smallest measurable signal, we show how various parameters, processing steps and surface modifications, affect the limit of detection. We also introduce the signal-to-noise ratio of bioFETs as a universal performance metric, which allows us to gain better insight into the design of more sensitive devices. Another aspect that places a limit on the performance of bioFETs is screening by the electrolyte environment, which reduces the signal that could be potentially measured. Alternative functionalization and detection schemes that could enable the use of these charge-based sensors in physiological conditions are highlighted. Finally, the binding kinetics of the receptor-analyte system are considered, both in the context of extracting information about molecular interactions using the bioFET sensor platform and as a fundamental limitation to the number of molecules that bind to the sensor surface at steady-state conditions and to the signal that is generated. Some strategies to overcome these limitations are also proposed. Taken together, these performance-limiting issues, if solved, would bring bioFET sensors closer to clinical applications. <s> BIB008 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Diffusion-based communication refers to the transfer of information using molecules as message carriers whos ep rop- agation is governed by the laws of molecular diffusion. It has been identified that diffusion-based communication is one of the most promising solutions for end-to-end communication between nanoscale devices. In this paper, the design of a diffusion-based communication system considering stochastic signaling, arbitrary orders of channel memory, and noisy receptio ni s proposed. The diffusion in the cases of one, two, and three dimensions are all considered. Three signal processing techniques for the molecular concentration with low computational complexity are proposed. For the detector design, both a low-complexity one-shot optimal detector for mutual information maximization and a near Max- imum Likelihood (ML) sequence detector are proposed. To the best of our knowledge, our paper is thefirst that gives an analytical treatment of the signal processing, estimation, and detection prob- lems for diffusion-based communication in the presence of ISI and reception noise. Numerical results indicate that the proposed signal processing technique followed by the one-shot detector achieves near-optimal throughput without the need of ap riori information in both short-range and long-range diffusion-based communication scenarios, whic hs uggests an ML sequence de- tector is not necessary. Furthermore, the proposed receiver design guarantees diffusion-based communication to operate without failure even in the case of infinite channel memory. A channel capacity of 1 bit per channel utilization can be ultimately achieved by extending the duration of the signaling interval. <s> BIB009 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> In this paper, a diffusion-based molecular communication channel between two nano-machines is considered. The effect of the amount of memory on performance is characterized, and a simple memory-limited decoder is proposed and its performance is shown to be close to that of the best possible imaginable decoder (without any restriction on the computational complexity or its functional form), using Genie-aided upper bounds. This effect is specialized for the case of Molecular Concentration Shift Keying; it is shown that a four-bits memory achieved nearly the same performance as infinite memory. Then a general class of threshold decoders is considered and shown not to be optimal for Poisson channel with memory, unless SNR is higher than a value specified in the paper. Another contribution is to show that receiver sampling at a rate higher than the transmission rate, i.e., a multi-read system, can significantly improve the performance. The associated decision rule for this system is shown to be a weighted sum of the samples during each symbol interval. The performance of the system is analyzed using the saddle point approximation. The best performance gains are achieved for an oversampling factor of three. <s> BIB010 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Within the domain of molecular communications, researchers mimic the techniques in nature to come up with alternative communication methods for collaborating nanomachines. This work investigates the channel transfer function for molecular communication via diffusion. In nature, information-carrying molecules are generally absorbed by the target node via receptors. Using the concentration function, without considering the absorption process, as the channel transfer function implicitly assumes that the receiver node does not affect the system. In this letter, we propose a solid analytical formulation and analyze the signal metrics (attenuation and propagation delay) for molecular communication via diffusion channel with an absorbing receiver in a 3-D environment. The proposed model and the formulation match well with the simulations without any normalization. <s> BIB011 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> In this paper, we consider the bacterial point-to-point and multiple-access molecular communications with ligand-receptors. For the point-to-point communication, we investigate common signaling methods, namely the Level Scenario (LS), which uses one type of a molecule with different concentration levels, and the Type Scenario (TS), which employs multiple types of molecules with a single concentration level. We investigate the trade-offs between the two scenarios from the capacity point of view. We derive an upper bound on the capacity using a Binomial Channel (BIC) model and the symmetrized Kullback-Leibler (KL) divergence. A lower bound is also derived when the environment noise is negligible. For the TS, we also consider the effect of blocking of a receptor by a different molecule type. Then, we consider multiple-access communications, for which we investigate three scenarios based on molecule and receptor types, i.e., same types of molecules with Different Labeling and Same types of Receptors (DLSR), Different types of Molecules and Receptors (DMDR), and Same types of Molecules and Receptors (SMSR). We investigate the trade-offs among the three scenarios from the total capacity point of view. We derive some inner bounds on the capacity region of these scenarios when the environment noise is negligible. <s> BIB012 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> In this paper, we present an analytical model for the diffusive molecular communication (MC) system with a reversible adsorption receiver in a fluid environment. The widely used concentration shift keying (CSK) is considered for modulation. The time-varying spatial distribution of the information molecules under the reversible adsorption and desorption reaction at the surface of a receiver is analytically characterized. Based on the spatial distribution, we derive the net number of newly-adsorbed information molecules expected in any time duration. We further derive the number of newly-adsorbed molecules expected at the steady state to demonstrate the equilibrium concentration. Given the number of newly-adsorbed information molecules, the bit error probability of the proposed MC system is analytically approximated. 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 error probability of reversible adsorption receiver with last transmit bit-1. Moreover, our analytical results simplify to the special cases of a full adsorption receiver and a partial adsorption receiver, both of which do not include desorption. <s> BIB013 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> In diffusion-based molecular communication, information transport is governed by diffusion through a fluid medium. The achievable data rates for these channels are very low compared to the radio-based communication system, since diffusion can be a slow process. To improve the data rate, a novel multiple-input multiple-output (MIMO) design for molecular communication is proposed that utilizes multiple molecular emitters at the transmitter and multiple molecular detectors at the receiver (in RF communication these all correspond to antennas). Using particle-based simulators, the channel’s impulse response is obtained and mathematically modeled. These models are then used to determine interlink interference (ILI) and intersymbol interference (ISI). It is assumed that when the receiver has incomplete information regarding the system and the channel state, low complexity symbol detection methods are preferred since the receiver is small and simple. Thus, four detection algorithms are proposed—adaptive thresholding, practical zero forcing with channel models excluding/including the ILI and ISI, and Genie-aided zero forcing. The proposed algorithms are evaluated extensively using numerical and analytical evaluations. <s> BIB014 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> This paper introduces the equivalent discrete-time channel model (EDTCM) to the area of diffusion-based molecular communication (DBMC). Emphasis is on an absorbing receiver, which is based on the so-called first passage time concept. In the wireless communications community the EDTCM is well known. Therefore, it is anticipated that the EDTCM improves the accessibility of DBMC and supports the adaptation of classical wireless communication algorithms to the area of DBMC. Furthermore, the EDTCM has the capability to provide a remarkable reduction of computational complexity compared to random walk based DBMC simulators. Besides the exact EDTCM, three approximations thereof based on binomial, Gaussian, and Poisson approximation are proposed and analyzed in order to further reduce computational complexity. In addition, the Bahl-Cocke-Jelinek-Raviv (BCJR) algorithm is adapted to all four channel models. Numerical results show the performance of the exact EDTCM, illustrate the performance of the adapted BCJR algorithm, and demonstrate the accuracy of the approximations. <s> BIB015 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> This work presents a new multi-chemical experimental platform for molecular communication where the transmitter can release different chemicals. This platform is designed to be inexpensive and accessible, and it can be expanded to simulate different environments including the cardiovascular system and complex network of pipes in industrial complexes and city infrastructures. To demonstrate the capabilities of the platform, we implement a time-slotted binary communication system where a bit-0 is represented by an acid pulse, a bit-1 by a base pulse, and information is carried via pH signals. The channel model for this system, which is nonlinear and has long memories, is unknown. Therefore, we devise novel detection algorithms that use techniques from machine learning and deep learning to train a maximum-likelihood detector. Using these algorithms the bit error rate improves by an order of magnitude relative to the approach used in previous works. Moreover, our system achieves a data rate that is an order of magnitude higher than any of the previous molecular communication platforms. <s> BIB016 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Recent research trends now offer new opportunities for developing the next generations of label-free biochemical sensors using graphene and other two-dimensional materials. While the physics of graphene transistors operated in electrolyte is well grounded, important chemical challenges still remain to be addressed, namely the impact of the chemical functionalizations of graphene on the key electrical parameters and the sensing performances. In fact, graphene – at least ideal graphene – is highly chemically inert. The functionalizations and chemical alterations of the graphene surface – both covalently and non-covalently – are crucial steps that define the sensitivity of graphene. The presence, reactivity, adsorption of gas and ions, proteins, DNA, cells and tissues on graphene have been successfully monitored with graphene. This review aims to unify most of the work done so far on biochemical sensing at the surface of a (chemically functionalized) graphene field-effect transistor and the challenges that lie ahead. The authors are convinced that graphene biochemical sensors hold great promise to meet the ever-increasing demand for sensitivity, especially looking at the recent progresses suggesting that the obstacle of Debye screening can be overcome. <s> BIB017 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Simple and easy to implement testbeds are needed to further advance molecular communication research. To this end, this paper presents an in-vessel molecular communication testbed using magnetic nanoparticles dispersed in an aqueous suspension as they are also used for drug targeting in biotechnology. The transmitter is realized by an electronic pump for injection via a Y-connector. A second pump provides a background flow for signal propagation. For signal reception, we employ a susceptometer, an electronic device including a coil, where the magnetic particles move through and generate an electrical signal. We present experimental results for the transmission of a binary sequence and the system response following a single injection. For this flow-driven particle transport, we propose a simple parameterized mathematical model for evaluating the system response. <s> BIB018 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> The possibility to guide and control magnetic nanoparticles in a non-invasive manner has spawned various applications in biotechnology, such as targeted drug delivery and sensing of biological substances. These applications are facilitated by the engineering of the size, selective chemical reactivity, and general chemical composition of the employed particles. Motivated by their widespread use and favorable properties, in this paper, we provide a theoretical study of the potential benefits of magnetic nanoparticles for the design of molecular communication systems. In particular, we consider a magnetic nanoparticle-based communication in a microfluidic channel where an external magnetic field is employed to attract the information-carrying particles to the receiver. We show that the particle transport affected by the Brownian motion, fluid flow, and an external magnetic field can be mathematically modeled as diffusion with drift. Thereby, we reveal that the key parameters determining the magnetic force are the particle size and the magnetic field gradient. Moreover, we derive an analytical expression for the channel impulse response, which is used to evaluate the potential gain in the expected number of observed nanoparticles due to the magnetic field. Furthermore, adopting the symbol error rate as performance metric, we show that using magnetic nanoparticles can enable a reliable communication in the presence of disruptive fluid flow. The numerical results obtained by the particle-based simulation validate the accuracy of the derived analytical expressions. <s> BIB019 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> B. Challenges for Physical Design and Implementation of MC-Rx <s> Biological cells naturally exchange information for adapting to the environment, or even influencing other cells. One of the latest frontiers of synthetic biology stands in engineering cells to harness these natural communication processes for tissue engineering and cancer treatment, amongst others. Although experimental success has been achieved in this direction, approaches to characterize these systems in terms of communication performance and their dependence on design parameters are currently limited. In contrast to more classical communication systems, information in biological cells is propagated through molecules and biochemical reactions, which in general result in nonlinear input-output behaviors with system-evolution-dependent stochastic effects that are not amenable to analytical closed-form characterization. In this paper, a computational approach is proposed to characterize the information exchange in these systems, based on stochastic simulation of biochemical reactions and the estimation of information-theoretic parameters from sample distributions. In particular, this approach focuses on engineered cell-to-cell communications with a single transmitter and receiver, and it is applied to characterize the performance of a realistic system. Numerical results confirm the feasibility of this approach to be at the basis of future forward engineering practices for these communication systems. <s> BIB020
Despite existing theoretical studies on the performance of MC BIB005 , BIB009 BIB006 BIB010 BIB011 BIB015 , BIB002 BIB012 BIB013 and few macroscale experimental setups BIB007 , BIB016 , BIB018 , BIB014 , BIB019 , the literature lacks comprehensive investigation of the physical design of micro/nano-scale MC-Rx structures. This leads to critical open challenges needed to be tackled for realization of the MC promising applications. • Ligand-Receptor Selection: As mentioned in Section III-C, both genetic circuit based and artificial architectures use ligand-receptor reactions to sense the concentration of target molecule by the MC antenna. This calls for careful selection of appropriate ligand-receptor pairs for MC paradigm. In this regards, the binding and dissociation, i.e., unbinding, rates of these reactions are among the important parameters that must be taken into consideration. The binding rate controls sensitivity, selectivity and the response time of the device. While high dissociation rates reduces the re-usability of the device, very low values are also not desired as they decrease the sensitivity of the receiver. The existing interferer molecules in the application environment and their affinities with the receptors are the next important design parameter that must be studied to minimize the background noise. • Realistic ICT-based modeling of artificial structures: For artificial biosensor-based MC-Rxs, the literature is lacking analytical models that can capture transient dynamics, as the available models developed from sensor application perspective are mostly based on equilibrium assumption. However, in MC applications, since the concentration signals are time-varying, equilibrium models may not be realistic. Therefore, devising MC detection methods for artificial receivers requires developing more complex models that can also capture the stochastic noise dynamics without steady-state assumption for different types of biosensors based on nanomaterials, e.g., graphene bioFET. The models should also include the effects of operating voltages for bioFETs, receiver geometry and gate configuration, channel ionic concentration determining the strength of Debye screening. The models should be validated through wet-lab experiments, and microfluidic platforms stand as a promising option for implementing testbeds for MC systems with artificial MC-Rxs. • Biological Circuits Complexity: In the case of implementing MC-Rxs with genetic circuits, the information transmission is through molecules and biochemical reactions, which results in nonlinear input-output behaviors with system-evolution-dependent stochastic effects. This makes the analytically studying the performance metrics difficult, if not impossible. Moreover, the existing noise in genetic circuits must be comprehensively studied and methods to mitigate this noise must be derived as it significantly reduces the achievable mutual information of the MC BIB020 . • Bio-Cyber Interface: While MC expands the functionality of nanomachines by connecting them to each other and making nanonetworks BIB003 , connection of these nanonetworks to the cyber-networks, i.e., making IoBNT, further extend the applications of these nanomachines  . Continuous health monitoring and bacterial sensoractor networks inside human body are two promising examples of these applications. To this aim, implementation of micro/nanoscale bio-cyber interfaces are required. The bio-cyber interface needs to decode the molecular messages, process it and send the decoded information to a macroscale network node through a wireless link. In bioFET-based MC-Rxs, thanks to the molecular-toelectrical transducer unit, the electrical signal generated by the receiver can be sent to the cyber-networks through EM wireless communications. However, connection of biological MC-Rxs to the cyber-networks remains as an open issue. Lastly, it is worthwhile to mention that the physical architecture of the device is mainly dictated by the application requirements. As an example, the biological MC-Rxs are only promising and feasible for in vivo applications. On the other hand, utilizing artificial structures for in vivo applications necessitates comprehensive investigation of the receiver biocompatibility. Moreover, the physiological conditions imply solutions with high ionic concentrations, abundance of interferers and contaminants, and existence of disruptive flows and fluctuating temperature, which may degrade the receivers performance in several aspects. First, high ionic concentration creates strong screening effect reducing the Debye length, thus, impedes the sensitivity of the receiver BIB008 . Moreover, contaminants and disruptive flows may alter the binding kinetics, impede the stability of the receptors, even separate them from the dielectric layer. These call for comprehensive investigation of these factors, their impact on the performance of the device and methods to control their effects. To control screening problem, using highly charged ligands and very small size receptors like aptamers are theoretically efficient. However, frequency domain technique promises for much more realistic solutions. In BIB001 , the authors reveal that frequency domain detection outperforms the conventional time domain technique in terms of sensitivity in highly ionic solutions. An alternative solution to overcome the Debye screening limitations in detection is proposed in BIB004 , where it is shown that applying a highfrequency alternating current between the source and the drain electrodes, instead of a DC current, weakens the double layer capacitance generated by the solution ions. They show that the effective charges of the ligands become inversely dependent on the Debye length instead of the exponential dependence. As a result, the screening effect on the bound ligands is significantly reduced, and the FET-based biosensing becomes feasible even for physiological conditions. Similar approaches are taken by others to overcome the Debye screening with radio-frequency operation of graphene bioFETs, which are summarized in BIB017 .