Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Factors that affect the probability of genetic transformation of Escherichia coli by plasmids have been evaluated. A set of conditions is described under which about one in every 400 plasmid molecules produces a transformed cell. These conditions include cell growth in medium containing elevated levels of Mg2+, and incubation of the cells at 0 degrees C in a solution of Mn2+, Ca2+, Rb+ or K+, dimethyl sulfoxide, dithiothreitol, and hexamine cobalt (III). Transformation efficiency declines linearly with increasing plasmid size. Relaxed and supercoiled plasmids transform with similar probabilities. Non-transforming DNAs compete consistent with mass. No significant variation is observed between competing DNAs of different source, complexity, length or form. Competition with both transforming and non-transforming plasmids indicates that each cell is capable of taking up many DNA molecules, and that the establishment of a transformation event is neither helped nor hindered significantly by the presence of multiple plasmids. <s> BIB001 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract ::: The negative-strand RNA viruses are a broad group of animal viruses that comprise several important human pathogens, including influenza, measles, mumps, rabies, respiratory syncytial, Ebola, and hantaviruses. The development of new strategies to genetically manipulate the genomes of negative-strand RNA viruses has provided us with new tools to study the structure-function relationships of the viral components and their contributions to the pathogenicity of these viruses. It is also now possible to envision rational approaches--based on genetic engineering techniques--to design live attenuated vaccines against some of these viral agents. In addition, the use of different negative-strand RNA viruses as vectors to efficiently express foreign polypeptides has also become feasible, and these novel vectors have potential applications in disease prevention as well as in gene therapy. <s> BIB002 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Forced expression of gap junction proteins, connexins, enables gap junction-deficient cell lines to propagate intercellular calcium waves. Here, we show that ATP secretion from the poorly coupled cell lines, C6 glioma, HeLa, and U373 glioblastoma, is potentiated 5- to 15-fold by connexin expression. ATP release required purinergic receptor-activated intracellular Ca2+ mobilization and was inhibited by Cl- channel blockers. Calcium wave propagation also was reduced by purinergic receptor antagonists and by Cl- channel blockers but insensitive to gap junction inhibitors. These observations suggest that cell-to-cell signaling associated with connexin expression results from enhanced ATP release and not, as previously believed, from an increase in intercellular coupling. <s> BIB003 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Delivery of therapeutic proteins into tissues and across the blood-brain barrier is severely limited by the size and biochemical properties of the proteins. Here it is shown that intraperitoneal injection of the 120-kilodalton β-galactosidase protein, fused to the protein transduction domain from the human immunodeficiency virus TAT protein, results in delivery of the biologically active fusion protein to all tissues in mice, including the brain. These results open new possibilities for direct delivery of proteins into patients in the context of protein therapy, as well as for epigenetic experimentation with model organisms. <s> BIB004 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> A conserved biological response to double-stranded RNA, known variously as RNA interference (RNAi) or post-transcriptional gene silencing, mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes. RNAi has been cultivated as a means to manipulate gene expression experimentally and to probe gene function on a whole-genome scale. <s> BIB005 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Polymer translocation through a nanopore in a membrane is investigated theoretically. Recent experiments on voltage-driven DNA and RNA translocations through a nanopore indicate that the size and geometry of the pore are important factors in polymer dynamics. A theoretical approach is presented which explicitly takes into account the effect of the nanopore length and diameter for polymer motion across the membrane. It is shown that the length of the pore is crucial for polymer translocation dynamics. The present model predicts that for realistic conditions (long nanopores and large external fields) there are two regimes of translocation depending on polymer size: for polymer chains larger than the pore length, the velocity of translocation is nearly constant, while for polymer chains smaller than the pore length the velocity increases with decreasing polymer size. These results agree with experimental data. <s> BIB006 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> PURPOSE ::: Although oral delivery has become a widely accepted route of administration of therapeutic drugs, the gastrointestinal tract presents several formidable barriers to drug delivery. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon but also for its potential for the delivery of proteins and therapeutic peptides. To achieve successful colonic delivery, a drug needs to be protected from absorption and /or the environment of the upper gastrointestinal tract (GIT) and then be abruptly released into the proximal colon, which is considered the optimum site for colon-targeted delivery of drugs. Colon targeting is naturally of value for the topical treatment of diseases of colon such as Chron's diseases, ulcerative colitis, colorectal cancer and amebiasis. Peptides, proteins, oligonucleotides and vaccines pose potential candidature for colon targeted drug delivery. ::: ::: ::: METHODS ::: The various strategies for targeting orally administered drugs to the colon include covalent linkage of a drug with a carrier, coating with pH-sensitive polymers, formulation of timed released systems, exploitation of carriers that are degraded specifically by colonic bacteria, bioadhesive systems and osmotic controlled drug delivery systems. Various prodrugs (sulfasalazine, ipsalazine, balsalazine and olsalazine) have been developed that are aimed to deliver 5-amino salicylic acid (5-ASA) for localized chemotherapy of inflammatory bowl disease (IBD). Microbially degradable polymers especially azo crosslinked polymers have been investigated for use in targeting of drugs to colon. Certain plant polysaccharides such as amylose, inulin, pectin and guar gum remains unaffected in the presence of gastrointestinal enzymes and pave the way for the formulation of colon targeted drug delivery systems. The concept of using pH as a rigger to release a drug in the colon is based on the pH conditions that vary continuously down the gastrointestinal tract. Times dependent drug delivery systems have been developed that are based on the principle to prevent release of drug until 3-4 h after leaving the stomach. Redox sensitive polymers and bioadhesive systems have also been exploited to deliver the drugs into the colon. ::: ::: ::: RESULTS ::: The approach that is based on the formation of prodrug involves covalent linkage between drug and carrier. The type of linkage that is formed between drug and carrier would decide the triggering mechanism for the release of drug in colon. The presence of azo reductase enzymes play pivotal role in the release of drug from azo bond prodrugs while glycosidase activity of the colonic microflora is responsible for liberation of drugs from glycosidic prodrugs. Release of drugs from azo polymer coated dosage forms is supposed to take place after reduction and thus cleavage of the azo bonds by the azoreductase enzymes present in the colonic microflora. Natural polysaccharides have been used as tools to deliver the drugs specifically to the colon. These polysaccharides remain intact in the physiological environment of stomach and small intestine but once the dosage form enters into colon, it is acted upon by polysaccharidases, which degrades the polysaccharide and releases the drug into the vicinity of bioenvironment of colon. However, they should be protected while gaining entry into stomach and small intestine due to enormous swelling and hydrophilic properties of polysaccharides. This has been achieved either by chemical crosslinking or by addition of a protective coat. Formulation coated with enteric polymers releases drug when pH move towards alkaline range while as the multicoated formulation passes the stomach, the drug is released after a lag time of 3-5 h that is equivalent to small intestinal transit time. Drug coated with a bioadhesive polymer that selectively provides adhesion to the colonic mucosa may release drug in the colon. ::: ::: ::: CONCLUSIONS ::: Improved drug delivery systems are required for drugs currently in use to treat localized diseases of the colon. The advantages of targeting drugs specifically to the diseased colon are reduced incidence of systemic side effects, lower dose of drug, supply of the drug to the biophase only when it is required and maintenance of the drug in its intact form as close as possible to the target site. <s> BIB007 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Precise control over the release of drug from devices implanted in the body, such as quantity, timing, is highly desirable in order to optimise drug therapy. In this paper, the research on electrically-responsive drug delivery is reviewed. Electrically-controllable drug release from polyelectrolyte hydrogels has been demonstrated in vitro and in vivo (in rats). Pulsatile drug release profiles, in response to alternating application and removal of the electric field have been achieved. Responsive drug release from hydrogels results from the electro-induced changes in the gels, which may deswell, swell or erode in response to an electric field. The mechanisms of drug release include ejection of the drug from the gel as the fluid phase synereses out, drug diffusion along a concentration gradient, electrophoresis of charged drugs towards an oppositely charged electrode and liberation of the entrapped drug as the gel complex erodes. Electrically-responsive drug release is influenced by a number of factors such as the nature of the drug and of the gel, the experimental set-up, magnitude of the electric field etc. In this paper, electrically-responsive hydrogels, response of gels to an electric field and electrically-stimulated drug release are discussed. <s> BIB008 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular communication is engineered biological communication (e.g., cell-to-cell signaling) that allows nanomachines (e.g., engineered organisms, artificial devices) to communicate through chemical signals in an aqueous environment. This paper describes the design of a molecular communication system based on intercellular calcium signaling networks. This paper also describes possible functionalities (e.g., signal switching and aggregation) that may be achieved in such networks. <s> BIB009 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Oxygen plasma treatment of poly(dimethylsiloxane) (PDMS) thin films produced a hydrophilic surface that was biocompatible and resistant to biofouling in microfluidic studies. Thin film coatings of PDMS were previously developed to provide protection for semiconductor-based microoptical devices from rapid degradation by biofluids. However, the hydrophobic surface of native PDMS induced rapid clogging of microfluidic channels with glial cells. To evaluate the various issues of surface hydrophobicity and chemistry on material biocompatibility, we tested both native and oxidized PDMS (ox-PDMS) coatings as well as bare silicon and hydrophobic alkane and hydrophilic oligoethylene glycol silane monolayer coated under both cell culture and microfluidic studies. For the culture studies, the observed trend was that the hydrophilic surfaces supported cell adhesion and growth, whereas the hydrophobic ones were inhibitive. However, for the fluidic studies, a glass-silicon microfluidic device coated with the hydrophilic ox-PDMS had an unperturbed flow rate over 14 min of operation, whereas the uncoated device suffered a loss in rate of 12%, and the native PDMS coating showed a loss of nearly 40%. Possible protein modification of the surfaces from the culture medium also were examined with adsorbed films of albumin, collagen, and fibrinogen to evaluate their effect on cell adhesion. <s> BIB010 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> We investigate single-molecule electrophoretic translocation of A(50), C(50), A(25)C(50), and C(50)A(25) RNA molecules through the alpha-hemolysin transmembrane protein pore. We observe pronounced bilevel current blockages during translocation of A(25)C(50) and C(50)A(25) molecules. The two current levels observed during these bilevel blockages are very similar to the characteristic current levels observed during A(50) and C(50) translocation. From the temporal ordering of the two levels within the bilevel current blockages, we infer whether individual A(25)C(50) and C(50)A(25) molecules pass through the pore in a 3'-->5' or 5'-->3' orientation. Correlation between the level of current obstruction and the inferred A(25)C(50) or C(50)A(25) orientation indicates that 3'-->5' translocation of a poly C segment causes a significantly deeper current obstruction than 5'-->3' translocation. Our analysis also suggests that the 3' ends of C(50) and A(25)C(50) RNA molecules are more likely to initiate translocation than the 5' ends. Orientation dependent differences in a smaller current blockage that immediately precedes many translocation events suggest that this blockage also contains information about RNA orientation during translocation. These findings emphasize that the directionality of polynucleotide molecules is an important factor in translocation and demonstrate how structure within ionic current signals can give new insights into the translocation process. <s> BIB011 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> RNA-interference (RNAi) is a potent mechanism, conserved from plants to humans for specific silencing of genes, which holds promise for functional genomics and gene-targeted therapies. Here we show that bacteria engineered to produce a short hairpin RNA (shRNA) targeting a mammalian gene induce trans-kingdom RNAi in vitro and in vivo. Nonpathogenic Escherichia coli were engineered to transcribe shRNAs from a plasmid containing the invasin gene Inv and the listeriolysin O gene HlyA, which encode two bacterial factors needed for successful transfer of the shRNAs into mammalian cells. Upon oral or intravenous administration, E. coli encoding shRNA against CTNNB1 (catenin beta-1) induce significant gene silencing in the intestinal epithelium and in human colon cancer xenografts in mice. These results provide an example of trans-kingdom RNAi in higher organisms and suggest the potential of bacteria-mediated RNAi for functional genomics, therapeutic target validation and development of clinically compatible RNAi-based therapies. <s> BIB012 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular communication is one solution for nano-scale communication between nanomachines. Nanomachines (e.g., biological molecules, artificial devices) represent small devices or components that perform computation, sensing, or actuation. Molecular communication provides a mechanism for one nanomachine to encode or decode information into molecules and to send information to another nanomachine. This paper describes a molecular motor communication system in terms of a high level architecture for molecular communication. We also briefly discuss current and future work in molecular communication. <s> BIB013 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> We have proposed Molecular Communication [1][2], a solution for nano-scale communication between nanomachines (e.g., biological molecules, artificial devices). Molecular communication provides a mechanism for one nanomachine to encode or decode information into molecules (information molecules) and to send the information molecules to another nanomachine. Using molecular communication to control communication between nanomachines is inspired by the observation of biological systems which already commonly communicate through molecules. This paper describes the design of a molecular communication system that uses molecular motors and rail molecules (such as microtubules) as a basis for the high-level architecture of molecular communication. <s> BIB014 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The passage of individual molecules through nanosized pores in membranes is central to many processes in biology. Previously, experiments have been restricted to naturally occurring nanopores, but advances in technology now allow artificial solid-state nanopores to be fabricated in insulating membranes. By monitoring ion currents and forces as molecules pass through a solid-state nanopore, it is possible to investigate a wide range of phenomena involving DNA, RNA and proteins. The solid-state nanopore proves to be a surprisingly versatile new single-molecule tool for biophysics and biotechnology. <s> BIB015 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> We demonstrate universal computation in an all-fluidic two-phase microfluidic system. Nonlinearity is introduced into an otherwise linear, reversible, low-Reynolds number flow via bubble-to-bubble hydrodynamic interactions. A bubble traveling in a channel represents a bit, providing us with the capability to simultaneously transport materials and perform logical control operations. We demonstrate bubble logic AND/OR/NOT gates, a toggle flip-flop, a ripple counter, timing restoration, a ring oscillator, and an electro-bubble modulator. These show the nonlinearity, gain, bistability, synchronization, cascadability, feedback, and programmability required for scalable universal computation. With increasing complexity in large-scale microfluidic processors, bubble logic provides an on-chip process control mechanism integrating chemistry and computation. <s> BIB016 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular communication is engineered biological communication that allows nanomachines to communicate through chemical signals. Nanomachines are small scale biological devices that either exist in nature or are artificially engineered from biological materials, and that perform simple functions such as sensing, processing, and actuation. As nanomachines are too small and simple to communicate through a traditional communication means (e.g. electromagnetic waves), molecular communication provides a mechanism for nanomachines to communicate by propagating molecules that represent information. In this paper, we propose to explore biological cells for engineering a molecular communication system. Its system characteristics and key networking services are first discussed, and then our current status of experimental and modeling studies is briefly reported. <s> BIB017 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Significant advances have been made in the understanding of the pathophysiology, molecular targets and therapies for the treatment of a variety of nervous-system disorders. Particular therapies inv ... <s> BIB018 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Natural inter-neuronal communication is mediated primarily via neurotransmitter-gated ion channels. While most of the methods for neural interfacing have been based upon electrical stimulation, neurotransmitter-based approaches for the spatially and temporally controlled delivery of neurotransmitters are relatively new. Methods of neurotransmitter stimulation retinal prosthesis may provide new ways to control neural excitation. Experimental results for retinal ganglion cell stimulation demonstrate the feasibility of a neurotransmitter-based retinal prosthesis. <s> BIB019 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract Molecular communication uses molecules (i.e., biochemical signals) as an information medium and allows biologically and artificially created nano- or microscale entities to communicate over a short distance. It is a new communication paradigm; it is different from the traditional communication paradigm, which uses electromagnetic waves (i.e., electronic and optical signals) as an information medium. Key research challenges in molecular communication include design of system components (i.e., a sender, a molecular propagation system, a receiver, and a molecular communication interface) and mathematical modeling of each system component as well as entire systems. We review all research activities in molecular communication to date, from its origin to recent experimental studies and theoretical approaches for each system component. As a model molecular communication system, we describe an integrated system that combines a molecular communication interface (using a lipid vesicle embedded with channel-forming proteins), a molecular propagation system (using microtubule motility on kinesin molecular motors and DNA hybridization), and a sender/receiver (using giant lipid vesicles embedded with gemini-peptide lipids). We also present potential applications and the future outlook of molecular communication. <s> BIB020 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Interest in the mechanisms of subcellular localization of mRNAs and the effects of localized translation has increased over the last decade. Polarized eukaryotic cells transport mRNA-protein complexes to subcellular sites, where translation of the mRNAs can be regulated by physiological stimuli. The long distances separating distal neuronal processes from their cell body have made neurons a useful model system for dissecting mechanisms of mRNA trafficking. Both the dendritic and axonal processes of neurons have been shown to have protein synthetic capacity and the diversity of mRNAs discovered in these processes continues to increase. Localized translation of mRNAs requires a co-ordinated effort by the cell body to target both mRNAs and necessary translational machinery into distal sites, as well as temporal control of individual mRNA translation. In addition to altering protein composition locally at the site of translation, some of the proteins generated in injured nerves retrogradely signal to the cell body, providing both temporal and spatial information on events occurring at distant subcellular sites. <s> BIB021 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> a b s t r a c t This paper describes a Bacteria-based Nanonetwork for communication between eukaryotic cell sized nano devices. The communication is achieved by the exchange of DNA molecules which are transported by bacteria guided by chemotaxis. First, the modules of the network are described and all the biological phenomena that support the basic communication steps are explained in detail. Then an analytical model is developed to assess the communication range and the network performance in terms of capacity and end-to-end delay by considering the available information about the biological mechanisms used. As there are no appropriate estimates of the propagation delay introduced by bacterial chemotaxis, our newly developed simulator is introduced which helps us to obtain the statistics on bacteria propagation. Finally, by combining the analytical model with the simulation results, a network performance in terms of end-to-end delay, capacity and end-to-end throughput is obtained which is 4 orders of magnitude higher than the other molecular communication approaches. <s> BIB022 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract The ability to create communication networks of biological nanoscale devices has the potential to open up new opportunities and applications, particularly in areas such as health care and information processing. Inspired by recent developments in molecular communication and biomolecular computing, we present in this paper a biological cell based molecular communication transmitting platform using synthetic molecular computing techniques. We investigated two protocol solutions which include DNA based computing coupled with viral particles and enzyme based computing coupled with calcium signaling. Each of these solutions is designed for different applications and environments. For each of these approaches we demonstrate how elements from various layers in the communication stack are developed using the molecular computing mechanisms. Simulation results are also presented to illustrate the functionality and performance of each solution. <s> BIB023 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Investigators have recently turned to the soil nematode Caenorhabditis elegans as a small animal infection model to study infectious disease. To extrapolate findings concerning bacterial pathogenesis from non-mammals to mammals, virulence factors should be conserved in function, independent of the infection model. Emerging from these studies is the observation that bacterial virulence regulatory networks function in a conserved manner across multiple hosts, including nematodes, mice and plants. Several regulatory networks have been implicated in nematode innate immune function and are being exploited in the C. elegans infection model to develop novel chemical therapies against bacterial pathogens. <s> BIB024 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The pentameric ATPase motor gp16 packages double-stranded DNA into the bacteriophage phi29 virus capsid. On the basis of the results of single-molecule experimental studies, we propose a push and roll mechanism to explain how the packaging motor translocates the DNA in bursts of four 2.5 bp power strokes, while rotating the DNA. In this mechanism, each power stroke accompanies P(i) release after ATP hydrolysis. Since the high-resolution structure of the gp16 motor is not available, we borrowed characterized features from the P4 RNA packaging motor in bacteriophage phi12. For each power stroke, a lumenal lever from a single subunit is electrostatically steered to the DNA backbone. The lever then pushes sterically, orthogonal to the backbone axis, such that the right-handed DNA helix is translocated and rotated in a left-handed direction. The electrostatic association allows tight coupling between the lever and the DNA and prevents DNA from slipping back. The lever affinity for DNA decreases towards the end of the power stroke and the DNA rolls to the lever on the next subunit. Each power stroke facilitates ATP hydrolysis in the next catalytic site by inserting an Arg -finger into the site, as captured in phi12-P4. At the end of every four power strokes, ADP release happens slowly, so the cycle pauses constituting a dwell phase during which four ATPs are loaded into the catalytic sites. The next burst phase of four power strokes starts once spontaneous ATP hydrolysis takes place in the fifth site without insertion of an Arg finger. The push and roll model provides a new perspective on how a multimeric ATPase transports DNA, and it might apply to other ring motors as well. <s> BIB025 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract In addition to intracellular organelles, eukaryotic cells also contain extracellular organelles that are released, or shed, into the microenvironment. These membranous extracellular organelles include exosomes, shedding microvesicles (SMVs) and apoptotic blebs (ABs), many of which exhibit pleiotropic biological functions. Because extracellular organelle terminology is often confounding, with many preparations reported in the literature being mixtures of extracellular vesicles, there is a growing need to clarify nomenclature and to improve purification strategies in order to discriminate the biochemical and functional activities of these moieties. Exosomes are formed by the inward budding of multivesicular bodies (MVBs) and are released from the cell into the microenvironment following the fusion of MVBs with the plasma membrane (PM). In this review we focus on various strategies for purifying exosomes and discuss their biophysical and biochemical properties. An update on proteomic analysis of exosomes from various cell types and body fluids is provided and host-cell specific proteomic signatures are also discussed. Because the ectodomain of ~ 42% of exosomal integral membrane proteins are also found in the secretome, these vesicles provide a potential source of serum-based membrane protein biomarkers that are reflective of the host cell. ExoCarta, an exosomal protein and RNA database ( http://exocarta.ludwig.edu.au ), is described. <s> BIB026 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In this paper, we consider a molecular relay channel in which signal molecules are transmitted by a sender of communication, propagated, amplified, removed in the channel, and sensed by the receiver of communication that decodes the signal molecules. To understand and characterize the communication capacity of the molecular relay channel, we develop an information communication model that consists of the transmitter, channel, and receiver. Mutual information is used to quantify the amount of information that is transfered from the transmitter through the channel to the receiver. The method employed and results presented in this paper may help elucidate design principles of biological systems as well as help in the design and engineering of synthetic biological systems from the perspective of information theory. <s> BIB027 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In this paper, we consider molecular communication, with information conveyed in the time of release of molecules. These molecules propagate to the transmitter through a fluid medium, propelled by a positive drift velocity and Brownian motion. The main contribution of this paper is the development of a theoretical foundation for such a communication system; specifically, the additive inverse Gaussian noise (AIGN) channel model. In such a channel, the information is corrupted by noise that follows an IG distribution. We show that such a channel model is appropriate for molecular communication in fluid media. Taking advantage of the available literature on the IG distribution, upper and lower bounds on channel capacity are developed, and a maximum likelihood receiver is derived. Results are presented which suggest that this channel does not have a single quality measure analogous to signal-to-noise ratio in the additive white Gaussian noise channel. It is also shown that the use of multiple molecules leads to reduced error rate in a manner akin to diversity order in wireless communications. Finally, some open problems are discussed that arise from the IG channel model. <s> BIB028 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In molecular communication, information is encoded and transmitted as a pattern of molecules or other very small information carriers (in this paper, vesicles are used). Nanoscale techniques, such as molecular motors or Brownian motion, are used to convey the vesicles from the transmitter to the receiver, where the transmitted message is deciphered. In this paper, the microchannel environment is considered, and the achievable information rates are compared between the use of Brownian motion and molecular motors, which are evaluated through simulation. Communication is viewed as a mass transfer problem, where messages are sent by transporting a number of vesicles from transmitter to receiver. Results are provided which suggest that active transport is best when the available number of vesicles is small, and Brownian motion is best when the number of vesicles is large. <s> BIB029 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> MicroRNAs are short RNA molecules that regulate gene expression, and have been investigated as potential biomarkers because their expression levels are correlated with various diseases. However, detecting microRNAs in the bloodstream remains difficult because current methods are not sufficiently selective or sensitive. Here, we show that a nanopore sensor based on the α-haemolysin protein can selectively detect microRNAs at the single molecular level in plasma samples from lung cancer patients without the need for labels or amplification of the microRNA. The sensor, which uses a programmable oligonucleotide probe to generate a target-specific signature signal, can quantify subpicomolar levels of cancer-associated microRNAs and can distinguish single-nucleotide differences between microRNA family members. This approach is potentially useful for quantitative microRNA detection, the discovery of disease markers and non-invasive early diagnosis of cancer. <s> BIB030 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Nanonetworks are the interconnection of nanomachines and as such expand the limited capabilities of a single nanomachine. Several techniques have been proposed so far to interconnect nanomachines. For short distances (nm-mm ranges), researchers are proposing to use molecular motors and calcium signaling. For long distances (mm-m), pheromones are envisioned to transport information. In this work we propose a new mechanism for medium-range communications (nm-µm): flagellated bacteria. This technique is based on the transport of DNA-encoded information between emitters and receivers by means of a bacterium. We present a physical channel characterization and a simulator that, based on the previous characterization, simulates the transmission of a DNA packet between two nanomachines. <s> BIB031 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> a b s t r a c t Nanotechnology is enabling the development of devices in a scale ranging from one to hundreds of nanometers. Communication between these devices underlying in the nanoscale greatly expands the possible applications, increasing the complexity and range of operation of the system. However, synchronization may be required to build a network architecture. In this work, we propose Quorum Sensing as a novel way to achieve synchronization between nodes of a nanonetwork. Quorum Sensing is a mechanism used by bacteria to sense their own population and coordinate their actions, through the emission and sensing of molecules called autoinducers. Here, the authors model the behavior of each bacterium as an individual finite state automaton, capturing its course of action. This model serves as the control unit of a ''quorum nanomachine'', which would be able to synchronize with its fellows in a distributed manner by means of molecular communication. Finally, this configuration is implemented and simulated, and the results are later discussed. <s> BIB032 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <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> BIB033 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> An emerging concept is that cellular communication in mammals can be mediated by the exchange of genetic information, mainly in the form of microRNAs. This can occur when extracellular vesicles, such as exosomes, secreted by a donor cell are taken up by an acceptor cell. Transfer of genetic material can also occur through intimate membrane contacts between donor and acceptor cells. Specialized cell-cell contacts, such as synapses, have the potential to combine these modes of genetic transfer. <s> BIB034 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract Currently, Communication via Diffusion (CvD) is one of the most prominent systems in nanonetworks. In this paper, we evaluate the effects of two major interference sources, Intersymbol Interference (ISI) and Co-channel Interference (CCI) in the CvD system using different modulation techniques. In the analysis of this paper, we use two modulation techniques, namely Concentration Shift Keying (CSK) and Molecule Shift Keying (MoSK) that we proposed in our previous paper. These techniques are suitable for the unique properties of messenger molecule concentration waves in nanonetworks. Using a two transmitting couple simulation environment, the channel capacity performances of the CvD system utilizing these modulation techniques are evaluated in terms of communication range, distance between interfering sources, physical size of devices, and average transmission power. <s> BIB035 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> We consider a confined space molecular communication system, where molecules or information carrying particles are used to transfer information on a microfluidic chip. Considering that information-carrying particles can follow two main propagation schemes: passive transport, and active transport, it is not clear which achieves a better information transmission rate. Motivated by this problem, we compare and analyze both propagation schemes by deriving a set of analytical and mathematical tools to measure the achievable information rates of the on-chip molecular communication systems employing passive to active transport. We also use this toolbox to optimize design parameters such as the shape of the transmission area, to increase the information rate. Furthermore, the effect of separation distance between the transmitter and the receiver on information rate is examined under both propagation schemes, and a guidepost to design an optimal molecular communication setup and protocol is presented. <s> BIB036 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Analysis of the capacity and the delay of a bacteria-based communication system in the nano-scale <s> BIB037 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <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> BIB038 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Nanotechnology is enabling the development of devices in a scale ranging from a few to hundreds of nanometers. The nanonetworks that result from interconnecting these devices greatly expand the possible applications, by increasing the complexity and range of operation of the system. Molecular communication is regarded as a promising way to realize this interconnection in a bio-compatible and energy efficient manner, enabling its use in biomedical applications. However, the transmission range of molecular signals is strongly limited due to the large and inherent losses of the diffusion process. In this paper, we propose the employment of Quorum Sensing so as to achieve cooperative amplification of a given signal. By means of Quorum Sensing, we aim to synchronize the course of action of a certain number of emitters, which will transmit the same signal. Under the assumption of a linear channel, such signal will be amplified and thus the transmission range will be consequently extended. Finally, we validate our proposal through simulation. <s> BIB039 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The ability of engineered biological nanomachines to communicate with biological systems at the molecular level is anticipated to enable future applications such as monitoring the condition of a human body, regenerating biological tissues and organs, and interfacing artificial devices with neural systems. From the viewpoint of communication theory and engineering, molecular communication is proposed as a new paradigm for engineered biological nanomachines to communicate with the natural biological nanomachines which form a biological system. Distinct from the current telecommunication paradigm, molecular communication uses molecules as the carriers of information; sender biological nanomachines encode information on molecules and release the molecules in the environment, the molecules then propagate in the environment to receiver biological nanomachines, and the receiver biological nanomachines biochemically react with the molecules to decode information. Current molecular communication research is limited to small-scale networks of several biological nanomachines. Key challenges to bridge the gap between current research and practical applications include developing robust and scalable techniques to create a functional network from a large number of biological nanomachines. Developing networking mechanisms and communication protocols is anticipated to introduce new avenues into integrating engineered and natural biological nanomachines into a single networked system. In this paper, we present the state-of-the-art in the area of molecular communication by discussing its architecture, features, applications, design, engineering, and physical modeling. We then discuss challenges and opportunities in developing networking mechanisms and communication protocols to create a network from a large number of bio-nanomachines for future applications. <s> BIB040 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In this paper, we propose three novel modulation techniques, i.e., concentration-based, molecular-type-based, and molecular-ratio-based, using isomers as messenger molecules for nano communication networks via diffusion. To evaluate achievable rate performance, we compare the proposed techniques with conventional insulin-based concepts under practical scenarios. Analytical and numerical results confirm that the proposed modulation techniques using isomers achieve higher data transmission rate performance than the insulin based concepts. We also investigate the tradeoff between messenger sizes and modulation orders and provide guidelines for selecting from among several possible candidates. <s> BIB041 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <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> BIB042 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <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> BIB043 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In order to understand information processing in neural circuits, it is necessary to detect both electrical and chemical signaling with high spatial and temporal resolution. Although the primary currency of neural information processing is electrical, many of the downstream effects of the electrical signals on the circuits that generate them are dependent on activity-dependent increases in intracellular calcium concentration. It is therefore of great utility to be able to record electrical signals in neural circuits at multiple sites, while at the same time detecting optical signals from reporters of intracellular calcium levels. We describe here a microfluidic multi-electrode array (MMEA) capable of high-resolution extracellular recording from brain slices that is optically compatible with calcium imaging at single cell resolution. We show the application of the MMEA device to record waves of spontaneous activity in developing cortical slices and to perform multi-site extracellular recordings during simultaneous calcium imaging of activity. The MMEA has the unique capability to simultaneously allow focal electrical and chemical stimuli at different locations of the surface of a brain slice. <s> BIB044 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <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> BIB045 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular Communication is an emerging communication paradigm which uses biological particles to encode and transport information. In this paper we present a mathematical analysis of a molecular communication based nanonetwork which uses virus particles as information carriers. The analysis examines the reliability of a multi-path virus based nanonetwork and the effects of physiochemical properties such as diffusion coefficient and particle decay. Based on our analysis, our objective is to create nanonetworks of biological devices within a tissue to support future medical applications. <s> BIB046 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular communication is a new communication paradigm that allows nanomachines to communicate using biological mechanisms and/or components to transfer information (e.g., molecular diffusion, molecular motors). One possible approach for molecular communication is through the use of virus particles that act as carriers for nucleic acid-based information. This paper analyzes multihop molecular nanonetworks that utilize virus particles as information carrier. The analysis examines the physiochemical and biological characteristics of virus particles such as diffusion, absorption, and decay, and how they affect the reliability of multihop communication in molecular nanonetworks. The paper also analyzes the use of a simple implicit acknowledgement protocol for a single-path topology, and compare its performance to defined and random multipath topologies that do not use acknowledgments. Numerical results show that commensurate reliability is achievable for single-path with implicit acknowledgement and multipath topologies. However, the single-path topology exhibits increased communication delay and more uncertain end-to-end communication time. <s> BIB047 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Ca(2+) is a universal carrier of biological information: it controls cell life from its origin at fertilization to its end in the process of programmed cell death. Ca(2+) is a conventional diffusible second messenger released inside cells by the interaction of first messengers with plasma membrane receptors. However, it can also penetrate directly into cells to deliver information without the intermediation of first or second messengers. Even more distinctively, Ca(2+) can act as a first messenger, by interacting with a plasma membrane receptor to set in motion intracellular signaling pathways that involve Ca(2+) itself. Perhaps the most distinctive property of the Ca(2+) signal is its ambivalence: while essential to the correct functioning of cells, Ca(2+) becomes an agent that mediates cell distress, or even (toxic) cell death, if its concentration and movements inside cells are not carefully tuned. Ca(2+) is controlled by reversible complexation to specific proteins, which could be pure Ca(2+) buffers, or which, in addition to buffering Ca(2+), also decode its signal to pass it on to targets. The most important actors in the buffering of cell Ca(2+) are proteins that transport it across the plasma membrane and the membrane of the organelles: some have high Ca(2+) affinity and low transport capacity (e.g., Ca(2+) pumps), others have opposite properties (e.g., the Ca(2+) uptake system of mitochondria). Between the initial event of fertilization, and the terminal event of programmed cell death, the Ca(2+) signal regulates the most important activities of the cell, from the expression of genes, to heart and muscle contraction and other motility processes, to diverse metabolic pathways involved in the generation of cell fuels. <s> BIB048 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> DNA nanotechnology has enabled the construction of DNA origami nanopores; synthetic nanopores that present improved capabilities for the area of single molecule detection. Their extraordinary versatility makes them a new and powerful tool in nanobiotechnology for a wide range of important applications beyond molecular sensing. In this review, we briefly present the recent developments in this emerging field of research. We discuss the current challenges and possible solutions that would enhance the sensing capabilities of DNA origami nanopores. Finally, we anticipate novel avenues for future research and highlight a range of exciting ideas and applications that could be explored in the near future. <s> BIB049 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents. <s> BIB050 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular communication is a relatively new communication paradigm for nanomachines where the communication is realized by utilizing existing biological components found in nature. In recent years ... <s> BIB051 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In this paper, an approach for links reliability estimation in bacterial nanonetworks is presented. In particular, we focus on the usage of replication coding to increase the network performance (i.e., the transmitter nanomachine sends a set of bacteria with equal plasmid messages towards the receiver nanomachine). Unfortunately, the analysis of accurate bacteria mobility model in both 2D and 3D is quite complicated. Therefore, a 2D lattice grid is proposed as a reasonable simplification of the bacterial mobility model, while the success delivery estimation technique is based on the First Passage Time approach. This step allows us to derive the rough and scalable estimation for network characteristics. When being compared to results obtained by simulation of the network with realistic bacteria mobility model, achieved approximation seams being a lower bound, accurate enough for the distance of few millimetres between nanomachines --- distance bacterial nano networks were originally proposed for. The presented analysis leads to a method that is capable of predicting the amount of bacteria to transmit, which is dependent on the environment characteristics in order to satisfy the link quality requirements. By developing an analytical model, this provides a scalable approach for studying bacterial nanonetworks that is far more efficient compared to current simulation techniques. <s> BIB052 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract Bacteria has been proposed in recent years as one approach to achieve molecular communication. Bacterial cells can harbour DNA encoded information and can deliver this information from one nanomachine to another by swimming (motility). One aspect of bacterial communication that could further enhance the performance of information delivery in bacterial nanonetworks is conjugation . Conjugation involves forming a physical connection between the bacteria in order to transfer DNA molecules (i.e., plasmids or chromosomes). However, the fragile physical connection between the bacteria is prone to breakage, in particular under mechanical stress. In this paper, a simple Forward and Reverse coding process is proposed to enhance the performance of information delivery in bacterial nanonetworks. The coding process involves segmenting messages into blocks and integrating this into the bacterial chromosome. Simulation work have been conducted to validate the efficiency of the coding process, where the results have shown positive performance compared to approaches that do not utilize coding or pure conjugation. <s> BIB053 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular communications is a new paradigm that enables nanomachines to communicate within a biological environment. One form of molecular communications is calcium (Ca 2+ ) signaling, which occurs naturally in living biological cells. Ca 2+ signaling enables cells in a tightly packed tissue structure to communicate at short ranges with neighboring cells. The achievable mutual information of Caa 2+ signaling between tissue embedded nanomachines is investigated in this paper, focusing in particular on the impact that the deformation of the tissue structure has on the communication channel. Based on this analysis, a number of transmission protocols are proposed; nanomachines can utilize these to communicate using Ca 2+ signaling. These protocols are static time-slot configuration, dynamic time-slot configuration, dynamic time-slot configuration with silent communication, and improved dynamic time-slot configuration with silent communication (IDTC-SC). The results of a simulation study show that IDTC-SC provides the maximum data rate when tissues experience frequent deformation. <s> BIB054 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Calcium-signaling-based molecular communication has been proposed as one form of communication for short range transmission between nanomachines. This form of communication is naturally found within cellular tissues, where Ca(2+) ions propagate and diffuse between cells. However, the naturally flexible structure of cells usually leads to the cells dynamically changing shape under strain. Since the interconnected cells form the tissue, a change in shape of one cell will change the shape of the neighboring cells and the tissue as a whole. This will in turn dramatically impair the communication channel between the nanomachines. We propose a process for nanomachines utilizing Ca(2+) based molecular communication to infer and detect the state of the tissue, which we term the Molecular Nanonetwork Inference Process. The process employs a threshold based classifier that identifies its threshold boundaries based on a training process. The inference/detection mechanism allows the destination nanomachine to determine: i) the type of tissue deformation; ii) the amount of tissue deformation; iii) the amount of Ca(2+) concentration emitted from the source nanomachine; and iv) its distance from the destination nanomachines. We evaluate the use of three information metrics: mutual information, mutual information with generalized entropy and information distance. Our analysis, which is conducted on two different topologies, finds that mutual information with generalized entropy provides the most accurate inferencing/detection process, enabling the classifier to obtain 80% of accuracy on average. <s> BIB055 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Solid-state nanopores are single-molecule sensors that measure changes in ionic current as charged polymers such as DNA pass through. Here, we present comprehensive experiments on the length, voltage, and salt dependence of the frequency of double-stranded DNA translocations through conical quartz nanopores with mean opening diameter 15 nm. We observe an entropic barrier-limited, length-dependent translocation frequency at 4M LiCl salt concentration and a drift-dominated, length-independent translocation frequency at 1M KCl salt concentration. These observations are described by a unifying convection-diffusion equation, which includes the contribution of an entropic barrier for polymer entry. <s> BIB056 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The new paradigm of molecular communication aims to utilize biological components and systems for developing communication systems. One promising candidate for molecular communication is the use of bacteria to carry information between different nanomachines. However, there is a lack of connection between molecular communication and the design of nanomachines for payload delivery. Utilizing molecular communication to support the transport of payload will further ensure high reliability of delivery to the targeted location. In this paper, we propose the use of bacteria to carry information (which is encoded into plasmids ) for a nano sensor network application. We base the structure of the sensor nanomachine compartments on solutions that have been developed and experimentally validated, and utilize a number of bacterial properties to pick up the plasmids and deliver them to a target. This paper presents the analytical and numerical models for the each of the processes as well as their combination, in particular focusing on the end-to-end delay and reliability for the transfer of information. Extensive analysis have been conducted for the proposed approach by varying a number of parameters (e.g., quantity of bacteria, area of deployment, and number of target sites) to determine the overall system performance. <s> BIB057 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Molecular Communication (MC) is a nano-scale communication paradigm where the information is carried by molecular signals. To establish information transmission using molecules, biological nanomachines can be utilized as transmitters and receivers. A bacteria can be programmed as a biotransceiver by modifying their genetic code to implement biological circuits. In this paper, genetically engineered bacteria-based biotransceivers are investigated for MC, where bacteria can generate and respond to the molecular signals. A biochemical model of biological circuits is presented, and both analog and digital signaling are studied. The challenges in connecting basic biological circuits to build these blocks are revealed. A biotransceiver architecture is introduced that combines sensing, transmitting, receiving and processing blocks. Furthermore, biological circuit design framework is proposed for transmission of signals with M-ary pulse amplitude modulation. The biological circuits designed for biotransceiver are elaborated via numerical results based on biochemical parameters of the genetically engineered bacteria. The provided results show that using biological circuits, bacteria can function as a transmitter and receiver node for MC. Our work stands as a basis for future biotransceiver design for MC. <s> BIB058 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Calcium (Ca2+)-signaling-based molecular communication is a short-range communication process that diffuses and propagates ions between the cells of a tissue. The communication process is initiated via stimulation and amplification of the production of Ca2+ ions within a cell; these ions then diffuse through a physical connection between cells called a gap junction. Ca2+ signaling can be found in different classes of cell. In excitable cells, initiation of the Ca2+-signaling process is accompanied by an electrical component; for nonexcitable cell types, the electrical component is absent; while hybrid cells exhibit both behaviors. This paper provides a comparison and analysis of the communication behavior in tissues comprised three specific cell types that utilize Ca2+ signaling: epithelium cells (nonexcitable), smooth muscle cells (excitable), and astrocytes (hybrid). The analysis focuses on spatiotemporal Ca2+ concentration dynamics and how they are influenced by the intracellular signaling process, the molecular diffusion delay, the gain and capacity of the communication channel, as well as intracellular signaling interference. This analysis of the communication behavior in the context of tissues provides insights useful for, inter alia , the design of nanomachines that are situated within tissues and that use analysis of the communication channel to infer tissue health. <s> BIB059 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Lab-on-chip devices and point-of-care diagnostic chip devices are composed of many different components such as nanosensors that must be able to communicate with other components within the device. Molecular communication is a promising solution for on-chip communication. In particular, kinesin driven microtubule (MT) motility is an effective means of transferring information particles from one component to another. However, finding an optimal shape for these channels can be challenging. In this paper we derive a mathematical optimization model that can be used to find the optimal channel shape and dimensions for any transmission period. We derive three specific models for the rectangular channels, regular polygonal channels, and regular polygonal ring channels. We show that the optimal channel shapes are the square-shaped channel for the rectangular channel, and circular-shaped channel for the other classes of shapes. Finally, we show that among all 2 dimensional shapes the optimal design choice that maximizes information rate is the circular-shaped channel. <s> BIB060 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Multiplexed sensing of single molecules can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures, allowing four different antibodies to be simultaneously detected at nanomolar concentrations. <s> BIB061 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The threading of a polymer chain through a small pore is a classic problem in polymer dynamics and underlies nanopore sensing technology. However important experimental aspects of the polymer motion in a solid-state nanopore, such as an accurate measurement of the velocity variation during translocation, have remained elusive. In this work we analysed the translocation through conical quartz nanopores of a 7 kbp DNA double-strand labelled with six markers equally spaced along its contour. These markers, constructed from DNA hairpins, give direct experimental access to the translocation dynamics. On average we measure a 5% reduction in velocity during the translocation. We also find a striking correlation in velocity fluctuations with a decay constant of 100s of {\mu}s. These results shed light on hitherto unresolved problems in the dynamics of DNA translocation and provide guidance for experiments seeking to determine positional information along a DNA strand. <s> BIB062 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, γ-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional “neural pixel” creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents. <s> BIB063 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Artificial chemical stimulation could provide improvements over electrical neurostimulation. Physiological neurotransmission between neurons relies on the nanoscale release and propagation of specific chemical signals to spatially-localized receptors. Current knowledge of nanoscale fluid dynamics and nanofluidic technology allows us to envision artificial mechanisms to achieve fast, high resolution neurotransmitter release. Substantial technological development is required to reach this goal. Nanofluidic technology — rather than microfluidic — will be necessary; this should come as no surprise given the nanofluidic nature of neurotransmission. This perspective reviews the state of the art of high resolution electrical neuroprostheses and their anticipated limitations. Chemical release rates from nanopores are compared to rates achieved at synapses and with iontophoresis. A review of microfluidic technology justifies the analysis that microfluidic control of chemical release would be insufficient. Novel nanofluidic mechanisms are discussed, and we propose that hydrophobic gating may allow control of chemical release suitable for mimicking neurotransmission. The limited understanding of hydrophobic gating in artificial nanopores and the challenges of fabrication and large-scale integration of nanofluidic components are emphasized. Development of suitable nanofluidic technology will require dedicated, long-term efforts over many years. <s> BIB064 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Utilizing bacteria as information carriers is a promising technique for molecular communication to establish connections and networking capabilities between micro- and nanoscale devices. A particular process, that is of interest in this paper, and vital to achieve reliable networking performance in bacterial nanonetwork, is conjugation. Conjugation is a process where bacteria come within close range to form physical connections to allow plasmids to be transferred. However, there are a number of processes that could cause loss or damage during the transfer process, such as external vibrations. Message encoding techniques are envisioned as a promising technique to mitigate these effects. In this study we first define the concept of optimal message encoding for bacterial nanonetworks providing the upper bound on the message delivery time and the probability of message delivery within the specified time. We then investigate the effect of encoding on the performance of these metrics by proposing and numerically comparing several feasible encoding techniques. The performance comparison has been done using a specifically developed simulation environment capturing bacteria movement and interactions. Numerical results demonstrate that even the simple encoding strategies allow to significantly improve the performance compared to the baseline system. <s> BIB065 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> This paper describes packet fragmentation and reassembly to achieve reliable molecular communication among bionanomachines. In the molecular communication described in this paper, a sender bionanomachine performs packet fragmentation, dividing a large molecular message into smaller pieces and embedding into smaller molecular packets, so that molecular packets have higher diffusivity to reach the receiver bionanomachine. The receiver bionanomachine then performs packet reassembly to retrieve the original molecular message from a set of molecular packets that it receives. To examine the effect of packet fragmentation and reassembly, we develop analytical models and conduct numerical experiments. Numerical results show that packet fragmentation and reassembly can improve the message delivery performance. Numerical results also indicate that packet fragmentation and reassembly may degrade the performance in the presence of drift in the environment. <s> BIB066 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> This work studies communication over diffusion- based molecular timing (DBMT) channels. The transmitter {\em simultaneously} releases {\em multiple} small information particles, where the information is encoded in the time of release. The receiver decodes the transmitted information based on the random time of arrival of the information particles, which is represented as an additive noise channel. For a DBMT channel, without flow, this noise follows the L\'evy distribution. Under this channel model, the maximum- likelihood (ML) detector is derived and shown to have high computational complexity. It is further shown that for {\em any} additive noise channel with $\alpha$-stable noise, $\alpha < 1$, such as the DBMT channel, a linear receiver is {\em not able to take advantage} of the release of multiple information particles. Thus, instead of the common low-complexity linear approach, a new detector, which is based on the first arrival (FA) among all the transmitted particles, is derived. Numerical simulations indicate that for a small to medium number of released particles, the performance of the FA detector is very close to the performance of the ML detector. <s> BIB067 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Nanopore sensors show great potential for rapid, single-molecule determination of DNA sequence information. Here, we develop an ionic current-based method for determining the positions of short sequence motifs in double-stranded DNA molecules with solid-state nanopores. Using the DNA-methyltransferase M.TaqI and a biotinylated S-adenosyl-l-methionine cofactor analogue we create covalently attached biotin labels at 5'-TCGA-3' sequence motifs. Monovalent streptavidin is then added to bind to the biotinylated sites giving rise to additional current blockade signals when the DNA passes through a conical quartz nanopore. We determine the relationship between translocation time and position along the DNA contour and find a minimum resolvable distance between two labeled sites of ∼200 bp. We then characterize a variety of DNA molecules by determining the positions of bound streptavidin and show that two short genomes can be simultaneously detected in a mixture. Our method provides a simple, generic single-molecule detection platform enabling DNA characterization in an electrical format suited for portable devices for potential diagnostic applications. <s> BIB068 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The authors encode pixel values of a short motion picture into the DNA of a population of Escherichia coli. <s> BIB069 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Implantable devices offer an alternative to systemic delivery of drugs for the treatment of neurological disorders. A microfluidic ion pump (µFIP), capable of delivering a drug without the solvent through electrophoresis, is developed. The device is characterized in vitro by delivering γ-amino butyric acid to a target solution, and demonstrates low-voltage operation, high drug-delivery capacity, and high ON/OFF ratio. It is also demonstrated that the device is suitable for cortical delivery in vivo by manipulating the local ion concentration in an animal model and altering neural behavior. These results show that µFIPs represent a significant step forward toward the development of implantable drug-delivery systems. <s> BIB070 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> From a systematic study of the concentration driven diffusion of positive and negative ions across porous 2D membranes of graphene and hexagonal boron nitride (h-BN), we prove their cation selectivity. Using the current–voltage characteristics of graphene and h-BN monolayers separating reservoirs of different salt concentrations, we calculate the reversal potential as a measure of selectivity. We tune the Debye screening length by exchanging the salt concentrations and demonstrate that negative surface charge gives rise to cation selectivity. Surprisingly, h-BN and graphene membranes show similar characteristics, strongly suggesting a common origin of selectivity in aqueous solvents. For the first time, we demonstrate that the cation flux can be increased by using ozone to create additional pores in graphene while maintaining excellent selectivity. We discuss opportunities to exploit our scalable method to use 2D membranes for applications including osmotic power conversion. <s> BIB071 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Abstract Nanomedicine is revolutionizing current methods for diagnosing, treatment and prevention of diseases with the integration of molecular biology, biotechnology as well as nanotechnology for sensing and actuation capabilities at the molecular scale using nanoscale devices, namely nanomachines. While numerous examples of these applications have been tested in vivo , the real deployments are far from reality. Limitations in controlling, monitoring, miniaturization, and computing inhibit access and manipulation of information at the nano-scale. Integrating communication and networking functionalities provide new opportunities for such challenges with the newly introduced Molecular Communications. These natural communication systems are found with plurality inside the human body. The current challenge is to utilize these natural systems to create artificial biocompatible communication networks that can interconnect multiple nanomachines in multiple parts of the body and connected to the cloud, is defined as the Internet of Bio-Nano Things ( IoBNT ). Nanonetworks inside cellular tissues perform communication using a signaling process such as Ca 2+ . This specifically signaling process is very important for many regulatory functions in tissues and its control and communication is crucial to allow nanomedicine capabilities towards diagnosis and treatments of diseases at the nano-scale. This paper presents a review of techniques that enable the design of the Ca 2+ -signaling-based molecular communication system for cellular tissues, essential tools for its deployment, application and, lastly, the research future direction in this field. In the end, one must acquire the sufficient knowledge to understand both biological and telecommunication concepts that encompass this technology to bring it further. <s> BIB072 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Synthetic DNA is durable and can encode digital data with high density, making it an attractive medium for data storage. However, recovering stored data on a large-scale currently requires all the DNA in a pool to be sequenced, even if only a subset of the information needs to be extracted. Here, we encode and store 35 distinct files (over 200 MB of data), in more than 13 million DNA oligonucleotides, and show that we can recover each file individually and with no errors, using a random access approach. We design and validate a large library of primers that enable individual recovery of all files stored within the DNA. We also develop an algorithm that greatly reduces the sequencing read coverage required for error-free decoding by maximizing information from all sequence reads. These advances demonstrate a viable, large-scale system for DNA data storage and retrieval. <s> BIB073 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Local drug presentation made possible by drug-eluting depots has demonstrated benefits in a vast array of diseases, including in cancer, microbial infection and in wound healing. However, locally-eluting depots are single-use systems that cannot be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. New strategies to noninvasively refill drug-eluting depots could dramatically enhance their clinical use. In this report we present a refillable hydrogel depot system based on bioorthogonal click chemistry. The click-modified hydrogel depots capture prodrug refills from the blood and subsequently release active drugs locally in a sustained manner. Capture of the systemically-administered refills serves as an efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills achieve sustained release at precancerous tumor sites to improve cancer therapy while eliminating systemic side effects. The ability to target tissues without enhanced permeability could allow the use of refillable depots in cancer and many other medical applications. <s> BIB074 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use. An epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium provides therapeutic benefits in a rat model of myocardial infarction. <s> BIB075 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> Our ability to generate bacterial strains with unique and increasingly complex functions has rapidly expanded in recent times. The capacity for DNA synthesis is increasing and costing less; new tools are being developed for fast, large-scale genetic manipulation; and more tested genetic parts are available for use, as is the knowledge of how to use them effectively. These advances promise to unlock an exciting array of 'smart' bacteria for clinical use but will also challenge scientists to better optimize preclinical testing regimes for early identification and validation of promising strains and strategies. Here, we review recent advances in the development and testing of engineered bacterial diagnostics and therapeutics. We highlight new technologies that will assist the development of more complex, robust and reliable engineered bacteria for future clinical applications, and we discuss approaches to more efficiently evaluate engineered strains throughout their preclinical development. <s> BIB076 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> For therapies targeting diseases of the gastrointestinal tract, we and others envision probiotic bacteria that synthesize and excrete biotherapeutics at disease sites. Toward this goal, we have engineered commensal E. coli that selectively synthesize and secrete a model biotherapeutic in the presence of nitric oxide (NO), an intestinal biomarker for Crohn's disease (CD). This is accomplished by co-expressing the pore forming protein TolAIII with the biologic, granulocyte macrophage-colony stimulating factor (GM-CSF). We have additionally engineered these bacteria to accumulate at sites of elevated NO by engineering their motility circuits and controlling pseudotaxis. Importantly, because we have focused on in vitro test beds, motility and biotherapeutics production are spatiotemporally characterized. Together, the targeted recognition, synthesis, and biomolecule delivery comprises a "smart" probiotics platform that may have utility in the treatment of CD. Further, this platform could be modified to accommodate other pursuits by swapping the promoter and therapeutic gene to reflect other disease biomarkers and treatments, respectively. <s> BIB077 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> BACKGROUND Nearly five decades ago, visionary scientists hypothesized that genetic modification by exogenous DNA might be an effective treatment for inherited human diseases. This “gene therapy” strategy offered the theoretical advantage that a durable and possibly curative clinical benefit would be achieved by a single treatment. Although the journey from concept to clinical application has been long and tortuous, gene therapy is now bringing new treatment options to multiple fields of medicine. We review critical discoveries leading to the development of successful gene therapies, focusing on direct in vivo administration of viral vectors, adoptive transfer of genetically engineered T cells or hematopoietic stem cells, and emerging genome editing technologies. ADVANCES The development of gene delivery vectors such as replication-defective retro viruses and adeno-associated virus (AAV), coupled with encouraging results in preclinical disease models, led to the initiation of clinical trials in the early 1990s. Unfortunately, these early trials exposed serious therapy-related toxicities, including inflammatory responses to the vectors and malignancies caused by vector-mediated insertional activation of proto-oncogenes. These setbacks fueled more basic research in virology, immunology, cell biology, model development, and target disease, which ultimately led to successful clinical translation of gene therapies in the 2000s. Lentiviral vectors improved efficiency of gene transfer to nondividing cells. In early-phase clinical trials, these safer and more efficient vectors were used for transduction of autologous hematopoietic stem cells, leading to clinical benefit in patients with immunodeficiencies, hemoglobinopathies, and metabolic and storage disorders. T cells engineered to express CD19-specific chimeric antigen receptors were shown to have potent antitumor activity in patients with lymphoid malignancies. In vivo delivery of therapeutic AAV vectors to the retina, liver, and nervous system resulted in clinical improvement in patients with congenital blindness, hemophilia B, and spinal muscular atrophy, respectively. In the United States, Food and Drug Administration (FDA) approvals of the first gene therapy products occurred in 2017, including chimeric antigen receptor (CAR)–T cells to treat B cell malignancies and AAV vectors for in vivo treatment of congenital blindness. Promising clinical trial results in neuromuscular diseases and hemophilia will likely result in additional approvals in the near future. In recent years, genome editing technologies have been developed that are based on engineered or bacterial nucleases. In contrast to viral vectors, which can mediate only gene addition, genome editing approaches offer a precise scalpel for gene addition, gene ablation, and gene “correction.” Genome editing can be performed on cells ex vivo or the editing machinery can be delivered in vivo to effect in situ genome editing. Translation of these technologies to patient care is in its infancy in comparison to viral gene addition therapies, but multiple clinical genome editing trials are expected to open over the next decade. OUTLOOK Building on decades of scientific, clinical, and manufacturing advances, gene therapies have begun to improve the lives of patients with cancer and a variety of inherited genetic diseases. Partnerships with biotechnology and pharmaceutical companies with expertise in manufacturing and scale-up will be required for these therapies to have a broad impact on human disease. Many challenges remain, including understanding and preventing genotoxicity from integrating vectors or off-target genome editing, improving gene transfer or editing efficiency to levels necessary for treatment of many target diseases, preventing immune responses that limit in vivo administration of vectors or genome editing complexes, and overcoming manufacturing and regulatory hurdles. Importantly, a societal consensus must be reached on the ethics of germline genome editing in light of rapid scientific advances that have made this a real, rather than hypothetical, issue. Finally, payers and gene therapy clinicians and companies will need to work together to design and test new payment models to facilitate delivery of expensive but potentially curative therapies to patients in need. The ability of gene therapies to provide durable benefits to human health, exemplified by the scientific advances and clinical successes over the past several years, justifies continued optimism and increasing efforts toward making these therapies part of our standard treatment armamentarium for human disease. <s> BIB078 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> In recent years, progresses in nanotechnology have established the foundations for implementing nanomachines capable of carrying out simple but significant tasks. Under this stimulus, researchers have been proposing various solutions for realizing nanoscale communications, considering both electromagnetic and biological communications. Their aim is to extend the capabilities of nanodevices, so as to enable the execution of more complex tasks by means of mutual coordination, achievable through communications. However, although most of these proposals show how devices can communicate at the nanoscales, they leave in the background specific applications of these new technologies. Thus, this paper shows an overview of the actual and potential applications that can rely on a specific class of such communications techniques, commonly referred to as molecular communications. In particular, we focus on health-related applications. This decision is due to the rapidly increasing interests of research communities and companies to minimally invasive, biocompatible, and targeted health-care solutions. Molecular communication techniques have actually the potentials of becoming the main technology for implementing advanced medical solution. Hence, in this paper we provide a taxonomy of potential applications, illustrate them in some detail, along with the existing open challenges for them to be actually deployed, and draw future perspectives. <s> BIB079 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> 1) Information Carrying Molecules: <s> We study diversity in one-shot communication over molecular timing channels. We consider a channel model where the transmitter simultaneously releases a large number of information particles, while the information is encoded in the time of release. The receiver decodes the information based on the random time of arrival of the information particles. The random propagation is characterized by the general class of right-sided unimodal densities. We characterize the asymptotic exponential decrease rate of the probability of error as a function of the number of released particles, and denote this quantity as the system diversity gain. Four types of detectors are considered: the maximum-likelihood (ML) detector, a linear detector, a detector that is based on the first arrival (FA) among all the transmitted particles, and a detector based on the last arrival (LA). When the density characterizing the random propagation is supported over a large interval, we show that the simple FA detector achieves a diversity gain very close to that of the ML detector. On the other hand, when the density characterizing the random propagation is supported over a small interval, we show that the simple LA detector achieves a diversity gain very close to that of the ML detector. <s> BIB080
Reliable and robust MC necessitates chemically stable IMs that can be selectively received at the receiver. In addition, environmental factors, such as molecular deformation due to enzymes and changes in pH can have severe effects on IMs BIB020 and degrade the performance of MC. Next, we provide a discussion on several types of IMs that can be utilized for MC. a) Nucleic Acids: Nucleic acids, i.e., deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), are promising candidates as IMsby being biocompatible and chemically stable especially in in-body applications. In the nature, DNA is carrying information one generation to another. RNA is utilized as messenger molecules for intercellular communication in plants and animals to catalyze biological reactions such as localized protein synthesis and neuronal growth BIB021 , BIB034 . In a similar manner, nucleic acids can be exploited in MC-Tx to carry information. DNA has a double stranded structure whereas RNA is single stranded molecule often folded on to itself, and the existence of hydroxyl groups in RNA makes it less stable to hydrolysis compared to DNA. Hence, DNA can be expected to outperform RNA as an information carrying molecule. Recent advancements in DNA/RNA sequencing and synthesis techniques have enabled DNA-encoded MC BIB061 BIB068 BIB006 . For information transmission, communication symbols can be realized with DNA/RNA strands having different properties, i.e., length BIB056 , dumbbell hairpins BIB061 , BIB062 , short sequence motifs/labels BIB068 and orientation BIB011 . For information detection, solid-state BIB068 , BIB015 and DNA-origami BIB049 based nanopores can be utilized to distinguish information symbols based on the properties of DNA/RNA strands by examining the ionic current characteristics during translocation, i.e., while DNA/RNA strands pass through the nanopores as illustrated in Fig. 3 . The utilization of nanopores for DNA symbol detection also enables the miniaturization of MC-capable devices towards the realization of IoNT. According to BIB061 , 3-bit barcode-coded DNA strands with dumbbell hairpins can be detected through nanopores with 94% accuracy. In BIB011 , four different RNA molecules having different orientations are translocated with more than 90% accuracy while passing through transmembrane protein nanopores. Nanopore-based detection can also pave the way for detecting cancer biomarkers from RNA molecules for early detection of cancers as in BIB030 . However, this requires high sensitivity and selectivity. Translocation time of DNA/RNA molecules through nanopores depends on the voltage, concentration and length of the DNA/RNA symbols, and the translocation of symbols can take from a few ms up to hundred ms time frames BIB061 , BIB062 . Considering the slow diffusion channel in MC, transmission/detection of DNA-encoded symbols do not introduce a bottleneck and multiple detections can be performed during each symbol transmission. Therefore, the utilization of DNA/RNA strands is promising for high capacity communication between nanomachines as the number of symbols in the modulation scheme can be increased by exploiting multiple properties of DNA/RNA at the same time. Hence, the utilization of DNA as information carrying molecule paves the way for high capacity links between nanomachines by enabling higher number of molecules that can be selectively received at the Rx. In addition, information can be encoded into the base sequences of DNAs, which is also known as nucleotide shiftkeying (NSK). In BIB073 , 35 distinct data files over 200MB were encoded and stored by using more than 13 million nucleotides. More importantly, this work proposes a method for reading the stored data in DNA sequences using a randomaccess approach. Thanks to high information density of DNA, application of NSK in DNA-based MC may boost the typically low data rates of MC up to the extend of competing with traditional wireless communication standards. In NSK, information carrying DNA and RNA strands can be placed into bacteria and viruses. In BIB022 , bacteria based nanonetworks, where bacteria are utilized as a carrier of IMs, have been proposed and analytically analyzed. In BIB069 , a digital movie is encoded into DNA sequences and these strands are placed into bacteria. However, DNA/RNA reading/writing speed and cost at the moment limit the utilization of NSK in a practical system. Theoretical ++ ions are utilized in many complex signaling mechanisms in biology including neuronal transmission in an excitatory synapse, exocytosis, cellular motility, apoptosis and transcription  . This renders elemental ions one of the viable ways to communicate with living organisms for possible applications. Correspondingly, many transmitter device  and nanonetwork architectures BIB009 based on elemental ion signaling have been proposed in literature. c) Neurotransmitters: Neural interfacing is one of the hottest contemporary research topics with a diverse range of applications. In this respect, stimulation of neurons using their own language, i.e., neurotransmitters, stands out as the best practice. Various transmitter architectures for the most common neurotransmitters, e.g., glutamate, γ-amino butyric acid (GABA), aspartate and acetylcholine have been reported in literature BIB018 , BIB070 ,  . d) Proteins: Proteins comprise the basic building blocks of all mechanisms in life. They are synthesized by cells from amino acids utilizing information encoded inside DNA, and regulate nearly all processes within the cell, including the protein synthesis process itself, so that they form a self regulatory network. Proteins are commonly used as IMs by biological systems both in intracellular pathways, e.g., enzymes within vesicles between the endoplasmic reticulum and the Golgi apparatus  , and intercellular pathways, e.g., hormones within exosomes, vesicles secreted from a multitude of cell types via exocytosis  . Artificial transmission of proteins have been long considered within the context of applications such as protein therapy BIB004 . From MC point of view, use of proteins as IMs by genetically engineered bacteria is regarded as one of the possible biological MC architectures, where engineered genetic circuits have been proposed to implement various logic gates and operations necessary for networking BIB023 . e) Other Molecules: Many other types of molecules have been used or considered as IMs in literature. These include synthetic pharmaceuticals BIB007 , therapeutic nanoparticles  , as well as organic hydrofluorocarbons BIB035 and isomers BIB041 . 2) Nanomaterial-based MC-Tx Architectures: In the literature, MC-Tx is generally assumed to be an ideal point source capable of perfectly transmitting molecular messages encoded in the number, type or release time of molecules to the channel instantly or continuously, neglecting the stochasticity in the molecule generation process, and the effect of Tx geometry and channel feedback. Despite of the various studies investigating MC, physical implementation of MC-Tx stands as an important open research issue especially in micro/nanoscale. However, there exist some works on macroscale demonstration of MC. In BIB042 , the authors implemented a macroscale MC system with an electronically controlled spray as MC-Tx, which is capable of releasing alcohol, and alcohol metal-oxide sensor as MC-Rx. According to this experiment, the macroscale MC setup achieves 0.2bps with 2m communication range. Since there are almost no micro/nanoscale implementation of MC-Tx, we investigate and propose MC-Tx architectures by exploiting recent advancements in nanotechnology, novel materials and microfluidics. As discussed in Section II-A, design of MC-Tx in micro/nanoscale is an extremely challenging task including various requirements such as biocompability, miniaturization and lifetime of the device. For reducing the dimensions of MCTx architectures to microscales, microfluidics and microfluidic droplet technologies are promising. Inside droplets, IMs can be transmitted in a precisely controlled manner, such that even logic gates can be implemented with microfluidic chips as demonstrated in BIB016 . Feasibility of utilizing droplets for communication purposes has been suggested in  . In addition, microfluidic chips can be fabricated by using Polydimethylsiloxane (PDMS), which is a biocompatible polymer BIB010 . The authors of BIB036 theoretically compare achievable data rates of passive transport, i.e., diffusive channel, and active transport, i.e., flow-assisted channel via external pressure or molecular motors, in a microfluidic environment. According to this study, active transport improves achievable data rates thanks to faster movement of IMs from Tx to Rx compared to passive transport. A new modulation scheme based on distance between droplets has been introduced in BIB043 by exploiting hydrodynamic microfluidic effects. Although it is not originally proposed as MC-Tx, microfluidic neural interfaces with chemical stimulation capabilities, i.e., devices that release neurotransmitters such as glutamate or γ-aminobutyric acid (GABA) to stimulate or inhibiting neural signals BIB044 , BIB063 , BIB019 , operates same as MC-Tx. Therefore, the studies on neural interfaces with chemical stimulation capabilities can be considered as baseline for designing micro/nanoscale MC-Tx. However, leakage of IM molecules while there is no signal transmission stands as a significant challenge for microfluidic based MC-Txs. It is not possible to eliminate the problem, but there are some possible solutions to reduce or control the amount of leakage. Hydrophobic nanopores can be utilized as shown in Figure  4 (a) such that the liquid inside the container can be separated from the medium when there is no pressure inside the MCTx. This solution has two drawbacks. Since there is a need for external pressure source, it is hard to design a practical standalone MC-Tx with this setup. Secondly, this solution does not completely eliminate the IM leakage; hence, the authors of BIB064 suggest the utilization of porous membranes and electrical control of fluids to further improve MC-Tx against IM leakage. Nanoporous graphene membranes can provide molecule selectivity BIB071 by adjusting pore size depending on the size of IM. In addition, graphene is also proven to be biocompatible as demonstrated in  . If the pore size of the graphene membrane can be adjusted in a way that IMs can barely pass through, negatively charging the graphene membrane can decrease the pore size with the additional electrons such that some level of control can be introduced to reduce lM leakage. In addition, an electrode plate placed at the bottom of the container can be utilized to pull and push charged IMs as illustrated in Figure 4 (b). This way, an electric field (E-field) can be generated in the liquid containing charged IMs and the direction of E-field can be utilized to ease or harden the release of charged IMs. MC-Tx can be also realized with electrical stimuliresponsive thin film hydrogels by performing E-field modulated release and uptake of IMs BIB008 as in Figure 4 (c). Hydrogels, widely utilized in smart drug delivery, are biocompatible polymers that can host molecules, and reversibly swell/deswell in water solution upon application of a stimuli, resulting in release/uptake of molecules. This architecture can be further improved via a porous graphene controlling its micro-environment. E-field stimuli can be generated by two electrodes placed at the opposite walls of the reservoir. Refilling the IM reservoirs is another significant challenge in MC-Tx design, which can be solved with the replenishable drug delivery methods, e.g., oligodeoxynucleotides (ODN) modification BIB050 , click chemistry BIB074 , and refill lines BIB075 . Up to this point, we consider the design of MC-Tx only in liquid medium. For airborne MC, we propose an MCTx architecture consisting of a molecular reservoir sealed by a porous graphene membrane, accommodating a wax layer containing IMs as in Figure 4 (d). The rest of the reservoir is filled with water, in which the IMs dissolve. Upon application of heat via E-field through conducting walls of the reservoir, the module sweats IM-rich water through membrane pores, and IMs become airborne upon evaporation, and provide a continuous release of IMs. 3) Biological MC-Tx Architectures: An alternative approach to nanomaterial-based architectures for MC, which in most cases are inspired by their biological counterparts, resides in rewiring the already established molecular machinery of biological realm to engineer biological nanomachines that network via MC to accomplish specific tasks. At the cost of increased complexity, this approach has various advantages over nanomaterial-based designs including inherent biocompatibility and already integrated production, transport and transmission modules for a wealthy selection of IMs and architectures. a) Bacterial Conjugation-based Transmission: Bacterial conjugation is one of the lateral gene transfer processes between two bacteria. More specifically, some plasmids inside bacteria, mostly circular small double-stranded DNA molecules physically distinct from the main bacterial DNA, can replicate and transfer itself into a new bacteria BIB001 . These plasmids encode the conjugative "sex" pilus, which upon receiving a right molecular stimulus from a neighboring bacteria is translated. The produced pilus extends out of the donor cell, attaches to the recipient cell, and then retracts to get the two cells in contact with their intracellular media joined through the pilus hole. Single strand DNA (ssDNA) of the plasmid is then transferred from the donor cell to the recipient cell. utilizing bacterial conjugation as a means of information transmission for MC necessitates at least partial control over bacteria behavior, which is achieved by means of genetically engineering the bacteria. At the core of all genetical engineering schemes lies the concept of gene regulation via a process known as RNA interference (RNAi), which has provided us with the means of manipulating gene expressions in targeted cells or bacteria, paving the way for genetical engineered bacteria based MC architectures BIB005 . RNAi is observed to serve as a mediator of inter-kingdom MC BIB024 . In particular, it is shown that short hairpin RNA (shRNA) expressing bacteria elicit RNAi in mammals BIB012 , rendering bacteria mediated RNAi-based diagnosis and therapeutics a promising prospect BIB076 . In this respect, recently BIB077 proposed a platform of genetically engineered bacteria as vehicles for localized delivery of therapeutics towards applications for Crohn's disease. From MC perspective, genetically engineered bacteria have been envisioned to be utilized in various ways with different transmitter architectures. Below, we collate various novel research directions in biological transmitter architectures for MC enabled by the recent advancements in genetic engineering. It is important to note that, conjugative pili are typically few microns in length, which from MC point of view dramatically decreases the transmission radius. Accordingly, BIB022 has proposed engineered bacteria with flagella, e.g., E. coli as the carriers of information, i.e., sequenced DNA strands, which establish a communication link between two nanomachine nodes that can interface and exchange DNA strands with the bacteria. The sequenced DNA message resides within a plasmid. The behavior of bacteria is controlled via chemotaxis by release of attractants from the nodes, and is regulated by encoded active regions on the plasmid. To avoid interference with behavior regulation the message section of the plasmid is inactivated, i.e., it is not expressed, which can be achieved by avoiding consensus promoter sequences within the message. Consensus promoters are necessary for the RNA polymerase to attach to the DNA and start transcription. The message section of the plasmid also contains the destination address, which renders message relaying across nodes possible. The authors develop a simulator for flagellated bacteria propagation, which they combine with analytical models for biological processes involved to obtain the end-to-end delay and capacity of the proposed MC channel for model networking tasks. In BIB031 , utilization of flagellated bacteria for medium range (µm-mm) MC networks is suggested, where authors present a physical channel characterization of the setup together with a simulator based on it. BIB037 extends the model in BIB022 by accounting for mutations in the bacteria population, and also considering asynchronous mode of operation of the nodes. In BIB038 , the authors also consider a similar setup utilizing bacterial conjugation, but employ opportunistic routing, where opportunistic conjugation between bacteria is allowed in contrast to strict bacteria-node conjugation assumed in BIB022 . However, it requires node labeling of bacteria, and additional attractant release by bacteria to facilitate bacteria-bacteria contact for opportunistic routing. The authors extend this work with BIB045 by additionally assuming the nanomachine nodes as capable of releasing antibiotics that kill bacteria with useless or no content to decrease noise levels by avoiding overpopulation. Moreover, they allow multiple number of plasmids per bacterium, which, contrary to their previous work and BIB022 , allows simultaneous communication between multiple source and destination nodes over the same network. Later, BIB051 considers the design of the nanomachine node in more detail, and BIB052 derives an analytical model to estimate the successful delivery rates within proposed framework. BIB057 analyzes via simulations the end-to-end delay and reliability of conjugation based transmission within the same scenario for varying system parameters such as quantity of bacteria, area of deployment and number of target sites. An important factor that restricts reliable successful delivery in conjugation based bacterial networks is incomplete DNA transfer due fragile nature of the process, the effect of which is pronounced over multiple transfers. To mitigate losses due to this effect, which always results in a loss of information from the tail part of DNA, BIB053 devises a Forward-Reverse Coding (FRC) scheme, where messages are encoded in both directions and sent simultaneously over the same channel via dedicated sets of bacteria, to equally distribute losses to both ends of DNA. The performance of FRC is later compared with a cyclic shift coding (CSC) scheme, in which DNA message is partitioned into N smaller blocks and is cyclically shifted to create N versions of the same content starting with corresponding blocks, and similar to FRC transmitted simultaneously via dedicated bacteria populations BIB065 . Expectedly, CSC provided higher link probability than FRC, which outperformed straight encoding. In a very similar spirit, BIB066 considers packet fragmentation at transmitter and reassembly at receiver, which has the additional advantage of faster propagation due to diminished size of carriers. They observe that this protocol increases reliability over diffusive channels, however, it degrades communication when there is strong enough drift, which can be attributed to the heightened diffusion rates. The MC transmitter module of the architecture based on bacterial conjugation outlined above, indeed, is composed of several submodules, i.e., the transmitter module of the nanomachine node, the bacteria itself via chemotaxis and the pilus-based sexual conjugation module, which is a reflection of the trademark high complexity involved with biological architectures. In return, the reward is the achievement of unprecedented data rates via MC thanks to the high information density of DNA. b) Virus-based Transmission: Viruses have initially been studied as infectious agents and as tools for investigating cell biology, however, their use as templates for transferring genetic materials to cells has provided us with the means of genetically engineering bacteria BIB002 , and unlocked a novel treatment technique in medicine, e.g., gene therapy BIB078 . A virus is a bio-molecular complex that carries DNA (or RNA), which is packed inside a protein shell, called capsid, that is enveloped by a lipid layer. The capsid has (at least) an entrance to its interior, through which the nucleic payload is packed via a ring ATPase motor protein BIB025 . Located near the entrance are functional groups that facilitate docking on a cell by acting as ligands to receptors on it. Once docked, the nucleic content is injected into the cell, which triggers the cell's production line to produce more of virus' constituent parts and DNA. These self-organize into fully structured viruses, which finally burst out of the host cell to target new ones. From MC perspective, viral vectors are considered to be one of the possible solutions in transmitting DNA between nanonetworking agents. The concept is similar to bacterial conjugation based transmission, as both encode information into transmitted DNA, but, in contrast viral vectors are immotile and their propagation is dictated by passive diffusion. However, they are comparatively smaller than bacteria, so that more of them can be deployed in a given channel, and they diffuse faster. Moreover, the ligand-receptor docking mechanism, which serves as a header for receptor/cell specific long range targeting, enables the possibility of design of very complex and large scale networking schemes with applications in gene therapy BIB079 . Furthermore, considering high information density of DNA, virus based MC stands out as one of the MC protocols viable to support high data rates. Yet, models of MC networks utilizing viral vectors are still very few. In particular, BIB023 proposes utilization of engineered cells as platforms for devices and sensors to interface to nanonetworks. These engineered cells are assumed to be capable of virus production and excretion to facilitate desired networking, where a modular approach is presented for modeling of the genetic circuitry involved in the modulation of viral expression based on incoming extracellular signaling. Based on the model developed in BIB023 , BIB046 and BIB047 investigate viral MC networking between nanomachines that communicate with each other in a diffusive medium via DNA messages transmitted within viruses, where the former analyses the reliability of a multi-path topology, and the latter derives reliability and delay in multi-hop relay networks. c) Genetic Circuit Regulated Protein Transmission: We have so far investigated biological transmitter architectures, where the message to be conveyed has been encoded in sequences of nucleotides, e.g., DNA or RNA. Yet, the most abundant form of intercellular MC interaction in nature occurs via proteins, whose expression levels are determined by the genetic circuitry and metabolic state within the cells. Typically, proteins that are produced within a cell via transcriptional processes are either excreted out via specialized transmembrane protein channels, or packed into vesicles and transported to extracellular medium via exocytosis. As a result of exocytosis, either the vesicle is transported out wholly, e.g., an exosome BIB026 , or it fuses with the cell membrane and only the contents are spewed out. Proteins on the membranes of exosomes provide addressing via ligand-receptor interactions with membrane proteins of recipient cell. Upon a match, the membranes of exosome and the recipient cell merge, and exosome contents enter recipient cell. This establishes a one-to-one MC link between two cells. In case the contents are merely spewed out to the external medium, they diffuse around contributing to the overall concentrations within the extracellular medium. This corresponds to local message broadcast, and it has been long observed that populations of bacteria regulate their behavior according to resulting local molecule concentrations resulting from these broadcast messages, referred to as the phenomenon of quorum sensing. This mode of communication, even though lacking the information density of nucleotide chains, and therefore supporting lower data rates, are commonly employed by nature as MC schemes. They are considerably more energy efficient compared to DNA transmission schemes, which justifies their use by nature as signaling agents for comparatively simple nanonetworking tasks. In this respect, BIB032 proposes quorum sensing as a means to achieve synchronization amongst bacteria nodes of a nanonetwork, where they model a bacterium as a finite state automaton, and BIB039 investigates quorum sensing as a tool for power amplification of MC signals increasing the range of transmitted signals. In contrast, BIB040 considers exosome secretion as a possible means for realization of nanonetworks composed of large number of bionanomachines. BIB058 presents a detailed model of engineered genetic circuitry based on mass action laws that regulate gene expressions, which in turn dictate transmitter protein production. Their work stands as a basis for future engineered genetic circuitry based protein transmission. d) Enzyme Regulated Ca ++ Circuits: Ca ++ ions are utilized in many complex signaling mechanisms in biology including neuronal transmission in an excitatory synapse, exocytosis, cellular motility, apoptosis and transcription  . Moreover, they play a major role in intracellular and intercellular signal transduction pathways, where the information is encoded into local Ca ++ concentration waves under the control of enzymatic processes. Intracellular organelles including mitochondria and endoplasmic reticulum accumulate excess Ca ++ ions, and serve as Ca ++ storages. Certain cellular events, such as an extracellular signal generated by a toxin, trigger enzymatic processes that release bound Ca ++ from organelles effectively increasing local cytosolic Ca ++ concentrations BIB048 . These local concentrations can propagate like waves within cells, and can be injected to adjacent cells through transmembrane protein gap junction channels called connexins BIB003 . Establishing controlled MC using this inherent signaling mechanism was first suggested by BIB017 , where authors consider communicating information between two nanomachines over a densely packed array of cells that are interconnected via connexins. The authors simulate MC within this channel to analyze system parameter dependent behavior of intercellular signal propagation and its failure. They also report on experiments relating to so-called cell wires, where an array of gap junction transfected cells are confined in a wire configuration and signals along the wire are propagated via Ca ++ ions. The communication was characterized as limited range and slow speed. Later, Ca ++ relay signaling over 1 cell thick cell wires were investigated in BIB023 and BIB027 via dedicated simulations, where the former explored amplitude and frequency modulation characteristics and the latter aimed at understanding the communication capacity of the channel under stochastic effects. Simulations to determine the effects of tissue deformation on Ca ++ propagation and the capacity of MC between two nanomachines embedded within twodimensional cell wires with thickness of multiple cells were carried out in BIB054 . As part of their study, authors propose various transmission protocols and compare their performance in terms of achieved rates. In a later study BIB055 , authors employ Ca ++ signaling nanomachines embedded within deformable cell arrays to infer deformation status of the array as model for tissue deformation detection. This is achieved by estimating the distance between nanomachines from observed information metrics coupled with strategic placements of nanomachines. Motivated by tissue health inference via embedded nanomachines, the authors of BIB059 identify three categories of cells that employ Ca ++ signaling, namely excitable, non-excitable and hybrid, which respectively model muscle cells, epithe- Isomer-based ratio shift keying (IRSK) BIB041 Molecule ratio Moderate k k Release time shift keying (RTSK) BIB028 , BIB080 , BIB067 Release BIB072 for a more detailed discussion of existing literature, theoretical models, experiments, applications and future directions in this field of MC. e) Other Biological Architectures: In addition to the biological transmission architectures described above, molecular motors sliding on cytoskeletal protein structures, e.g., microtubules, and carrying cargo, i.e., vesicles, between cells is another option that has been considered by the MC community. In particular, BIB013 and BIB014 both describe a high level architecture design for MC over such channels. The comparison of active, i.e., molecular motors on microtubules, and passive, i.e., diffusion, vesicle exchange among cells shows that, active transport is a better option for intercellular MC in case of low number of available vesicles, and passive transport can support higher rates when large numbers of vesicles are available BIB029 . Two design options to form a microtubule nanonetwork in a self-organizing manner, i.e., via a polymerization/depolymerization process and molecular motor assisted organization, are proposed in BIB033 . A complementary approach to molecular motor based microtubular MC is presented in BIB060 , where an on-chip MC testbed design based on kinesin molecular motors is presented. In this approach, instead of molecular motors gliding over microtubules as carriers of molecules, microtubules are the carriers of molecules, e.g., ssDNA, gliding over a kinesin covered substrate. Other transmitter approaches that involve the use of biological entities are biological-nanomaterial hybrid approaches. A promising approach is to utilize IM production mechanisms of bacteria in nanomaterial based transmitter architectures. In this direction,  reports on an optogenetically controlled living hydrogel, that is, a permeable hydrogel matrix embedded with bacteria from an endotoxin-free E. coli strain, which release IMs, i.e., anti-microbial and anti-tumoral drug deoxyviolacein, in a light-regulated manner. The hydrogel matrix is permeable to deoxyviolacein, however spatially restricts movement of the bacteria. This hybrid approach proposes a solution the the reservoir problem of nanomaterial based architectures. Moreover, to cover a variety of IMs simultaneously this approach can be built upon by utilizing many engineered bacteria, and controlling their states via external stimulus to control their molecular output  .