Applications of molecular communications to medicine: a survey
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paper_title: Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine

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The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ~1018 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.
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paper_title: Characterization of signal propagation in neuronal systems for nanomachine-to-neurons communications

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In the next decade nanocommunications will have great impact on biomedical engineering applications, for example in the view of allowing rehabilitation of patients which suffer for irreversible damage to the vertebral column. In such a case, the impossibility to move caused by an interruption in the propagation of nervous impulses, could be solved by exploiting nanomachines that employ the same communication paradigm of neurons to interact with them, thus allowing signal propagation across the body critical area. Accordingly, in this paper we perform a characterization and provide a model of the signal propagation between two entities which use a neuronal paradigm of communication, e.g. two neurons or a neuron and a nanomachine, so as to derive expressions of the transfer function, gain and delay incurred during the transmission. This could allow to design nanomachines compatible with the biological structures and able to integrate and substitute them when needed.
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paper_title: From P0 to P6 medicine, a model of highly participatory, narrative, interactive, and “augmented” medicine: some considerations on Salvatore Iaconesi’s clinical story

paper_content:

Salvatore Iaconesi was recently diagnosed with a brain tumor. He decided to share his clinical records not only with doctors but with everybody who wishes to find him a cure. “Because cure is not unique,” he emphasizes “there are cures for the body and cures for the soul, and everyone, from a painter to a musician, can find me a cure. Please, feel free to take my clinical history for example and let it become a game, a video, a music, a picture, whatever you like.” The emblematic hallmark of the changing times, Salvatore Iaconesi’s case is an example of how many profound revolutions and steps medicine has undertaken during the past few centuries. Stemming from a form of remote medical paternalism and arriving at the concept of a therapeutic alliance, medicine nowadays faces challenges and opportunities at a level before unforeseeable and unimaginable. The new concept of P6 medicine (personalized, predictive, preventive, participatory, psychocognitive, and public) is discussed, together with its profound implications.
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paper_title: Joint Energy Harvesting and Communication Analysis for Perpetual Wireless Nanosensor Networks in the Terahertz Band

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Wireless nanosensor networks (WNSNs) consist of nanosized communicating devices, which can detect and measure new types of events at the nanoscale. WNSNs are the enabling technology for unique applications such as intrabody drug delivery systems or surveillance networks for chemical attack prevention. One of the major bottlenecks in WNSNs is posed by the very limited energy that can be stored in a nanosensor mote in contrast to the energy that is required by the device to communicate. Recently, novel energy harvesting mechanisms have been proposed to replenish the energy stored in nanodevices. With these mechanisms, WNSNs can overcome their energy bottleneck and even have infinite lifetime (perpetual WNSNs), provided that the energy harvesting and consumption processes are jointly designed. In this paper, an energy model for self-powered nanosensor motes is developed, which successfully captures the correlation between the energy harvesting and the energy consumption processes. The energy harvesting process is realized by means of a piezoelectric nanogenerator, for which a new circuital model is developed that can accurately reproduce existing experimental data. The energy consumption process is due to the communication among nanosensor motes in the terahertz band (0.1-10 THz). The proposed energy model captures the dynamic network behavior by means of a probabilistic analysis of the total network traffic and the multiuser interference. A mathematical framework is developed to obtain the probability distribution of the nanosensor mote energy and to investigate the end-to-end successful packet delivery probability, the end-to-end packet delay, and the achievable throughput of WNSNs. Nanosensor motes have not been built yet and, thus, the development of an analytical energy model is a fundamental step toward the design of WNSNs architectures and protocols.
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paper_title: A simulation tool for nanoscale biological networks

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a b s t r a c t Nanonetworking is a new interdisciplinary research area including nanotechnology, biotechnology, and ICT. In this paper, we present a novel simulation platform designed for modeling information exchange at nanoscales. This platform is adaptable to any kind of nano bearer, i.e. any mechanism used to transport information, such as electromagnetic waves or calcium ions. Moreover, it includes a set of configuration functions in order to adapt to different types of biological environments. In this paper, we provide a throughout description of the simulation libraries. In addition, we demonstrate their capabilities by modeling a section of a lymph node and the information transfer within it, which happens between antibody molecules produced by the immune system during the humoral immune response.
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paper_title: Diffusion-based Physical Channel Identification in Molecular Nanonetworks

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Catala: El treball es una exploracio del canal de difusio molecular per nanoredes moleculars, en el qual s'identifica la resposta impulsional i en frequencia del canal, es comprova la seva linealitat i invariancia i s'extreuen les principals caracteristiques de comunicacio. S'avaluen diferents tecniques de modulacio.
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paper_title: Simulating Wireless Nano Sensor Networks in the NS-3 Platform

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The Wireless nanosensor network paradigm is rapidly gaining the attention of researchers within the scientific and industrial communities, thanks to the progress of nanotechnology. The envisioned concept is based on integrated machines at the nano scale, which interact on cooperative basis by means of wireless communications. At the present stage, the design of the protocol suite for wireless nanosensor networks represents a fundamental issue to address for accelerating the deployment process of such a technology. In this direction, the availability of an open source simulator would be surely of help in the development of participated design methodologies, in enforcing the collaboration among different teams, and in easing the verifiability of scientific outcomes. Despite the evident advantages that such a platform could bring, currently available tools only support molecular-based approaches without accounting for the relevant impact that electromagnetic communications may have in this field. To cover this lack, the present contribution proposes a modular and easy upgradeable simulation platform, intended for wireless nanosensor networks based on electromagnetic communication in the terahertz band. Preliminary results drawn from a a simple, yet significant, health monitoring scenario are also provided along with a study on computational requirements and future upgrades.
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paper_title: A systems-theoretic model of a biological circuit for molecular communication in nanonetworks

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Abstract Recent advances in synthetic biology, in particular towards the engineering of DNA-based circuits, are providing tools to program man-designed functions within biological cells, thus paving the way for the realization of biological nanoscale devices, known as nanomachines. By stemming from the way biological cells communicate in the nature, Molecular Communication (MC), i.e., the exchange of information through the emission, propagation, and reception of molecules, has been identified as the key paradigm to interconnect these biological nanomachines into nanoscale networks, or nanonetwork. The design of MC nanonetworks built upon biological circuits is particularly interesting since cells possess many of the elements required to realize this type of communication, thus enabling the design of cooperative functions in the biological environment. In this paper, a systems-theoretic modeling is realized by analyzing a minimal subset of biological circuit elements necessary to be included in an MC nanonetwork design where the message-bearing molecules are propagated via free diffusion between two cells. The obtained system-theoretic models stem from the biochemical processes underlying cell-to-cell MC, and are analytically characterized by their transfer functions, attenuation and delay experienced by an information signal exchanged by the communicating cells. Numerical results are presented to evaluate the obtained analytical expressions as functions of realistic biological parameters.
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paper_title: Predictive, personalized, preventive, participatory (P4) cancer medicine

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Medicine will move from a reactive to a proactive discipline over the next decade--a discipline that is predictive, personalized, preventive and participatory (P4). P4 medicine will be fueled by systems approaches to disease, emerging technologies and analytical tools. There will be two major challenges to achieving P4 medicine--technical and societal barriers--and the societal barriers will prove the most challenging. How do we bring patients, physicians and members of the health-care community into alignment with the enormous opportunities of P4 medicine? In part, this will be done by the creation of new types of strategic partnerships--between patients, large clinical centers, consortia of clinical centers and patient-advocate groups. For some clinical trials it will necessary to recruit very large numbers of patients--and one powerful approach to this challenge is the crowd-sourced recruitment of patients by bringing large clinical centers together with patient-advocate groups.
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paper_title: Exploratory Design in Medical Nanotechnology: A Mechanical Artificial Red Cell

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Molecular manufacturing promises precise control of matter at the atomic and molecular level, allowing the construction of micron-scale machines comprised of nanometer-scale components. Medical nanomachines will be among the earliest applications. The artificial red blood cell or “respirocyte” proposed here is a bloodborne spherical 1-micron diamondoid 1000-atm pressure vessel with active pumping powered by endogenous serum glucose, able to deliver 236 times more oxygen to the tissues per unit volume than natural red cells and to manage carbonic acidity. An onboard nanocomputer and numerous chemical and pressure sensors enable complex device behaviors remotely reprogrammable by the physician via externally applied acoustic signals.
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paper_title: Molecular Communication and Networking: Opportunities and Challenges

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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.
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paper_title: Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma

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Circulating microRNAs (miRNAs) are emerging as promising biomarkers for cancer; however, the significance of circulating miRNAs in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains largely unknown. Based on our prior observations that miRNA-101 (miR-101) is downregulated by HBV and induces epigenetic modification, we sought to test whether circulating miR-101 may serve as a potential biomarker for HCC. The expression of miR-101 in HCCs and serum was evaluated by real-time polymerase chain reaction. Tissue and serum miR-101 levels were assessed in samples from patients with HBV-related HCC and healthy controls. A potential correlation was also evaluated between miR-101 expression and the clinicopathological features and prognosis of HCC patients. miR-101 was downregulated in HBV-related HCC tissues compared with adjacent noncancerous tissues. Furthermore, the miR-101 levels in these tissues from HCC patients were significantly lower than those in tissues from control subjects. Notably, serum miR-101 levels were found to have an inverse correlation with tissue miR-101 expression levels. The expression of serum miR-101 in patients with HBV-related HCC was significantly higher than that in the healthy controls, and this increase correlated with hepatitis B surface antigen positivity, HBV DNA levels and tumor size. These results indicate that different factors govern the levels of miR-101 in the tissue and serum of HCC patients. Given the marked and consistent increase in serum miR-101 levels in HCC patients, circulating miR-101 may serve as a promising biochemical marker for monitoring the progression of tumor development in HBV-related HCC.
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paper_title: Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer

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We recently demonstrated that plectin is a robust biomarker for pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive malignancies. In normal physiology, plectin is an intracellular scaffolding protein, but we have demonstrated localization on the extracellular surface of PDAC cells. In this study, we confirmed cell surface localization. Interestingly, we found that plectin cell surface localization was attributable to its presence in exosomes secreted from PDAC cells, which is dependent on the expression of integrin β4, a protein known to interact with cytosolic plectin. Moreover, plectin expression was necessary for efficient exosome production and was required to sustain enhanced tumor growth in immunodeficient and in immunocompetent mice. It is now clear that this PDAC biomarker plays a role in PDAC, and further understanding of plectin’s contribution to PDAC could enable improved therapies.
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paper_title: Programmable probiotics for detection of cancer in urine

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Rapid advances in the forward engineering of genetic circuitry in living cells has positioned synthetic biology as a potential means to solve numerous biomedical problems, including disease diagnosis and therapy. One challenge inexploitingsynthetic biologyfortranslationalapplicationsistoengineermicrobesthatarewelltoleratedbypatients and seamlessly integrate with existing clinical methods. We use the safe and widely used probiotic Escherichia coli Nissle 1917 to develop an orally administered diagnostic that can noninvasively indicate the presence of liver metastasis by producing easily detectable signals in urine. Our microbial diagnostic generated a high-contrast urine signal through selective expansion in liver metastases (10 6 -fold enrichment) and high expression of a lacZ reporter maintained by engineering a stable plasmid system. The lacZ reporter cleaves a substrate to produce a small molecule that can be detected in urine. E. coli Nissle 1917 robustly colonized tumor tissue in rodent models of liver metastasis after oral delivery but did not colonize healthy organs or fibrotic liver tissue. We saw no deleterious health effects on the mice for more than 12 months after oral delivery. Our results demonstrate that probiotics can be programmed to safely and selectively deliver synthetic gene circuits to diseased tissue microenvironments in vivo.
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paper_title: CD164 regulates the tumorigenesis of ovarian surface epithelial cells through the SDF-1α/CXCR4 axis

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BackgroundCD164 (endolyn), a sialomucin, has been reported to play a role in the proliferation, adhesion, and differentiation of hematopoietic stem cells. The potential association of CD164 with tumorigenicity remains unclear.MethodsThe clinicopathological correlation of ovarian cancer with CD164 was assessed in a 97-patient tumor tissue microarray. Overexpression or silence CD164 was to analyze the effect of CD164 on the proliferation, colony formation and apoptosis via a mouse xenograft and western blotting analysis. The subcellular localization of CD164 was collected in the immunohistochemical and confocal analysis.ResultsOur data demonstrated that higher expression levels of CD164 were identified in malignant ovarian cancer cell lines, such as SKOV3 and HeyA8. The clinicopathological correlation analysis showed that the upregulation of CD164 protein was significantly associated with tumor grade and metastasis. The overexpression of CD164 in human ovarian epithelial surface cells promoted cellular proliferation and colony formation and suppressed apoptosis. These tumorigenicity effects of CD164 were reconfirmed in a mouse xenograft model. We also found that the overexpression of CD164 proteins increased the amounts of CXCR4 and SDF-1α and activated the SDF-1α/CXCR4 axis, inducing colony and sphere formation. Finally, we identified the subcellular localization of CD164 in the nucleus and cytosol and found that nuclear CD164 might be involved in the regulation of the activity of the CXCR4 promoter.ConclusionsOur findings suggest that the increased expression of CD164 is involved in ovarian cancer progression via the SDF-1α/CXCR4 axis, which promotes tumorigenicity. Thus, targeting CD164 may serve as a potential ovarian cancer biomarker, and targeting CD164 may serve as a therapeutic modality in the management of high-grade ovarian tumors.
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paper_title: Plasma Osteopontin Is a Useful Diagnostic Biomarker for Advanced Non-Small Cell Lung Cancer

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Background ::: Osteopontin (OPN) and carbonic anhydrase IX (CAIX), which are expressed on the surface of tumor cells, are associated with hypoxia during tumor development and progression. However, the roles of these proteins in the plasma of patients with non-small cell lung cancer (NSCLC) are poorly understood. Herein, we hypothesized that plasma OPN and CAIX levels could be used as diagnostic and prognostic tumor markers in patients with NSCLC.
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paper_title: A Molecular Communication System in Blood Vessels for Tumor Detection

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This paper shows a proposal of a biological nano-communication system established in a blood vessel, aiming to support the detection and treatment of tumors. This system could either be used for diagnostic purposes in the early stage of a disease or to check any relapse of a previous disease already treated. In our proposal, the tumor detection happens through revealing tumor biomarkers on the cell surface, such as the CD47 protein. This detection takes advantage of some recent proposal if implementing nanorobot transport systems through modified flagellated bacteria. When a biomarker is detected, a molecular communication system is used for distributing the information over a number of nano-machines. These machines have a size similar to the white blood cells, so that they can flow through the vessel at the speed of the largest particles. The transported information is detected extra-body, through the use of smart probes, which triggers a decision tree in order to estimate the nature of the tumor and its most likely location.
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paper_title: Apolipoprotein C-II is a potential serum biomarker as a prognostic factor of locally advanced cervical cancer after chemoradiation therapy.

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PURPOSE ::: To determine pretreatment serum protein levels for generally applicable measurement to predict chemoradiation treatment outcomes in patients with locally advanced squamous cell cervical carcinoma (CC). ::: ::: ::: METHODS AND MATERIALS ::: In a screening study, measurements were conducted twice. At first, 6 serum samples from CC patients (3 with no evidence of disease [NED] and 3 with cancer-caused death [CD]) and 2 from healthy controls were tested. Next, 12 serum samples from different CC patients (8 NED, 4 CD) and 4 from healthy controls were examined. Subsequently, 28 different CC patients (18 NED, 10 CD) and 9 controls were analyzed in the validation study. Protein chips were treated with the sample sera, and the serum protein pattern was detected by surface-enhanced laser desorption and ionization-time-of-flight mass spectrometry (SELDI-TOF MS). Then, single MS-based peptide mass fingerprinting (PMF) and tandem MS (MS/MS)-based peptide/protein identification methods, were used to identify protein corresponding to the detected peak. And then, turbidimetric assay was used to measure the levels of a protein that indicated the best match with this peptide peak. ::: ::: ::: RESULTS ::: The same peak 8918 m/z was identified in both screening studies. Neither the screening study nor the validation study had significant differences in the appearance of this peak in the controls and NED. However, the intensity of the peak in CD was significantly lower than that of controls and NED in both pilot studies (P=.02, P=.04) and validation study (P=.01, P=.001). The protein indicated the best match with this peptide peak at 8918 m/z was identified as apolipoprotein C-II (ApoC-II) using PMF and MS/MS methods. Turbidimetric assay showed that the mean serum levels of ApoC-II tended to decrease in CD group when compared with NED group (P=.078). ::: ::: ::: CONCLUSION ::: ApoC-II could be used as a biomarker for detection in predicting and estimating the radiation treatment outcome of patients with CC.
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paper_title: Endovascular mobile sensor network for detecting circulating tumoral cells

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This paper analyzes the communications and medical potentials arising from establishing nano-scale communications making use of the stent tubular structures in blood vessels. Most of stent implants (both bare metal and drug eluiting stents) happens in coronary arteries for supporting weak endothelial points and counteracting the obstructing effects of arthrosclerosis. Such structures have continuously inspired researchers for introducing additional functions to the mere mechanical sustain of vessels. After a review of the current literature, we propose an original use of stents for monitoring CD47 receptors bearing cells and provide effective diagnostic and prognostic information. We can also perform the detection of different cancer markers, and then integrate this information. These monitoring functions and the event notifications makes used of nano-scale communications. Through a well established simulator of biological nano-scale communications, we will gain significant insights about the establishment of these types of communications happening between different sections of the stent structure. The information exchanges is assumed to be collected by nano-sensors of tumor cells. The outcome of the research is the characterization of the channel transmission capabilities. When considering cost benefit of these expensive smart stents, we suggest a wider perspective where oncologists may join the team of future interventional cardiologists. Thus, our system creates a link between cancer detection, stent devices, and body area networks to P5 medicine.
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paper_title: Carcinoembryonic antigen (CEA) as tumor marker in lung cancer.

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The use of CEA as a prognostic and predictive marker in patients with lung cancer is widely debated. The aim of this review was to evaluate the results from studies made on this subject. Using the search words "CEA", "tumor markers in lung cancer", "prognostic significance", "diagnostic significance" and "predictive significance", a search was carried out on PubMed. Exclusion criteria was articles never published in English, articles before 1981 and articles evaluating tumor markers in lung cancer not involving CEA. Initially 217 articles were found, and 34 were left after selecting those relevant for the present study. Four of these included both Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) patients, and 31 dealt solely with NSCLC patients. Regarding SCLC no studies showed that serum level of CEA was a prognostic marker for overall survival (OS). The use of CEA serum level as a prognostic marker in NSCLC was investigated in 23 studies and the use of CEA plasma level in two. In 18 (17 serum, 1 plasma) of these studies CEA was found to be a useful prognostic marker for either OS, recurrence after surgery or/and progression free survival (PFS) in NSCLC patients. Interestingly, an overweight of low stage (stage I-II) disease and adenocarcinoma (AC) patients were observed in this group. The remaining 7 studies (6 serum, 1 plasma) contained an overweight of patients with squamous carcinoma (SQ). One study found evidence for that a tumor marker index (TMI), based on preoperative CEA and CYFRA21-1 serum levels, is useful as a prognostic marker for OS in NSCLC. Six studies evaluated the use of CEA as a predictive marker for risk of recurrence and risk of death in NSCLC patients. Four of these studies found, that CEA was useful as a predictive marker for risk of recurrence and risk of death measured over time. No studies found CEA levels useful as a diagnostic marker for lung cancer. With regard to NSCLC the level of CEA measured in tumor tissue in NSCLC patients, were not of prognostic, diagnostic or predictive significance for OS or recurrence after treatment. In one study CEA level was measured in Pleural Lavage Fluid (PLF) it was here found to be useful as prognostic markers for overall survival (OS) after surgery. In conclusion serum level of CEA carries prognostic and predictive information of risk of recurrence and of death in NSCLC independent of treatment or study design. The observation that TMI index could be a potential prognostic marker for OS in NSCLC is interesting. Future studies may benefit from evaluating more than one marker at a time, which may possibly create a more precise index for prognosis and recurrence in lung cancer, than is possible by the use of single biomarkers.
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paper_title: Mobile Ad Hoc Nanonetworks with Collision-Based Molecular Communication

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Recent developments in nanotechnology have enabled the fabrication of nanomachines with very limited sensing, computation, communication, and action capabilities. The network of communicating nanomachines is envisaged as nanonetworks that are designed to accomplish complex tasks such as drug delivery and health monitoring. For the realization of future nanonetworks, it is essential to develop novel and efficient communication and networking paradigms. In this paper, the first step toward designing a mobile ad hoc molecular nanonetwork (MAMNET) with electrochemical communication is taken. MAMNET consists of mobile nanomachines and infostations that share nanoscale information using electrochemical communication whenever they have a physical contact with each other. In MAMNET, the intermittent connectivity introduced by the mobility of nanomachines and infostations is a critical issue to be addressed. An analytical framework that incorporates the effect of mobility into the performance of electrochemical communication among nanomachines is presented. Using the analytical model, numerical analysis for the performance evaluation of MAMNET is obtained. Results reveal that MAMNET achieves adequately high throughput to enable frontier nanonetwork applications with acceptable communication latency.
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paper_title: New paradigm for tumor theranostic methodology using bacteria-based microrobot

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We propose a bacteria-based microrobot (bacteriobot) based on a new fusion paradigm for theranostic activities against solid tumors. We develop a bacteriobot using the strong attachment of bacteria to Cy5.5-coated polystyrene microbeads due to the high-affinity interaction between biotin and streptavidin. The chemotactic responses of the bacteria and the bacteriobots to the concentration gradients of lysates or spheroids of solid tumors can be detected as the migration of the bacteria and/or the bacteriobots out of the central region toward the side regions in a chemotactic microfluidic chamber. The bacteriobots showed higher migration velocity toward tumor cell lysates or spheroids than toward normal cells. In addition, when only the bacteriobots were injected to the CT-26 tumor mouse model, Cy5.5 signal was detected from the tumor site of the mouse model. In-vitro and in-vivo tests verified that the bacteriobots had chemotactic motility and tumor targeting ability. The new microrobot paradigm in which bacteria act as microactuators and microsensors to deliver microstructures to tumors can be considered a new theranostic methodology for targeting and treating solid tumors.
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paper_title: Multi-input RNAi-based logic circuit for identification of specific cancer cells.

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Engineered biological systems that integrate multi-input sensing, sophisticated information processing, and precisely regulated actuation in living cells could be useful in a variety of applications. For example, anticancer therapies could be engineered to detect and respond to complex cellular conditions in individual cells with high specificity. Here, we show a scalable transcriptional/posttranscriptional synthetic regulatory circuit--a cell-type "classifier"--that senses expression levels of a customizable set of endogenous microRNAs and triggers a cellular response only if the expression levels match a predetermined profile of interest. We demonstrate that a HeLa cancer cell classifier selectively identifies HeLa cells and triggers apoptosis without affecting non-HeLa cell types. This approach also provides a general platform for programmed responses to other complex cell states.
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paper_title: Selective glycoprotein detection through covalent templating and allosteric click-imprinting

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Many glycoproteins are intimately linked to the onset and progression of numerous heritable or acquired diseases of humans, including cancer. Indeed the recognition of specific glycoproteins remains a significant challenge in analytical method and diagnostic development. Herein, a hierarchical bottom-up route exploiting reversible covalent interactions with boronic acids and so-called click chemistry for the fabrication of glycoprotein selective surfaces that surmount current antibody constraints is described. The self-assembled and imprinted surfaces, containing specific glycoprotein molecular recognition nanocavities, confer high binding affinities, nanomolar sensitivity, exceptional glycoprotein specificity and selectivity with as high as 30 fold selectivity for prostate specific antigen (PSA) over other glycoproteins. This synthetic, robust and highly selective recognition platform can be used in complex biological media and be recycled multiple times with no performance decrement.
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paper_title: Extracellular vesicles: biology and emerging therapeutic opportunities

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Within the past decade, extracellular vesicles have emerged as important mediators of intercellular communication, being involved in the transmission of biological signals between cells in both prokaryotes and higher eukaryotes to regulate a diverse range of biological processes. In addition, pathophysiological roles for extracellular vesicles are beginning to be recognized in diseases including cancer, infectious diseases and neurodegenerative disorders, highlighting potential novel targets for therapeutic intervention. Moreover, both unmodified and engineered extracellular vesicles are likely to have applications in macromolecular drug delivery. Here, we review recent progress in understanding extracellular vesicle biology and the role of extracellular vesicles in disease, discuss emerging therapeutic opportunities and consider the associated challenges.
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paper_title: Nanonetworks: a new frontier in communications

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Nanotechnology is enabling the development of devices in a scale ranging from one to a few one hundred nanometers. Nanonetworks, i.e., the interconnection of nano-scale devices, are expected to expand the capabilities of single nano-machines by allowing them to cooperate and share information. Traditional communication technologies are not directly suitable for nanonetworks mainly due to the size and power consumption of existing transmitters, receivers and additional processing components. All these define a new communication paradigm that demands novel solutions such as nano-transceivers, channel models for the nano-scale, and protocols and architectures for nanonetworks. In this talk, first the state-of-the-art in nano-machines, including architectural aspects, expected features of future nano-machines, and current developments are presented for a better understanding of the nanonetwork scenarios. Moreover, nanonetworks features and components are explained and compared with traditional communication networks. Novel nano-antennas based on nano-materials as well as the terahertz band are investigated for electromagnetic communication in nanonetworks. Furthermore, molecular communication mechanisms are presented for short-range networking based on ion signaling and molecular motors, for medium-range networking based on flagellated bacteria and nanorods, as well as for long-range networking based on pheromones and capillaries. Finally, open research challenges such as the development of network components, molecular communication theory, and new architectures and protocols, which need to be solved in order to pave the way for the development and deployment of nanonetworks within the next couple of decades are presented.
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paper_title: From P0 to P6 medicine, a model of highly participatory, narrative, interactive, and “augmented” medicine: some considerations on Salvatore Iaconesi’s clinical story

paper_content:

Salvatore Iaconesi was recently diagnosed with a brain tumor. He decided to share his clinical records not only with doctors but with everybody who wishes to find him a cure. “Because cure is not unique,” he emphasizes “there are cures for the body and cures for the soul, and everyone, from a painter to a musician, can find me a cure. Please, feel free to take my clinical history for example and let it become a game, a video, a music, a picture, whatever you like.” The emblematic hallmark of the changing times, Salvatore Iaconesi’s case is an example of how many profound revolutions and steps medicine has undertaken during the past few centuries. Stemming from a form of remote medical paternalism and arriving at the concept of a therapeutic alliance, medicine nowadays faces challenges and opportunities at a level before unforeseeable and unimaginable. The new concept of P6 medicine (personalized, predictive, preventive, participatory, psychocognitive, and public) is discussed, together with its profound implications.
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paper_title: Internalization of CD40 regulates its signal transduction in vascular endothelial cells

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Abstract The CD40 ligand (CD40L)-CD40 dyad can ignite proinflammatory and procoagulatory activities of the vascular endothelium in the pathogenesis and progression of atherosclerosis. Besides being expressed on the activated CD4 + T cell surface (mCD40L), the majority of circulating CD40L reservoir (sCD40L) in plasma is released from stimulated platelets. It remains debatable which form of CD40L triggers endothelial inflammation. Here, we demonstrate that the agonistic antibody of CD40 (G28.5), which mimics the action of sCD40L, induces rapid endocytosis of CD40 independent of TRAF2/3/6 binding while CD40L expressed on the surface of HEK293A cells captures CD40 at the cell conjunction. Forced internalization of CD40 by constitutively active mutant of Rab5 preemptively activates NF-κB pathway, suggesting that CD40 was able to form an intracellular signal complex in the early endosomes. Internalized CD40 exhibits different patterns of TRAF2/3/6 recruitment and Akt phosphorylation from the membrane anchored CD40 complex. Finally, mCD40L but not sCD40L induces the upregulation of proinflammatory cytokines and cell adhesion factors in the primary human vascular endothelial cells in vitro, although both forms of CD40L activate NF-κB pathway. These results therefore may help understand the molecular mechanism of CD40L signaling that contributes to the pathophysiology of atherosclerosis.
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paper_title: Simulating an in vitro experiment on nanoscale communications by using BiNS2

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Abstract Nanoscale communications is an emergent research topic with potential applications in many fields. In order to design nanomachines able to exploit the communication potentials of nanoscale environments, it is necessary to identify the basic communication mechanisms and the relevant parameters. In this paper, we show how system parameters can be derived by suitably matching the results of in vitro experiments with those obtained via simulations by using the BiNS2 simulator. In order to scale the simulation from micrometric settings, with timescale in the order of seconds, to real experiments lasting tens of minutes with millimetric size, we enhanced the BiNS2 simulator by introducing a space partition algorithm based on the octree. In this way, the simulator can exploit the high level of parallelism of modern multicore computer architectures. We have used this technique for simulating an experiment focused on the communication between platelets and endothelium through the diffusion of nanoparticles. Simulation results match experimental data, thus allowing us to infer useful information on the receiver operation.
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paper_title: Simulation of Molecular Signaling in Blood Vessels: Software Design and Application to Atherogenesis

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Abstract This paper presents a software platform, named BiNS2, able to simulate diffusion-based molecular communications with drift inside blood vessels. The contribution of the paper is twofold. First a detailed description of the simulator is given, under the software engineering point of view, by highlighting the innovations and optimizations introduced. Their introduction into the previous version of the BiNS simulator was needed to provide the functions for simulating molecular signaling and communication potentials inside bounded spaces. The second contribution consists of the analysis, carried out by using BiNS2, of a specific communication process happening inside blood vessels, the atherogenesis, which is the initial phase of the formation of atherosclerotic plaques, due to the abnormal signaling between platelets and endothelium. From a communication point of view, platelets act as mobile transmitters, endothelial cells are fixed receivers, sticky to the vessel walls, and the transmitted signal is made of bursts of molecules emitted by platelets. The simulator allows for the evaluation of the channel latency and the footprint on the vessel wall of the transmitted signal as a function of the transmitter distance from the vessels wall, the signal strength, and the receiver sensitivity.
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paper_title: Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation

paper_content:

Multifunctional nanomedicine holds considerable promise as the next generation of medicine that allows for targeted therapy with minimal toxicity. Most current studies on nanoparticle (NP) drug delivery consider a Newtonian fluid with suspending NPs. However, blood is a complex biological fluid composed of deformable cells, proteins, platelets, and plasma. For blood flow in capillaries, arterioles and venules, the particulate nature of the blood needs to be considered in the delivery process. The existence of the cell-free-layer and NP–cell interaction will largely influence both the dispersion and binding rates, thus impact targeted delivery efficacy. In this paper, a particle–cell hybrid model is developed to model NP transport, dispersion, and binding dynamics in blood suspension. The motion and deformation of red blood cells (RBCs) is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell–particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of red blood cells, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increasing as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications.
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paper_title: Modeling CD40-Based Molecular Communications in Blood Vessels

paper_content:

This paper presents a mathematical characterization of the main features of the molecular communication between platelets and endothelial cells via CD40 signaling during the initial phases of atherosclerosis, known also as atherogenesis. We demonstrate through laboratory experimentation that the release of soluble CD40L molecules from platelets in a fluid medium is enough to trigger expression of adhesion molecules on endothelial cell’s surface; that is, physical contact between the platelets and the endothelial cells is not necessary. We also propose the mathematical model of this communication, and we quantify the model parameters by matching the experiment results to the model. In addition, this mathematical model of platelet-endothelium interaction, along with propagation models typical of blood vessels, is incorporated into a simulation platform. Analysis of the simulation results indicates that these enhancements render the simulator a useful tool upon which to base discussion for planning research, and has the potential to be an important step in the understanding, diagnosis, and treatment of cardiovascular diseases.
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paper_title: Predictive, personalized, preventive, participatory (P4) cancer medicine

paper_content:

Medicine will move from a reactive to a proactive discipline over the next decade--a discipline that is predictive, personalized, preventive and participatory (P4). P4 medicine will be fueled by systems approaches to disease, emerging technologies and analytical tools. There will be two major challenges to achieving P4 medicine--technical and societal barriers--and the societal barriers will prove the most challenging. How do we bring patients, physicians and members of the health-care community into alignment with the enormous opportunities of P4 medicine? In part, this will be done by the creation of new types of strategic partnerships--between patients, large clinical centers, consortia of clinical centers and patient-advocate groups. For some clinical trials it will necessary to recruit very large numbers of patients--and one powerful approach to this challenge is the crowd-sourced recruitment of patients by bringing large clinical centers together with patient-advocate groups.
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paper_title: The Role of Platelets in Atherothrombosis

paper_content:

Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis; therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modulators, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrombotic process and that future therapeutic strategies to combat this disease need to take into consideration both the prothrombotic and proinflammatory function of platelets.
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paper_title: Multi-Step FRET-Based Long-Range Nanoscale Communication Channel

paper_content:

Nanoscale communication based on Forster Resonance Energy Transfer (FRET) is a promising paradigm that allows future molecular-size machines to communicate with each other over distances up to 10 nm using the excited state energies of fluorescent molecules. In this study, we propose a novel nanoscale communication method based on multi-step FRET using identical fluorophores as relay nodes between communicating nanomachines, and utilizing multi-exciton transmission scheme in order to improve the limited range of the communication and achievable transmission rate over the nanoscale channel. We investigate two communication scenarios: immobile nanomachines communicating through a channel in a host material with linearly located relay nodes, and mobile nanomachines communicating through a channel in a 3-dimensional aqueous environment with randomly deployed relay nodes. We simulate the communication over these channels with realistic algorithms considering the high degree of randomness intrinsic to FRET phenomenon. Using the simulation results and following a Monte Carlo approach, we evaluate the performance of the channels by means of information theoretical capacity and interference probability. We show that multi-step FRET-based communication significantly outperforms the other biologically inspired nanocommunication techniques proposed so far in terms of maximum achievable data transmission rates. The results underline the compatibility and practicality of the FRET-based communication for several applications ranging from molecular computers to nanosensor networks.
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paper_title: Aptamers and Their Applications in Nanomedicine

paper_content:

Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity and affinity. Although functionally similar to protein antibodies, oligonucleotide aptamers offer several advantages over protein antibodies in biomedical and clinical applications. Through the enhanced permeability and retention effect, nanomedicines can improve the therapeutic index of a treatment and reduce side effects by enhancing accumulation at the disease site. However, this targets tumors passively and, thus, may not be ideal for targeted therapy. To construct ligand-directed "active targeting" nanobased delivery systems, aptamer-equipped nanomedicines have been tested for in vitro diagnosis, in vivo imaging, targeted cancer therapy, theranostic approaches, sub-cellular molecule detection, food safety, and environmental monitoring. This review focuses on the development of aptamer-conjugated nanomedicines and their application for in vivo imaging, targeted therapy, and theranostics.
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paper_title: QDs-DNA nanosensor for the detection of hepatitis B virus DNA and the single-base mutants.

paper_content:

We report here a quantum dots-DNA (QDs-DNA) nanosensor based on fluorescence resonance energy transfer (FRET) for the detection of the target DNA and single mismatch in hepatitis B virus (HBV) gene. The proposed one-pot DNA detection method is simple, rapid and efficient due to the elimination of the washing and separation steps. In this study, the water-soluble CdSe/ZnS QDs were prepared by replacing the trioctylphosphine oxide (TOPO) on the surface of QDs with 3-mercaptopropionic acid (MPA). Subsequently, oligonucleotides were attached to the QDs surface to form functional QDs-DNA conjugates. Along with the addition of DNA targets and Cy5-modified signal DNAs into the QDs-DNA conjugates, sandwiched hybrids were formed. The resulting assembly brings the Cy5 fluorophore, the acceptor, and the QDs, the donor, into proximity, leading to fluorescence emission from the acceptor by means of FRET on illumination of the donor. In order to efficiently detect single-base mutants in HBV gene, oligonucleotide ligation assay was employed. If there existed a single-base mismatch, which could be recognized by the ligase, the detection probe was not ligated and no Cy5 emission was produced due to the lack of FRET. The feasibility of the proposed method was also demonstrated in the detection of synthetic 30-mer oliginucleotide targets derived from the HBV with a sensitivity of 4.0nM by using a multilabel counter. The method enables a simple and efficient detection that could be potentially used for high throughput and multiplex detections of target DNA and the mutants.
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paper_title: A Communication Theoretical Analysis of FRET-Based Mobile Ad Hoc Molecular Nanonetworks

paper_content:

Nanonetworks refer to a group of nanosized machines with very basic operational capabilities communicating to each other in order to accomplish more complex tasks such as in-body drug delivery, or chemical defense. Realizing reliable and high-rate communication between these nanomachines is a fundamental problem for the practicality of these nanonetworks. Recently, we have proposed a molecular communication method based on Forster Resonance Energy Transfer (FRET) which is a nonradiative excited state energy transfer phenomenon observed among fluorescent molecules, i.e., fluorophores. We have modeled the FRET-based communication channel considering the fluorophores as single-molecular immobile nanomachines, and shown its reliability at high rates, and practicality at the current stage of nanotechnology. In this study, for the first time in the literature, we investigate the network of mobile nanomachines communicating through FRET. We introduce two novel mobile molecular nanonetworks: FRET-based mobile molecular sensor/actor nanonetwork (FRET-MSAN) which is a distributed system of mobile fluorophores acting as sensor or actor node; and FRET-based mobile ad hoc molecular nanonetwork (FRET-MAMNET) which consists of fluorophore-based nanotransmitter, nanoreceivers and nanorelays. We model the single message propagation based on birth-death processes with continuous time Markov chains. We evaluate the performance of FRET-MSAN and FRET-MAMNET in terms of successful transmission probability and mean extinction time of the messages, system throughput, channel capacity and achievable communication rates.
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paper_title: A Physical Channel Model and Analysis for Nanoscale Molecular Communications With Förster Resonance Energy Transfer (FRET)

paper_content:

In this study, a novel and physically realizable nanoscale communication paradigm is introduced based on a well-known phenomenon, Forster resonance energy transfer (FRET), for the first time in the literature. FRET is a nonradiative energy transfer process between fluorescent molecules based on the dipole-dipole interactions of molecules. Energy is transferred rapidly from a donor to an acceptor molecule in a close proximity such as 0 to 10 nm without radiation of a photon. Low dependence on the environmental factors, controllability of its parameters, and relatively wide transfer range make FRET a promising candidate to be used for a high-rate nanoscale communication channel. In this paper, the simplest form of the FRET-based molecular communication channel comprising a single transmitter-receiver nanomachine pair and an extended version of this channel with a relay nanomachine for long-range applications are modeled considering nanomachines as nanoscale electromechanical devices with some sensing, computing, and actuating capabilities. Furthermore, using the information theoretical approach, the capacities of these communication channels are investigated and the dependence of the capacity on some environmental and intrinsic parameters is analyzed. It is shown that the capacity can be increased by appropriately selecting the donor-acceptor pair, the medium, the intermolecular distance, and the orientation of the molecules.
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paper_title: A nanoscale communication channel with fluorescence resonance energy transfer (FRET)

paper_content:

In this study, a novel and physically realizable nanoscale communication paradigm is introduced based on a well-known phenomenon, Fluorescence Resonance Energy Transfer (FRET) for the first time in the literature. FRET is a nonradiative energy transfer process between fluorescent molecules based on the dipole-dipole interactions of molecules. Energy is transferred rapidly from a donor to an acceptor molecule in a close proximity such as 0 to 10 nm without radiation of a photon. Low dependency on the environmental factors, controllability of its parameters and relatively wide transfer range make FRET a promising candidate to be used for a high rate nanoscale communication channel. In this paper, the simplest form of the FRET-based molecular communication channel for a single transmitter and a single receiver nanomachine is modeled. Furthermore, using the information theoretical approach, the capacity of the point-to-point communication channel is investigated and the dependency of the capacity on some environmental and intrinsic parameters is analyzed. It is shown that the capacity can be increased by appropriately selecting the donor-acceptor pair, the medium, the intermolecular distance and the orientation of the molecules.
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paper_title: Diffusive Molecular Communication with Disruptive Flows

paper_content:

In this paper, we study the performance of detectors in a diffusive molecular communication environment where steady uniform flow is present. We derive the expected number of information molecules to be observed in a passive spherical receiver, and determine the impact of flow on the assumption that the concentration of molecules throughout the receiver is uniform. Simulation results show the impact of advection on detector performance as a function of the flow's magnitude and direction. We highlight that there are disruptive flows, i.e., flows that are not in the direction of information transmission, that lead to an improvement in detector performance as long as the disruptive flow does not dominate diffusion and sufficient samples are taken.
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paper_title: A Molecular Communication System Model for Particulate Drug Delivery Systems

paper_content:

The goal of a drug delivery system (DDS) is to convey a drug where the medication is needed, while, at the same time, preventing the drug from affecting other healthy parts of the body. Drugs composed of micro- or nano-sized particles (particulate DDS) that are able to cross barriers which prevent large particles from escaping the bloodstream are used in the most advanced solutions. Molecular communication (MC) is used as an abstraction of the propagation of drug particles in the body. MC is a new paradigm in communication research where the exchange of information is achieved through the propagation of molecules. Here, the transmitter is the drug injection, the receiver is the drug delivery, and the channel is realized by the transport of drug particles, thus enabling the analysis and design of a particulate DDS using communication tools. This is achieved by modeling the MC channel as two separate contributions, namely, the cardiovascular network model and the drug propagation network. The cardiovascular network model allows to analytically compute the blood velocity profile in every location of the cardiovascular system given the flow input by the heart. The drug propagation network model allows the analytical expression of the drug delivery rate at the targeted site given the drug injection rate. Numerical results are also presented to assess the flexibility and accuracy of the developed model. The study of novel optimization techniques for a more effective and less invasive drug delivery will be aided by this model, while paving the way for novel communication techniques for Intrabody communication networks.
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paper_title: Transmission Rate Control for Molecular Communication among Biological Nanomachines

paper_content:

In this paper, we discuss issues concerned with transmission rate control in molecular communication, an emerging communication paradigm for bio-nanomachines in an aqueous environment. In molecular communication, a group of bio-nanomachines acting as senders transmit molecules, the molecules propagate in the environment, and another group of bio-nanomachines acting as receivers chemically react to the molecules propagating in the environment. In the model of molecular communication considered in this paper, senders may transmit molecules at a high rate to accelerate the receiver reactions or to increase the throughput. However, if the senders transmit molecules faster than the receivers react, the excess molecules remain in the environment and eventually degrade or diffuse away, which results in loss of molecules or degradation in efficiency. Such a potential issue associated with throughput and efficiency is in this paper discussed as an optimization problem. A mathematical expression for an upper-bound on the throughput and efficiency is first derived to provide an insight into the impact of model parameters. The optimal transmission rates that maximize the throughput and efficiency are then numerically calculated and presented, and throughput and efficiency are shown to be in trade-off relationships in a wide range of transmission rates. Further, two classes of feedback-based transmission rate control schemes are designed for autonomous bio-nanomachines to dynamically control their transmission rates, respectively based on negative and positive feedback from the receivers. The numerical evaluation of the two transmission rate control schemes is then shown to provide useful guidelines for application developers to satisfy their design goals.
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paper_title: Simulation of Molecular Signaling in Blood Vessels: Software Design and Application to Atherogenesis

paper_content:

Abstract This paper presents a software platform, named BiNS2, able to simulate diffusion-based molecular communications with drift inside blood vessels. The contribution of the paper is twofold. First a detailed description of the simulator is given, under the software engineering point of view, by highlighting the innovations and optimizations introduced. Their introduction into the previous version of the BiNS simulator was needed to provide the functions for simulating molecular signaling and communication potentials inside bounded spaces. The second contribution consists of the analysis, carried out by using BiNS2, of a specific communication process happening inside blood vessels, the atherogenesis, which is the initial phase of the formation of atherosclerotic plaques, due to the abnormal signaling between platelets and endothelium. From a communication point of view, platelets act as mobile transmitters, endothelial cells are fixed receivers, sticky to the vessel walls, and the transmitted signal is made of bursts of molecules emitted by platelets. The simulator allows for the evaluation of the channel latency and the footprint on the vessel wall of the transmitted signal as a function of the transmitter distance from the vessels wall, the signal strength, and the receiver sensitivity.
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paper_title: TCP-like molecular communications

paper_content:

In this paper, we present a communication protocol between a pair of biological nanomachines, i.e., a transmitter and a receiver, built upon molecular communications in an aqueous environment. In our proposal, the receiver, acting as a control node, sends a connection setup signal to the transmitter, which stokes molecules, to start molecule transmission. The molecules transmitted by the transmitter propagate in the environment and are absorbed by the receiver through its receptors. When the receiver absorbs the desired quantity of molecules, it releases a tear-down signal to notify the transmitter to stop the transmission. The proposed protocol implements a bidirectional communication by using a number of techniques originally designed for the TCP. In fact, the proposed protocol is connection-oriented and uses the TCP-like probing to find a suitable transmission rate between the transmitter and the receiver to avoid receiver congestion. Unlike the TCP, however, explicit acknowledgments are not used since they would degrade the communication throughput due to the large delay, which is a characteristic feature of molecular communications. Thus, the proposed protocol uses implicit acknowledgments, and feedback signals are sent by the receiver to throttle the transmission rate at the transmitter, i.e., explicit negative feedback. We also present the results of an extensive simulation campaign, used to validate the proposed protocol and to properly dimension the main protocol parameters.
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paper_title: Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation

paper_content:

Multifunctional nanomedicine holds considerable promise as the next generation of medicine that allows for targeted therapy with minimal toxicity. Most current studies on nanoparticle (NP) drug delivery consider a Newtonian fluid with suspending NPs. However, blood is a complex biological fluid composed of deformable cells, proteins, platelets, and plasma. For blood flow in capillaries, arterioles and venules, the particulate nature of the blood needs to be considered in the delivery process. The existence of the cell-free-layer and NP–cell interaction will largely influence both the dispersion and binding rates, thus impact targeted delivery efficacy. In this paper, a particle–cell hybrid model is developed to model NP transport, dispersion, and binding dynamics in blood suspension. The motion and deformation of red blood cells (RBCs) is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell–particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of red blood cells, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increasing as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications.
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paper_title: Advection, diffusion and delivery over a network

paper_content:

Many biological, geophysical, and technological systems involve the transport of a resource over a network. In this paper, we present an efficient method for calculating the exact quantity of the resource in each part of an arbitrary network, where the resource is lost or delivered out of the network at a given rate, while being subject to advection and diffusion. The key conceptual step is to partition the resource into material that does or does not reach a node over a given time step. As an example application, we consider resource allocation within fungal networks, and analyze the spatial distribution of the resource that emerges as such networks grow over time. Fungal growth involves the expansion of fluid filled vessels, and such growth necessarily involves the movement of fluid. We develop a model of delivery in growing fungal networks, and find good empirical agreement between our model and experimental data gathered using radio-labeled tracers. Our results lead us to suggest that in foraging fungi, growth-induced mass flow is sufficient to account for long-distance transport, if the system is well insulated. We conclude that active transport mechanisms may only be required at the very end of the transport pathway, near the growing tips.
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paper_title: Reliability and Delay Analysis of Multihop Virus-Based Nanonetworks

paper_content:

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.
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paper_title: Stable Escherichia coli-Clostridium acetobutylicum shuttle vector for secretion of murine tumor necrosis factor alpha

paper_content:

Recombinant plasmids were constructed to secrete mouse tumor necrosis factor alpha (mTNF-α) from Clostridium acetobutylicum. The shuttle plasmids contained the clostridial endo-β1,4-glucanase (eglA) promoter and signal sequence that was fused in frame to the mTNF-α cDNA. The construction was first tested in Escherichia coli and then introduced in C. acetobutylicum DSM792 by electroporation. Controls confirmed the presence and stability of the recombinant plasmids in this organism. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and an in vitro cytotoxic assay were used to monitor expression and secretion of mTNF-α during growth. Significant levels of biologically active mTNF-α were measured in both lysates and supernatants. The present report deals with investigations on the elaboration of a gene transfer system for cancer treatment using anaerobic bacteria.
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paper_title: Bacterial targeted tumour therapy-dawn of a new era.

paper_content:

Original observation of patients' spontaneous recovery from advanced tumours after an infection or a "fever" inspired extensive research. As a result, Coley's toxin for the therapy of sarcomas and live Bacillus Calmette-Guerin (BCG) for bladder cancer were born. In addition, three genera of anaerobic bacteria have been shown to specifically and preferentially target solid tumours and cause significant tumour lyses. Initial research had focused on determining the best tumour colonizing bacteria, and assessing the therapeutic efficacy of different strategies either as a single or combination treatment modalities. However, although clinical trials were carried out as early as the 1960s, lack of complete tumour lyses with injection of Clostridial spores had limited their further use. Recent progress in the field has highlighted the rapid development of new tools for genetic manipulation of Clostridia which have otherwise been a hurdle for a long time, such as plasmid transformation using electroporation that bore the problems of inefficiency, instability and plasmid loss. A new Clostridium strain, C. novyi-NT made apathogenic by genetic modification, is under clinical trials. New genetic engineering tools, such as the group II intron has shown promise for genetic manipulation of bacteria and forecast the dawn of a new era for a tumour-targeted bacterial vector system for gene therapy of solid tumours. In this review we will discuss the potential of genetically manipulated bacteria that will usher in the new era of bacterial therapy for solid tumours, and highlight strategies and tools used to improve the bacterial oncolytic capability.
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paper_title: Forward and Reverse Coding for Chromosome Transfer in Bacterial Nanonetworks

paper_content:

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.
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paper_title: Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy.

paper_content:

Hypoxic areas are a characteristic property of solid tumors. Hypoxia results from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the emergence of hypoxia are (1) structural and functional abnormalities in the tumor microvasculature; (2) an increase in diffusion distances; and (3) tumor- or therapy-associated anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histopathologic type, and grade. Local recurrences have a higher hypoxic fraction than primary tumors. Tumor hypoxia is intensified in anemic patients, especially in tumors with low perfusion rates. Tumor hypoxia is a therapeutic problem, as it makes solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy. Hypoxia also may modulate the proliferation and cell cycle position of tumor cells and, in turn, the amount of cells destroyed following therapy. Recent clinical studies suggest that hypoxia can enhance malignant progression and increase aggressiveness through clonal selection and genome changes. As a result, loss of differentiation and apoptosis, chaotic angiogenesis, increased locoregional spread, and enhanced metastasis can further increase resistance to therapy and affect long-term prognosis. Hypoxia is a powerful, independent prognostic factor in cervix cancers, carcinomas of the head and neck, and in soft-tissue sarcomas.
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paper_title: Secretory production of biologically active rat interleukin-2 by Clostridium acetobutylicum DSM792 as a tool for anti-tumor treatment.

paper_content:

The search for effective means of selectively delivering high therapeutic doses of anti-cancer agents to tumors has explored a variety of systems in the last decade. The ability of intravenously injected clostridial spores to infiltrate and thence selectively germinate in the hypoxic regions of solid tumors is exquisitely specific, making this system an interesting addition to the anti-cancer therapy arsenal. To increase the number of therapeutic proteins potentially useful for cancer treatment we have tested the possibility of Clostridium acetobutylicum to secrete rat interleukin-2 (rIL2). Therefore, rIL2 cDNA was placed under the control of the endo-beta-1,4-glucanase promoter and signal sequence of C. saccharobutylicum. Recombinant C. acetobutylicum containing the relevant construct secreted up to 800 microgl(-1) biologically active rIL2. The obtained yield should be sufficient to provoke in vivo effects.
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paper_title: Universal computing by DNA origami robots in a living animal

paper_content:

Nanoscale robots made from DNA origami can dynamically interact with each other and perform logic computations in a living animal.
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paper_title: Amplifying Genetic Logic Gates

paper_content:

Organisms must process information encoded via developmental and environmental signals to survive and reproduce. Researchers have also engineered synthetic genetic logic to realize simpler, independent control of biological processes. We developed a three-terminal device architecture, termed the transcriptor, that uses bacteriophage serine integrases to control the flow of RNA polymerase along DNA. Integrase-mediated inversion or deletion of DNA encoding transcription terminators or a promoter modulates transcription rates. We realized permanent amplifying AND, NAND, OR, XOR, NOR, and XNOR gates actuated across common control signal ranges and sequential logic supporting autonomous cell-cell communication of DNA encoding distinct logic-gate states. The single-layer digital logic architecture developed here enables engineering of amplifying logic gates to control transcription rates within and across diverse organisms.
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paper_title: A Molecular Communication System Model for Particulate Drug Delivery Systems

paper_content:

The goal of a drug delivery system (DDS) is to convey a drug where the medication is needed, while, at the same time, preventing the drug from affecting other healthy parts of the body. Drugs composed of micro- or nano-sized particles (particulate DDS) that are able to cross barriers which prevent large particles from escaping the bloodstream are used in the most advanced solutions. Molecular communication (MC) is used as an abstraction of the propagation of drug particles in the body. MC is a new paradigm in communication research where the exchange of information is achieved through the propagation of molecules. Here, the transmitter is the drug injection, the receiver is the drug delivery, and the channel is realized by the transport of drug particles, thus enabling the analysis and design of a particulate DDS using communication tools. This is achieved by modeling the MC channel as two separate contributions, namely, the cardiovascular network model and the drug propagation network. The cardiovascular network model allows to analytically compute the blood velocity profile in every location of the cardiovascular system given the flow input by the heart. The drug propagation network model allows the analytical expression of the drug delivery rate at the targeted site given the drug injection rate. Numerical results are also presented to assess the flexibility and accuracy of the developed model. The study of novel optimization techniques for a more effective and less invasive drug delivery will be aided by this model, while paving the way for novel communication techniques for Intrabody communication networks.
---
paper_title: Antibody-Based Immunotherapy of Cancer

paper_content:

By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. We discuss these innovative strategies and propose how they will impact the future of antibody-based cancer therapy.
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paper_title: Aptamers and Their Applications in Nanomedicine

paper_content:

Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity and affinity. Although functionally similar to protein antibodies, oligonucleotide aptamers offer several advantages over protein antibodies in biomedical and clinical applications. Through the enhanced permeability and retention effect, nanomedicines can improve the therapeutic index of a treatment and reduce side effects by enhancing accumulation at the disease site. However, this targets tumors passively and, thus, may not be ideal for targeted therapy. To construct ligand-directed "active targeting" nanobased delivery systems, aptamer-equipped nanomedicines have been tested for in vitro diagnosis, in vivo imaging, targeted cancer therapy, theranostic approaches, sub-cellular molecule detection, food safety, and environmental monitoring. This review focuses on the development of aptamer-conjugated nanomedicines and their application for in vivo imaging, targeted therapy, and theranostics.
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paper_title: Antibody therapy of cancer

paper_content:

The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody-drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.
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paper_title: Antibody-based molecular communication for targeted drug delivery systems

paper_content:

Antibody-based drug delivery systems (ADDS) are established as the most promising therapeutic methods for the treatment of human cancers and other diseases. ADDS are composed of small molecules (antibodies) that selectively bind to receptors (antigens) expressed by the diseased cells. In this paper, the Molecular Communication (MC) paradigm, where the delivery of molecules is abstracted as the delivery of information, is extended to be applied to the design and engineering of ADDS. The authors have previously developed a straightforward framework for the modeling of Particulate Drug Delivery Systems (PDDS) using nano-sized molecules. Here, the specificities of antibody molecules are taken into account to provide an analytical model of ADDS transport. The inputs of the MC model of PDDS are the geometric properties of the antibodies and the topology of the blood vessels where they are propagated. Numerical results show that the analytical MC model is in good agreement with finite-element simulations, and that the anisotropy is an important factor influencing ADDS.
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paper_title: Semiconductor Quantum Dots for Photodynamic Therapy

paper_content:

The applicability of semiconductor QDs in photodynamic therapy (PDT) was evaluated by studying the interaction between CdSe QDs with a known silicon phthalocyanine PDT photosensitizer, Pc4. The study revealed that the QDs could be used to sensitize the PDT agent through a fluorescence resonance energy transfer (FRET) mechanism, or interact directly with molecular oxygen via a triplet energy-transfer process (TET). Both mechanisms result in the generation of reactive singlet oxygen species that can be used for PDT cancer therapy.
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paper_title: In vivo molecular and cellular imaging with quantum dots.

paper_content:

Quantum dots (QDs), tiny light-emitting particles on the nanometer scale, are emerging as a new class of fluorescent probe for in vivo biomolecular and cellular imaging. In comparison with organic dyes and fluorescent proteins, QDs have unique optical and electronic properties: size-tunable light emission, improved signal brightness, resistance against photobleaching, and simultaneous excitation of multiple fluorescence colors. Recent advances have led to the development of multifunctional nanoparticle probes that are very bright and stable under complex in vivo conditions. A new structural design involves encapsulating luminescent QDs with amphiphilic block copolymers and linking the polymer coating to tumor-targeting ligands and drug delivery functionalities. Polymer-encapsulated QDs are essentially nontoxic to cells and animals, but their long-term in vivo toxicity and degradation need more careful study. Bioconjugated QDs have raised new possibilities for ultrasensitive and multiplexed imaging of molecular targets in living cells, animal models and possibly in humans.
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paper_title: A soluble receptor for interleukin-1β encoded by vaccinia virus: A novel mechanism of virus modulation of the host response to infection

paper_content:

Vaccinia virus gene B15R is shown to encode an abundant, secretory glycoprotein that functions as a soluble interleukin-1 (IL-1) receptor. This IL-1 receptor has novel specificity since, in contrast with cellular counterparts, it binds only IL-1 beta and not IL-1 alpha or the natural competitor IL-1 receptor antagonist. The vaccinia IL-1 beta receptor is secreted when expressed in a baculovirus system and competitively inhibited binding of IL-1 beta to the natural receptor on T cells. Deletion of B15R from vaccinia virus accelerated the appearance of symptoms of illness and mortality in intranasally infected mice, suggesting that the blockade of IL-1 beta by vaccinia virus can diminish the systemic acute phase response to infection and modulate the severity of the disease. The IL-1 beta binding activity is present in other orthopoxviruses.
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paper_title: Regulatory pathways in inflammation.

paper_content:

Tuning is a key aspect of inflammatory reaction essential in homeostasis and pathology. An emerging mechanism for negative regulation of proinflammatory cytokines is based on non-signaling IL-1/TLR receptors and chemokine receptors competing with signaling receptors for ligand binding and sustaining ligand internalization and degradation. Biological activities of IL-1R/TLR receptors are under control of membrane-bound binding molecules lacking the signaling domain, soluble receptor antagonists, and intracellular signaling inhibitors. The chemokine system includes at least three 'silent' receptors with distinct specificity and tissue distribution. D6 is the best characterized representative member of this class of negative regulators, binds most inflammatory, but not homeostatic, CC chemokines and shuttles in a ligand-independent way from the plasma membrane to endocytic compartments where chemokines are targeted to degradation. In vitro and in vivo evidence, including results with gene targeted mice, is consistent with the view that these non-signaling receptors for proinflammatory cytokines possess unique functional and structural features which make them ideally adapted to act as a decoy and scavenger receptors, with a non redundant role in dampening tissue inflammation and tuning draining lymph nodes reactivity.
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paper_title: Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems

paper_content:

RNA molecules perform diverse regulatory functions in natural biological systems, and numerous synthetic RNA-based control devices that integrate sensing and gene-regulatory functions have been demonstrated, predominantly in bacteria and yeast. Despite potential advantages of RNA-based genetic control strategies in clinical applications, there has been limited success in extending engineered RNA devices to mammalian gene-expression control and no example of their application to functional response regulation in mammalian systems. Here we describe a synthetic RNA-based regulatory system and its application in advancing cellular therapies by linking rationally designed, drug-responsive, ribozyme-based regulatory devices to growth cytokine targets to control mouse and primary human T-cell proliferation. We further demonstrate the ability of our synthetic controllers to effectively modulate T-cell growth rate in response to drug input in vivo. Our RNA-based regulatory system exhibits unique properties critical for translation to therapeutic applications, including adaptability to diverse ligand inputs and regulatory targets, tunable regulatory stringency, and rapid response to input availability. By providing tight gene-expression control with customizable ligand inputs, RNA-based regulatory systems can greatly improve cellular therapies and advance broad applications in health and medicine.
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paper_title: Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines.

paper_content:

The canonical concept of a receptor includes specific ligand recognition, usually with high affinity and specificity, and signaling. Decoy receptors recognize certain inflammatory cytokines with high affinity and specificity, but are structurally incapable of signaling or presenting the agonist to signaling receptor complexes. They act as a molecular trap for the agonist and for signaling receptor components. The interleukin-1 type II receptor (IL-1RII) was the first pure decoy to be identified. Decoy receptors have subsequently been identified for members of the tumor necrosis factor receptor and IL-1R families. Moreover, silent nonsignaling receptors could act as decoys for chemokines. Therefore, the use of decoy receptors is a general strategy to regulate the action of primary pro-inflammatory cytokines and chemokines.
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paper_title: Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor

paper_content:

Abstract ::: Vascular endothelial cell growth factor, a mitogen selective for vascular endothelial cells in vitro that promotes angiogenesis in vivo, functions through distinct membrane-spanning tyrosine kinase receptors. The cDNA encoding a soluble truncated form of one such receptor, fms-like tyrosine kinase receptor, has been cloned from a human vascular endothelial cell library. The mRNA coding region distinctive to this cDNA has been confirmed to be present in vascular endothelial cells. Soluble fms-like tyrosine kinase receptor mRNA, generated by alternative splicing of the same pre-mRNA used to produce the full-length membrane-spanning receptor, encodes the six N-terminal immunoglobulin-like extracellular ligand-binding domains but does not encode the last such domain, transmembrane-spanning region, and intracellular tyrosine kinase domains. The recombinant soluble human receptor binds vascular endothelial cell growth factor with high affinity and inhibits its mitogenic activity for vascular endothelial cells; thus this soluble receptor could act as an efficient specific antagonist of vascular endothelial cell growth factor in vivo.
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paper_title: A simulation tool for nanoscale biological networks

paper_content:

a b s t r a c t Nanonetworking is a new interdisciplinary research area including nanotechnology, biotechnology, and ICT. In this paper, we present a novel simulation platform designed for modeling information exchange at nanoscales. This platform is adaptable to any kind of nano bearer, i.e. any mechanism used to transport information, such as electromagnetic waves or calcium ions. Moreover, it includes a set of configuration functions in order to adapt to different types of biological environments. In this paper, we provide a throughout description of the simulation libraries. In addition, we demonstrate their capabilities by modeling a section of a lymph node and the information transfer within it, which happens between antibody molecules produced by the immune system during the humoral immune response.
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paper_title: Using Information Metrics and Molecular Communication to Detect Cellular Tissue Deformation

paper_content:

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.
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paper_title: Molecular signaling in bioengineered tissue microenvironments.

paper_content:

Biological tissues and organs consist of specialized living cells arrayed within a complex structural and functional framework known generally as the extracellular matrix (ECM). The great diversity observed in the morphology and composition of the ECM contributes enormously to the properties and function of each organ and tissue. For example, the ECM contributes to the rigidity and tensile strength of bone, the resilience of cartilage, the flexibility and hydrostatic strength of blood vessels, and the elasticity of skin. The ECM is also important during growth, development, and wound repair: its own dynamic composition acts as a reservoir for soluble signaling molecules and mediates signals from other sources to migrating, proliferating, and differentiating cells. Artificial three-dimensional substitutes for ECM, called tissue scaffolds, may consist of natural or synthetic polymers or a combination of both. Scaffolds have been used successfully alone and in combination with cells and soluble factors to induce tissue formation or promote tissue repair. Appropriate numbers of properly functioning living cells are central to many tissue-engineering strategies, and significant efforts have been made to identify and propagate pluripotent stem cells and lineage-restricted progenitor cells. The study of these and other living cells in artificial microenvironments, in turn, has led to the identification of signaling events important for their controlled proliferation, proper differentiation, and optimal function.
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paper_title: Calcium Wave Propagation in Networks of Endothelial Cells: Model-based Theoretical and Experimental Study

paper_content:

In this paper, we present a combined theoretical and experimental study of the propagation of calcium signals in multicellular structures composed of human endothelial cells. We consider multicellular structures composed of a single chain of cells as well as a chain of cells with a side branch, namely a ‘‘T’’ structure. In the experiments, we investigate the result of applying mechano-stimulation to induce signaling in the form of calcium waves along the chain and the effect of single and dual stimulation of the multicellular structure. The experimental results provide evidence of an effect of architecture on the propagation of calcium waves. Simulations based on a model of calcium-induced calcium release and cell-to-cell diffusion through gap junctions shows that the propagation of calcium waves is dependent upon the competition between intracellular calcium regulation and architecture-dependent intercellular diffusion.
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paper_title: Mechanical stimulation initiates cell-to-cell calcium signaling in ovine lens epithelial cells.

paper_content:

Although abnormalities in calcium regulation have been implicated in the development of most forms of cataract, the mechanisms by which Ca2+ is regulated in the cells of the ocular lens remain poorly defined. Cell-to-cell Ca2+ signaling was investigated in primary cultures of ovine epithelial cells using the Ca(2+)-reporter dye fura-2 and fluorescence microscopy. Mechanical stimulation of a single cell with a micropipette initiated a propagated increase in cytosolic free Ca2+ that spread from the stimulated cell through 2-8 tiers of surrounding cells. During this intercellular Ca2+ wave, cytosolic Ca2+ increased 2- to 12-fold from resting levels of approximately 100 nM. Nanomolar extracellular Ca2+ did not affect the cell-to-cell propagation of the Ca2+ wave, but reduced the magnitude of the cytosolic Ca2+ increases, which was most evident in the mechanically-stimulated cell. Depletion of intracellular Ca2+ stores with thapsigargin eliminated the propagated intercellular Ca2+ wave, but did not prevent the cytosolic Ca2+ increase in the mechanically-stimulated cell, which required extracellular Ca2+ and was attenuated by the addition of the Ca2+ channel blockers Ni2+, Gd3+ and La3+ to the medium. These results are most easily explained by a mechanically-activated channel in the plasma membrane of the stimulated cell. The propagated increase in cytosolic Ca2+ appeared to be communicated to adjacent cells by the passage of an intracellular messenger other than Ca2+ through gap junction channels. However, if the plasma membrane of the mechanically-stimulated cell was ruptured such that there was loss of cytosolic contents, the increase in cytosolic Ca2+ in the surrounding cells was elicited by both a messenger passing through gap junction channels and by a cytosolic factor(s) diffusing through the extracellular medium. These results demonstrate the existence of intercellular Ca2+ signaling in lens cells, which may play a role in regulating cytosolic Ca2+ in the intact lens.
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paper_title: Molecular communication for nanomachines using intercellular calcium signaling

paper_content:

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.
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paper_title: DIRECT: A model for molecular communication nanonetworks based on discrete entities

paper_content:

A number of techniques have been recently proposed to implement molecular communication, a novel method which aims to implement communication networks at the nanoscale, known as nanonetworks. A common characteristic of these techniques is that their main resource consists of molecules, which are inherently discrete. This paper presents DIRECT, a novel networking model which differs from conventional models by the way of treating resources as discrete entities; therefore, it is particularly aimed to the analysis of molecular communication techniques. Resources can be involved in different tasks in a network, such as message encoding, they do not attenuate in physical terms and they are considered 100% reusable. The essential properties of DIRECT are explored and the key parameters are investigated throughout this paper.
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paper_title: Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration

paper_content:

Emerging evidence suggests that bone marrow‐derived endothelial, hematopoietic stem and progenitor cells contribute to tissue vascularization during both embryonic and postnatal physiological processes. Recent preclinical and pioneering clinical studies have shown that introduction of bone marrow‐derived endothelial and hematopoietic progenitors can restore tissue vascularization after ischemic events in limbs, retina and myocardium. Corecruitment of angiocompetent hematopoietic cells delivering specific angiogenic factors facilitates incorporation of endothelial progenitor cells (EPCs) into newly sprouting blood vessels. Identification of cellular mediators and tissue-specific chemokines, which facilitate selective recruitment of bone marrow‐derived stem and progenitor cells to specific organs, will open up new avenues of research to accelerate organ vascularization and regeneration. In addition, identification of factors that promote differentiation of the progenitor cells will permit functional incorporation into neo-vessels of specific tissues while diminishing potential toxicity to other organs. In this review, we discuss the clinical potential of vascular progenitor and stem cells to restore long-lasting organ vascularization and function.
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paper_title: Protein-based signaling systems in tissue engineering.

paper_content:

Tissue engineering aims to replace damaged tissues or organs using either transplanted cells or host cells recruited to the target site. Protein signaling is crucial to regulate cell phenotype and thus engineered tissue structure and function. Biomaterial vehicles are being designed to incorporate and locally deliver various molecules involved in this signaling, including both growth factors and peptides that mimick whole proteins. Controlling the concentration, local duration and spatial distribution of these factors is key to their utility and efficacy. Recent advances have been made in the development of polymeric delivery systems intended to achieve this control.
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paper_title: A synthetic multicellular system for programmed pattern formation

paper_content:

Pattern formation is a hallmark of coordinated cell behaviour in both single and multicellular organisms. It typically involves cell–cell communication and intracellular signal processing. Here we show a synthetic multicellular system in which genetically engineered ‘receiver’ cells are programmed to form ring-like patterns of differentiation based on chemical gradients of an acyl-homoserine lactone (AHL) signal that is synthesized by ‘sender’ cells. In receiver cells, ‘band-detect’ gene networks respond to user-defined ranges of AHL concentrations. By fusing different fluorescent proteins as outputs of network variants, an initially undifferentiated ‘lawn’ of receivers is engineered to form a bullseye pattern around a sender colony. Other patterns, such as ellipses and clovers, are achieved by placing senders in different configurations. Experimental and theoretical analyses reveal which kinetic parameters most significantly affect ring development over time. Construction and study of such synthetic multicellular systems can improve our quantitative understanding of naturally occurring developmental processes and may foster applications in tissue engineering, biomaterial fabrication and biosensing.
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paper_title: Controlled differentiation of human bone marrow stromal cells using magnetic nanoparticle technology.

paper_content:

Targeting and differentiating stem cells at sites of injury and repair is an exciting and promising area for disease treatment and reparative medicine. We have investigated remote magnetic field activation of magnetic nanoparticle-tagged mechanosensitive receptors on the cell membrane of human bone marrow stromal cells (HBMSCs) for use in osteoprogenitor cell delivery systems and activation of differentiation in vitro and in vivo toward an osteochondral lineage. HBMSC-labeled with magnetic beads coated with antibodies or peptides to the transmembrane ion channel stretch activated potassium channel (TREK-1) or arginine–glycine–aspartic acid were cultured in monolayer or encapsulated into polysaccharide alginate/chitosan microcapsules. Upregulation in gene expression was measured in magnetic particle-labeled HBMSCs in response to TREK-1 activation over a short period (7 days) with an increase in mRNA levels of Sox9, core binding factor alpha1 (Cbfa1), and osteopontin. Magnetic particle-labeled HBMSCs encaps...
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paper_title: Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition.

paper_content:

The in vivo mitogenicity of basic fibroblast growth factor (bFGF) for arterial smooth muscle cells relies on the removal of endothelium, raising the question of whether the endothelium serves as a mechanical barrier preventing contact of circulating bFGF with underlying smooth muscle cells or as a biochemical barrier that produces a local inhibitor of bFGF activity. To better define the role of the intact endothelium in modulating the vascular and tissue deposition of bFGF, we compared the fate of intravenous injections of 125I-labeled bFGF with perivascular controlled growth factor release. Peak serum bFGF levels were detected within 1 min of injection, and the growth factor was cleared thereafter with a serum half-life of almost 3 min. Polymeric controlled release devices delivered bFGF to the extravascular space without transendothelial transport. Deposition within the blood vessel wall was rapidly distributed circumferentially and was substantially greater than that observed following intravenous injection. The amount of bFGF deposited in arteries adjacent to the release devices was 40 times that deposited in similar arteries in animals who received a single intravenous bolus of bFGF. Endothelial denudation had a minimal effect on deposition following perivascular release, and it increased deposition following intravenous delivery 2-fold. The presence of intimal hyperplasia increased deposition of perivascularly released bFGF 2.4-fold but decreased the deposition of intravenously injected bFGF by 67%. In contrast, bFGF was 5- to 30-fold more abundant in solid organs after intravenous injection than it was following perivascular release. Deposition was greatest in the kidney, liver, and spleen and was substantially lower in the heart and lung. Thus, bFGF is rapidly cleared following intravenous injection and is deposited within both solid organs and the walls of blood vessels. Unlike the mitogenic potential of bFGF within blood vessels, vascular deposition is virtually independent of the presence of endothelium. Perivascular delivery is far more efficient than intravenous delivery at depositing bFGF within the arterial wall, and an increased neointima may provide added substrate for potential bFGF deposition but has limited contact with intravascular growth factor as a result of dilutional and flow-mediated effects.
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paper_title: Molecular Communication and Networking: Opportunities and Challenges

paper_content:

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.
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paper_title: Cellular-Level Surgery Using Nano Robots

paper_content:

The atomic force microscope (AFM) is a popular instrument for studying the nano world. AFM is naturally suitable for imaging living samples and measuring mechanical properties. In this article, we propose a new concept of an AFM-based nano robot that can be applied for cellular-level surgery on living samples. The nano robot has multiple functions of imaging, manipulation, characterizing mechanical properties, and tracking. In addition, the technique of tip functionalization allows the nano robot the ability for precisely delivering a drug locally. Therefore, the nano robot can be used for conducting complicated nano surgery on living samples, such as cells and bacteria. Moreover, to provide a user-friendly interface, the software in this nano robot provides a “videolized” visual feedback for monitoring the dynamic changes on the sample surface. Both the operation of nano surgery and observation of the surgery results can be simultaneously achieved. This nano robot can be easily integrated with extra modules that have the potential applications of characterizing other properties of samples such as local conductance and capacitance.
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paper_title: Investigating bioconjugation by atomic force microscopy

paper_content:

Nanotechnological applications increasingly exploit the selectivity and processivity of biological molecules. Integration of biomolecules such as proteins or DNA into nano-systems typically requires their conjugation to surfaces, for example of carbon-nanotubes or fluorescent quantum dots. The bioconjugated nanostructures exploit the unique strengths of both their biological and nanoparticle components and are used in diverse, future oriented research areas ranging from nanoelectronics to biosensing and nanomedicine. Atomic force microscopy imaging provides valuable, direct insight for the evaluation of different conjugation approaches at the level of the individual molecules. Recent technical advances have enabled high speed imaging by AFM supporting time resolutions sufficient to follow conformational changes of intricately assembled nanostructures in solution. In addition, integration of AFM with different spectroscopic and imaging approaches provides an enhanced level of information on the investigated sample. Furthermore, the AFM itself can serve as an active tool for the assembly of nanostructures based on bioconjugation. AFM is hence a major workhorse in nanotechnology; it is a powerful tool for the structural investigation of bioconjugation and bioconjugation-induced effects as well as the simultaneous active assembly and analysis of bioconjugation-based nanostructures.
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paper_title: Remote electronic control of DNA hybridization through inductive coupling to an attached metal nanocrystal antenna

paper_content:

Increasingly detailed structural1 and dynamic2,3 studies are highlighting the precision with which biomolecules execute often complex tasks at the molecular scale. The efficiency and versatility of these processes have inspired many attempts to mimic or harness them. To date, biomolecules have been used to perform computational operations4 and actuation5, to construct artificial transcriptional loops that behave like simple circuit elements6,7 and to direct the assembly of nanocrystals8. Further development of these approaches requires new tools for the physical and chemical manipulation of biological systems. Biomolecular activity has been triggered optically through the use of chromophores9,10,11,12,13,14, but direct electronic control over biomolecular ‘machinery’ in a specific and fully reversible manner has not yet been achieved. Here we demonstrate remote electronic control over the hybridization behaviour of DNA molecules, by inductive coupling of a radio-frequency magnetic field to a metal nanocrystal covalently linked to DNA15. Inductive coupling to the nanocrystal increases the local temperature of the bound DNA, thereby inducing denaturation while leaving surrounding molecules relatively unaffected. Moreover, because dissolved biomolecules dissipate heat in less than 50 picoseconds (ref. 16), the switching is fully reversible. Inductive heating of macroscopic samples is widely used17,18,19, but the present approach should allow extension of this concept to the control of hybridization and thus of a broad range of biological functions on the molecular scale.
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paper_title: A genetically encoded photoactivatable Rac controls the motility of living cells

paper_content:

The precise spatiotemporal dynamics of protein activity remain poorly understood, yet they can be critical in determining cell behaviour. A genetically encoded, photoactivatable version of the protein Rac1, a key GTPase regulating actin cytoskeletal dynamics, has now been produced; this approach enables the manipulation of the activity of Rac1 at precise times and places within a living cell, thus controlling motility.
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paper_title: Cationic thermosensitive liposomes: A novel dual targeted heat-triggered drug delivery approach for endothelial and tumor cells

paper_content:

Developing selectively targeted and heat-responsive nanocarriers holds paramount promises in chemotherapy. We show that this can be achieved by designing liposomes combining cationic charged and thermosensitive lipids in the bilayer. We demonstrated, using flow cytometry, live cell imaging, and intravital optical imaging, that cationic thermosensitive liposomes specifically target angiogenic endothelial and tumor cells. Application of mild hyperthermia led to a rapid content release extra- and intracellularly in two crucial cell types in a solid tumor.
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paper_title: Externally Controllable Molecular Communication

paper_content:

In molecular communication, a group of biological nanomachines communicates through exchanging molecules and collectively performs application dependent tasks. An open research issue in molecular communication is to establish interfaces to interconnect the molecular communication environment (e.g., inside the human body) and its external environment (e.g., outside the human body). Such interfaces allow conventional devices in the external environment to control the location and timing of molecular communication processes in the molecular communication environment and expand the capability of molecular communication. In this paper, we first describe an architecture of externally controllable molecular communication and introduce two types of interfaces for biological nanomachines; bio-nanomachine to bio-nanomachine interfaces (BNIs) for bio-nanomachines to interact with other biological nanomachines in the molecular communication environment, and inmessaging and outmessaging interfaces (IMIs and OMIs) for bio-nanomachines to interact with devices in the external environment. We then describe a proof-of- concept design and wet laboratory implementation of the IMI and OMI, using biological cells. We further demonstrate, through mathematical modeling and numerical experiments, how an architecture of externally controllable molecular communication with BNIs and IMIs/OMIs may apply to pattern formation, a promising nanomedical application of molecular communication.
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paper_title: A Molecular Communication System in Blood Vessels for Tumor Detection

paper_content:

This paper shows a proposal of a biological nano-communication system established in a blood vessel, aiming to support the detection and treatment of tumors. This system could either be used for diagnostic purposes in the early stage of a disease or to check any relapse of a previous disease already treated. In our proposal, the tumor detection happens through revealing tumor biomarkers on the cell surface, such as the CD47 protein. This detection takes advantage of some recent proposal if implementing nanorobot transport systems through modified flagellated bacteria. When a biomarker is detected, a molecular communication system is used for distributing the information over a number of nano-machines. These machines have a size similar to the white blood cells, so that they can flow through the vessel at the speed of the largest particles. The transported information is detected extra-body, through the use of smart probes, which triggers a decision tree in order to estimate the nature of the tumor and its most likely location.
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paper_title: Design and Analysis of Wireless Communication Systems Using Diffusion-Based Molecular Communication Among Bacteria

paper_content:

The design of biologically-inspired wireless communication systems using bacteria as the basic element of the system is initially motivated by a phenomenon called Quorum Sensing. Due to high randomness in the individual behavior of a bacterium, reliable communication between two bacteria is almost impossible. Therefore, we have recently proposed that a population of bacteria in a cluster is considered as a bio node in the network capable of molecular transmission and reception. This proposition enables us to form a reliable bio node out of many unreliable bacteria. In this paper, we study the communication between two nodes in such a network where information is encoded in the concentration of molecules by the transmitter. The molecules produced by the bacteria in the transmitter node propagate through the diffusion channel. Then, the concentration of molecules is sensed by the bacteria population in the receiver node which would decode the information and output light or fluorescent as a result. The uncertainty in the communication is caused by all three components of communication, i.e., transmission, propagation and reception. We study the theoretical limits of the information transfer rate in the presence of such uncertainties. Finally, we consider M-ary signaling schemes and study their achievable rates and corresponding error probabilities.
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paper_title: Caged compounds: photorelease technology for control of cellular chemistry and physiology

paper_content:

Caged compounds are light-sensitive probes that functionally encapsulate biomolecules in an inactive form. Irradiation liberates the trapped molecule, permitting targeted perturbation of a biological process. Uncaging technology and fluorescence microscopy are 'optically orthogonal': the former allows control, and the latter, observation of cellular function. Used in conjunction with other technologies (for example, patch clamp and/or genetics), the light beam becomes a uniquely powerful tool to stimulate a selected biological target in space or time. Here I describe important examples of widely used caged compounds, their design features and synthesis, as well as practical details of how to use them with living cells.
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paper_title: Modeling of Pathological Traits in Alzheimer's Disease Based on Systemic Extracellular Signaling Proteome

paper_content:

The study of chronic brain diseases including Alzheimer’s disease in patients is typically limited to brain imaging or psychometric testing. Given the epidemic rise and insufficient knowledge about pathological pathways in sporadic Alzheimer’s disease, new tools are required to identify the molecular changes underlying this disease. We hypothesize that levels of specific secreted cellular signaling proteins in cerebrospinal fluid or plasma correlate with pathological changes in the Alzheimer’s disease brain and can thus be used to discover signaling pathways altered in the disease. Here we measured 91 proteins of this subset of the cellular communication proteome in plasma or cerebrospinal fluid in patients with Alzheimer’s disease and cognitively normal controls to mathematically model disease-specific molecular traits. We found small numbers of signaling proteins that were able to model key pathological markers of Alzheimer’s disease, including levels of cerebrospinal fluid -amyloid and tau, and classify disease in independent samples. Several of these factors had previously been implicated in Alzheimer’s disease supporting the validity of our approach. Our study also points to proteins which were previously unknown to be associated with Alzheimer’s disease thereby implicating novel signaling pathways in this disorder. Molecular & Cellular Proteomics 10:
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paper_title: Universal computing by DNA origami robots in a living animal

paper_content:

Nanoscale robots made from DNA origami can dynamically interact with each other and perform logic computations in a living animal.
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paper_title: CRISPR interference: RNA-directed adaptive immunity in bacteria and archaea

paper_content:

Sequence-directed genetic interference pathways control gene expression and preserve genome integrity in all kingdoms of life. The importance of such pathways is highlighted by the extensive study of RNA interference (RNAi) and related processes in eukaryotes. In many bacteria and most archaea, clustered, regularly interspaced short palindromic repeats (CRISPRs) are involved in a more recently discovered interference pathway that protects cells from bacteriophages and conjugative plasmids. CRISPR sequences provide an adaptive, heritable record of past infections and express CRISPR RNAs — small RNAs that target invasive nucleic acids. Here, we review the mechanisms of CRISPR interference and its roles in microbial physiology and evolution. We also discuss potential applications of this novel interference pathway.
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paper_title: Short-Range Exosomal Transfer of Viral RNA from Infected Cells to Plasmacytoid Dendritic Cells Triggers Innate Immunity

paper_content:

Viral nucleic acids often trigger an innate immune response in infected cells. Many viruses, including hepatitis C virus (HCV), have evolved mechanisms to evade intracellular recognition. Nevertheless, HCV-permissive cells can trigger a viral RNA-, TLR7-, and cell-contact-dependent compensatory interferon response in nonpermissive plasmacytoid dendritic cells (pDCs). Here we report that these events are mediated by transfer of HCV-RNA-containing exosomes from infected cells to pDCs. The exosomal viral RNA transfer is dependent on the endosomal sorting complex required for transport (ESCRT) machinery and on Annexin A2, an RNA-binding protein involved in membrane vesicle trafficking, and is suppressed by exosome release inhibitors. Further, purified concentrated HCV-RNA-containing exosomes are sufficient to activate pDCs. Thus, vesicular sequestration and exosomal export of viral RNA may serve both as a viral strategy to evade pathogen sensing within infected cells and as a host strategy to induce an unopposed innate response in replication-nonpermissive bystander cells.
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paper_title: Extracellular vesicles: biology and emerging therapeutic opportunities

paper_content:

Within the past decade, extracellular vesicles have emerged as important mediators of intercellular communication, being involved in the transmission of biological signals between cells in both prokaryotes and higher eukaryotes to regulate a diverse range of biological processes. In addition, pathophysiological roles for extracellular vesicles are beginning to be recognized in diseases including cancer, infectious diseases and neurodegenerative disorders, highlighting potential novel targets for therapeutic intervention. Moreover, both unmodified and engineered extracellular vesicles are likely to have applications in macromolecular drug delivery. Here, we review recent progress in understanding extracellular vesicle biology and the role of extracellular vesicles in disease, discuss emerging therapeutic opportunities and consider the associated challenges.
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paper_title: Self-Folding Thermo-Magnetically Responsive Soft Microgrippers

paper_content:

Hydrogels such as poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAM-AAc) can be photopatterned to create a wide range of actuatable and self-folding microstructures. Mechanical motion is derived from the large and reversible swelling response of this cross-linked hydrogel in varying thermal or pH environments. This action is facilitated by their network structure and capacity for large strain. However, due to the low modulus of such hydrogels, they have limited gripping ability of relevance to surgical excision or robotic tasks such as pick-and-place. Using experiments and modeling, we design, fabricate, and characterize photopatterned, self-folding functional microgrippers that combine a swellable, photo-cross-linked pNIPAM-AAc soft-hydrogel with a nonswellable and stiff segmented polymer (polypropylene fumarate, PPF). We also show that we can embed iron oxide (Fe2O3) nanoparticles into the porous hydrogel layer, allowing the microgrippers to be responsive and remotely guided using magnetic fields. Usi...
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Title: Applications of molecular communications to medicine: a survey

Section 1: Introduction
Description 1: Introduce the concept of molecular communications and the significance of their application in medicine.

Section 2: Diagnostic Applications
Description 2: Illustrate some applications proposed for diagnostic purposes, including disease detection, personalized diagnosis, and imaging techniques.

Section 3: Treatment of Diseases
Description 3: Describe applications for advanced treatments, focusing on disease treatment methodologies such as drug delivery, virus-based techniques, bacteria-based techniques, nanorobots, antibody-based techniques, QD and FRET-based techniques, immune system activation, tissue engineering, and nanosurgery.

Section 4: Implementation Mechanisms and Interfaces
Description 4: Present the current mechanisms and interfaces being studied and developed for implementing molecular communication systems in medical applications, and discuss how they interconnect the nanoscale biological environment with external devices and systems.

Section 5: Future Research Challenges
Description 5: Identify the future research challenges of molecular communications for medical purposes.

Section 6: Conclusion
Description 6: Summarize the surveyed medical applications developed through molecular communications and potential future directions.