Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Drug delivery systems (DDS) such as lipid- or polymer-based nanoparticles can bedesigned to improve the pharmacological and therapeutic properties of drugs adminis-tered parenterally. Many of the early problems that hindered the clinical applications ofparticulate DDS have been overcome, with several DDS formulations of anticancer andantifungal drugs now approved for clinical use. Furthermore, there is considerableinterest in exploiting the advantages of DDS for in vivo delivery of new drugs derivedfrom proteomics or genomics research and for their use in ligand-targeted therapeutics.Many of the pharmacological properties ofconventional (“free”) drugs can be im-proved through the use of drug deliverysystems (DDS), which include particulatecarriers, composed primarily of lipids and/or polymers, and their associated therapeu-tics. DDS are designed to alter the pharma-cokinetics (PK) and biodistribution (BD) oftheir associated drugs, or to function asdrug reservoirs (i.e., as sustained releasesystems), or both. Table 1 gives examplesof problems exhibited by free drugs thatcan be ameliorated by the use of DDS.Here we analyze the opportunities andproblems associated with the use of small-scale DDS (nanoparticles and micropar-ticles with diameters of 200 nm or less)for parenteral (primarily intravenous) ap-plications. These include liposomes and oth-er lipid-based carriers such as micelles, lipidemulsions, and lipid-drug complexes; alsoincluded are polymer-drug conjugates,polymer microspheres, and various ligand-targeted products such as immunoconjugates( <s> BIB001 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> This thesis explores transport phenomena in nanochannels on a chip. Fundamental nanofluidic ionic studies form the basis for novel separation and preconcentration applications for proteomic purposes. The measurements were performed with 50-nm-high 1D nanochannels, which are easily accessible from both sides by two microchannels. Nanometer characteristic apertures were manufactured in the bonded structure of Pyrex-amorphous silicon – Pyrex, in which the thickness of the amorphous silicon layer serves as a spacer to define the height of the nanochannels. The geometry of the nanometer-sized apertures is well defined, which simplifies the modeling of the transport across them. Compared to biological pores, the present nanochannels in Pyrex offer increased stability. Fundamental characteristics of nanometer-sized apertures were obtained by impedance spectroscopy measurements of the nanochannel at different ionic strengths and pH values. A conductance plateau (on a log-log scale) was modeled and measured, establishing due to the dominance of the surface charge density in the nanochannels, which induces an excess of mobile counterions to maintain electroneutrality. The nanochannel conductance can be regulated at low ionic strengths by pH adjustment, and by an external voltage applied on the chip to change the zeta potential. This field-effect allows the regulation of ionic flow which can be exploited for the fabrication of nanofluidic devices. Fluorescence measurements confirm that 50-nm-high nanochannels show an exclusion of co-ions and an enrichment of counterions at low ionic strengths. This permselectivity is related to the increasing thickness of the electrical double layer (EDL) with decreasing salt concentrations, which results in an EDL overlap in an aperture if the height of the nanochannel and the thickness of the EDL are comparable in size. The diffusive transport of charged species and therefore the exclusion-enrichment effect was described with a simple model based on the Poisson-Boltzmann equation. The negatively charged Pyrex surface of the nanometer characteristic apertures can be inversed with chemical surface pretreatments, resulting in an exclusion of cations and an enrichment of anions. When a pressure gradient is applied across the nanochannels, charged molecules are electrostatically rejected at the entrance of the nanometer-sized apertures, which can be used for separation processes. Proteomic applications are presented such as the separation and preconcentration of proteins. The diffusion of Lectin proteins with different isoelectric points and very similar compositions were controlled by regulating the pH value of the buffer. When the proteins are neutral at their pI value, the diffusion coefficient is maximal because the biomolecules does not interact electrostatically with the charged surfaces of the nanochannel. This led to a fast separation of three Lectin proteins across the nanochannel. The pI values measured in this experiment are slightly shifted compared to the values obtained with isoelectric focusing because of reversible adsorption of proteins on the walls which affects the pH value in the nanochannel. An important application in the proteomic field is the preconcentration of biomolecules. By applying an electric field across the nanochannel, anionic and cationic analytes were preconcentrated on the cathodic side of the nanometer-sized aperture whereas on the anodic side depletion of ions was observed. This is due to concentration polarization, a complex of effects related to the formation of ionic concentration gradients in the electrolyte solution adjacent to an ion-selective interface. It was measured that the preconcentration factor increased with the net charge of the molecule, leading to a preconcentration factor of > 600 for rGFP proteins in 9 minutes. Such preconcentrations are important in micro total analysis systems to achieve increased detection signals of analytes contained in dilute solutions. Compared to cylindrical pores, our fabrication process allows the realization of nanochannels on a chip in which the exclusion-enrichment effect and a big flux across the nanometer-sized aperture can be achieved, showing the interest for possible micro total analysis system applications. The described exclusion-enrichment effect as well as concentration polarization play an important role in transport phenomena in nanofluidics. The appendix includes preliminary investigations in DNA molecule separation and fluorescence correlation spectroscopy measurements, which allows investigating the behavior of molecules in the nanochannel itself. <s> BIB002 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Nanotechnologies promise new solutions for several applications in biomedical, industrial and military fields. At nano-scale, a nano-machine can be considered as the most basic functional unit. Nano-machines are tiny components consisting of an arranged set of molecules, which are able to perform very simple tasks. Nanonetworks. i.e., the interconnection of nano-machines are expected to expand the capabilities of single nano-machines by allowing them to cooperate and share information. Traditional communication technologies are not suitable for nanonetworks mainly due to the size and power consumption of transceivers, receivers and other components. The use of molecules, instead of electromagnetic or acoustic waves, to encode and transmit the information represents a new communication paradigm that demands novel solutions such as molecular transceivers, channel models or protocols for nanonetworks. In this paper, first the state-of-the-art in nano-machines, including architectural aspects, expected features of future nano-machines, and current developments are presented for a better understanding of nanonetwork scenarios. Moreover, nanonetworks features and components are explained and compared with traditional communication networks. Also some interesting and important applications for nanonetworks are highlighted to motivate the communication needs between the nano-machines. Furthermore, nanonetworks for short-range communication based on calcium signaling and molecular motors as well as for long-range communication based on pheromones are explained in detail. Finally, open research challenges, such as the development of network components, molecular communication theory, and the development of new architectures and protocols, are presented which need to be solved in order to pave the way for the development and deployment of nanonetworks within the next couple of decades. <s> BIB003 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <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> BIB004 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Nanoscience has matured significantly during the last decade as it has transitioned from bench top science to applied technology. Presently, nanomaterials are used in a wide variety of commercial products such as electronic components, sports equipment, sun creams and biomedical applications. There are few studies of the long-term consequences of nanoparticles on human health, but governmental agencies, including the United States National Institute for Occupational Safety and Health and Japan's Ministry of Health, have recently raised the question of whether seemingly innocuous materials such as carbon-based nanotubes should be treated with the same caution afforded known carcinogens such as asbestos. Since nanomaterials are increasing a part of everyday consumer products, manufacturing processes, and medical products, it is imperative that both workers and end-users be protected from inhalation of potentially toxic NPs. It also suggests that NPs may need to be sequestered into products so that the NPs are not released into the atmosphere during the product's life or during recycling. Further, non-inhalation routes of NP absorption, including dermal and medical injectables, must be studied in order to understand possible toxic effects. Fewer studies to date have addressed whether the body can eventually eliminate nanomaterials to prevent particle build-up in tissues or organs. This critical review discusses the biophysicochemical properties of various nanomaterials with emphasis on currently available toxicology data and methodologies for evaluating nanoparticle toxicity (286 references). <s> BIB005 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <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> BIB006 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Although bacteria are generally regarded as the causative agents of infectious diseases, most bacteria inhabiting the human body are non-pathogenic and some of them can be turned, after proper engineering, into ‘smart’ living therapeutics of defined properties for the treatment of different illnesses. This review focuses on recent developments to engineer bacteria for the treatment of diverse human pathologies, including inflammatory bowel diseases, autoimmune disorders, cancer, metabolic diseases and obesity, as well as to combat bacterial and viral infections. We discuss significant advances provided by synthetic biology to fully reprogram bacteria as human therapeutics, including novel measures for strict biocontainment. <s> BIB007 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Nano-communication-based devices have the potential to play a vital role in future healthcare technologies by improving the quality of human life. Its application in medical diagnostics and treatment has a great potential, because of its ability to access small and delicate body sites noninvasively, where conventional medical devices fall short. In this paper, the state of the art in this field is presented to provide a comprehensive understanding of current models, considering various communication paradigms, antenna design issues, radio channel models based on numerical and experimental analysis and network, and system models for such networks. Finally, open research areas are identified for the future directions within the field. <s> BIB008 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Plastic bioelectronics is a research field that takes advantage of the inherent properties of polymers and soft organic electronics for applications at the interface of biology and electronics. The resulting electronic materials and devices are soft, stretchable and mechanically conformable, which are important qualities for interacting with biological systems in both wearable and implantable devices. Work is currently aimed at improving these devices with a view to making the electronic-biological interface as seamless as possible. <s> BIB009 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> In this paper, we investigate a binary two-way diffusion channel from an information theoretical perspective. Molecule harvesting is considered by which molecules can be reused by the receiver for subsequent transmissions. An outer bound of the capacity region for the general case and inner bounds for specific cases are derived. With the proposed outer bound, we show that no signaling rate is achievable in the considered system if messenger molecules perform free diffusion in an unconfined space and the nodes are not replenished with extra molecules. The proposed lower bounds are tighter than the ones resulted from the traditional joint typicality decoding method. <s> BIB010 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> In this paper, we analyze molecular communications (MCs) in a proposed artificial synapse (AS), whose main difference from biological synapses (BSs) is that it is closed, i.e., transmitter molecules cannot diffuse out from AS. Such a setup has both advantages and disadvantages. Besides higher structural stability, being closed, AS never runs out of transmitters. Thus, MC in AS is disconnected from outer environment, which is very desirable for possible intra-body applications. On the other hand, clearance of transmitters from AS has to be achieved by transporter molecules on the presynaptic membrane of AS. Except from these differences, rest of AS content is taken to be similar to that of a glutamatergic BS. Furthermore, in place of commonly used Monte Carlo-based random walk experiments, we derive a deterministic algorithm that attacks for expected values of desired parameters such as evolution of receptor states. To assess validity of our algorithm, we compare its results with average results of an ensemble of Monte Carlo experiments, which shows near exact match. Moreover, our approach requires significantly less amount of computation compared with Monte Carlo approach, making it useful for parameter space exploration necessary for optimization in design of possible MC devices, including but not limited to AS. Results of our algorithm are presented in case of single quantal release only, and they support that MC in closed AS with elevated uptake has similar properties to that in BS. In particular, similar to glutamatergic BSs, the quantal size and the density of receptors are found to be main sources of synaptic plasticity. On the other hand, the proposed model of AS is found to have slower decaying transients of receptor states than BSs, especially desensitized ones, which is due to prolonged clearance of transmitters from AS. <s> BIB011 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Molecule filtering or particle separation is a complex task in microfluidics. Passive structures or polymer based systems like hydrogels are normally used elements. PNIPAAm (poly-N-isopropylacrylamide) hydrogels are known for their capability to work as nano-filters to separate small molecules from their environment and protect them from degrading enzymes by the polymer network. PNIPAAm based active micro-pores were also demonstrated for particle separation. Normally, changes in temperature are used to alter the permeation properties of such hydrogel elements. To handle limiting factors such as separate temperature control for each element, chemical signals can be used to alter the permeation. Here, we present a new way to adapt the size exclusion functionality of PNIPAAm-based nano-filters or micro-pores. PNIPAAm hydrogels respond to organic solvent concentrations by shrinking or swelling. We use this responsiveness to alter the hydrogel mesh size or to adjust the size of a micro-pore. We show the filter functionality for two model molecules: the enzyme horse radish peroxidase and the fluorescence molecule fluorescein. Furthermore, the adjustment of the size of a micro-pore in a continuous way is demonstrated, so that pore sizes between the closed and open state can be addressed and kept permanently. <s> BIB012 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Since so many years ago, tissue damages that are caused owing to various reasons attract scientists' attention to find a practical way to treat. In this regard, many studies were conducted. Nano scientists also suggested some ways and the newest one is called tissue engineering. They use biodegradable polymers in order to replace damaged structures in tissues to make it practical. Biodegradable polymers are dominant scaffolding materials in tissue engineering field. In this review, we explained about biodegradable polymers and their application as scaffolds. <s> BIB013 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> Over the past decades, biopolymer-based nanomaterials have been developed to overcome the limitations of other macro- and micro- synthetic materials as well as the ever increasing demand for the new materials in nanotechnology, biotechnology, biomedicine and others. Owning to their high stability, biodegradability, low toxicity, and biocompatibility, biopolymer-based nanomaterials hold great promise for various biomedical applications. The pursuit of this review is to briefly describe our recent studies regarding biocompatible biopolymer-based nanomaterials, particularly in the form of dendrimers, hydrogels, and hydrogel composites along with the synthetic and modification approaches for the utilization in drug delivery, tissue engineering, and biomedical implants. Moreover, in vitro and in vivo studies for the toxicity evaluation are also discussed. <s> BIB014 </s> Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding and Detection Techniques <s> II. MOLECULAR COMMUNICATION TRANSMITTER <s> This paper studies the impact of a transmitter's molecule generation process on the capacity of a concentration based Molecular Communication (MC) system. Constraints caused by the molecule generation process affect the availability of the molecules at the transmitter. The transmitter has a storage of molecules, and should decide whether to release or save the currently produced molecules. As a result, the MC system has conceptual connections with energy harvesting systems. In this paper, we consider two scenarios on the propagation channel. The first scenario assumes a channel with no Inter-symbol Interference (ISI), \emph{i.e.,} a memoryless channel. We derive bounds on the capacity of the MC system in this scenario. The second scenario assumes the MC network with ISI, in which the output of the channel depends on the history of released molecules in the previous time-slots. Based on the assumptions that either the transmitter or the receiver knows the channel statistics, we compute a lower bound on the channel capacity. <s> BIB015
MC transmitter (MC-Tx) encodes information in a physical property of molecules such as concentration, type, ratio, order or release time, and releases information molecules (IMs) accordingly. To this aim, information to be transmitted is required to be mapped to a sequence of bits through source and channel coding to represent the information with less number of bits, and to introduce additional bits to the information with the purpose of providing error correction, respectively. Then, the modulator unit encodes the information in a property of molecules and control the release of IMs according to a predetermined modulation scheme. Finally, a power source and IM generator/container are required to provide energy and IM molecules for MC-Tx. The interconnection of these components in an MC-Tx is illustrated in Fig. 2 . In this section, we first discuss the requirements of an MC-Tx and investigate the utilization of different IMs. Then, we review the available approaches in physical design of MC-Txs, which can be categorized into two main groups, (i) nanomaterialbased artificial MC-Tx and (ii) biological MC-Tx based on synthetic biology. A. Design Requirements for MC-Tx 1) Miniaturization: Many novel applications promised by MC impose size restrictions on their enabling devices, requiring them to be micro/nanoscale. Despite the avalanching progress in nanofabrication of bioelectronics devices over the last few decades  , fabrication of fully functional nanomachines capable of networking with each other and their surroundings in order to accomplish a desired task still evades us BIB008 . Moreover, with miniaturization the surface area to volume ratio increases, causing surface charges to become dominant in molecular interactions. This causes the behavior of molecules passing through openings with one characteristic dimension less than 100nm to be significantly different than that observed in larger dimensions BIB002 . Consequently, as the release aperture of many considered molecular transmitter architectures are commonly in nanoscale, peculiarities arising from this phenomenon need to be taken into account in transmitter design. 2) Molecule Reservoir: The size restriction introduces, besides the need for energy harvesting due to infeasibility of deploying a battery unit, which is a problem for the whole nanomachine in general, another very important problem for any transmitter architecture, namely, limited resources of IMs BIB003 . Typically, a transmitter module would contain reservoirs, where the IMs are stored to be released. However, at dimensions in question, without any replenishment these reservoirs will inevitably deplete, rendering the nanomachine functionally useless in terms of MC. Moreover, the replenishment rate of transmitter reservoirs has direct effect on achievable communication rates BIB010 , BIB015 . Possible theoretically proposed scenarios for reservoir replenishment include local synthesis of IMs, e.g., use of genetically engineered bacteria whose genes are regulated to produce desired transmitter proteins BIB006 , as well as, employment of transmitter harvesting methods BIB011 . Corresponding technological breakthroughs necessary for realization of these approaches are emerging with advancements in the relevant fields of genetic engineering BIB007 , and materials engineering BIB012 ,  . 3) Biocompatibility: Most profound applications of nanodevices with MC networking capabilities, such as, neural prosthetics, tissue engineering, targeted drug delivery, BMIs, immune system enhancement, etc., require the implantation of corresponding enabling devices into biological tissue  . Combined with increased toxicity of materials at nanoscale BIB005 , the issue of biocompatibility of these devices stands out as one of the most challenging research issues to be addressed. Moreover, corrosion of implants inside body is another commonly known issue BIB013 restricting device durability, which due to increased surface to volume ratio at nanoscale has an effectively amplified effect on nanoscale implants compared to their larger versions. In addition to biochemical toxicity and durability, flexibility of implanted devices is another important aspect of biocompatibility, as mechanical mismatch between soft biological tissue and the implanted device triggers inflammation followed by scar tissue formation  , which eventually restricts the implant to carry out its intended task. Accordingly, the last decade has witnessed extensive research on novel biocompatible materials such as polymers BIB013 , soft organic electronics BIB009 , dendrimers, and hydrogels BIB014 . It is imperative to note that, all issues of biocompatibility mentioned here specifically apply to nanomaterial-based device architectures, and they can be almost completely avoided by the choice of a biological architecture, e.g., genetically engineered organisms  . 4) Transmission Performance: Performance of a molecular transmitter should also be evaluated by how much control it has over the transmission of molecules. Important performance metrics include off-state leakage, transmission rate precision, resolution and range, as well as transmission delay. Off-state leakage, or unwanted leakage of molecules from transmitter, from MC perspective, degrades communication significantly by contributing to background channel noise. On the other hand, it is unacceptable for some niche applications, such as targeted drug delivery BIB001 , where leakage of drug molecules would cause undesired toxicity to the body. During operation, control over rate of transmission is essential. For instance, in neural communications information is encoded, among other fashions, in the number of neurotransmitters released at a chemical synapse, and accordingly transmitter architectures envisioned to stimulate neurons via release of neurotransmitters, e.g., glutamate BIB004 , will need to encode information in neurotransmitter concentrations via very precise transmissions. In this respect, transmission rate precision, resolution and range are all variables that are determinant in the capacity of communication with the recipient neuron. Finally, transmission delay is in general a quantity to be minimized, as it contributes to degradation in communication rates. Moreover, for instance in neural communications, where information is also encoded in frequency of signals, there is an upper bound on permissible transmission delay of a transmitter in order to satisfy a given lower bound on maximum frequency transmittable.