Terahertz Induced Protein Interactions in a Random Medium

Folding of proteins into their correct native structure is key to their function. Simultaneously, the intricate interplay between cell movement and protein conformation highlights the complex nature of cellular processes. In this work, we demonstrate the impact of Terahertz (THz) signaling on controlling protein conformational changes in a random medium. Our system of interest consists of a communication link that involves a nanoantenna transmitter, a protein receiver, and a channel composed of moving red blood cells. Due to the system dynamics, we investigate the influence of both the fast and slow channel variations on protein folding. Specifically, we analyze the system's selectivity to asses the effectiveness of the induced THz interaction in targeting a specific group of proteins under fading conditions. By optimizing the selectivity metric with respect to the nanoantenna power and frequency, it is possible to enhance the controllability of protein interactions. Our probabilistic analysis provides a new perspective regarding electromagnetically triggered protein molecules, their microenvironment and their interaction with surrounding particles. It helps elucidate how external conditions impact the protein folding kinetics and pathways. This results in not only understanding the mechanisms underlying THz-induced protein interactions but also engineering these still-emerging tools.Comment: Accepted for publication in the IEEE Transactions on Molecular, Biological and Multi-Scale Communication

What Really is `Molecule' in Molecular Communications? The Quest for Physics of Particle-based Information Carriers

Molecular communication, as implied by its name, uses molecules as information carriers for communication between objects. It has an advantage over traditional electromagnetic-wave-based communication in that molecule-based systems could be biocompatible, operable in challenging environments, and energetically undemanding. Consequently, they are envisioned to have a broad range of applications, such as in the Internet of Bio-nano Things, targeted drug delivery, and agricultural monitoring. Despite the rapid development of the field, with an increasing number of theoretical models and experimental testbeds established by researchers, a fundamental aspect of the field has often been sidelined, namely, the nature of the molecule in molecular communication. The potential information molecules could exhibit a wide range of properties, making them require drastically different treatments when being modeled and experimented upon. Therefore, in this paper, we delve into the intricacies of commonly used information molecules, examining their fundamental physical characteristics, associated communication systems, and potential applications in a more realistic manner, focusing on the influence of their own properties. Through this comprehensive survey, we aim to offer a novel yet essential perspective on molecular communication, thereby bridging the current gap between theoretical research and real-world applications

Transmitter and Receiver Architectures for Molecular Communications: A Survey on Physical Design with Modulation, Coding, and Detection Techniques

Inspired by nature, molecular communications (MC), i.e., the use of molecules to encode, transmit, and receive information, stands as the most promising communication paradigm to realize the nanonetworks. Even though there has been extensive theoretical research toward nanoscale MC, there are no examples of implemented nanoscale MC networks. The main reason for this lies in the peculiarities of nanoscale physics, challenges in nanoscale fabrication, and highly stochastic nature of the biochemical domain of envisioned nanonetwork applications. This mandates developing novel device architectures and communication methods compatible with MC constraints. To that end, various transmitter and receiver designs for MC have been proposed in the literature together with numerable modulation, coding, and detection techniques. However, these works fall into domains of a very wide spectrum of disciplines, including, but not limited to, information and communication theory, quantum physics, materials science, nanofabrication, physiology, and synthetic biology. Therefore, we believe it is imperative for the progress of the field that an organized exposition of cumulative knowledge on the subject matter can be compiled. Thus, to fill this gap, in this comprehensive survey, we review the existing literature on transmitter and receiver architectures toward realizing MC among nanomaterial-based nanomachines and/or biological entities and provide a complete overview of modulation, coding, and detection techniques employed for MC. Moreover, we identify the most significant shortcomings and challenges in all these research areas and propose potential solutions to overcome some of them.This work was supported in part by the European Research Council (ERC) Projects MINERVA under Grant ERC-2013-CoG #616922 and MINERGRACE under Grant ERC-2017-PoC #780645

Enzyme Powered Nanomotors Towards Biomedical Applications

[eng] The advancements in nanotechnology enabled the development of new diagnostic tools and drug delivery systems based on nanosystems, which offer unique features such as large surface area to volume ratio, cargo loading capabilities, increased circulation times, as well as versatility and multifunctionality. Despite this, the majority of nanomedicines do not translate into clinics, in part due to the biological barriers present in the body. Synthetic nano- and micromotors could be an alternative tool in nanomedicine, as the continuous propulsion force and potential to modulate the medium may aid tissue penetration and drug diffusion across biological barriers. Enzyme-powered motors are especially interesting for biomedical applications, owing to their biocompatibility and use of bioavailable substrates as fuel for propulsion. This thesis aims at exploring the potential applications of urease-powered nanomotors in nanomedicine. In the first work, we evaluated these motors as drug delivery systems. We found that active urease- powered nanomotors showed active motion in phosphate buffer solutions, and enhanced in vitro drug release profiles in comparison to passive nanoparticles. In addition, we observed that the motors were more efficient in delivering drug to cancer cells and caused higher toxicity levels, due to the combination of boosted drug release and local increase of pH produced by urea breakdown into ammonia and carbon dioxide. One of the major goals in nanomedicine is to achieve localized drug action, thus reducing side-effects. A commonly strategy to attain this is the use moieties to target specific diseases. In our second work, we assessed the ability of urease-powered nanomotors to improve the targeting and penetration of spheroids, using an antibody with therapeutic potential. We showed that the combination of active propulsion with targeting led to a significant increase in spheroid penetration, and that this effect caused a decrease in cell proliferation due to the antibody’s therapeutic action. Considering that high concentrations of nanomedicines are required to achieve therapeutic efficiency; in the third work we investigated the collective behavior of urease-powered nanomotors. Apart from optical microscopy, we evaluated the tracked the swarming behavior of the nanomotors using positron emission tomography, which is a technique widely used in clinics, due to its noninvasiveness and ability to provide quantitative information. We showed that the nanomotors were able to overcome hurdles while swimming in confined geometries. We observed that the nanomotors swarming behavior led to enhanced fluid convection and mixing both in vitro, and in vivo within mice’s bladders. Aiming at conferring protecting abilities to the enzyme-powered nanomotors, in the fourth work, we investigated the use of liposomes as chassis for nanomotors, encapsulating urease within their inner compartment. We demonstrated that the lipidic bilayer provides the enzymatic engines with protection from harsh acidic environments, and that the motility of liposome-based motors can be activated with bile salts. Altogether, these results demonstrate the potential of enzyme-powered nanomotors as nanomedicine tools, with versatile chassis, as well as capability to enhance drug delivery and tumor penetration. Moreover, their collective dynamics in vivo, tracked using medical imaging techniques, represent a step-forward in the journey towards clinical translation.[spa] Recientes avances en nanotecnología han permitido el desarrollo de nuevas herramientas para el diagnóstico de enfermedades y el transporte dirigido de fármacos, ofreciendo propiedades únicas como encapsulación de fármacos, el control sobre la biodistribución de estos, versatilidad y multifuncionalidad. A pesar de estos avances, la mayoría de nanomedicinas no consiguen llegar a aplicaciones médicas reales, lo cual es en parte debido a la presencia de barreras biológicas en el organismo que limitan su transporte hacia los tejidos de interés. En este sentido, el desarrollo de nuevos micro- y nanomotores sintéticos, capaces de autopropulsarse y causar cambios locales en el ambiente, podrían ofrecer una alternativa para la nanomedicina, promoviendo una mayor penetración en tejidos de interés y un mejor transporte de fármacos a través de las barreras biológicas. En concreto, los nanomotores enzimáticos poseen un alto potencial para aplicaciones biomédicas gracias a su biocompatibilidad y a la posibilidad de usar sustancias presentes en el organismo como combustible. Los trabajos presentados en esta tesis exploran el potenical de nanomotores, autopropulsados mediante la enzima ureasa, para aplicaciones biomédicas, y investigan su uso como vehículos para transporte de fármacos, su capacidad para mejorar penetración de tejidos diana, su versatilidad y movimiento colectivo. En conjunto, los resultados presentados en esta tesis doctoral demuestran el potencial del uso de nanomotores autopropulsados mediante enzimas como herramientas biomédicas, ofreciendo versatilidad en su diseño y una alta capacidad para promover el transporte de fármacos y la penetración en tumores. Por último, su movimiento colectivo observado in vivo mediante técnicas de imagen médicas representan un significativo avance en el viaje hacia su aplicación en medicina

Biohybrid robotics: From the nanoscale to the macroscale

Biohybrid robotics is a field in which biological entities are combined with artificial materials in order to obtain improved performance or features that are difficult to mimic with hand-made materials. Three main level of integration can be envisioned depending on the complexity of the biological entity, ranging from the nanoscale to the macroscale. At the nanoscale, enzymes that catalyze biocompatible reactions can be used as power sources for self-propelled nanoparticles of different geometries and compositions, obtaining rather interesting active matter systems that acquire importance in the biomedical field as drug delivery systems. At the microscale, single enzymes are substituted by complete cells, such as bacteria or spermatozoa, whose self-propelling capabilities can be used to transport cargo and can also be used as drug delivery systems, for in vitro fertilization practices or for biofilm removal. Finally, at the macroscale, the combinations of millions of cells forming tissues can be used to power biorobotic devices or bioactuators by using muscle cells. Both cardiac and skeletal muscle tissue have been part of remarkable examples of untethered biorobots that can crawl or swim due to the contractions of the tissue and current developments aim at the integration of several types of tissue to obtain more realistic biomimetic devices, which could lead to the next generation of hybrid robotics. Tethered bioactuators, however, result in excellent candidates for tissue models for drug screening purposes or the study of muscle myopathies due to their three-dimensional architecture

Nano/Bio-Receiver Architectures and Detection Methods for Molecular Communications

Internet of Nano Things (IoNT) is an emerging technology, which aims at extending the connectivity into nanoscale and biological environments with collaborative networks of artificial nanomachines and biological entities integrated into the Internet. To enable the IoNT and its groundbreaking applications, such as real-time intrabody health monitoring, it is imperative to devise nanoscale communication techniques with low-complexity transceiver architectures. Bio-inspired molecular communications (MC), which uses molecules to transfer information, is the most promising technique to realise IoNT due to its inherent biocompatibility and reliability in physiologically-relevant environments. Despite the substantial body of work concerning MC, the implications of an interface between MC channel and practical MC transceiver architectures are largely neglected, leading to a major gap between theory and practice. As the first step to remove this discrepancy, in this thesis, I develop a realistic analytical ICT model for microfluidic MC with surface-based receivers as a convection-diffusion-reaction system. In the second part, I focus on biological MC receivers, which can be implemented in living cells using synthetic biology tools. In this direction, I theoretically develop low-complexity and reliable MC detection methods exploiting the various statistics of the stochastic ligand-receptor interactions at the membrane of biological MC receivers. The estimation and detection theoretical analysis of these detection methods demonstrate that even single type of receptors can provide sufficient statistics to overcome the receptor saturation problem, cope with the interference of non-cognate molecules, and simultaneously sense the concentration of multiple types of ligands. I also propose synthetic receptor designs for the transduction of decision statistics into a representation by concentration of intracellular molecules, and design chemical reaction networks performing decoding with intracellular reactions. Finally, I fabricate a micro/nanoscale MC receiver based on graphene field-effect transistor biosensors and perform its ICT characterisation in a custom-designed microfluidic MC system with the information encoded into the concentration of DNAs. This experimental platform is the first practical demonstration of micro/nanoscale MC, and can serve as a testbed for developing realistic MC methods

Synthetic Micro/Nanomotors for Drug Delivery

Synthetic micro/nanomotors (MNMs) are human-made machines characterized by their capacity for undergoing self-propelled motion as a result of the consumption of chemical energy obtained from specific chemical or biochemical reactions, or as a response to an external actuation driven by a physical stimulus. This has fostered the exploitation of MNMs for facing different biomedical challenges, including drug delivery. In fact, MNMs are superior systems for an efficient delivery of drugs, offering several advantages in relation to conventional carriers. For instance, the self-propulsion ability of micro/nanomotors makes possible an easier transport of drugs to specific targets in comparison to the conventional distribution by passive carriers circulating within the blood, which enhances the drug bioavailability in tissues. Despite the promising avenues opened by the use of synthetic micro/nanomotors in drug delivery applications, the development of systems for in vivo uses requires further studies to ensure a suitable biocompatibility and biodegradability of the fabricated engines. This is essential for guaranteeing the safety of synthetic MNMs and patient convenience. This review provides an updated perspective to the potential applications of synthetic micro/nanomotors in drug delivery. Moreover, the most fundamental aspects related to the performance of synthetic MNMs and their biosafety are also discussed.This work was funded in part by MICINN under Grant PID2019-106557GB-C21 and by E.U. on the framework of the European Innovative Training Network—Marie Sklodowska-Curie Action Nano Paint (Grant Agreement 955612)

Current status and future application of electrically controlled micro/nanorobots in biomedicine

Using micro/nanorobots (MNRs) for targeted therapy within the human body is an emerging research direction in biomedical science. These nanoscale to microscale miniature robots possess specificity and precision that are lacking in most traditional treatment modalities. Currently, research on electrically controlled micro/nanorobots is still in its early stages, with researchers primarily focusing on the fabrication and manipulation of these robots to meet complex clinical demands. This review aims to compare the fabrication, powering, and locomotion of various electrically controlled micro/nanorobots, and explore their advantages, disadvantages, and potential applications