A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> This paper proposes a biological cell-based communication protocol to enable communication between biological nanodevices. Inspired by existing communication network protocols, our solution combines two molecular computing techniques (DNA and enzyme computing), to design a protocol stack for molecular communication networks. Based on computational requirements of each layer of the stack, our solution specifies biomolecule address encoding/decoding, error correction and link switching mechanisms for molecular communication networks. <s> BIB001 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Molecular communication has been recently proposed for interconnected nano-scale devices as an alternative to classical communication paradigms such as electromagnetic waves, acoustic or optical communication. In this novel approach, the information is encoded as molecules that are transported between nano-scale devices within different distances. For short distances (nm-mm ranges) there exist molecular motors and calcium signaling techniques to realize the communication. For long distances (mm-m ranges), pheromones are used to transport information. In this work, the medium-range is explored to cover distances from ?m to mm and a molecular network architecture is proposed to realize the communication between nano-machines that can be deployed over different (short, medium and long) distances. In addition, two new communication techniques, flagellated bacteria and catalytic nanomotors, are proposed to cover the medium-range. Both techniques are based on the transport of DNA encoded information between emitters and receivers by means of a physical carrier. Finally, a qualitative comparison of both communication techniques is carried out and some future research topics are pointed out. <s> BIB002 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Abstract A transmitter nanomachine performs molecular communication to transmit information to a receiver nanomachine by modulating the concentration of molecules over time (e.g., concentration of ions, peptides, or DNA). In many designs for molecular communication systems, a transmitter selects a receiver nanomachine by using a predetermined type of molecule (e.g., type of ion, type of peptide, or specific sequence of DNA). The type of molecule represents the address of the receiver. In the proposed system, a transmitter addresses receivers by location. Molecular beacons use molecular communication to provide distance measurements and establish a coordinate system. The address of a receiver is the set of distances to molecular beacons at the location of the receiver. The transmitter is assumed to have the address of the receiver. A transmitter communicates to a receiver by encapsulating information into a carrier. The carrier uses distances to molecular beacons and applies a movement technique similar to bacterial chemotaxis to move to the location matching the address. The proposed system is simulated and evaluated in terms of probability of successfully contacting the receiver and propagation delay to arrive at the receiver. <s> BIB003 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Abstract In this paper, we investigated approaches to form a self-organizing microtubule network. Microtubules are protein filaments naturally occurring in the aqueous environment of cells. A microtubule network connects multiple nano- or micro-scale objects (i.e., nanomachines). In the paper, we propose two approaches to form an in vitro microtubule network in a self-organizing manner. The first approach utilizes polymerization and depolymerization of microtubules. The second approach utilizes molecular motors to reorganize a microtubule network. In addition, we conducted preliminary in vitro experiments to investigate the feasibility of the proposed approaches. In the preliminary experiments, we observed that a few sender and receiver nanomachines were interconnected with the first approach, and that distinct topologies of microtubules were reorganized with the second approach. <s> BIB004 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> This paper will provide a guidepost to design an optimal molecular communication setup and protocol. A barrier to the design of vesicle-based molecular communication nanonetworks is the computational complexity of simulating them. In this paper, a computationally efficient transport model is presented, which could be employed to design active transport molecular communication systems, particularly to optimize the shape of the transmission zone. Furthermore, a vesicular encapsulation model is presented as an addition to the transport model, and it is shown that there exists an optimal vesicle size for each molecular communication channel. As an application, our transport model is used to estimate the channel capacity of a molecular communication <s> BIB005 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> In this paper, a guideline is provided for design and optimization of the shape of active transport molecular communication channels. In particular rectangular channels are considered and it is shown that for channels employing a single microtubule as the carrier of the information particles, the smaller the perimeter of the channel, the higher the channel capacity. Furthermore, it is shown that when channels with similar perimeters are considered, square-like channels achieve higher channel capacity for small values of time per channel use, while narrower channels achieve higher information rates for larger values of time per channel use. <s> BIB006 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Abstract As the field of molecular communication continues to grow, numerous solutions have been proposed to enable communication between nanomachines. Amongst these solutions, bacteria communication nanonetworks has been proposed as a promising approach for molecular communication. This is driven by a number of attractive properties found in bacteria, which includes biased motility toward the destination through chemotaxis process, as well as the ability of bacteria to transfer genetic information between each other using conjugation. Bacterial conjugation is a major mechanism for Lateral Gene Transfer (LGT) that enables information transfer among bacteria. In this paper, we propose an opportunistic routing process in bacteria communication network using these two properties. The paper presents the simulation work to analyze the performance of message delivery for three different topology shapes, which includes grid, hexagon, and T-shape topologies. The aim of simulating on different shape topologies is to determine the impact that conjugation will have to improve message delivery. In all topologies, the use of conjugation helped improve the reliability of message delivery to the destination point. The paper will analyze various commonly used metrics used in communication networks, such as the average delay, the number of messages, as well as the distribution of messages and their originating node. The conjugation process is most beneficial in complexed shaped topologies, where the directionality from the source to the destination is a number of hops apart, as represented in the T-shape topology. <s> BIB007 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Abstract Microfluidics is a science and a technology which deals with manipulation and control of small volumes of fluids flowing in channels of micro-scale size. It is currently used for Labs-On-a-Chip (LoCs) applications mainly. In this context, recently fluids have been used in the discrete form of droplets or bubbles dispersed into another immiscible fluid. In this case, droplets or bubbles can be exploited as a means to transport digital information between microfluidic components, with sequences of particles (i.e. droplets or bubbles) representing sequences of binary values. LoCs are today realized through monolithic devices in which samples are processed by passing them through a predetermined sequence of elements connected by fixed and preconfigured microfluidic channels. To increase the reusability of LoCs, effectiveness and flexibility, networking functionalities can be introduced so that the sequence of elements involved in the processing can be dynamically selected. Accordingly, in this paper we introduce the Networked LoC (NLoC) paradigm that brings networking concepts and solutions into microfluidic systems such as LoCs. More specifically, in this paper the need for the introduction of the NLoC paradigm is motivated, its required functions are identified, a system architecture is proposed, and the related physical level design aspects, such as channel characterization, information representation and information capacity are investigated. <s> BIB008 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Systems of bionanomachines may benefit future applications which require interaction with biological systems at the nano- to microscale. Molecular communication is a suitable communication mechanism for autonomous bionanomachines which are limited in size and capability and for interfacing with biological systems. In molecular communication, a bionanomachine transmits information to a receiver bionanomachine by modulating the concentration of molecules in the environment. One promising direction for molecular communication is for a bionanomachine to measure the distance to another bionanomachine in order to perform location-based functionality or to adapt communications using the measured distance. In this paper, a bionanomachine measures the distance to another bionanomachine by requesting the other bionanomachine to transmit a feedback signal of many molecules transmitted over a short time interval (i.e., a single spike of molecules). Upon receiving the feedback signal, the bionanomachine which requested the feedback signal then estimates distance by measuring the Round Trip Time (RTT) or Signal Attenuation (SA) of the received feedback signal. The propagation of molecules and the receiving of molecules are modeled to investigate how distance impacts measured RTT and SA. Simulations are performed to measure the accuracy of the distance measurement, the time required to measure distance, and how the number of molecules transmitted affects accuracy. <s> BIB009 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> In this paper, a mathematical optimization formula for estimating the optimal channel dimensions of active transport molecular communication is presented. More specifically, rectangular channels with constant microtubule (MT) concentration are considered. It is shown, both using our formula and using Monte Carlo simulations, that square-shaped channels are optimal. Furthermore, when the value of time per channel use is on the order of a few minutes, which is the range of interest for a lot of potential applications such as diagnostic chips for healthcare, it is shown that our optimization formula can quickly and accurately estimate the optimal channel dimensions. <s> BIB010 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> One of the most prominent forms of information transmission between nano- or micro-scale devices is molecular communication, where molecules are used to transfer information inside a fluidic channel. The effects of channel shape on achievable information transmission rates is considered in this work. Specifically, regular convex polygons are studied. A mathematical framework for finding the optimal channel among this class of geometric shapes is derived. Using this framework it is shown that the optimal channel tends to be circular. This result is verified using computer simulations. <s> BIB011 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Molecular communication is a new paradigm for nanomachines to exchange information, by utilizing biological mechanism and/or components to transfer information (e.g., molecular diffusion, neuronal networks, molecular motors). One possible approach for molecular communication is through the use of bacteria, which can act as carriers for DNA-based information, i.e., plasmids. This paper analyzes multi-hop molecular nanonetworks that utilize bacteria as a carrier. The proposed approach combines different properties of bacteria to enable multi-hop transmission, such as conjugation and chemotaxis-based motility. Various analyses have been performed, including the correlation between the success rate of plasmid delivery to the destination node, and the role of conjugation in enabling this; as well as analyses on the impact of large topology shapes (e.g., Grid, Random, and Scale-free) on the success rate of plasmid delivery for multiple source-destination nanonetworks. A further solution proposed in this paper is the application of antibiotics to act as filters on illegitimate messages that could be delivered by the bacteria. Our evaluation, which has been conducted through a series of simulations, has shown that numerous bacteria properties fit to properties required for communication networking (e.g., packet filtering, routing, addressing). <s> BIB012 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Abstract Microfluidics is a multidisciplinary field with practical applications to the design of systems, called lab-on-chip (LoC), where tiny volumes of fluids are circulated through channels with millimeter size and driven into structures where precise chemical/physical processes take place. One subcategory of microfluidics is droplet-based microfluidics, in which discrete volumes of fluids disperse into a continuous stream of another immiscible fluid, which acts as the droplet carrier. Droplets can then be moved, merged, split, or processed in many other ways by suitably managing the hydrodynamic parameters of the LoC. A very interesting research challenge consists in developing basic microfluidic structures that are able to interconnect specialized LoCs or, more generally, microfluidic machines (MMs), by means of a flexible and modular microfluidic network. The aim of this paper is to exploit the properties of droplet-based microfluidics to realize purely hydrodynamic microfluidic elements that provide basic networking functionalities, such as addressing and switching. We define some simple mathematical models that capture the macroscopic behavior of droplets in microfluidic networks, and use such models to design and analyze a simple microfluidic network system with bus topology. The study points out some tradeoffs that need to be accounted for when designing a microfluidic network, and proposes a first approach to the performance analysis of this kind of network, while listing a number of open research challenges that call for further study. <s> BIB013 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> In this paper, we consider the Hydrodynamic Controlled microfluidic Network (HCN) paradigm which is based on purely hydrodynamic microfluidic switching and medium access control. The HCN paradigm can be applied to build programmable microfluidic devices, i.e., Lab-on-a-Chips (LoCs), that by exploiting hydrodynamic effects only, route chemical or biological samples in a microfluidic network, in a controlled way. These microfluidic devices will be highly flexible and inexpensive, and thus are expected to become extremely competitive as compared to the alternative solutions for chemical and biological analysis and synthesis or cheap sensing. This paper provides the design guidelines for the microfluidic circuits implementing the switching function and the medium access control and illustrates through simulations the feasibility of the proposed idea. <s> BIB014 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> Microfluidics deals with manipulation and control of fluids which flow in constrained sub-millimetric media. In this paper communication concepts and networking approaches, typical of telecommunications, are extended to the microfluidic domain. The work illustrated in this paper investigates on possible approaches to information encoding and evaluation of the corresponding channel capacity as well as design of switching solutions. Based on the results of this study, the Hydrodynamic Controlled Microfluidic Network (HCN) paradigm is proposed, which is based on a pure hydrodynamic microfluidic switching function. The HCN paradigm can be applied to interconnect Labs-on-a-Chip (LoCs) in a microfluidic network in which chemical/biological samples are routed between the LoCs by exploiting hydrodynamic effects only. The resulting LoCs are expected to be highly flexible and inexpensive, and thus to become extremely useful in chemical/biological analysis and synthesis. <s> BIB015 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> A number of techniques have been recently proposed to implement molecular communication, a novel method which aims to implement communication networks at the nanoscale, known as nanonetworks. A common characteristic of these techniques is that their main resource consists of molecules, which are inherently discrete. This paper presents DIRECT, a novel networking model which differs from conventional models by the way of treating resources as discrete entities; therefore, it is particularly aimed to the analysis of molecular communication techniques. Resources can be involved in different tasks in a network, such as message encoding, they do not attenuate in physical terms and they are considered 100% reusable. The essential properties of DIRECT are explored and the key parameters are investigated throughout this paper. <s> BIB016 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <s> In this paper, we discuss issues concerned with transmission rate control in molecular communication, an emerging communication paradigm for bio-nanomachines in an aqueous environment. In molecular communication, a group of bio-nanomachines acting as senders transmit molecules, the molecules propagate in the environment, and another group of bio-nanomachines acting as receivers chemically react to the molecules propagating in the environment. In the model of molecular communication considered in this paper, senders may transmit molecules at a high rate to accelerate the receiver reactions or to increase the throughput. However, if the senders transmit molecules faster than the receivers react, the excess molecules remain in the environment and eventually degrade or diffuse away, which results in loss of molecules or degradation in efficiency. Such a potential issue associated with throughput and efficiency is in this paper discussed as an optimization problem. A mathematical expression for an upper-bound on the throughput and efficiency is first derived to provide an insight into the impact of model parameters. The optimal transmission rates that maximize the throughput and efficiency are then numerically calculated and presented, and throughput and efficiency are shown to be in trade-off relationships in a wide range of transmission rates. Further, two classes of feedback-based transmission rate control schemes are designed for autonomous bio-nanomachines to dynamically control their transmission rates, respectively based on negative and positive feedback from the receivers. The numerical evaluation of the two transmission rate control schemes is then shown to provide useful guidelines for application developers to satisfy their design goals. <s> BIB017 </s> A Comprehensive Survey of Recent Advancements in Molecular Communication <s> D. Architectures, Protocols, and Optimal Design <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> BIB018
Because molecular communication is still in its infancy, most of the research has been focused on modeling the channel as well as the modulation and coding schemes necessary for setting up a reliable communication link. However, one the link is established another important aspect of any communication network is the network architecture and protocols. Open Systems Interconnection (OSI) model is a conceptual model that characterizes and standardizes the internal functions of a communication system by partitioning it into abstraction layers. For example, TCP/IP model of the Internet partitions the communication system into 4 layers: link layer, Internet layer, transport layer, and the application layer. When we are considering molecular communication, one might think that we may be able to use the same layered architecture over a molecular communication physical link. However, one issue is that we may not be trying to connect electronic devices. Instead we may be trying to connect biological entities. Therefore, it is not perfectly clear if using the same layering structure would be appropriate. Moreover, even if we use the conventional laying architectures, it is not clear how each layer should communicate with the layer above or below. One of the early works that looked at network architectures for molecular communication was BIB001 . The authors assumed that the intended transmission information can be divided into two categories: sensor data, and command data. They then assumed that the command data has higher priority and as such would be encoded with error correction codes, where as sensor data are uncoded. to solve the computing problem required for carrying out the network protocol, the authors proposed DNA and Enzyme based computations. In particular, DNA based computations was proposed for application interface stack, which encodes messages and addresses, network stack which routes messages, and error correction stack which encodes and decodes error correction codes. Enzyme based computation was proposed for link switching stack. In BIB002 network architecture for nanonetworks was presented, where each nano-node could communication with other nano-nodes over the short range (nm to µm) using diffusion, the medium range (µm to mm) using bacteria transport and catalytic nanomotors, and the long range (mm to m) using pheromones. In the proposed architecture, it was assumed that each nanodevice was connected to a gateway over the short range and the gateways are distributed over the medium to long range. It was assumed that instead of bits, DNA base pairs are used for addressing and carrying information. In BIB003 the authors proposed establishing a coordinate system using beacon nodes to transmit information from the transmitter to a specific location (i.e., a specific receiver). This idea was analogous to the way geographical positioning systems (GPS) work. It is assumed that each beacon node releases a specific type of chemical at an specific rate. Therefore, there is a concentration gradient generated by each beacon. Distances from a receiver to a beacons was measured using this concentration gradient and the fading of concentration over a distance. The information particles was then assumed to be carried by bacteria and using chemotaxis. In BIB007 the authors proposed a routing mechanism for bacterial based molecular communication. In this scheme, it was assumed that each node in the network released chemoattractant to attract the bacteria from neighboring nodes. It was also assumed that information particles are DNA sequences that are embedded in bacteria. The node A embedded a DNA sequence inside bacteria that pass through neighboring nodes (say node B) until they arrive at the destination (say node C). At the relay node (node B), it was assumed that the bacteria transfer their information to a new set of bacteria that are sensitive to node B's neighboring chemoattractants. The DNA sequences were transferred from bacteria to bacteria using bacterial conjugation, a process that involves transfer of single stranded DNA from one cell to another. In BIB012 , the authors extended the results in BIB007 and proposed the use of antibiotics to kill bacteria that embed incomplete DNA sequences. In this scheme bacteria resistance genes were inserted at the end in the DNA sequence carrying the information. If bacterial conjugation results in an incomplete DNA sequence, the bacteria carrying the information particles was assumed to be killed by the antibiotics. The effects of topology on this network was then simulated and analyzed. In BIB004 an architecture for design os self-organizing microtubule tracks for molecular communication was proposed. In particular, two different approaches were considered: one based on polymerization and depolymerization of microtubules, and the other based on molecular motors for reorganizing the tracks. Preliminary in vitro experiments were conducted then to investigate the feasibility of the proposed techniques. In BIB008 the problem of networking in droplet microfluidics was considered. The authors first gave an overview of droplet microfluidics, and then discussed some of the issues and problems in creating network architecture for hydrodynamic based microfluidics. It was shown that a ring topology, where each processing module is connected to a main ring through a microfluidic network interface (MNI) circuit could be an effective architecture for networking hydrodynamic droplet microfuidics. In this scheme the main ring starts and ends at the central processing unit, and the network interface circuits control the flow of droplets through and from each processing module. A general introduction to hydrodynamic microfluidics was also provided in BIB013 . The work in BIB008 was extended in BIB014 , where the authors used the similarity between Ohm's law and Hagen-Poiseuille's law to design a switch circuit for the MNI. In this scheme, the circuit was designed in such a way that depending on the distance between a header droplet and a payload droplet, the payload droplet was either delivered to the corresponding processing unit or it continued flowing in the ring. A medium access control circuit was also proposed for releasing a payload into the ring such that the released droplet would not collide with the other droplets flowing in the ring. In BIB015 , channel capacity expressions for the different droplet encoding schemes are provided. In BIB016 molecular communication in confined environ-ments was considered. It was assumed that the number of information particles within the environment was constant, and therefore, different nodes needed to harvest the information particles that were within the environment for communication. The authors then simulate this particular architecture and present some preliminary results. In BIB017 the authors considered optimizing the transmission rate of a number of bio-nanomachines such that the throughput and the efficiency of transmission was maximized. In their model it was assumed that there are N transmitters and M receivers. At the receiver, it was assumed that the information particles were detected through Michaelis Menten enzyme kinetics. The throughput was defined as the number of information particles processes at the receiver per unit time. The efficiency was defined as the throughput divided by number of information particles transmitted per unit time. A simplified optimization model where all transmitters are at origin and all receivers are at distance r was presented, and the solution was provided with an upper bounds on throughput and efficiency. A feedback mechanism was also presented that would adjust the optimal transmission rate in dynamic environments. In BIB009 a protocol for measuring distance between two nanomachines by exchanging information particles and measuring the concentration was proposed. In this scheme, first node A released N a particles of type a into the environment, where these particles diffuse in the environment. At node B the change in concentration was measured and N b particles of type b were released into the environment according to a process that was based on some property of the detected concentration of type-a particles. Using a property of the detected concentration of type-b particles back at node A, the distance measure is estimated. Different detection processes such as round time trip and signal attenuation were then considered. In BIB018 a protocol for blind synchronization between nodes in a diffusion based molecular communication system was proposed. In particular, a MoSK channel was assumed, where during each symbol duration different molecules are used to encode different messages. Then a non-decision directed maximum likelihood criterion was used to estimate the channel delay, which would be used for synchronization. The Cramer-Rao lower bound for the estimation was also derived, and the results were compared to simulation models. In BIB005 , molecular communication channels employing stationary kinesin and microtubule filaments for information particle transport were considered. In the paper the authors found an optimal design for the shape of the transmission zone and the optimal size for encapsulated information particles. All these parameters were optimized through maximizing the channel capacity of the communication system. In BIB010 , BIB006 , the authors continued optimizing this channel further by finding the optimal channel shape. It was shown for rectangular channels, the square-shaped channel maximizes channel capacity for this type of active transport. In BIB011 the results were extended to include regular polygon shapes, and it was shown that circular-shaped channel tends to be capacity maximizing for these systems.