274 Nano Biomed. Eng., 2016, Vol. 8, Iss. 4

Nano Biomed Eng 2016, 8(4): 274-287. doi: 10.5101/nbe.v8i4.p274-287. Review Molecular Communication in Nanonetworks

Hao Yan1 , Ge Chang1, Tianhao Sun1, Yingzhan Xu1, Zhongke Ma1, Tao Zhou1, Lin Lin2

1Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Center for Intelligent Diagnosis and Therapy Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering; National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China. 2College of Electronics and Information Engineering, Tongji University, Shanghai 201804, China.

Corresponding authors. E-mail: [email protected] ; [email protected]

Received: Dec. 4, 2016; Accepted: Dec. 7, 2016; Published: Dec. 20, 2016.

Citation: Hao Yan, Ge Chang, Tianhao Sun, Yingzhan Xu, Zhongke Ma, Tao Zhou, and Lin Lin. Molecular Communication in Nanonetworks. Nano Biomed. Eng., 2016, 8(4): 274-287. DOI: 10.5101/nbe.v8i4.p274-287.

Abstract

With the development of nanotechnology, bioengineering and biology, it is envisioned that biological nanomachines may flourish in assorted valuable applications considering their unique characteristics including energy efficiency, bio-compatibility and extremely small scale. However, current biological nanomachines are only able to perform simple tasks at nano-level. Therefore, nanonetworks which interconnect bio-nanomachines into a network have been proposed to overcome the limitations of individual biological nanomachine. Among the possible communication schemes for nanonetworks, modern electromagnetic communication techniques are not good solutions due to the limitation of antenna size. Inspired by nature, one promising candidate is molecular communication proposed from the perspective of communication and computer engineering. Integrated with the knowledge from communication and computer engineering, molecular communication enables biological nanomachines to interface with other biological nanomachines and existing biological systems. Their interconnections form a bio-nanonetwork which is capable to provide functions that individual nanomachines cannot accomplish. In this paper, we introduce the state-of-the-art progress in the emerging field of molecular communication. The framework, design and engineering of components and theoretical modeling of molecular communication are discussed. The research challenges and opportunities are also talked about to inspire future researches of more feasible molecular communication systems.

Keywords: Biological nanomachines; Molecular Communication; Nanonetworks

Introduction (bio-nanomachines) which are capable to interact with molecules and cells in nanometer to micrometer level Looking back in 1950s, the possibilities of have been engineered. Bio-nanomachines are referred functional and powerful nano-devices were noted in to nano-to-micro scale functional devices made up of Richard Feyman’s famous speech “There’s Plenty of biological materials and can perform simple chemical Room at the Bottom”. After more than 60 years, with tasks at nanoscale [1]. Examples of bio-nanomachines the development of biology, nanotechnology, and include genetically engineered cells, artificial material science, various biological nanomachines , bio-silicon hybrid devices [2] and nanoscale http://www.nanobe.org Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 275 molecular complexes such as protein motors [3]. purpose of this paper is to introduce computer and communication assisted MC to bio-engineering domain The advantages of bio-nanomachines include energy to advance collaborations and to promote development efficiency, bio-compatibility and extremely small scale. of MC. What is more important is that bio-nanomachines are capable to interface with other bio-nanomachines In this paper, the advancement of MC in and bio-system. Due to the above advantages, bio- nanonetworks is reviewed. First, an overview of MC nanomachines have the potential to deal with problems is provided. Its architecture, potential power sources, beyond the reach of traditional application, such as general characteristics and potential applications drug delivery and bio-hybrid implants in bio-medical are introduced. Second, approaches for design and applications, biochemical sensors for pollution control engineering the components of MC are discussed. The in environmental applications and etc. characteristics of bio-prototypes of bio-nanomachines discussed here could be further considered in the Though bio-nanomachines have many advantages, actual MC or for more realistic model of MC. And, current bio-nanomachines are only capable of different MC theoretical models for different situations performing simple tasks because of their limited are presented. Models also include general model and size and structure. To overcome this limitation, specific models. These models can be used to facilitate nanonetworks which interconnect bio-nanomachines MC design and analysis. Finally, possible future and integrate them into a network have been proposed. works are discussed. These works aim to solve the key Among the possible communication schemes for bio- research issues and promote the advancement of MC. nanonetworks, modern electromagnetic communication techniques are not good solutions due to the limitation This paper is organized as follows. In section two, of antenna size. On the other hand, molecular we introduce the MC including the architecture, communication which is universally distributed in characteristics and potential applications. The power and has proven to be energy efficient sources of the MC are discussed separately. Section as well as reliable. Inspired by nature and bio- three provides a summary of bio-prototypes that could nanomachines’ advantages, molecular communication be used in MC. And bio-nanotechnology approaches (MC) [4] is proposed as an ideal communication to engineer and design the components for MC are paradigm for bio-nanonetworks from the prospective of discussed. The approaches to mitigate the interference communication and computer engineering. Researchers are also included. In section four, we categorize the from communication and computer engineering have MC channel models into diffusion models and other made contributions to MC in nanonetworks. An initial emerging models based on its propagation ways. attempt to establish MC network was conducted Qualities of some frequently used models are discussed by Suda in 2005 [4]. Assorted MC models were correspondingly. Section five considers the challenges also proposed in [5-10]. Related experiments were of the potential MC systems and possible future works pioneered in [5, 11]. Current progress was included in are talked about. Finally, section six concludes this surveys which presented the general micro-scale MC paper. and characteristics of MC [1, 12-19]. Nevertheless, there are still many difficulties Overview of Molecular commu- to overcome before feasible applications. First of nication all, current MC system models, which are the key to a proper communication process, are based on The process of a MC system can be simplified as many unrealistic assumptions. They are too simple three main parts: generation and release of information and idealized. Some important factors for reliable particles, propagation of information particles in the applications are not well addressed, such as the environment, detection of information particles. We power source to support MC and synchronization can abstract the process above into an architecture between bio-nanomachines and etc. One of the to identify the key components of MC. As shown biggest challenges is experiment validation of bio- in Fig. 1, the MC architecture contains three main nanonetworks. This needs further collaboration of modules (transmitter, channel and receiver) and their multiple disciplines including bioengineering, biology, submodules. The transmitter generates information chemistry and communication engineering. The main particles, and then releases them to the channel. The

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Transmitter

Information Particle Information Particle Generation Unit Release Unit

Power Propagation Channel Source schemes

Information Information Demodulation Unit Particle Sensor

Receiver

Fig. 1 Key components of molecular communication. channel acts as the environment where information · Concentration of Particles. particles propagate by specific method, including · Type of Particles. diffusion, active transport, etc. It cannot be ignored that noise exists in the channel and influences the · Three-dimensional-structure of Particles. accuracy of information communication. Therefore, · Release Time of Particles. it is a big challenge for us to overcome the noise and In modern radio-based communication systems, realize a reliable MC. Finally, the receiver captures symbol bit is the fundamental unit of information the information particles and utilizes their features to and the propagation process of information can be obtain the intended information from the transmitter. regarded as transferring binary data (0 and 1). This In this section, based on the architecture discussed performs similarly in MC. Resembling in Fig. 2, above, we overview the three main modules at different binary data (0 or 1) is obtained by modulating first. Especially, the power source of the system is on concentration of Particles, type of Particles, three- introduced separately. We also discuss its general dimensional-structure of Particles [20] and release time characteristics and potential application to give us a of Particles. For example, for the graph in the left top, comprehensive view of MC and its promising future. three molecules in a column represent bit 0, while one molecule represents bit 1. Molecular communication architecture In addition, the release mechanism of information Transmitter particles is a significant issue of transmitters. There The transmitter of MC is required to generate and are many natural methods to release chemical particles release information particles, which is corresponding intracellularly or intercellularly, including budding to the Information Particle Generation Unit and vesicles from a , opening molecular gates, etc. Information Particle Release Unit in Fig. 1 (Power [16]. Therefore, the release mechanism of information Source will be introduced in the following part). The particles in MC can work in the similar ways. main function of a transmitter is to send different It is worth mentioning that because of the information, which is achievable easily in modern degradation of particles, the transmitter needs to radio-based communication systems. But in MC, release a large number of particles to make the the information carrier is the particle so that existing communication process more stable. The properties of theory about electromagnetic wave cannot support the information particles should also be considered, which transmitting process. So new approaches have been need to be chemically robust against the noise from the proposed for sending information by utilizing different environment. properties of information particles. The receiver can then decode the information particles to get the Channel propagation intended information. The properties used to modulate The channel in MC system is the environment where are shown below: the information particles propagate from transmitters http://www.nanobe.org Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 277

Modulation on Concentration Modulation on Type bit 0 bit 1 bit 0 bit 1

0 1 2 3 4 0 1 2 3 4 Time/s Time/s Modulation on Three-Dimensional-Structure Modulation on Release Time bit 0 bit 1 bit 0 bit 1

0 1 2 3 4 0 1 2 3 4 Time/s Time/s Fig. 2 Modulation techniques in molecular communication. to receivers. For example, the vessel provides the Receiver environment for erythrocyte, protein and many other In nature, one way that biological cells capture materials to transport between certain tissues at a signals is to use protein structures, which can bind to molecular level. In Table 1, schemes which have been specific ligand structures [21]. This mechanism can be proposed for the propagation of information particles used in MC to design Information Particle Sensor of a in the channel are listed. Among them, the diffusion receiver to detect and receive information particles [22, based propagation is the most frequently used scheme 23]. Another choice of receiver is to use a permeable in current studies. surface structure (e.g., plasma-membrane) or channels for specific molecules (e.g., ion channels) [16]. Table 1 Propagation Schemes in Molecular Communication Progation Schemes Based on When receiving the information particles, the Free Diffusion Diffusion receiver comes to a process called demodulation. Diffusion with First Hitting Diffusion The Information Demodulation Unit of the receiver Flow Assisted Diffusion Diffusion and Flow demodulates the intended information from the Motor Protein over Motor Protein properties of information particles, which include Microtubule Tracks the concentration, the type, the three-dimensional- Assisted Bacteria Motility structure and the release time of particles as mentioned Gap Junction Diffusion and Gates Neurochemical Diffusion and Enzyme in Transmitter. With receiver acting like a cell, the demodulation process works via certain chemical reactions with the information particles. For instance, free diffusion in Table 1 occurs when gaseous or aqueous molecules move without any Power source other force. The movement of the molecules obeys the Brownian rule. The mathematical modeling will be The transmitter, propagation in channel and the discussed in later section. Different schemes adapt to receiver all require adequate power to work regularly. different conditions of environment, and all of them The ways to harvest power for MC [24] can be are important for practical applications. summarized into three categories as follows: To have a further study of the channel in MC, we · Getting power present in the environment. Diffusion need to set up the channel model according to the based propagation utilizes the thermal energy from propagation schemes we choose. Frequently used the channel. This process can work without any models include diffusion based model, flow assisted external power source. diffusion model, etc. · Getting power through chemical reaction from the

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environment. For example, in a biological cell, movement of chemical particles as imformation chemical reactions are used to generate power for carrier and the chemical reactions. Therefore, it is motion to propagate chemical particles, such as possible that the bio-nanomachines could directly the utilization of adenosine-triphosphate (ATP) communicate with components of natural biological hydrolysis [25]. system. It also shows a potential application that MC · Getting power with an external power source [26, systems with bio-nanomachines can be implanted 27]. For instance, we have mentioned a propagation inside a human body to do medical treatment. scheme called Flow Assisted Diffusion, which · Slow propagation speed and high loss rate. utilizes a flow in the channel to provide the power Compared with electromagnetic wave, the propagation for particles’ movement in a certain direction while of information particles in MC is much slower diffusing. The flow can be regarded as a kind of and the propagation distance is much shorter. For external power sources. free diffusion, the propagation is even limited to It should be pointed out that the energy efficiency micrometer range. Due to the diffusion property of the is high when the MC process harvests power present propagation, the particle movement is unpredictable in the environment or through the reaction in the and the distribution range of the arriving time is large. environment. The diffusion-based propagation only Therefore, the loss rate is high, and those arriving at needs the thermal energy in the channel without any the receiver only account for a small percentage. external power source so that it is an energy efficient process. In addition, take myosin molecular motors as Potential applications an example. They work via converting chemical energy With the recent advancements in nanotechnology, like ATP with approximately 100 percent efficiency. the potential applications of MC systems have become increasingly feasible. The application areas include General characteristics medical field [29], environment [30], industry, military, Compared with traditional radio-based etc. Here we introduce some of important application communication, MC shows many differences such as areas as below: the information carrier, the information propagation Medical applications speed, and the medium [28]. As a result, the general characteristics of MC are much different from radio- Nowadays, the medical field has become the main based communication. Important characteristics of MC force for engineering MC. are introduced as follows: A potential application in medical field is the · Chemical particles as information carriers. In MC, artificial immune system [31]. In this application, bio- information is modulated on the properties of nanomachines are implanted into the human body and chemical particles, which include the type, the communicate with each other via the MC. One device concentration, the release time of particles, etc. A can only perform simple tasks, while complex work good example to describe this is neurotransmitter, a needs the cooperation among the devices. This process kind of chemical materials existing in synapse and is similar to the immune system in human body, in propagating information from our brain to muscles which T-cells and B-cells are required to work together. all over the body. In this case, the information from Drug delivery [32] is another promising application. the brain is modulated on the type of particles and Drug delivery systems perform accurate transport of other kinds of particles cannot convey the intended drugs to specific locations. Bio-nanomachines are information to muscles. In addition, because of implanted inside the body to detect the molecular the chemical properties of these particles, the signal from specific targets and precisely position their modulation and demodulation process can be accurate locations for drug delivery. This application performed with a series of chemical reactions. reduces the side-effects on locations which are not · Compatibility for biological systems. The targets. communication mechanism in MC is similar Other potential applications include the detection to the one used in biological systems, both of of brain aneurysm, transport of molecular payloads which implement communication process via the between tissues, lab-on-a-chip devices [33], etc.

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Environmental applications storage of information particles. There may also be a need for a mechanism that controls the release of Nanomachines and MC systems have the potential information particles, a processing unit that controls to help environmental monitoring and protection. the different processes within the transmitter. At the Feasible applications are as listed: receiver, there must be a sensor, or a receptor, or a · Pollution control. The toxic or radioactive agents in detector that can measure some arrival property of the the environment can be detected by nanomachines. received information particles. If coding techniques are And then the devices tag the pollution source with used there may also be a need for a central processing specific molecules as well as amplify the signal of unit for decoding and deciphering the received signal. pollution source to guide other devices to degrade In MC, one can synthesize the transmitter and the materials in the polluted area. receiver in two basic ways: shrinking existing · Bio-degradation assistance. electronic components to nano scale, and designing · Biodiversity control. and manufacture by bio nanotechnology. Dislike the difficulty and high cost for shrinking components, Industrial applications research results show that adopting bio technology The MC system can be used in quality control of can help us get more efficient transmitter and receiver. food and water, since the type or the concentration of And Two basic approaches for engineering bio- molecules in the goods can be a judge standard of the nanomachines with functionality for communication quality. Also, it can work on the manufacturing process are modification of existing biological cells and of intelligent functionalized materials. simplification of cell-like structures using biological material [34]. Other aspects like military applications (biological and chemical defenses, nano-functionalized equipment) Modification of existing cells are also popular in the society today. The first approach for engineering bio-nanomachines was proposed by synthetic biology [35-37]. To Design and Engineering of perform a sending function, a biological cell with a Components for Molecular Comm- modified a metabolic pathway is capable to synthesize and release specific signal molecules. Furthermore, unication another work considered both the transmitter and receiver are genetically modified cells and mobile The MC systems require interdisciplinary cooperation [38]. And an information transport mechanism for for their design and engineering, such as biology, the two genetically modified cells was designed. chemistry, and nanotechnology fields. And the systems Microbial colonies are also one of the prominent are realized from biological mechanisms and materials. transmitter and receiver entities in MC [39]. In this As shown in the previous section, many components scheme, the transmitter and receiver are made from for MC can be found the prototypes in biosystems transfected cells by the transfection of genetically or get implementation through biotechnology, modified bacteria. including the transmitter and receiver, information particles, guide and transport molecules, power Many other functions can be introduced into source molecules. There are errors in the process of biological cells with the help of synthetic biology, such propagation and detection, like ISI (Inter Symbol as logic gates, toggle switches, and oscillators. These Interference), we have to consider the component for functions can increase the complexity of transmitting error correction. In this section, we summarize research and receiving processes. An example of functions results for engineering components that are applicable which could be embedded in bio-nanomachines is to developing MC systems. oscillators to generate the clock for MC. Creating artificial cells Transmitter and receiver To engineer transmitter and receiver bio- Transmitter and receiver require some special nanomachines, simplified cell-like structures using functionalities for effective communication. At the biological materials is one solution. One example is transmitter, capabilities are required for generation or utilization of a liposome that separates the environment

http://www.nanobe.org 280 Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 and functional particles. functionality can be added molecules in body, DNA and RNA chains are both into liposome as necessary. The liposome is a made of 4 kinds of Deoxyribonucleic acids or structure wrapped by lipid bilayer which is similar Ribonuccleic acids with different bases (For DNA is to the membrane that encloses a cell [2]. In [40, 41], adenine, thymine, guanine, cytosine. And for RNA is transmitter and receiver bio-nanomachines were adenine, uracil, guanine, cytosine). Different bases synthesized from vesicles embedded with photo- combinations encode different messages [4]. responsive molecular switches. These devices were Besides the previous examples, in biological photo-controlled to transmit or react to chemical systems, information molecules can also be synthesized signals, and thus demonstrated the potential of this for specific purposes using bio-chemicial technology, approach for creating bio-nanomachines. for example, using nanoparticles to target particular tissue types in drug delivery [42]. Information particles

Information particles propagate from a transmitter Guide and transport molecules bio-nanomachine, carry information through the Guide and transport molecules provide reliable channel and finally detected by a receiver bio- mechanisms of directing information molecules toward nanomachine in the environment. The choice for target in propagation. Numerous examples in biological the information particles is important with the systems can be used to design and engineer guide and requirements of chemically stable and robust against transport molecules as below: environmental noise and interference from other molecules. And their size and structure may affect the Gap junction channels information transfer efficiency. There have been some Gap junction is an intercellular communication examples of information particles used in nature by pathway [43-45]. In the gap between the connecting biological systems as follows: points of two cells, a small molecule is allowed to Hormones flow directly from one cell to another through the gap. These channels regulate the propagation of information Hormones are some efficient active substances in molecules between cells through gap junctions. Thus body as a messenger to convey information to regulate receiver bio-nanomachines can be targeted by selecting the physiological processes of the body, secreted by the where gap junction channels lead. endocrine glands or endocrine cells [1]. Molecular motors and microtubules Pheromones Microtubules self-organize into a network and motor Pheromones (also named external hormones) play a proteins actively transport information molecules along key role in the communication between the individuals. tracks of the microtubules [5]. The specific patterns The receiver for the particles is olfactory organ which of microtubule filaments can be designed to form a reacts with the pheromones to lead a direction to pathway to direct molecular motors to target locations another individual [2]. of the network, just like the way that trains and tracks Neurotransmitter work. Acetylcholine (Ach) is one of the most widely used Self-propelling neurotransmitters. Ach performs at the information Self-propelling organisms like bacteria can function transport in Neuromuscular junction [3]. Ach is as transport molecule [46]. For example, bacteria released by the presynaptic terminal which is a can be guided by the concentration gradient of special structure of the junction that performs as attractant molecules to move toward a receiver in the the transmitter, and is detected by the postsynaptic environment. The attractant molecules, generated by terminals which performs as the receiver. The receiver the receiver, function as guide molecules to influence control the strain and relaxation of muscle according to the concentration of the received Ach. the direction in which the transport molecules move to the receiver through the environment. Deoxyribonucleic Acid (DNA) and Ribonuccleic Acid (RNA) DNA or RNA As the necessary genetic materials and message As shown in the previous subsection, DNA

http://www.nanobe.org Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 281 and RNA chains are both made of 4 kinds of hydrolysis reaction, dehydration condensation reaction Deoxyribonucleic acids or Ribonuccleic acids with and other chemical reaction which degrade information different bases. Above all, these Pairing of bases is molecules at receiver. only possible in a specific way, for DNA is A(adenine) Binding and absorbing with T(thymine), G(guanine) with C(cytosine), and for RNA is A(adenine) with U(uracil), G(guanine) In nature, some receptors remove the information with C(cytosine). A DNA segment can function as a molecules from the environment through binding and transport molecule with information molecules loading absorbing. These mechanisms can be adopted in MC to on it. With the fixed rule of base pairing, the transport degrade the unwanted information particles [48]. DNA segment binds with a specific site of the target DNA segment in the receiver and therefore transfers Theoretical Modeling of Molecular the information molecules to the receiver. Communication Power source molecules Theoretical models are the mathematical foundation of MC. They serve as the powerful tool in designing In MC, the processes of transmitting, receiving and analyzing new mechanisms as well as improving and propagation may require power [24]. Sometimes quality of MC. A number of channel models have the power is already present in the environment. been proposed based on different propagation schemes Sometimes it is harvested from the environment (e.g., diffusion, protein motor, micro-tubule Filament, through chemical or electrical reactions. There are and bacterium assisted). From the perspective of some sophisticated energy supplying mechanisms current MC research tendency. We categorize current relying on molecules in nature that we can used in MC. theoretical models work into diffusion models and For instance, transmitters and receivers made from some other promising models such as active transport synthetic cells run on adenosine triphosphate (ATP) model. The model’s characteristics of pure diffusion, molecules which is already present in the environment flow-assisted diffusion and diffusion with amplifier are [47]. discussed in the first subsection [16, 49]. The quality of different theoretical models of MC is evaluated in Error correction components terms of some pivotal factors such as channel capacity, When the information particles were detected by the average latency and loss rate. receiver, they will not immediately disappear and exist Diffusion based model for a period of time at the receiver side. Considering Diffusion, also known as Brownian motion, is used the pulse signal moduled by the number of information to describe the particle’s random walk during which it particles, the existing particles of the last pulse will collides with other particles [17]. Propagation from the affect the current information received, which is transmitter to the receiver can be achieved by diffusion called ISI (Inter Symbol Interference). To correct the ISI, numerous methods in bio-system can be used as without using external energy. Shown in Fig. 3, follows: Transmitter is usually abstracted as a point and receiver may contain various receptors to decode different Enzymes information molecules. Shown in Fig. 3, Transmitter is The enzyme is the initiator of the chemical reaction usually abstracted as a point and receiver may contain in the . For instance [6], at the receiver various receptors to decode different information area of neuromuscular junction , there are some molecules. Generic diffusion equation is used to acetylcholinesterases (enzyme for Ach) breaking down describe a large number of particles’ diffusion [17]: the Ach molecules when they are accumulated to a ∂ |,( dtdp ) certain concentration to avoid the cause of ISI. 0 ∇= 2 |,( dtdpD ) (1) ∂t 0 Changes in PH in the environment where D is the diffusion coefficient, p(d,|t0) is the Comparing to electronic components, molecules are concentration function of current location d and time more sensitive to the degree of PH in the environment t and d0 is the original location. Variable d is usually .The changes of PH in the environment may cause represented in a Cartesian coordinate. More specific

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Y

R (x, y, z) Molecule diffusion d T X (0, 0, 0)

Z

Fig. 3 Diffusion process in nolecular communication. diffusion models are discussed in the following based The average Latency is calculated as d2/2D and jitter is on this generic diffusion equation. ∞ 2 2 Pure diffusion-based model ∑ -∆ (( / 2 )) (ipDdi ∆) i=0 Pure diffusion-based model is the most fundamental where p(iΔ) is the probability mass function and Δ is MC channel model in literature as it doesn’t require the time step length in simulation. In this case, loss any additional propagation mechanism. Universally T distributed in nature, this kind of model is mostly rate is given as ∑ (1 ip ∆- ) where the monitoring found in biology. One example is neurotransmitter i=0 molecules Acetylcholine (ACh) used to convey motor duration of receiver nanomachine is T ** [F 2016]. action from nerve cell to neuromuscular junction [50]. Flow assisted diffusion model DNA binding propagated to the binding site is another Pure diffusion is a very slow process to propagate example of this model [49]. information molecules in terms of macro-scales. Different initial conditions may be set to solve Introducing flow is an effective method to speed up the diffusion equation of Eq. (1). M0 molecules are pure diffusion mechanism. Examples of this kind of assumed to be released from a point source suddenly at propagation are found in blood vessel which is adopted time t = 0 [49]. The solution of Eq. (1) with the above as the flow to propagate nano-medicine to reach target initial condition for three-dimensional diffusion is: cells [51].

3 −d 2 − The advection-diffusion equation is used to describe 2 4Dt (2) =0 π )4(),( eDtMtdc statistical movements of particles in this situation.

The lower bound on channel capacity is given in [12] ∂ dtdp )|,( 0 ∇+ dtdvp ))|,(( = ∇2 |,( dtdpD ) (3) a closed-form expression. This article demonstrated ∂t 0 0 that the bound was linear to the transmission’s signal where v is the velocity vector. The pdf of the hitting bandwidth positively. Shown in [16], average latency time is given in [52] as shown in Eq. (4) where M is for the receiver is infinite when there is no bound 0 the molecule number released by transmitter each time. for d and so is the jitter in this situation. The average 2 latency, however, is finite when the probability mass M −− dvt )( tf )( = 0 e 4Dt function and time t are obtained between [0, d] [49]. 4πDt3 (4) http://www.nanobe.org Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 283

2 2 Latency is calculated by replacing d with (d-vt) in where li is the location of the motor on the ith the probability mass function [17]. Average latency is d/v simulation step and vavg denotes the average velocity. and it will decrease in proportion to 1/v. Jitter is Dd/2v3 A mathematical model of microtuble filaments is also and it decreases as v increases. All the conclusions presented in [56]. Step size Δri and the Step angle are based on the assumption that velocity of medium change Δθi are the key parameters and they could be v is greater than zero. Loss rate can also be obtained obtained through Gaussian distribution in Eq. (7) and 2 2 by substituting d with (d-vt) in the probability mass (8) where Δt is the step time and Lp is the persistence function [16]. length of the microtube’s trajectory. Diffusion with amplifier ∆ i avg 2,(~ ∆∆ tDtvNr ) (7) Information molecules may react with other ∆θ ∆ molecules or chemicals in the channel. Diffusion with i (~ 0, avg LtvN p )/ (8) amplifier helps improve the reliability and efficiency Gap junction channel is a scheme where the of the MC. The amplifiers in the channel react with transmitter and receiver are attached to each other information molecules and then make copy with them. with the same lattice structures or cells. Calcium ions The number of information molecules will increase might be the information molecules travelling on these with respect to propagation. Proteins can be adopted lattices This process is called intercellular calcium to amplify calcium ions or some other molecules for wave (ICW). The channel model was considered in [57] amplifier diffusion [53]. As the increase of deployed as well as the proper symbol rate. Channel capacity is amplifiers number, latency decreases correspondingly. also discussed in [58]. An increase in the number of released molecules by amplifiers each time also decreases latency [16]. Possible Future Works Other models In this part, important research issues in current MC Aside from diffusion propagation, we also survey and possible future works are discussed. some other promising propagation schemes. Bacteria- based propagation is an effective active transportation Experiment investigation method. Information may be encoded in DNA strands Currently, one of the biggest challenges in MC and then transported by flagellated bacteria [46]. field is experiment validation of MC in nanonetworks. Attractant and repellent molecules are sometimes used The theoretical models need to be evaluated by to drive bacteria to the receiver [54]. Step angle is the experiments. Important parameters in models need key parameter in the rotational diffusion model [49] to be justified by experiments. The reliability and which affects the mobility pattern bacteria. With the effectiveness of various proposed MC schemes need to attractant and repellent molecules, step angle may be be tested by actual bio-nanonetworks with experiment. redefined as: The strong demand of experiment investigation Ψ = Ψ + Ψ + Ψ (5) 0 R A is without doubt. Few experiments have been performed. The challenge of experiment lies in the where Ψ0 is the original step angle and the effects from the attractant and repellent molecules is induced by multidisciplinary nature of the field. The theoretical models in MC are being developed by researcher from angle ΨR and ΨA. communication engineering field. To validate these Molecule motor based active transport is also models and apply them in envisioned applications promising in MC. Kinesin with stationary microtubule requires wet lab experimentation. However, researchers and microtube filaments gliding over kinesin-covered from communication engineering usually do not substrate are two feasible methods to perform active have expertise of and access to wet labs. Therefore, transport. This kind of propagation has a widely use in experiments can only be performed by collaboration the lab-on-chip applications. Channel model of kinsein of researchers from communication and computer moving over microtube has been proposed in [55]. engineering, bio-engineering, biology and chemistry. The trail of the motor protein can be modeled in one- dimensional system with attached state in Eq. (6): One possible convenient solution is utilization of the off-the-shelf technologies to develop the experimental li = li-1 + vavg Δt (6)

http://www.nanobe.org 284 Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 platforms. We could expect that the most valuable investigations are very limited and not sufficient. new contributions to MC field would be the validation However mobile MC is an important issue. For of the proposed models by experiments through instance, in drug delivery, bionanomachines are mobile collaboration of multi-disciplines. and move dynamically to track the target. Current models fail to accurately express such mobile MC. Below are some experimental platforms that if developed, would have significant effect on the Most of current works focus on diffusion-based advancement of the field. propagation. There are also other propagation approaches in MC including bacteria-based • MC in aqueous environments in micro-scales: propagation, motor protein-based propagation and Although experimental platforms over free-air at extracellular matrix-based propagation. Very few works macro-scales exist [59], there are no MC testbeds have considered the channels of these propagation for liquid environments, especially at micro-scales. ways. More investigation will be necessary. However, many expected applications are at micro- scales in aqueous environment. Developing such Modulation process experiment systems at micro-scales can be very Many modulation schemes have been proposed significant for the advancement of MC. for MC channels [19, 60]. However, there are a lot of simplifying assumptions in the schemes. And the • Demonstration of MC for synthetic biology and proposed schemes only are evaluated by simulations. nanotechnology: Therefore, one of the biggest challenges is to validate Modeling and simulation are the current ways these modulation schemes by experiments. of MC investigation. However, the main interests Synchronization is an open issue. Most of the of MC are in applications of systems biology and proposed modulation schemes for MC assume that nanotechnology. Therefore, experimental systems that the transmitter and the receiver are synchronized. demonstrate MC between synthetic biological devices However, how they are synchronized is unknown. or MC in nanotechnology are tremendous valuable. Some previous works have proposed solutions of this • Structure of molecules or particles as information problem [61-63]. But further investigations are still carriers: needed. A large amount of information can be encoded in the Parameter estimation is also an important issue. In structure of molecules (e.g. DNA molecules), which MC, channel parameters are required at the transmitter provide a high data rate. However, the techniques for or receiver sometimes. Typical channel parameter could rapid generation of different molecular structures are be distance between the transmitter and the receiver, not available and need to be developed. diffusion coefficient of medium and etc. [64, 65]. Propagation models In MC channel, ISI is the main interference source Various channel models have been proposed. and has a significant impact on the performance of However, they are too simplistic. For example, many modulation [66]. Therefore, effective ISI mitigation works on diffusion-based propagation assume infinite techniques are worthy of attention. boundary conditions and assume transmitter as a point source with infinite small size, which are not the case Conclusions for many applications. For examples, blood vessel MC is a multidisciplinary field at the intersection of environment is a finite boundary condition. Therefore, electronic communication and computer engineering, more realistic and accurate models are needed. biotechnology, biology, chemistry, and etc. Although MC is still in its infancy, much advancement has been What is more important is that current proposed achieved in developing theoretical models for MC in models are only verified with simulations. This is not the communication engineering society. But we are sufficient. The developed models should be validated still facing many challenges to be solved. At the same by experiments. time, the fields of biotechnology, synthetic biology, and Current models focus on the channel between fixed nanotechnology progress rapidly. Primitive devices transmitter and receiver. Channel models of mobile with limited capabilities have been developed and nanomachines are seldom considered. The related could be applied into implementation. http://www.nanobe.org Nano Biomed. Eng., 2016, Vol. 8, Iss. 4 285

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