Nanotechnology and nanomaterials

1 Nanotechnology and nanomaterials Chapter Outline 1.1 Introduction ............................................................................................................................. 1 1.2 Nanoscience and nanotechnology ......................................................................................... 5 1.3 Nanoparticles ......................................................................................................................... 15 1.4 Nanodevices ........................................................................................................................... 22 1.5 DNA-based smart nanostructures ......................................................................................... 34 1.6 Nanofabrication ..................................................................................................................... 40 1.7 Investigative tools ................................................................................................................. 47 1.8 Nanoarchitectures .................................................................................................................. 51 1.9 Nanobiotechnology ............................................................................................................... 55 1.10 Conclusion ............................................................................................................................. 68 References ...................................................................................................................................... 76

1.1 Introduction During the past decade, due to the emergence of a new generation of high-technology materials, the number of research groups involved in nanomaterials has increased exponentially. Nanomaterials are implicated in several domains such as chemistry, electronics, high-density magnetic recording media, sensors, biotechnology, etc. Nano-sized materials have now emerged as one of the focal points of modern research. We are achieving an uncanny ability to design, synthesize, and manipulate structures at the nanoscale. Nanomaterials are expected to be used in various applications based on their excellent and unique optical, electrical, magnetic, catalytic, biological, or mechanical properties. Such properties originate from their finely tuned nanoarchitectures and nanostructures. However, the fabrication and analysis of nanomaterials remains challenging and, therefore, considerable and continuous efforts have been made to explore novel synthetic and analytical methods for nanoarchitectures and nanostructures by many researchers all over the world. The fascinating world of these nanomaterials and their manifold applications becomes part of our life. Several important events have marked the nanotechnology story. At the beginning of the 1980s, scanning tunneling microscopes (STM) and atomic force microscopes (AFM) were invented providing thus the “experimental techniques, methods and approaches” required for nanostructure measurement and manipulation. Scanning probe microscopy (SPM) has opened up the new world of nanotechnology for observing and manipulating individual atoms and molecules on solid surfaces. Other techniques such as beam-probe Nanocomposite Structures and Dispersions. https://doi.org/10.1016/B978-0-444-63748-2.00001-8 © 2019 Elsevier B.V. All rights reserved.

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techniques, mechanical-probe techniques and particle-trapping techniques were introduced to atom manipulation with wider controllability. In a parallel development, expansion of computational capability enabled sophisticated simulations of material behavior at the nanoscale. They stimulated the research with the vision of exciting new discoveries if one could fabricate materials and devices at the atomic/molecular scale. The starting research pointed out that a new class of miniaturized instrumentation would be needed to manipulate and measure the properties of these small “nano” structures. There is also the possibility that the unique properties of nanostructures will result in novel applications and devices. Another reason for the great popularity of this field is that phenomena occurring on this length scale are of interest to physicists, chemists, biologists, electrical and mechanical engineers, and computer scientists. A motivation in nanoscience is also to try to understand how materials behave when sample sizes are close to atomic dimensions [1]. Making and manipulating matter on the sub-100 nm length scale is a grand challenge for both scientists and engineers. From an engineering standpoint, the sub-100 nm scale is extraordinarily small, and many of the tools that are used routinely to do microfabrication cannot be used for nanofabrication. However, from the chemist’s point of view, this length scale, especially above 10 nm, is extraordinarily large. Chemists are really “Angstromtechnologists,” not nanotechnologists. Even when they work with large molecules, chemists are often manipulating a bond or a localized set of bonds within a larger structure. Although great strides have been made in the area of supramolecular chemistry, the synthetic toolkit required to routinely build structures with control over shape, size, chirality, and function on this length scale does not yet exist. This statement also holds for biochemists and molecular biologists who routinely work with molecules on this length scale. In fact, the investigation of the nanostructure of cells and the development of an understanding of biomolecular interactions on the nanometer scale is a frontier that demands further exploration [2]. At the beginning of any investigation, one is confronted with the selection of the synthesis method, the experimental and simulation techniques to be used, and the choice of materials (metals, ceramics, polymers, organics or carbon-based composites, etc.). The main challenge is relating the final product properties and production rates to the material properties of the reaction components and precursors and process conditions. The product may be either homogeneous or composite nanostructured particles, with one or multichemical species, consolidated or aerogels, including coated and doped particles. The nanotechnology has been focused on new concepts and fundamental research to generate nanoparticles at high rates. The work has included contributions to fundamental physics and chemistry for nanoparticle generation with tailored properties via different synthetic methods. The synthetic methods include precipitation from solutions (colloids), gas condensation (aerosols), chemical, plasma, combustion, spray pyrolysis, laser ablation, supercritical fluid expansion, polymerization, modification, chemical reactions, micellar reactions, mechanical attrition, molecular self-assembling, hydrodynamic cavitation, and other processes. Recent scientific literature demonstrates a growing

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interest in new methods of metal nanoparticles (with more pronounced amorphous core), nanocrystals (with more developed crystalline core), quantum dots (QDs) (semiconductor nanocrystal) and metal/polymer or polymer (organic) particle synthesis, driven primarily by an ever-increasing awareness of the unique properties and technological importance of nanostructured materials. The term nanospheres is reserved for the particles generally with different shapes, the term nanoparticles for spherical structures with less defined crystalline with amorphous or multidomain inorganic cores. The most active nanoparticle research activities in the world include fundamental studies for generation, processing, characterization, and modeling; investigations on inorganic nanoparticles; studies on metallic, polymeric, and composite particles; studies on particle colloidal properties of metal, metal/polymer, and synthetic and natural polymer particles and self-assembling techniques. There are several important aspects of modern nanoparticle research: (i) the preparation of nanoparticles, (ii) the manipulation and study of individual nanospheres or nanoparticles, (iii) the assembly of two- and threedimensional materials and structures in which the particles are closely packed without allowing the onset of uncontrolled aggregation, (iv) fabrication of nanomaterials, (v) miniaturization of devices, etc. In the last century, we had a number of major changes in the fields of science and technology. Since the invention of transistors half a century ago, electronics has been intimately involved in our daily life, and now has grown to one of key industries. However, its high growth rate up to now will not necessarily be guaranteed in the coming century. For instance, in case of some memory chips, where the memory capacitance has increased with a rate of four times in 3 years, the pace is approaching to physical and technological limits, and the extrapolation of the current technology may suggest the presence of a nonsurmountable wall at 0.01-μm resolution 30 years later in this century. The same applies to the materials science. An artificial superlattice film fabricated by depositing a few atomsthick layers of different elements one over another is an assembly of interfaces, as it were. Hence, the main arena is the world of nonequilibrium, where no text book is available, and neither phase diagrams nor almanacs have authoritative power. Thus, some new concepts or approaches should be fruitful. The past two decades have seen the explosion of miniaturization, based on the development of nanotechnologies, and its use in an increasing number of scientific and technical fields, including biology, chemistry, microelectronics, high-density data storage, optics and optoelectronics, sensors, photonics, etc. Nanofabrication and nanoinstrumentation are recent popular research topics in the development of nanotechnology. Nanotechnology is the chance for the realization of that purpose. STM and AFM are two key equipment currently used in the development of nanotechnology. The tremendous amount of research works announced so far has focused on the applications of STM and AFM on nanofabrication and nanoinstrumentation. Due to the fact that SPM plays a major role in the development of nanotechnology, both STM and AFM were investigated in very great detail regarding their functions and working principles. Based on these investigations and obtained knowledge, a comprehensive curriculum in nanotechnology was possible [3].

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Every substance regardless of composition, when miniaturized to the sub-100 nm length scale, will have new properties. The optical, electrical, mechanical, magnetic, and chemical properties can be systematically manipulated by adjusting the size, composition, and shape of metal and semiconductor nanoparticles or nanospheres on the nanometer length scale. Electron transport, manifested in phenomena like Coulomb blockade, as well as the catalytic and thermodynamic properties of structures can be tailored when one can rationally design materials on this length scale. Therefore, analytical tools and synthetic methods that allow one to control composition and architecture on this length scale will yield important advances in almost all fields of science. The “top-down approach miniaturization” is based on a progressive reduction of dimensions. These technologies are mostly based on lithography and pattern transfer, and address dimensions down to 10 nm. It is the basis of today’s application fields, and most of the research. The demonstration during the past years of low-cost approaches using the “soft-lithography methods” is a key element for the introduction of the technology in all laboratories, and for the application to fields other than microelectronics. The “bottom-up approach” on the contrary relies on the atom per atom, or molecule per molecule building of functionalized elements. Still in its infancy, the research mainly addresses the first mechanical or electrical behavior of small building blocks. It largely uses the near-field methods, and self-assembly properties of atoms and molecules. Characterization at the small scale is necessary to control the fabrication and properties of the realized objects. It includes not only observation, in far field or near field, but also in many physical measurements of transport, optical, electrical, and magnetic properties [4]. In the bottom-up approach toward nanomaterials and nanodevice development, two important aspects must be investigated. The first is the synthesis of the nanobuilding block itself and the second is how to assemble these nanobuilding blocks together into predefined structures with desired properties. When one wants to fabricate materials or devices only by the atom and molecule manipulation technique, one has to spend too long a time to finish up. Obviously, actual fabrication of materials and devices should not be pursued by atom-by-atom or molecule-by-atom or molecule-by-molecule processes but by some sort of self-organization. We need a self-organization process including self-ordering, self-assembly, and self-limiting phenomena through which a huge number of nanostructures can be fabricated in parallel processing, with atomic accuracies and within a practically acceptable time. While there has been much success with the synthesis of nanobuilding blocks, the assembling of these materials remains a significant challenge. To prepare even more complex nanomaterial-based structures and devices, one must first be able to control accurately the chemical structure and functionality of the nanobuilding blocks at the molecular level [5]. Conferences on nanostructured materials had the ambitious aim of providing a meeting place for scientists from universities, research laboratories, and industry to learn about worldwide activities in nanomaterials research, and to initiate cooperation between the various fields of science and technology. A particular emphasis is placed on examining the synergy between the various scientific disciplines, and the links between the science, the potential applications, and the technical demands of nanoresearch.

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Large multinational companies have established specialized groups in their long-term research laboratories where the total precompetitive research expenditure for nanotechnology is estimated to be very important. They deal with the study of the mechanism of production of nanospheres, the production and applications of nanostructures and nanospheres, and the exploration of novel physical properties of materials in the nanometer scale. The ultrafine particle engineering initiatives include synthesis and processing of nanoparticles with controlled properties and with a focus on high-yield production processes. Small businesses have generated an innovative competitive environment in various technological areas including dispersions, filtration, nanoparticle synthesis, functional nanostructures, and various nanoparticle manufacturing processes. Interdisciplinary centers with focus on nanotechnology have been established in the past few years at universities, research centers, and private companies creating a continuously growing public research and education infrastructure for this field [6]. World governments, large computer, chemical and pharmaceutical companies, small and middle-size enterprises, as well as state and private foundations provide support for precompetitive nanotechnology. Governments around the world are investing billions of dollars to establish institutes and the infrastructure to carry out state-of-the-art research in this extraordinarily broad and exciting field. It is not an overstatement to say that the nanoscience revolution, in terms of sheer interest and investment, is one of the biggest things to happen to the scientific and engineering communities since the beginning of modern science. “Nano” is also focusing on new issues, such as the industrial applications of nanotechnology products, health and social issues, and business development in different countries. Increased funding opens up the potential of nanotechnology through research collaborations with important industrial sectors, such as information technology and the automotive business. Polymeric dispersions are used in a wide variety of applications such as synthetic rubber, paints, adhesives, binders for nonwoven fabrics, additives in paper and textiles, leather treatment, impact modifiers for plastic matrices, additives for construction materials and flocculants [7, 8]. They are also used in biomedical and pharmaceutical applications such as diagnostic tests and drug delivery systems. The rapid increase of this industry is due to environmental concerns and governmental regulations to substitute solvent-based systems by water-borne products, as well as to the fact that polymeric dispersions have unique properties that meet a wide range of market needs.

1.2 Nanoscience and nanotechnology Nanoscience and nanotechnology belong to the broad interdisciplinary area comprising polymers, composite and metal particles, nanoelectrics, supramolecular and colloid chemistry, nanostructured materials, biochemistry, and biology. Science is the most powerful means that mankind has to understand the working principles of the material world, as well as to change the world. In the early age of science, most scientists were engaged in discovering Nature. As time proceeds, scientists move more and more from discovering to

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inventing. Technology takes advantage of the progress of science to create novel opportunities for practical applications. Since experimental science and technology deal with material objects, it seems fair to say that nanoscience and nanotechnology are science and technology concerning objects of nanometer dimensions, which are atoms (on a scale of tenths of nanometers) and molecules (on a scale of nanometers). Since everything is made of atoms and molecules, nanoscience and nanotechnology could, in principle, be thought to cover all the branches of science and technology. A more satisfactory definition of nanoscience and nanotechnology can be achieved by focusing on the intrinsic properties of the nanoscale objects and on the possibility of organizing them into assemblies in order to perform specific functions. Nanotechnology is really a magic word. It covers any techniques that can manufacture patterns and devices below 1 μm and above a few nanometers. Over the past 5 years, the scientific and engineering communities have witnessed an explosion of interest and investment in the field of nanoscience and nanotechnology. The field of nanoscience has blossomed over the last 20 years and the need for nanotechnology will only increase as miniaturization becomes more important in areas such as computing, sensors, composites, and biomedical applications. Advances in this field largely depend on the ability to synthesize nanoparticles of various materials, sizes, and shapes, as well as to efficiently assemble them into complex architectures. The synthesis of nanoparticles, however, is a fairly established field as particles of submicron or nanosized dimensions have been synthesized for centuries. The first example of considerable recognition is the Roman Lycurgus Cup, a bronze cup lined with colored glass that dates to the 4th century AD. Small nanoparticles were often used in later centuries to create stained glass with small, ruby-red gold and lemon-yellow silver particles. Nanoscience and technology is a field that focuses on: (1) the development of synthetic methods and surface analytical tools for building structures and materials, typically on the sub-100 nm scale, (2) the identification of the chemical and physical consequences of miniaturization, and (3) the use of such properties in the development of novel and functional materials and devices. Thus, this field is of greatest interest to handle metal and polymer nanoparticles, nanostructured materials, silica porous nanomaterials, nanopigments, carbon nanotubes, nanoimprinting, nanocomposites, quantum dots (QDs), and so on and has already led to many innovative applications, particularly in materials science [9, 10]. Nanoscience and nanotechnology are still in their infancy. At present, new exciting results [11] and, sometimes, disappointments alternate on the scene, as always happens in fields that have not yet reached maturity. Surely, as Feynman said [12], “when we have some control of the arrangement of things on a molecular scale, we will get an enormously greater range of possible properties that substances can have,” and these new properties will lead to a wide variety of applications which we cannot even envisage today. Hopefully, nanoscience and nanotechnology will contribute in finding solutions for several big problems that face a large part of the earth’s population: food, health, energy, and pollution. Nanoscience and nanotechnology have become words that stir up enthusiasm and fear,

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since they are expected, for good or for bad, to have a strong influence on the nature of mankind. Everybody seems to know what the meaning of these two words is; yet, in fact, even within the scientific community they are not yet well defined and the universally accepted definitions of these two terms will never be attained. This is not surprising, since it is a common experience that, in the field of science, as soon as a definition is established, problems arise. Nanoscience is now an important, central thread in fundamental research, and it will soon become an important part of technology. It focuses on both nano and micro objects. Nanoscience is the science of objects with dimensions on the nanometer scale. This size regime is controlled by quantum mechanical effects, most notably, the quantum size effect. This scientific field is in the interaction zone of physics, chemistry, materials science, and biology. Nanoscience is truly interdisciplinary in nature, providing potential synergism among the various fields in natural science. For many applications, at present microtechnology is more important than nanotechnology. However, nanoscience becomes a thread woven into many fields of science. Nanotechnology—certainly evolutionary, and perhaps revolutionary—will emerge from it. It is thought that chemistry will play a role; whether this role is supporting or leading will depend in part on how the field develops and what opportunities emerge, and in part on how imaginative chemists and chemical engineers are, or become, in finding their place in it. We can expect similar behavior for physics or biology. Nanotechnology and biotechnology have both rapidly evolved in recent years, and are considered to be two key technologies for the 21st century. The interplay between these two technologies leads to a very promising and active research field, namely bionanotechnology or nanobiotechnology. It consists of two closely related sides; one focuses on developing nanotechnology with biologically related approaches while the other applies nanotechnology in biomedical studies. Biological systems such as cells and viruses are structured at the nanometer scale and function at the same scale. In that sense, they are natural, proven nanotechnology systems. In developing a human version of nanotechnology, we would like to directly exploit existing biological nanostructures, to mimic biological systems and synthesize nonbiological structures, and to extract and apply the principles of biological systems. Nanobiotechnology can deal, for example, with protein- and DNA-based nanostructures or devices. Proteins and DNA can self-assemble into various structures with nanometer-scale features. Such biological structures can be used as templates or scaffolds to prepare nanoconjugates with magnetic and semiconductive nanoparticles, inorganic additives, and polymer particles and materials. The resulting structures have interesting physical properties and can be utilized in many technological applications, including nanoelectronic devices, high-density data storage, molecular computations, nanomachines, optical devices, and biosensors. As nanotechnology advances, it provides many new tools for studies of biological systems that would otherwise be impossible. For example, atomic force microscopy allows visualization and manipulation of individual proteins or DNA molecules. Semiconducting nanocrystals are fluorescence labels that can survive for a much longer time than organic fluorescent

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dyes under strong luminescence. Nanoarrays offer a means to analyze large sets of chemicals or cells in parallel. Technology can be defined as the ability of taking advantage of the progress of science to create novel opportunities for practical applications. Technology is the main driving force for the progress of mankind since it provides a wealth of novel materials, devices, and machines capable of improving the quality of life. Taniguchi introduced the term “nanotechnology” in 1974 to describe the manufacturing of products with tolerances less than 1 μm [13]. Feynman introduced the concept of building with molecules, “bottom-up” manufacturing, in contrast with the “top-down” manufacturing we are familiar with [12]. He suggested that almost any chemically stable structure, that can be specified, can in fact be built. Furthermore, nanotechnology always will remind us of Feynman’s statement: “At any rate, it seems that the laws of physics present no barrier to reducing the size of computers until bits are the size of atoms, and quantum behavior holds dominant sway.” The pioneering work of Drexler in molecular nanotechnology is important here; in his works, he described nanoscale “assembler”—robots that build structures molecule by molecule and even replicate themselves [14, 15]. To image these tiny structures, special microscopes are needed. Scanning electron microscopes image structures by analyzing the scattered electrons on a substrate using a computer. Scanning probe microscopes use extremely sharp probes with tips of radius about 10 nm to scan the surface. The scanning tunneling microscope measures a tunneling current that occurs when the tip is about 1 nm above the surface and a voltage is applied; the current is held constant by moving the tip vertically while scanning the surface. The restriction that the substrate has to be an electrical conductor led to the invention of the atomic force microscope. This device also uses a probe, but this one is attached to a flexible (in vertical depiction) cantilever, which is pressed into light contact with the surface while scanning. The vertical movement is followed by detecting the reflections of a laser beam on it; this is one type of AFM; however, several short-range, very high-resolution displacement transducers are used in different types of AFMs. Computers construct the final images. These microscopes can also be used to move nanoscale objects (and even single atoms) on a surface, being important devices to handle nanotubes. To produce nanoscale shapes or lines, special processes are needed. The most important ones all deal with some kind of energy beam, which reduces the material by ablation (instant vaporization). These techniques are (in order of increasing power): photolithography, X-ray lithography, electron beam machining, focused ion beam machining, and laser beam machining (femtosecond lasers and excimer lasers) [16–18]. Technologies have been developed that use components that are as small as possible, and size reduction of the constituent components plays an important role in the development of these “nanotechnologies.” Nanomaterials appear at the interface between condensed matter and isolated atoms/molecules. The essence of nanotechnology is the ability to work at the molecular level, atom by atom, to create large structures with fundamentally new molecular organization. It is concerned with materials and systems whose structures and components exhibit novel and significantly improved physical, chemical, and biological properties, phenomena, and processes due to their nanoscale

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size and with development and utilization of structures and devices with organizational features at the intermediate scale between individual molecules and about 100 nm where novel properties occur as compared to bulk materials. It implies the capability to build up tailored nanostructures and devices for given functions by control at the atomic and molecular levels. It is estimated that nanotechnology is at a similar level of development as computer/information technology was in the 1950s. The size range and particularly the new phenomena set apart nanotechnology from MEMS (micro-electrical-mechanical systems, as known in the United States) or MST (microsystems technologies, as known in Europe). Search for effective ways for controlling the morphology of nanophase materials is of principal importance for nanotechnology and for development of advanced nanostructured materials. Nanotechnology is considered to be the technology of the future; it is perhaps today’s most advanced manufacturing technology and has been called “extreme technology,” because it reaches the theoretical limit of accuracy which is the size of a molecule or atom. In manufacturing industry, two interrelated trends are clearly seen: the trend toward miniaturization and the trend toward ultraprecision processing. Both trends are moving in the direction of nanotechnology, because both are tending to dimensions which lie in the range of several nanometers. Nanotechnology deals with materials and systems having the following key properties [19]: -

they have at least one dimension of about 1–100 nm; they are designed through processes that exhibit fundamental control over the physical and chemical attributes of molecular-scale structures; they can be combined to form larger structures.

Nanotechnology thus refers to techniques that offer the ability to design, synthesize (or manufacture), and control at the length scale below 50 or 100 nm. The emphasis in this definition of scope is “design and control,” and not only synthesis. Synthesis of materials at nanometer scale has already become routine practice for supported noble metal catalysts after decades of research on the subject. However, there is much room for development to design and control. Nanotechnology has gained substantial popularity recently due to the rapidly developing techniques both to synthesize and characterize materials and devices at the nanoscale, as well as the promises that such technology offers to substantially expand the achievable limits in many different fields including medicine, electronics, chemistry, and engineering. In the literature, there are constantly reports of new discoveries of unusual phenomena due to the small scale and new applications. It is creating a growing sense of excitement because we see an opportunity of unprecedented magnitude looming on the horizon: the ability to arrange and rearrange molecular structures in most of the ways consistent with physical law. If we can arrange atoms with greater precision and flexibility, and at lower cost, then almost all the familiar products in our world will be revolutionized. To name just three, we will: pack more computational power into a cubic centimeter than exists in the world today; make inexpensive structural materials that

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are as light and strong as diamond; and make surgical tools and instruments of molecular size and precision, able to intervene directly at the fundamental level where most sickness and disease are caused. Several important points should be noted in the nanotechnology area: -

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New behavior at the nanoscale is not necessarily predictable from that observed at large size scales. The most important changes in behavior are caused not by the order of magnitude size reduction, but by newly observed phenomena intrinsic to or becoming predominant at the nanoscale, such as size confinement, predominance of interfacial phenomena and quantum mechanics. Once it is possible to control feature size, it is also possible to enhance material properties and device functions beyond those that we currently know or even consider as feasible. Such new forms of materials and devices herald a revolutionary age for science and technology, provided we can discover and fully utilize the underlying principles. Nanotechnologies are multidisciplinary by nature. Experimental sciences are converging toward the “nanoworld”: nanosciences, nanotechnology, nanostructures, nanoelectronics. Thus, physics is converging from electrical engineering (m denotes meter), electronics (mm), microelectronics (μm) toward nanoelectronics (nm); biology from cellular biology (μm), molecular biology toward bio-nanostructures and ˚ ), molecular chemistry (nm) toward chemistry from atomic chemistry (A nanostructures (Fig. 1).

Current interest in nanotechnology is broad and there are several common themes among funding agencies, as well as particularities [6]: -

A main goal has been realization (synthesis, processing, properties, characterization, modeling, simulation) and use of nanostructured materials, including high-rate

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FIG. 1 Experimental sciences are converging toward the "nanoworld”: physics (electrical engineering, electronics, microelectronics, and nanoscience), biology (cellular biology, molecular biology, and nanotechnology), and chemistry (atomic chemistry, molecular chemistry, and nanostructures)

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production of nanoparticles for potential industrial use. Advanced generation techniques for nanostructures with controlled properties, methods to simulate structure growth at molecular and mesoscale levels, nanodevice applications, instruments and sensors based on novel concepts and principles, tools for quantum control and manipulation, and interdisciplinary research including biology, are important components of current research activities. Research and development on thermal spray processing and chemistry-based techniques for deposing multilayered nanostructured coatings, processing of nanoscale powders into bulk structures and coatings has been undertaken. Nanofabrication with particular focus on the electronic industry is another major theme. It includes development of technologies seeking improved speed, density power, and functionality beyond that achieved by simply scaling transistors, operation at room temperature, use of quantum well electronic devices, and computational nanotechnology addressing physics and chemistry related issues in nanofabrication. Research on nanoscale materials for energy applications has a focus on synthesis and processing of materials with controlled structures, surface passivation, and interface properties. The targeted energy-related applications are catalysis, optoelectronics, and soft magnets. Miniaturization of spacecraft systems and theoretical modeling addressing the physical and chemical aspects of nanostructures is another area of focus. Biomimetics, smart structures, microdevices for telemedicine, compact power sources, and superlattices are developed in an interdisciplinary environment. Neural communication and chip technologies have been investigated for biochemical applications and sensor development. Metrology activities for thermal, mechanical properties, magnetism, micromagnetic modeling, and thermodynamics of nanostructures have been initiated. Nanoprobes to study nanometer material structures and devices with nanometer length scale accuracy and picosecond time resolution have been developed and others are in development.

Basic research in nanotechnology and obtained results say that “the possibilities of nanotechnology are endless.” Entirely new classes of incredibly strong, extremely light, and environmentally benign materials could be “created” and went on to discuss inexpensive nanostructures for broad applications. For example, the computational molecularnanotechnology research group examined the ways in which this technology can be used to advance the exploration and human habitation of space. Storing one bit in a few atoms no longer seems outlandish, and molecular switches will someday replace the bulky devices made today using optical lithography. As we move beyond the vision and start asking how we are going to do this and how long it will take, opinions begin to diverge. The remarkable SPM instruments have already demonstrated an ability to move atoms and molecules on a surface in a controlled way, but have so far been confined to two dimensions. Thus, the principles of nanotechnology can be maneuvering things atom by atom.

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In chemistry, the range of sizes from a few nanometers to much less than 100 nm has historically been associated with colloids, micelles, polymer molecules, phase-separated regions in block copolymers, and similar structures—typically, very large molecules, or aggregates of many molecules. More recently, structures such as nanotubes, nanorods, nanowells, etc. and compound semiconductor QDs have emerged as particularly interesting classes of nanostructures. In physics and electrical engineering, nanoscience is most often associated with quantum behavior, and the behavior of electrons and photons in nanoscale structures. Biology and biochemistry also have a deep interest in nanostructures as components of the cell; many of the most interesting structures in biology—from DNA and viruses to subcellular organelles and gap junctions—can be considered as nanostructures [20]. Colloids and micelles and crystal nuclei have always been more difficult to prepare and to characterize; developing a “synthetic chemistry” of colloids that is as precise as that used to make molecules is a wonderful challenge for chemistry [21]. Synthesizing or fabricating ordered arrays and patterns of colloids poses a different and equally fascinating set of nanoobjects. The contribution of chemistry to nanoscience one can visualize into several areas as follows [22]: -

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Chemistry is unique in the sophistication of its ability to synthesize new forms of matter. The invention of new kinds of nanostructures will be crucial to the discovery of new phenomena. Chemistry has contributed to the invention and development of materials whose properties depend on nanoscale structure. Chemistry and chemical engineering will, ultimately, be important in producing these materials reproducibly, economically, and in quantity. The molecular mechanisms of functional nanostructures in biology—the lightharvesting apparatus of plants, the ribosome, the structures that package DNA—are areas where chemistry can make unique contributions. Physical and analytical chemistry will help to build the tools that define these nanostructures and further initiate the explosion of nanoscience [23]. Understanding the risks of nanostructures and nanomaterials will require cooperation across disciplines that range from chemistry to physiology, and from molecular medicine to epidemiology [24].

Chemistry is the ultimate angstrom technology and/or nanotechnology. Chemists can make new forms of matter by joining atoms and groups of atoms together with bonds. They carry out this subnanometer-scale activity—chemical synthesis—on megaton scales. Although the initial interest in nanotechnology centered predominantly on nanoelectronics, and on fanciful visions of the futurists, the first new and potentially commercial technologies to emerge from revolutionary nanoscience seem, in fact, to be in materials science; and materials are usually the products of chemical processes. For example, nanoballs were the first of the discrete, graphite-like nanostructures. They were followed rapidly by carbon nanotubes—which are long graphite rods. These structures have a range of

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remarkable properties, including metallic electrical conductivity, semiconductivity with very high carrier mobility, and extraordinary mechanical strength [25]. Nanotubes are, of course, in competition with inexpensive materials such as carbon black and silicon for some of these applications, and cost and safety will determine the winners. Chemistry and chemical engineering play an essential role in developing the catalytic and process chemistry required to make uniform nanotubes at acceptable costs. Nanotechnology is not an independent, isolated circle but rather one that overlaps all of the existing circles and will continue to grow as the field is developed (Fig. 2). This is what distinguishes the field from scientific fads that have focused on a particular class of materials. It is a field fueled by novel tool development that will impact and change almost every conventional scientific and engineering subdiscipline by providing new ways of fabricating or synthesizing structures with well-defined and tailorable properties through control over nanoscale architecture. This give rise to the developing of the new interdisciplinary topics by combination of two or more fields (Fig. 2). The example of such an interdisciplinary topic is nanophotonics. It is neither pure physics, nor chemistry, nor engineering; it is a combination of all three. It is a highly interdisciplinary topic where the level of understanding in each of the three areas has to be very high. This fact makes the topic extremely rich, but this is probably also a big limitation. Just to give one example, you have to be expert in supramolecular chemistry, quantum optics, and optical transmission technology. Differently from their macroscale counterparts, nanomaterials are characterized by lengths that span different scales to the nanometer size. The complexity in extended

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Nanotechnology FIG. 2 Nanotechnology encompasses all fields [2].

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dimensions brings about advantages and new functionalities that may be exploited in materials science, biomedical sciences, and bioengineering [26]. Nanotechnology entails the synthesis and manipulation of particles having dimensions in the nanometer range. One nanometer (nm) is one billionth, or 10
9, of a meter. To get an idea of the scale, the diameter of a DNA double helix is about 2 nm, the smallest atom, hydrogen, has a diameter of approximately 0.25 nm, and the distance between two bonded atoms of carbon in a molecule is about 0.1 nm. On the other hand, the smallest bacteria, those of the genus Mycoplasma, are about 200 nm (Fig. 3). Nanotechnology is a multidisciplinary field bringing together chemists, physicists, biologists, pharmacologists, physicians, clinicians, veterinarians, and many other specialists. This broad array of research fields is expected to yield new paradigms in the arsenal of tools used in clinical oncology [28]. The battlefield in the war against cancer must be broadened, and tomorrow’s oncologic therapy is likely to be very personalized, very complex, and very expensive. The medical applications of nanotechnology have expanded rapidly over the past few decades, and we believe that nanomedicine will have a profound

0.25 nm: hydrogen atom (the smallest atom)

2 nm: diameter of a DNA double-helix

200 nm: mycoplasma (the smallest bacteria)

8000 nm: red blood cell

FIG. 3 Illustration representing the size of different structures in the nanometer range [27].

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impact on future therapies. Nanomedicine—which already exists as a medical specialty— focuses on achieving better diagnostics, increased disease prevention, enhanced treatments, fewer side effects, and improved quality of life for patients [29].

1.3 Nanoparticles Nanoparticles have been empirically synthesized for thousands of years, for example, the generation of carbon black. It is noticeable that very few nanoparticle synthesis processes have developed their scientific base decades ago, long before other nanotechnology areas have emerged. One finds in this category the pyrolysis process for carbon black and the flame reaction for pigments, particle polymerization techniques, self-assembling of micelles in colloidal suspensions, and chemistry self-assembling. Several kinds of nanoparticles are routinely produced for commercial use via aerosol and colloid reactors in the world. The word “nanoparticle (NP)” has appeared in the literature as nanovehicle, nanovector, nanostructure, nanoconstruct, and others. The term “NP” can be chosen to refer to all of these types of nanoconstructs. NPs are solid particles that come in a plethora of sizes, compositions, and characteristics. Research programs on nanoparticles around the world suggest different strengths have developed in various countries, a fact that would suggest the need for international collaboration [6]. Nanoparticles are seen either as agents of change of various phenomena and processes, or as building blocks of materials and devices with tailored characteristics. Use of nanoparticles aims to take advantage of properties that are caused by the confinement effects, larger surface area, interactions at length scales where wave phenomena have comparable features to the structural features, and the possibility of generating new atomic and macromolecular structures. Important applications of nanoparticles are in dispersions and coatings, functional nanostructures, consolidated materials, biological systems, and the environment. Microparticles mostly exhibit physical properties the same as that of the bulk form. In the nanometer size regime, new mesoscopic phenomena characteristic of this intermediate state of materials can appear. Furthermore, the stability of crystal structures can decrease in nanometer sizes, the feromagnetics can be varied when particles reach the nanometer size, the magnetics can become superparamagnetics when materials shrunk to the nanometer scale and the metal nanoparticles can become or loose their catalytic activity, etc. This can be discussed in terms of the organization of atoms or molecules into condensed systems due to which new collective phenomena of materials are developed. Cooperative interaction is responsible for the physical properties of the materials and it varies with the size of agglomerates in the nanometer scale [30]. The production of ultrafine particles is nowadays one of the most important challenges of the new technologies [31]. There are several reasons for this importance: -

First, technologies today need to reduce as much as possible the size of the components being used. New applications arise due to the great value of the surface/volume ratio associated with ultrafine particles.

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The properties of ultrafine particles are in some cases very different from those of bulk materials and also from those of isolated atoms/molecules. The method of nanoparticle synthesis often influences the properties of the product, in particularly, synthesis of nanoparticles in confined geometries and structured reaction media can result in anisotropic and size-controlled nanoparticles [32].

Preparation of nanoparticles enables the systematic characterization of the structural, physical, electronic, and optical properties of materials as they evolve from atom or molecular from to bulk via the nanometer size regime. In recent times, new methods of synthesis (inert gas condensation, layer deposition, ultrarapid quenching, mechanical attrition, aerosol, etc.) have been used to fabricate magnetic systems with characteristic dimensions on a nanometer scale. Each fabrication technique has its own set of advantages and disadvantages. Among those techniques, the chemical synthesis of nanoparticles is a rapidly growing field with great potential in making useful materials. However, there are some difficulties to realize it. For example, one difficulty is the need to find the proper chemical reactions, the composition of the monomer feed, and processing conditions for each material or undesirable agglomeration at any stage of the synthesis process, which can change the properties. When the particles are very small the lattice constants of the entire particles are strongly reduced [33]. Furthermore, the large ratio of the surface to interior atoms is connected with a large surface energy and so with the thermodynamic instability of the nanomaterials. In order to prevent the nanomaterials from growing in size, the reduction of the surface energy by the insertion of surface active components into the particle surface is necessary. One of the great challenges in stabilization of nanoparticles is the adsorption and bonding of surface active components into the particle surface. In all cases the chemical stability of the nanoparticles is crucial to avoid degradation processes such as partial oxidation or undesired sintering of particles. The lack of sufficient stability of many nanoparticle preparations has, to some extent, impeded the development of real-world applications of nanomaterials. Particle synthesis at high production rates has been a major research objective in the past few years. Particle nucleation and growth mechanisms are important scientific challenges. An ultimate goal of nanoparticle and nanocrystal research is to develop the ability to manipulate the size, morphology, and arrangement of these “superatoms” in such a fashion that their unique optical, electrical, and magnetic properties can be utilized for different applications [34]. While colloid synthesis has the advantage of making bulk quantities of nanomaterials in a manner much simpler and of a smaller size than lithographic techniques, the problem of narrowing the particle size distribution has long plagued colloid scientists [35]. The significance of obtaining a monodisperse colloid is that it will allow us to correlate the physical properties of the entire colloid directly to the physical properties of each single size particle. It is also one of the key requirements in forming superlattice structures using nanocrystals as building blocks [36–38]. Monodisperse colloids, thus, provide ideal systems to study colloidal phase transitions without being affected by the complexity of

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particle size distribution [39]. Uniform micron-size particles were prepared by LaMer et al. half a century ago using a “growth by diffusion method” [40]; the preparation of single size nanocrystal colloids, however, is much more difficult due to their fast growth rate and their inherent stability [41]. There has been an increasing interest in semiconductor structures of different sizes and specifically those with dimensions in the order of a few nanometers. Although synthesis of nanodimensional colloids in a biphasic system was known earlier, problems such as their stability and precise control of reactivity have been tackled only recently using different strategies. Size control is often sought either through the attachment of appropriate protecting agents, such as gelatins, albumins, and other peptides, amphiphiles and macromolecules, such as polyethylene imine or polyvinylimidazole, on the surface of the clusters or to one another without leading to coalescence, which results in the loss of their size-induced electronic properties. Another expedient method involves the use of self-assembled monolayer (SAM) formation with alkanethiols and amines for noble metal surfaces leading to the successful synthesis of stable particles. It is very important to have general methods for obtaining particles by simple and reproducible techniques. As improved syntheses lead to highly characterized samples with narrow size distributions and regular shapes, the behavior of single nanoparticles is being examined with increasing rigor and detail. The production of particles in the nanometer range is one of the most important challenges of modern materials science. The possibility of a dramatic change in electronic properties by varying the size of metal particles has emerged as an area of important and fruitful research activity due to its fundamental and technological relevance. Nanoparticles are the core of this technology. These are particles ranging in size from 1 millionth to 100 millionths of a millimeter—more than 1000 times smaller than the diameter of a human hair. At this order of magnitude, it is not only the chemical composition but also the size and the shape of the particles that determine their properties. Synthesis of various particles of sizes varying from 1 to 100 nm have found promising applications in different fields. When the electrons and holes are confined within a three-dimensional potential well, the continuum of states in the conduction and valence bands is broken into discrete states with an energy spacing, relative to the band edge, which is approximately inversely proportional to the square of the particle size [42]. They have a characteristic high surface-to-volume ratio, providing sites for the efficient adsorption of the reacting substrates leading to unusual sizedependent chemical reactivity [43]. Atoms and molecules on the air/solid or liquid/solid surfaces have fewer neighbors than those in the subsurface or solid matrix. The unsatisfied bonds exposed to the surface initiate a dangling effect. Thus, the atoms at the surface are under the influence of an inwardly directed force and bond distance between the atoms at the surface is smaller than between the atoms in the bulk matrix. The ratio of the surface atoms to interior atoms changes abruptly when the object is strongly decreased. Such a dramatic increase in the ratio of the surface to bulk atoms can be correlated to the strong changes in the physical and chemical properties of the nanomaterials.

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Generally, nanomaterials include colloidal crystals, superlattices, metal and polymer nanoparticles, nanorods, nanobelts, nanotubes, nanowires, superlattices, composite nanostructures, micelles, liposomes, dendrimers, polymer micelles, etc. The properties of nanospheres are influenced and modified by reduced dimensions—confinement, reduced dimensionality, proximity effects and surface dominating over the bulk [44]. Owing to the fact that in nanospheres the surface/volume ratio can reach very high values, new applications associated with the inner surface have appeared, for example, the development of new catalysts, photonics, fluids, micro-, mini-, and polymer emulsion and dispersions, etc. [45]. Small, single-domain particles exhibit an exotic magnetic behavior that allows them to reach a limiting magnetism, that is, the disappearance of the coercively and remanence at a very high level of magnetization (superparamagnetism). Because of confinement and quantum-size effect, a reduction in the dimension of metal domains produces dramatic changes in the behavior of the massive metal properties. The small size also has very important effects on the magnetic behavior of ferromagnetic metals [46]. Polymer and polymer-mediated nanoparticle assemblies provide a versatile and effective method for the creation of structured nanocomposite materials where control over composite morphology is paramount. In addition to their role in assembling nanoparticles, functionalized polymers can be used to control interparticle distances, compatibility with a broad range of polymers, assembly shapes, sizes, and porosities, and to induce an anisotropic ordering of nanoparticles. The ability to control such structural parameters enables the creation of responsive materials. The compatibility or interaction of small particles with cells and tissues is not up to now well understood but there are diseases associated with a few of them: silicosis, asbestosis, and “black lung” [47, 48]. Most nanomaterials would be made and used in conditions in which the nanomaterial was relatively shielded from exposure to society (an example would be nanotubes compounded into plastics). Still, we do not know well how nanoparticles enter the body, how they are taken up by the cell, how they are distributed in the circulation, or how they affect the health of the organism. If the chemical industry intends to make a serious entry into nanostructured materials, it would be well advised to sponsor arms-length, careful, and entirely dispassionate studies on the effects of existing and new nanoparticles and nanomaterials on the behavior of cells and on the health of living beings. The use of nanoparticles in drug delivery is in progress, especially nanoparticulate and nanoporous materials for catalytic and biomaterials applications. This includes stimuli-responsive drug-delivery systems, which, for example, release insulin only when the glucose concentration is high. A novel synthesis of glucose-responsive nanoparticles for controlled insulin delivery is in progress; the glucose-sensitive polymeric nanoparticles are tailored by respective proteins. The controlled-release strategy uses a polymer with acidic degradation products to control the dissolution of a basic inorganic component, resulting in protein release. The potential risks of nanoparticles are well known and broadly discussed. Health issues arise from the altered properties of nanomaterials (such as solubility variations).

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Questions concerning the inhalation or disposition of nanoparticles (such as polymer or magnetic particles used for drug delivery or surface binding to endogenous proteins) still remain open. A roadmap to safe nanotechnology should include the development and validation of testing methods and increased awareness of the potential environmental and biological hazards of nanoparticles and nanotechnology. Some of the better known nanoparticles are shown in Scheme 1. NPs can be loaded with drugs, bioactive agents, and diagnostic tools that can be absorbed on the surface, entrapped inside, or dissolved within the matrix of the NP [50]. Thus armed, the NPs can serve as vectors inside a living body. NPs are usually made of lipids, metal or metal crystals, silicates, proteins, or polymers. Nanoparticles are small, and thus more difficult to analyze, compared with molecular pharmaceuticals with respect to characterizing their chemical composition and properties. For example, measurements of sizes require that several methods of analysis are employed both in solution and in the solid phase. Moreover, after in vivo administration NPs can differ considerably in size compared to the situation in vitro. In vivo, the particle’s

SCHEME 1 Nanomaterials in clinical practice; lipid-based nanoparticles (liposomes, stealth liposomes, solid lipid NPs, etc.), polymer-based nanocarriers (polymer NPs (PNPs), polymeric micelles, etc.), metal, silica and inorganic nanoparticles, viral nanoparticles [49].

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Nanocomposite Structures and Dispersions

surface can be covered by lipids and proteins (a so-called “biocorona”) depending on the particle’s material, electrical charge, and hydrophilicity, among others [51]. The size of the particle governs to a large extent the half-life, biological distribution, pharmacokinetics, and elimination route. Some works have also indicated that although size is an important parameter for determining the final fate of the NP, shape and NP flexibility also influence glomerular filtration [52]. A drawback is that the majority of the methods used to try to predict the behavior of NPs in vivo are inevitably based on analytical techniques applicable only under in vitro conditions. Therefore, toxicity might occur unexpectedly under in vivo conditions. These problems are extremely important for both the industrial use of NPs as well as for the environmental aspects and biomedical applications [53]. Significant research efforts are currently focused on understanding the in vivo fate of NPs, their excretion profiles, and their life cycle as well as the parameters that govern their effects such as the biocorona interface with blood proteins and lipids. Some of today’s more commonly used NPs in medicine are discussed below. Liposomes are vesicular bodies of biocompatible phospholipid bilayers 100–500 nm in diameter and represent the first materials that can be seen as true nanomedical drug delivery agents. Liposomes can be loaded in several ways. For example, hydrophobic drugs can be sequestered on the lipid bilayer and more hydrophilic drugs such as Paclitaxel can be sequestered within the aqueous interior of the lipid. Lipids can also be constructed to contain more than one drug so as to enable synergistic drug combinations or to add a contrasting agent for combined diagnostic imaging and therapy (so-called “theranostics”). Magnetic NPs incorporated into liposomes can also be used for magnetic localization [54], and the surface of the liposome can be constructed to bear monoclonal antibodies for targeting [55]. Release of the active components can be from passive diffusion or via external triggers such as heat and light or via physiological changes such as pH, which is a prerequisite for biologic effect, sine qua non. Micelles are lipid-based or polymer-based (plastic) constructs with a hydrophobic/ hydrophilic core@shell morphology [56]. They are smaller than liposomes and can, therefore, infiltrate tissues where liposomes are excluded. Polymer-based micelles are very versatile drug-delivery carriers because they can be tailored into almost infinite variations of size, electric charge, hydrophobicity, material characteristics, degradability, etc. Polymers such as poly(ethylene glycol) (PEG) have also been used to construct polymer therapeutics that are protein-polymer conjugates of interferon that protect interferon from rapid breakdown in vivo, which reduces the number of injections for the patient and increases compliance [57]. Similarly to liposomes, polymer micelles can be constructed to be triggered via the same mechanism of pH, temperature, and light. Micelles are particularly well suited for exploiting the enhanced permeability and retention effect (EPR). Polymer nanoparticles are among the most investigated nanomedicine agents. Polymer nanoparticles (PNPs) are light and flexible, and with modern polymer chemistry they can be produced with customized composition, molecular weight, and topology [58]. Polymers can serve as vectors or for formulating or protecting the drug [59]. Examples are poly(glutamic acid) coupled to Paclitaxel (against ovarian cancer) and PEG coupled to L-asparaginase (against acute lymphatic leukemia).

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Dendrimers are symmetrically branched polymers with a single molecular weight. Due to their exact size and composition, they offer precise control over pharmacokinetics and biodistribution. Dendrimers have multiple handles that are capable of simultaneously carrying drugs, imaging agents, and targeting ligands. Dendrimers are very expensive to produce, and this has limited their use in clinical applications. Currently, there is regulatory testing of dendrimers for use as antivirals in vaginal anti-HIV creams and as a taxane formulation system [60]. Particles in the nanometric size range are termed polymer or metal nanoparticles (PNPs or MNPs). The size greatly depends on the process used for their synthesis. PNPs or MNPs can be obtained by the bottom-up assembly of atoms (reduction of metal salts) or molecules (polymerization of monomers) through chemical process or, on the contrary, from top-down fragmentation of inorganic bulk material. The former method allows the synthesis of smaller particles. NP properties are governed by three main features: size, composition, and geometry [61]. The lower limit of NP size (d  10 nm) is set by the size of atoms since nanotechnology must build its particles from atoms and molecules. The upper limit (d < 100 nm) is somewhat arbitrary but relates to the size that permits the desired implementation that is not feasible at larger scales, such as penetration of cells [61]. The upper cut-off size for medical implementation can be therefore considered to be 1 μm, as this size permits penetration of nonphagocytic eukaryotic cells [62] even if, phagocytic cells such as dendritic cells and macrophages can eat by phagocytosis larger particles up to 4 μm in size [63]. The most intriguing property is their ability to escape the forces of the Newton’s laws of motion, being governed by the laws of quantum mechanics. When observing their behavior suspended in a solution, movements of NPs are very dynamic, and they move rapidly and are randomly driven by Brownian motion [64]. Of particular significance in medical applications is their very high surface-to-mass ratio—a property that increases progressively with decreasing in size. This large functional surface is able to bind, absorb, and carry many compounds such as probes, proteins, and drugs, thus making NPs particularly attractive for medical delivery purposes [65]. Nano-size is the cardinal property for interaction with biological systems since it determines the ability to penetrate cell membranes, thus facilitating the passage across biological barriers, interaction with the immune system, uptake, absorption, distribution, and metabolism [61]. For instance, the size of orally assumed NPs could somehow determine its fate addressing the kind of cell to interact with (i.e., epithelial or phagocytic cell), or the depth level in the intestinal mucosa [66]. Nowadays, experimental studies have mostly been conducted with spherical (liposomes, emulsions, capsules, spheres) or tubular (nanotubes) nanoparticles, due in part to fabrication technology limitations in controlling their shape. The energy-minimizing principles involved in the bottom-up production techniques for stable structures determine the spherical shape, because spheres have the least surface per unit volume and, thus, minimize the interfacial energies. The advancement of techniques involved in nanofabrication has enabled the development and production of various nonspherical NPs. A note of warning has to be given as it has been supposed that nanocrystalline particles by themselves may have a biologic effect on cells. For example, while the α-quartz form of

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silica is pro-inflammatory due to lysosomal rupture following cellular uptake, amorphous silica particles do not induce any lysosomal response [67]. To synthesize particles with nanosize, surface chemistry and shape confer to NPs an ability to enter cells, to carry compounds, and influence cellular functions much greater than corresponding conventional agents. These properties entailed the development of nanopharmacology, a new field of research meant to better drive drugs to specific targets. Composite nanoparticles may be of biologic or chemical origin. Biologic materials include phospholipids, lipids, lactic acid, dextran, chitosan, and albumin. Chemical materials include polymers, carbon, silica, and metals. Polymers, in turns, may have different chemical compositions. Chemistry is of crucial importance in safety issues as some nanosized constituents can be toxic [61]. The surface chemical composition determines the first interaction of NPs with solvent molecules and various additives and reactants, such as precursors, stabilizers, tissues, and cells, the surface charge being one of the major aspects together with their hydrophobicity/hydrophilicity characteristics. The charge has many properties such as that of stabilizing the dispersion of particles in solution, preventing their aggregation, and providing stability to the NP dispersion [65]. For medical purposes, the surface charge can be used to increase the proximity of NPs to the epithelium, increase their absorption, and determine their different interactions with the intestinal epithelium. For example, positively charged NPs have a strong affinity for healthy epithelium, whereas negatively charged particles preferentially adhere to inflamed mucosa [68]. Hydrophilicity, in turn, may contribute to tissue absorption enhancing penetration of the intestinal mucus layer [65]. Another important aspect of NPs is porosity that is a measure of void spaces in a material. Biosynthesis of nanoparticles, as an emerging highlight of the intersection of nanotechnology and biotechnology, has received increased attention due to a growing need to develop environmentally benign technologies in material synthesis [69]. Green synthesis provides advancement over chemical and physical methods as it is cost-effective, environment friendly, and is easily scaled up for large-scale synthesis, where there is no need to use high pressure, energy, temperature, and toxic chemicals.

1.4 Nanodevices Nanoscale devices and machines are either present in nature [70] or must be synthesized starting from more simple components [71–73]. Eric Drexler [14] presented his ideas on nanosystems and molecular manufacturing in a more scientific way claiming the possibility of constructing a general-purpose nanodevice. Such a nanorobot should be able to build almost anything, including copies of itself, by atomic-scale precision, “pick-andplace” machine-phase chemistry (mechanosynthesis) [74, 75]. The ideas of simple maneuvering of atoms or making molecular mechanosynthesis seem however somewhat against the complexity and subtlety of bond-breaking and bond-making processes [22, 75]. In the nanoscale area, each device is made of a countable number of atoms or molecules. At such small dimensions, the physics governing principal device functions

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eventually transitions from the classical laws, such as Maxwell’s equations [76] and Newton’s laws, into the quantum-mechanical interactions with discrete energy states. As a consequence, principal electronic and/or magnetic and/or mechanical properties of the device might become highly nonlinear if the scaling remains the main strategy for miniaturizing the device. The resulting nonlinearity can substantially degrade the performance of the device. The deviation from linear scaling laws in the nanoscale is of special significance for magnetic devices and materials because the characteristic magnetic domain wall width is in the nanoscale range [77]. The domain wall width defines the minimum length of the spatial nonuniformity of the magnetic properties. Therefore, for extending high technologies in the nanoscale, there is a strong need for other fundamental approaches, besides the traditional scaling. The ability to fairly quickly fabricate a nanoscale prototype device for further characterization and optimization becomes a critical factor for continuing technological progress [78]. A major driving force in R&D of new materials for future information technologies is aimed at the miniaturization of devices down to ultimate limits as determined by basic physics and quantum mechanical principles. Another driving force results from trying to match, in future devices, different performances that are currently achieved separately in biological and technical systems. An often-considered example concerns the human brain as compared with the man-made computer. Technologically unmatched performances of the brain concern high information density, low power consumption, high flexibility, excellent association memory, etc. Biologically unmatched performances of the computer concern quantitative information processing, high reproducibility, etc. [79]. With increasing complexity and demands for future information technologies, a trend is to be seen toward the design of “smart” nanostructures which will be interfaced to different substrates. These structures may consist either of chemically synthesized units such as molecules, supramolecules, and biologically active (biomimetic) recognition centers, or of natural and hence very complex biomolecular function units with high molecular weight which may be extracted from biological systems. An alternative and most promising strategy to exploit science and technology at the nanometer scale is offered by the bottom-up approach, which starts from nano- or subnanoscale objects (namely, atoms or molecules) to build up nanostructures. The bottomup approach distinguishes two different nanoscale “objects”: -

Nanoscales are very simple from a chemical viewpoint and do not exhibit any specific intrinsic function (atoms, clusters of atoms, small molecules). Nanoscales have complex chemical composition, exhibit characteristic structures, show peculiar properties, and perform specific functions.

All of the artificial molecular devices and machines belong to the bottom-up approach category [80]. Examples of such nanoscale “objects” are the light-driven rotary motors based on the geometrical isomerization of alkene-type compounds containing chiral centers [81], the prototype of a molecular muscle [82], the light-driven molecular shuttles [83], the artificial molecular elevator [84], the light-driven hybrid systems for producing

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biocompounds and pumping calcium ions [71], and the DNA biped walking device [85]. All of the natural molecular devices and machines [70], from the light-harvesting antennae of the photosynthetic systems to the linear and rotary motors present in our bodies, also belong to this category. The “bottom-up” approach opens virtually unlimited possibilities regarding the design and construction of artificial molecular devices and machines capable of performing specific functions upon stimulation with external energy inputs [86]. Furthermore, such an approach can provide invaluable contributions to give a better understanding of the molecular-level aspects of the extremely complicated devices and machines that are responsible for biological processes. Molecular devices and machines operate via electronic and nuclear rearrangements, that is, through some kind of chemical reaction. The problem of finding the energy supply to make artificial molecular devices and machines work is of the greatest importance [87]. Since their operation is always based on some kind of chemical reaction, the most obvious way to supply energy to these systems is through the addition of suitable reactants. If an artificial molecular device or machine has to work by inputs of chemical energy, it will need the addition of fresh reactants (“fuel”) at any step of its working cycle, with the concomitant formation of waste products. It is well known for a long time that photochemical and electrochemical energy inputs can cause the occurrence of chemical reactions. In recent years, the outstanding progress made by supramolecular photochemistry and electrochemistry has led to the design and construction of molecular devices and machines powered by light or electrical energy, which work without the formation of waste products [86]. In the late 1970s, a new branch of chemistry called supramolecular chemistry emerged and expanded very rapidly [88, 89]. In the same period, research into molecular electronic devices began to flourish and the idea arose that molecules are much more convenient building blocks than atoms to construct nanoscale devices and machines [90]. The main reasons that provide the basis of this idea are as follows [80]: -

-

molecules are stable species, whereas atoms are difficult to handle; nature starts from molecules, not from atoms, to construct the great number and variety of nanodevices and nanomachines that sustain life; most laboratory chemical processes deal with molecules rather than with atoms; molecules are objects that already exhibit distinct shapes and exhibit device-related properties (e.g., properties that can be manipulated by photochemical and electrochemical inputs); and molecules can self-assemble or can be covalently connected to make larger structures.

The promising route for the fabrication of nanodevices is the use of metal, polymer, and composite nanoparticles as the building blocks [91]. Efforts have been made to assemble nanoparticles into various nanostructures, such as one-, two-, and three-dimensional nanoparticle arrangements (1D, 2D, and 3D) [92]. In addition to the size and composition, the morphology and orientation of the nanoparticles play an important role in modulating the electronic and chemical properties [93]. Million-fold fluorescence enhancement in

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gold nanorods [94] and distinct quadruple plasmon resonances in silver nanoprisms [93] are some exciting shape-dependent properties that have already been reported. There has been a great deal of interest in the study and application of the unique optical, electronic, and catalytic properties of nano- and micrometer-sized particles. Part of the reason lies in the fact that these colloidal particles are useful in a broad range of areas, such as photography [95], catalysis [96], biological labeling [97], photonics [98], optoelectronics [99], surface-enhanced Raman scattering (SERS) detection [100], etc. In the manufacture of electronic devices such as hybrid integrated circuits and multiplayer ceramic capacitors, the technology of making conductive thick films from metal powders is of considerable importance. By using different functional nanoparticles and nanomaterials, it should be possible to give micro-/nanostructures, that is, micro-/nanodevices and micro-/nanomachines, unique properties which may allow for various applications. The accomplishment of high-quality photonic band structures has been confirmed by their bandgap effect. For example, Duan et al. [101] have synthesized Ti4+ ions-doped urethane acrylate photopolymerisable resins and investigated their two-photon polymerization, which is applied to three-dimensional (3D) micro-/nanostructure fabrication. TiO2 nanoparticles were generated in the polymer matrix of micron-sized polymer structures. A 3D diamond photonic crystal structure, which consisted of polymer composite materials of TiO2 nanoparticles, was successfully fabricated by direct laser writing, and its photonic bandgap was confirmed. The absorption of electromagnetic radiation by nanocrystallite material is relatively straightforward, but the luminescent behavior of such particles is more complicated to understand. In a keynote paper, Chestnoy et al. [102] explained, on the basis of theoretical and experimental studies, the features expected in the luminescence spectra of quantum-confined semiconductors and successfully anticipated the results of many subsequent experiments. Progress in nanotechnology demands the capability to fabricate nanostructures in a variety of materials with an accuracy in the nanometer scale and sometimes in the atomic scale. Stringent nanofabrication specifications have to be met in industrially relevant processes due to manufacturability and costs considerations as, for example, in the electronics industry. However, less demanding conditions are needed for developments in optics, sensors, and biological applications. In a laboratory environment, at the level of enabling nanofabrication techniques as tools for experiments to understand the underlying science and engineering in the nanometer scale, easily accessible and flexible nanofabrication approaches are required for investigations in, for example, materials science, organic optoelectronics, nano-optics, and life sciences. Alternative techniques to cost-intensive or limited-access fabrication methods with nanometer resolution have been under development for nearly two decades. One clear example is the evolving set of scanning probes techniques, which has become ubiquitous in many research areas. If one considers planar structures, that is, where nanostructuring is carried out on a surface, as distinct from a three-dimensional nanofabrication or multilayer self-assembly, then several emerging nanofabrication techniques can be discussed. Their classification depends on whether

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the nature of the patterning is chemical or physical, or its modality in time is parallel or sequential, or a hard or a soft mold or stamp is used, etc. This subject is increasing very rapidly and, for example, one can observe progress in micro-contact printing [103], scanning probe-based techniques [104], nanoimprint-based lithography (NIL) technique [105], etc. The single most important fabrication technology of our time is micro- and/or nanolithography: the microprocessors and memories that it generates are the basis for the information technology that has so transformed society in the last half-century. Microelectronic technology has relentlessly followed Moore’s law; the popular expression of this law is “smaller is cheaper and faster” [106]. Besides this enthusiasm for “smaller” other features, heat dissipation, power distribution, clock synchronization, intrachip communication, have become increasingly important. Still, technical evolution in the semiconductor industry has brought the components of commercial semiconductor devices to sizes close to 100 nm, and miniaturization continues unabated. Understanding the behaviors of matter in <100 nm structures is, and will continue to be, a part of this evolution, as microelectronics becomes nanoelectronics. Nanolithography is the branch of nanotechnology concerned with the study and application of fabricating nanometer-scale structures, meaning patterns with at least one lateral dimension between 1 and 100 nm. Different approaches can be categorized in serial or parallel, mask or maskless/direct-write, topdown or bottom-up, beam or tip-based, resist-based or resist-less methods. Applications of nanolithography include among others: multigate devices such as field effect transistors (FETs), QDs, nanowires, gratings, zone plates and photomasks, NEMS, or semiconductor integrated circuits (nanocircuitry). Focused ion beam (FIB) is a rapid way to fabricate a nanoscale magnetic device for further prototyping [107, 108]. Magnetic recording at areal densities beyond 1 Tbit in
2 is presented as an example of a technology for which the implementation of FIB has played the most critical role for its successful transition into the nanoscale range. The FIB column is very similar to the electron beam (E-beam) column used for electron microscopy (SEM, TEM, and others) and E-beam-based lithography, with the main difference being the polarity of the voltages applied to the accelerating and focusing plates and coils in the system. The two main competitors to FIB for defining nanoscale-size patterns are UV-optical and electron-beam lithography [109]. The smallest feature size in the UV-optical case is limited by the UV wavelength and is believed to be of the order of 50 nm. Ideally, both electron beam and FIB can provide substantially smaller feature sizes, limited only by the quality of the electron/ion columns utilized. E-beam and FIB are capable of feature sizes of 30 and 10 nm, respectively. E-beam-based fabrication has been more extensively explored in the semiconductor industry because of its more traditional approach to defining small features via lithographical masks, thus to some degree reminding one of optical lithography. This is the quality that makes implementation of E-beam fabrication for mass production fairly straightforward [109]. At the same time, the use of mask patterning makes the E-beam a fairly “slow” tool for making individual nanoscale prototype devices necessary for proving a concept.

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That is exactly when FIB becomes helpful and/or complementary. Although FIB-based fabrication is more different from traditional optical lithography, it has its advantages compared to the E-beam-based fabrication method, especially with respect to magnetic devices and materials [108]. There is a new class of quantum devices being developed, which require very small sizes to operate [110]. Although lithography with focused electron beams and/or ion beams has been applied to fabricating small features, there is still a need to develop new fabrication techniques for nanometer devices. Scanning tunneling microscopy (STM) developed by Binning et al. has proven to be a powerful technique for the study of atomic resolution in ultrahigh vacuum (UHV), air, and liquid environments [111]. Soon after the invention of STM, researchers begun to investigate the possibility of utilizing it for the manipulation and modification of solid-state surfaces at an atomic scale [112]. It can generate high electric fields between the tip and substrate, as well as provide an intense and finally focused source of electrons. This capability makes the STM an ideal tool for nanometer lithography [113]. Two-photon polymerization, which is initiated through the nonlinear process of twophoton absorption (TPA) of a photoinitiator, has been gaining greater interest among a number of multidisciplinary areas, particularly in the rapidly developing fields of 3D micro-nanofabrication by using infrared lasers without photomasks. This kind of structure has been used as micro-nanodevices for photonic and electronic applications [114, 115]. However, nanoparticles of noble metals and metallic oxides are interesting species because when size is downscaled to the order of nanometers, materials demonstrate novel optical, electronic, magnetic, and mechanical properties, which are the major motivation of the current intense research on nanoparticles. The 3D structures of polymermetal/metallic oxide nanoparticles composite materials can be expected to play an important role in the field of functional devices for future applications. Interfacing biological molecules and supramolecular assemblies with the synthetic world is critical to many applications in nanotechnology [116]. A particularly exciting class of such hybrid devices utilizes biomolecular motors, which can add active, chemically powered force generation and movement to the functionality of the device. Applications of devices based on biomolecular motors have been explored for nanoscale transport systems (molecular shuttles) [117], surface imaging [118], force measurements [119], single molecule manipulation [120], and lab-on-a-chip systems [121]. These studies have proven the feasibility of utilizing motor proteins, such as kinesin, and the specific “roads” supporting their movements, such as microtubules, in synthetic environments for a variety of technological purposes. In hybrid devices, the synthetic materials themselves often introduce additional challenges for proteins. Immediate loss of motor protein function upon adsorption has been reported for a number of surfaces, and a significant effort has been devoted to finding surfaces that permit micro- and nanopatterning but also support motor function after adsorption [122, 123]. Now a number of suitable photoresists, which can be used to pattern a glass surface covered with active motor proteins, have been identified. However, not only the material of the surface directly in contact with the motor protein, but also the material properties of surfaces in contact with the buffer solution can

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affect the lifetime of the proteins. For example, poly(dimethylsiloxane) (PDMS), which is widely used as a biocompatible material [124], has been found to be incompatible with motor protein activity. Different nanotechnologies have developed devices for a continuous drug delivery over an extended period of time. However, most of them suffer from major drawbacks. Degradable polymer implants exhibit an initial “burst effect” prior to sustained release and are typically not as efficient in controlling release rates of small molecules [125]. Implantable devices with percutaneous components such as ambulatory peritoneal dialysis, catheters, intravenous catheters, and orthopedic implants are often associated with different failure modes. Infection, marsupialization, permigration, and avulsion are common occurrences [126]. Osmotic pumps lack the capabilities of electronic integration for achieving higher levels of functionality and are limited with respect to the type of drug they can deliver. Silicon micro- and nanofabrication technology can permit the creation of drug-delivery devices that possess a combination of structural, mechanical, and electronic features that may surmount some of these challenges [127]. Ease of reproducibility, tightly controlled dimensions, and ability to manufacture in high volume are other advantages. A nanochannel filter fabricated between two silicon substrates is a potential solution for the bioapplication, proposed in Refs. [128, 129]. This device offers good control of channel size and pore distribution, making it possible to control the release rate. The level of integration that can be achieved on a single silicon substrate provides major advantages over other materials used for making drug-delivery devices. These sandwich-structure nanochannel filters are fabricated using photolithography, selective oxide growth, and removal. They have envisioned nanochannel delivery systems (nDSs) for the delivery of therapeutic molecules. These devices will present progressively increasing degrees of functionality. The device dimensions were optimized for high mechanical strength so that they are suitable for implantation. Nanochannel devices with 60-nm channel height were fabricated in silicon [130]. These nanochannels are in between two directly bonded silicon wafers, and therefore pose very high mechanical strength, compared to nanopores through thin membranes. The nanochannels were defined by selectively growing an oxide and then etching that oxide. The glucose flow through a 60-nm channel shows a zero-order release rate for the period investigated. One of the barriers to use in practice is optimizing the size of the nanochannels for a desired drug-delivery rate. Different nanochannel sizes deliver different drugs with different rates. A particular drug will require to be delivered at a specified rate, and that will require changing the size of nanochannels. This barrier can be addressed with the integration of electronics on board. The flow through the nanochannels will then be electrically controlled and changing the voltage externally will change the flow rate. Overall, Brunner et al. [131] have shown that a number of polymers (poly(urethane) (PU), poly(methyl methacrylate) (PMMA), PDMS, and ethylene-vinyl alcohol copolymer (EVOH)) can replace glass as the packaging material for hybrid nanodevices integrating kinesin motors and microtubules, but that special care has to be taken when intense illumination is needed, for example, for fluorescence imaging. Prolonging the lifetime of

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biomolecules in their functional states is critical for many applications where biomolecules are integrated into synthetic materials or devices. A simplified molecular shuttle system, which consists of fluorescently labeled microtubules propelled by kinesin motor proteins bound to the surface of a flow cell, can serve as a model system to probe the lifetime of a hybrid device. In this system, the functional decay can easily be assayed by utilizing optical microscopy to detect the motility and disintegration of microtubules. It was found that the lifetimes of these hybrid systems were mainly limited by the stability of microtubules (MTs), rather than of kinesin. Without illumination, only PU had a substantial negative impact on MT stability, while PMMA, PDMS, and EVOH showed stabilities comparable to glass. Under the influence of light, however, the MTs degraded rapidly in the presence of PDMS or PMMA, even in the presence of oxygen scavengers. A similar effect was observed on glass if oxygen scavengers were not added to the medium. Strong bleaching of the fluorophores was again only found on the polymer substrates and photobleaching coincided with an accelerated depolymerization of the MTs. PDMS and PMMA, two widely used materials in micro- and nanofabrication, cause rapid disintegration of microtubules under exposure to light, presumably via release of oxygen into the solution. Many efforts in the field of organic light-emitting diodes (OLEDs) have been made during recent years motivated by their potential for applications in display technology, for instance, to replace liquid-crystal displays (LCDs), which are currently used in computer and television screens. Small-molecule OLEDs (SMOLEDs) [132] as well as polymer-based LEDs (PLEDs) [133] have gained serious industrial interest, and some device displays based on small organic molecules are already on the market. Recently, significant improvements were made possible by making use of new processing technologies. Improved deposition technologies such as inject printing [134] open the way for full-color applications. On the other hand, the ongoing design of new materials leads to higher efficiencies, enhanced brightness, and improved lifetimes of optoelectronic devices. Recently, the additional use of phosphorescent emitters gained much attention because such emitters proved to increase the efficiency of SMOLEDs enormously. Light-emitting electrochemical cells (LECs) provide an alternative to LEDs because of their simple design. Generally, polymeric LECs consist of just one layer, which is a mixture of a conjugated polymer, an ion-conducting polymer, and a salt [135]. In small-molecule devices (thin layers from 5 to 100 nm), each of these layers fulfills a specified function, such as charge injection, charge transport, or light emission [136]. SMOLEDs utilizing phosphorescent dopants such as Pt(II) or Ir(III) complexes are highly efficient (internal efficiency of 100%), but usually require multilayer architectures. In a first step, glass substrates with a conducting transparent electrode such as indium tin oxide (ITO) are prepared (and often coated by hole-concluding polymers such as poly (3,4-ethylenedioxythiophene)/poly(styrene sulfonate) (PEDOT/PStS) [137]. Secondly, a thin organic hole-transporting layer (HTL) composed of carbazole derivatives [137], or triarylamines is applied. Onto this layer, an organic light-emitting host-guest layer of comparable thickness is deposited: this layer contains phosphorescent emitters such as Pt(II) porphyrins or Ir(III) complexes. The choice of the host material (hole transporting) is of

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high importance since the transfer of triplet excitons from the phosphorescent emitter to the host materials has to be prevented. Generally, the triplet energy levels of the host materials need to be higher than those of the employed triplet emitters. For SMOLEDs, the family of carbazoles [138] could be extended to be suitably for red, green, and blue light, and therefore they can be used in full-color displays [139]. Within the science of nanomaterials, there has been some focus on novel methods for engineering thermoelectric micro- and nanodevices. In particular, thermoelectric devices were fabricated and evaluated for power generation and cooling performance. Thermoelectrics (TEs) convert heat into electricity (Seebeck effect) and vice versa (Peltier effect). Thermoelectric devices consist of many n-type and p-type thermoelectric elements connected electrically in series and arranged thermally in parallel. The many advantages of TE devices include solid-state operation, zero emission, vast scalability, no maintenance, and a long operating lifetime. Nonetheless, because of their limited energy-conversion efficiencies. Thermoelectrics have a rather specific range of applications. Examples of applications include radioisotope thermoelectric generators (RTGs) for power generation and optoelectronic thermal management for cooling purposes. Throughout the microelectronics industry, miniaturization has become affordable, versatile, and readily accessible. The immediate advantages of miniaturizing thermoelectric devices to the micrometer scale are, as predicted by scaling factors, an increase in specific power (W cm
2) and improvements in maximum cooling with greater cooling densities. Potentially thousands of thermoelectric microelements could be concentrated within a small area, and they can generate greater voltages at even small temperature differentials. In addition, since the Seebeck effect and the Peltier effect are directly related, optimizing thermoelectric materials for power generation will also optimize them for cooling. Further miniaturization down to the nanoscale affords additional benefits due to quantum-confinement effects. Thermoelectric nanowires less than 10 nm in diameter are predicted to exhibit higher efficiency. This enhanced efficiency would result from a higher change-carrier mobility due to a greater density of states and more limited phonon transport. In fact, thermoelectric nanobased devices open a more diverse avenue of applications for increased spot cooling or for use as sensors, such as infrared or micro- and nanocalorimeter sensors [140]. The versatility of physical and chemical properties thus afforded by metal and semiconductor nanoparticles makes them promising as the ultimate miniature devices. In many instances, the ability to explore nanoparticle properties for device fabrication will require the formation of morphologically controlled or highly ordered arrays of nanoparticles (Scheme 2) [30]. In microelectronics, this is the key challenge in the process of transforming nanoparticles from promising materials into integrated devices [142]. Being able to control the structural arrangement of nanoparticles will make the “bottom-up” approach a powerful adjunct to current top-down technologies (e.g., photolithography and electron-beam lithography) in achieving high resolution concomitant with parallel fabrication, and especially in creating complex 3D structures. Incorporation of a polymer component in nanoparticle-based sensor devices provides greater flexibility than simple nanoparticle assemblies. First, the utilization of flexible

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SCHEME 2 Polymer-mediated assembly approaches to the fabrication of ordered nanocomposites [30, 141].

polymers to space nanoparticles increases the interparticle space and film porosity, leading to efficient uptake of analyte molecules. Second, the polymer provides multiple interaction sites that can be designed to allow for specific interaction with analyte molecules. Third, the polymer can be designed to enable crosslinking of the nanoparticles, resulting in a mechanically reinforced film and facilitating the controlled creation of a multiplelayer device through the layer-by-layer deposition technique [143]. Taken together, these virtues of nanoparticle/polymer composites all contribute to enhanced selectivity and sensitivity. The specific quantum mechanical properties of many nanodevices require radically novel architecture approaches. Concepts like fault-tolerant architecture, parallel

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processing, and neural nets are directly translatable into conventional (Si) hardware, whereas more advanced concepts like nondissipative and quantum computing and DNA-based computing will certainly require the implementation of novel nanodevices. Quantum mechanics (emphasis on tunneling effect); physics (including mechanics, electricity, electromagnetism, optics, and photoelectric effect); chemistry (including models of the atom, chemical bonding; aqueous-solution reactions; electrochemistry, photochemistry); stress and strain analysis; vibrations; electronics; circuit analysis; control systems; application of microprocessor; mechatronics (including sensors, actuators, control circuit, piezoelectric actuator); etc., are by the complex way engaged into the nanotechnology area. Biomolecular electronics (BME) is raising increasing interest worldwide, due to the appealing possibility of realizing cheap and easy-to-fabricate devices exploiting the natural self-assembling, self-recognition, and self-repairing capability of biological matter. Although very recent, BME has deep roots in the field of organic molecular electronics, whose flagships are carbon nanotubes and molecular junctions [144–146]. Biomolecules are in general more robust than other organic molecules, thus envisaging a more reliable utilization in electronic devices. Moreover, they are characterized by a number of unique electron transport phenomena, such as charge transfer in proteins, hopping, and/or band-like transport (π-π) in self-assembled systems. Finally, both their electronic structure and their ligands can be engineered in a very flexible way, thus allowing a fine tuning of the oxidation potential, and of the selective bonding to different surfaces. The attention of BME has been directed toward the identification of molecules combining good conductivity with good self-assembling and self-recognition properties. DNA has been one of the most investigated class of biomolecules [147–149], leading to a somewhat controversial description of its electrical properties, and, hence, of its potentiality for electronic applications. Depending on the interconnection mechanism (chemical bonding of the DNA on a metal by a selected sequence of oligonucleotides [147], mechanical contact with a gold interdigitated patterns [148], or single DNA molecule immobilized in a metal contact [149]), the DNA molecules have been found to be conductive, nonconductive, or rectifying. From a totally different point of view, some groups are trying to use biological methods to control the formation of semiconductors and metals [150, 151] by investigating the peptide-driven formation of gold crystals, as a prototype mechanism for the formation of natural solids like bones and teeth in the human body. Millions of peptides with specific peptide sequences can be used to distinguish among different crystallographic planes of the most important semiconductors used in technology (GaAs and Si). The peptides could therefore be used to control the positioning and the assembly of materials at the nanoscale, which has a tremendous impact on future electronic technologies or nanodevices. High-efficiency photodetectors based on a solid-state self-organized DNA basis, whose figure of merits become appealing even for solar cell applications. The most surprising thing is that most of these groups have discovered the enormous potentiality of biomolecular self-assembling even though they started from different backgrounds and with totally different targets. This gives a clear favor of how general is the cultural revolution we are experiencing.

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The terms “actuator,” “sensor,” and “transducer” are widely used in the description of measurement device systems [152]. In the broadest sense, a transducer receives energy from one system and transmits this energy to another system, often in a different form. A sensor monitors a system; it responds to physical stimuli, such as heat, light, pressure, or motion, and generates an electronic impulse for detection. An actuator, on the other hand, imposes a state upon a system. Most commonly, this involves converting an input electrical impulse into motion. Actuators and sensors are both transducers intended for different tasks. In accord with these general definitions, an electromechanical transducer converts electrical energy into mechanical energy, and vice versa. An electromechanical system refers to a mechanical element coupled to electronic circuits via electromechanical transducers. For example, the input transducer takes electrical signals from the input circuit and provides mechanical stimuli to the mechanical system; this is generally referred to as actuation. The response of the mechanical element, namely, its motion or displacement, is sensed by the output transducer, which generates electrical signals in the output circuit. These electrical signals in the form of currents and voltages can subsequently be measured. The overall purpose of this conversion of energy back and forth between the mechanical and electrical domains may be to accomplish a mechanical task in a controllable manner, for example, the microscopic electromechanical systems that researchers have long been fashioning using the materials and processes of microelectronics. These micromechanical elements—beams, cantilevers, gears, and membranes—along with the enabling microelectronic circuits are called microelectromechanical systems (MEMS). MEMS perform a variety of tasks in present day technology, such as opening and closing valves, turning mirrors, and regulating electric current flow. With microelectronics technology now pushing deep into the submicrometer-size regime, a concerted effort has surfaced to realize even smaller electromechanical systems: nanoelectromechanical systems (NEMS) [153, 154]. Recent demonstrations of NEMS-based nanomechanical electrometry [155], signal processing [156], and mass detection [157] have attracted much attention. NEMS are a class of devices integrating electrical and mechanical functionality on the nanoscale. NEMS typically integrate transistor-like nanoelectronics with mechanical actuators, pumps, or motors, and may thereby form physical, biological, and chemical sensors. The name derives from typical device dimensions in the nanometer range, leading to low mass, high mechanical resonance frequencies, potentially large quantum mechanical effects such as zero point motion, and a high surface-to-volume ratio useful for surface-based sensing mechanisms. Uses include accelerometers, or detectors of chemical substances in the air. As noted by Richard Feynman, there are many potential applications of machines at smaller and smaller sizes; by building and controlling devices at smaller scales, all technology benefits. Among the expected benefits include greater efficiencies and reduced size, decreased power consumption and lower costs of production in electromechanical systems.

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1.5 DNA-based smart nanostructures A well-formed homogenous structure, thus, is essential for any nanodevice to ensure reproducibility and rational control. Several classes of nanoparticle systems exist today [158], for example, lipid-based, polymer-based, protein-based, and inorganic (metal) nanoparticles. However, these nanoparticle systems are often characterized by being poorly structural defined, heterogeneous in size, and with low spatial addressability. For a molecular device to act in vivo it should preferably (i) constitute a well-defined structural entity, (ii) be biocompatible, (iii) target the relevant bodily compartment or cells, and (iv) execute a desired function (Scheme 3). DNA nanostructures hold tremendous structural powers. Rothemund [160] demonstrated these capabilities by forming a diverse set of DNA nanostructures, each homogeneous in population and with fully addressable surfaces. Especially the latter property is a key attribute of DNA structures’ success as it enables decoration of assemblies with any desired functionality in complex patterns. In this way, DNA nanostructures can serve as a molecular peg-board, where the engineering scientist can freely add new properties to his device. Today a wide array of predesigned smart nanostructures ranging from complete solid rigid structures, twisted, hollow boxed to curved spherical structures [161] have been reported. Especially structures with inner cavities could potentially serve as carriers of therapeutic payload, keeping the cargo protected from the external environment throughout its journey.

SCHEME 3 Schematic illustration of the four key components a molecular machine must contain to engage living organisms. Top left; (A) a well-defined structural entity. Top right; (B) biocompatibility allows for prolonged circulation with minimum toxicity. Bottom left; (C) ability to target the relevant body compartment. Bottom right; (D) ability to execute a desired function in a controlled fashion [159].

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For any artificial molecular device aimed at in vivo applications, a primary requirement is stability and biocompatibility. The nucleic acid structures must remain structurally intact during the functional relevant time period when exposed to bodily fluids. At the same time the devices should be sufficiently biocompatible such that they can be excreted from, or naturally degraded in, the human body to avoid toxicity. Furthermore, the devices must be able to evade immune recognition to avoid rapid clearance and reduce the risk of acute anaphylaxis shock. DNA is a naturally occurring molecule in any known organism, and thus, in its nature, highly biocompatible. However, inside the eukaryotic cell DNA is spatially confined to the nucleus and smaller organelles. Occurrence of DNA outside these compartments is often recognized as a danger signal by the vertebrate innate immune system triggering its activation through nucleic acid immune receptors such as TLR9. Another challenge for the stability of DNA-based devices in vivo resides in the ion concentrations of both intraand extracellular body fluids being well below the relatively high cationic concentration required for keeping many DNA assemblies intact. Hahn et al. [162] found that DNA nanostructures often denatured owing to low cation concentration in cell media. In addition, the presence of nucleases in serum led to degradation and digestion of structures due to nuclease activity. Later, Benson et al. [163] published a set a new scaffolded DNA nanostructures built on polygonal meshes. These structures, in contrast to the ones tested by Hahn et al. [162], consisted of a more open conformation with only one helix per edge and proved stable at lower ionic conditions relevant for biological assays. However, the more open structure could also pose disadvantages, especially with regard to nuclease vulnerability and exposed interior leaving potential cargo unprotected. The cellular stability of DNA origami has also been investigated by Mei et al. [164]. Rather surprisingly, and in contrast to the above-mentioned studies, the researchers found that both two- and three-dimensional DNA origami were relatively stable in cellular lysates when incubated at temperatures up to 25°C. However, the study was conducted in the presence of various nuclease inactivating components including SDS, deoxycholic acid, and trypsin, thus lowering the relevance to physiological conditions. Furthermore, the stability of the structures was only assayed at temperatures well below the biological relevant 37°C. Castro et al. [165] tested the vulnerability of multilayered DNA origami structures to various nucleases and, interestingly, found a relatively high structural resistance toward degradation by several of the tested nucleases. Moreover, for nucleases that succeeded in degrading structures, kinetic studies showed a 10-times slower degradation of origami structures than a double-stranded DNA (dsDNA) plasmid of similar size. Steven Perrault and William Shih [166] presented an interesting approach for the improvement of the stability and pharmacokinetic behavior of DNA nanostructures. Inspired by viral particles, the researchers decorated their DNA nanostructure with lipophilic tails to direct the assembly of an adjacent PEGylated lipid bilayer around their structure. The encapsulation was shown to confer protection against DNase I digestion, reduce stimulatory cytokine production, and evade uptake by splenocytes. In addition, the researchers examined the in vivo pharmacokinetic properties of the formulation in

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muridae animals comparing three DNA species: a nonencapsulated origami structure, the encapsulated origami, and a naked oligo. Interestingly, the circulation half-life of encapsulated structure was found to increase nine times compared to the nonencapsulated origami and with the naked oligo being rapidly cleared by renal secretion. Cassinelli et al. [167] attempted to “chain-armor” their DNA structures in order to resist cation depletion, nuclease attacks, and adverse pH conditions. Utilizing click chemistry, the researchers catenated a six-helix bundled DNA tube through covalently linking singlestranded (ss) DNA tiles. The procedure conferred increased resistance to DNase digestion and complete structural stability of the assemblies in pure water. While addressing many of the individual challenges, the field of DNA nanotechnology, however, still lacks an easy, scalable, and efficient method that ensures structural stability and desirable pharmacokinetic properties of DNA-based nanostructures. To alleviate side effects and increase the concentration of nucleic acid nanostructures at the relevant tissue, it is desirable to implement a targeting system. Naked DNA nanostructures transfect cells rather poorly [168]; thus numerous protocols based on lipid and polymer formulations have been described to facilitate this process. However, many of these reagents may interfere with the function of DNA nanodevices by charge competition and condensation of structures. During the past decade, several reports investigating the addition of targeting ligands to DNA nanostructures to facilitate less disruptive translocation of DNA nanostructures over the cell membrane have surfaced [169]. Examples of such cell targeting moieties comprise antibodies, aptamers, or receptor ligands including proteins, peptides, and small molecules. In cancer therapy, for example, common targets include overexpressed receptors related to angiogenesis (e.g., vascular endothelial growth factor (VEGF)), uncontrolled cell proliferation (e.g., folate), or metabolic demands (e.g., transferrin). Binding to such cellular receptors may cause receptor-mediated endocytosis enabling the release of the drug inside the cell. In DNA nanotechnology, an interesting folate-siRNA-conjugated DNA tetrahedron [170] was reported by Lee and coworkers’ group. The researchers demonstrated targeted delivery accompanied with gene silencing in HeLa cells and an in vivo mouse model. Notably, they found that only structures displaying at least three folate molecules exhibited efficient delivery and gene silencing underlining the importance of multivalency and pattern-recognition in cellular uptake. A similar DNA structure coated with DNA aptamers showed specific uptake into cancerous cells and selectively inhibited cell proliferation [171]. Recently, Schaffert et al. [172] demonstrated efficient uptake of a planar DNA structure decorated with the iron transfer protein transferrin. The researchers were able to increase intracellular uptake by up to 22-fold compared to bare structures and depending on the number of transferrin molecules attached. € et al. Another interesting approach for cellular targeting was published by Mikkila [173]. The researchers electrostatically coated their DNA origami structures with a positively charged virus capsid coating protein. Using this approach, the group found a 13-fold improved delivery efficiency into human embryonic kidney cells compared to bare origami. The addition of the cationic viral protein likely neutralized the negative

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charge of the DNA to some extent, making it more prone to uptake. Similarly, Brglez et al. [174] showed how increasing the surface hydrophobicity, using acridine-based DNA intercalators, can enhance cellular uptake. Importantly, the addition of these tailor-made intercalators could be added without disturbance of the structural integrity of the DNA nanostructures. The above findings reinforce the prospective of DNA-based nanostructures for therapeutic applications. DNA is commonly introduced into cells with the functional purpose of encoding RNA or proteins. However, DNA nanostructures have taken on more diverse roles like, for instance, dynamic structural switches, facilitating enzymatic activity, inducing therapeutic responses, and incorporating computational and sensing capabilities. Dynamic behavior often requires an energy input to generate mechanical forces. Many of nature’s molecular motors thus utilize the energy-rich triphosphate bonds in NTPs to drive movement and/or enzymatic reactions. Another example is the duplex formation of DNA driven by a cooperative interplay of hydrogen-bonding, π-stacking, hydrophobic, and electrostatic interactions. These latter energy sources are currently among the most frequently used in artificial DNA devices. The very first mechanical controllable DNA-based device was introduced by Mao et al. [175]. The group succeeded in switching the structural conformation of their DNA device between B- and Z-DNA conformation depending on ionic conditions, leading to rotary motion. Later, changes in ionic conditions were also used to drive dynamic behavior in larger DNA assemblies [176]. Utilizing shape complementarity and base stacking between structures, the researchers created highly complex macromolecular devices with fully reversible movements. Another approach for directed dynamic behavior of DNA-based structures was taken by Yurke et al. [177], who exploited singlestranded DNA overhangs, so-called “toeholds,” to initiate and drive structural oscillations by strand displacement using external DNA oligos. Thereby, the researchers could perform reversible tweezer-like movement of a DNA nanodevice fueled by a set of input DNA strands. This utilization of DNA as fuel molecules has since been fundamental in driving multiple dynamic DNA-based machines, both in strand displacement cascades and in enzymatically driven motors [178]. A special subset of dynamic DNA machines, that often utilizes strand displacement to control dynamic behavior, is DNA walkers. A DNA walker is a molecular complex with “legs” made up from DNA that can move along a predesigned DNA-based track. The first reported DNA walker [179] utilized DNA as a fuel molecule for their movement using a strand displacement cascade. However, the use of DNA as both track and fuel limits the walker to unidirectional behavior due to destruction of the track. To overcome this problem, various approaches have been used to fabricate fully autonomous walkers built on DNAzymes [180], photolysis [181], ionic, or enzymatic approaches [182]. With the introduction of DNA origami, larger devices, including the tripped walker from Gu et al. [183] began to appear. In addition to its three “legs,” Gu’s structure contained three separate “hands,” which could be programmed to collect cargo at specific locations along its track like a molecular assembly line. Directed movements have also been achieved using the cellular motor proteins, kinesin and dynein, which in nature “walks” along

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the cellular microtubule filaments [184]. Castro et al. expanded the landscape of dynamic DNA-based devices [185]. Analogous to macroscopic machines, the group introduced discrete ssDNA joints in their structures allowing for specified rotational and/or translational movement of more rigid dsDNA components. Doing so, the researchers succeeded in constructing several interesting molecular motors resembling common macroscopic tools such as a crank slider, hinge, and scissor lift [186]. An important characteristic of any molecular device is the ability to sense and respond to surrounding signals. Several types of nucleic acid-based biosensors have been constructed throughout the years with a wide range of sensor capabilities usually leading to structural rearrangements. Many DNA-based devices with various abilities to detect, for instance, ions [187], small molecules, proteins and peptides [188], nucleic acid sequences [189], and pH [190] have been designed. One of the first and most successful DNA sensors developed is the “molecular beacon” published by Tyagi and Kramer [191]. Upon hybridization with its target, the device shifts conformation from a fluorescently quenched hairpin-like structure to a fluorescence linear state. The original design could detect specific nucleic acid sequences, for example, miRNAs, single-nucleotide polymorphism (SNP) products of real-time PCR reactions. Subsequently, the sensing capabilities have been further extended to include detection of temperature [192] and macromolecules including antibodies [193]. In addition, molecular beacons have also been incorporated into larger DNA structures [194]. One of the first examples of a larger DNA device responding to an external signal was the three-dimensional DNA origami box. The top face of the box could be opened in a controlled manner as a response to specific DNA or RNA oligos as “keys.” In the original design the opening of the top face was nonreversible, but, has since been extended with a reversible locking system and Boolean logic-based gating [195]. Several reports have successfully demonstrated the ability to encapsulate molecules inside DNA nanostructures [196] enabling controlled delivery of enzymatic or therapeutic payload. The addressability of DNA nanostructures makes them extremely suitable for arranging and displaying molecular patterns and arrays on their surface [197]. One approach has been to arrange enzymes in spatially proximity to speed up multistep enzymatic processes [198]. One interesting example is the modular nanoreactor recently published by Linko et al. [199]. The researchers dimerized two tube-like DNA origami structures, enzymatically functionalized with either three glucose oxidase (GOx) or three horseradish peroxidase (HRP) enzymes in a barrel-like three-dimensional geometry. The barrel-like structure confined any entering substrate in the barrel, thereby increasing the likelihood of interacting with the enzymes in a serial pattern and thus the turnover rate. Another interesting dynamic DNA structure with the ability to control enzymatic activity was reported by Liu et al. [200]. This group fabricated a large tweezer-actuated nanostructure and functionalized both of its arms separately: one with the enzyme glucose 6-phosphate dehydrogenase, and the other with the enzymes, essential cofactor, NAD+. Using DNA-fuel strands, the structure could open and close, bringing the enzyme and cofactor into sufficient proximity to allow for the enzymatic reaction to occur. The team was able to show reversible

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inhibition/activation cycling of the enzyme. Similar tweezer-like DNA structures have been utilized for protein capturing using aptamers as fangs, thereby regulating protein activity [201]. Several notable approaches have been made using DNA nanostructures for therapeutic purposes as well. Among the more widespread approaches is the delivery of chemotherapeutic agents [202] such as doxorubicin (dox) to cancer cells utilizing the intercalating properties of the agents to trigger apoptosis. Jiang et al. [203] and Zhao et al. [204] both demonstrated increased apoptotic effect in vitro on a breast cancer cell line upon delivery of dox-loaded origami carriers. Intriguingly, the study from Yan’s lab [203] showed that origami carriers could help circumvent drug resistance gained by cancer cells. A similar study, using another DNA intercalator similar to dox, also reported the ability to circumvent drug resistance [202]. In the study by Zhao et al. [204], the designed structures accounted for the helical twist induced by intercalation of dox by having 12.0 bp/turn instead of the standard 10.5 bp/turn. Using TEM images, the researchers demonstrated how the assembly of these heavily underwounded structures greatly improved in the presence of dox. In addition, loading efficiency and drug release kinetics were shown to be improved in twisted origami structures compared to standard origami and dsDNA plasmid. As tools for immunotherapy, DNA structures were used to enhance immune expression. Acting as adjuvants, the structures carried several strands with CpG-rich motifs on their surface for stimulation of TLR9 both in vitro and in vivo [205]—a topic which has been extensively reviewed elsewhere [206]. Another exciting approach in DNA nanotechnology is the cytotoxic pore-forming lipid-coated DNA nanostructures first demonstrated in cell culture by the group of Burns et al. [207]. One could easily imagine coupling these pore-forming structures with a logic-based gate, dynamically controlling the exposing of the cytotoxic machinery only when applicant. One of the most impressive therapeutic DNA nanodevices is the logic-gated DNA nanorobot constructed by Douglas et al. [208] (Scheme 4). Instead of relying on the delivery of a therapeutic cargo to the interior of targeted cells, the researchers induced cellsignaling pathways through binding of exterior receptors yielding a desired therapeutic response. Douglas’ origami was of a hexagonal barrel-shaped design. On the interior, protruding DNA handles functioned as attachment sites for various fluorescently labeled antibody fragments (Fab’). The structure was kept closed through an aptamer-based lock system forming duplexes in one end and hinged through the scaffold at the other end. The lock system constituted a logic-based AND gate, made up of three different aptamers, which would be disrupted only upon binding of two cancer specific extracellular membrane proteins. The dehybridization resulted in a drastic conformational change of the device acting similar to an entropic spring, exposing the interior of the barrel. The therapeutic potential was demonstrated by showing its ability to discriminate target cells from a complex background of whole-blood leukocytes. The device proved capable of arresting cell growth in an aggressive natural killer cell line or inducing activation of T cells in vitro, depending on the choice of Fab’ molecules. The system successfully demonstrated the

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SCHEME 4 Underwounded DNA origami structure delivering the chemotherapeutic agent doxorubicin (dox) to cancer cells. Logic-gated DNA nanorobot with aptamer-based locks with the ability to induce cell-signaling through binding of external cell receptors [208].

capability of DNA nanostructures to sense and deliver molecular signals to biological systems in a programmed manner. This device have been reported working in vivo in a DNAbased biocomputing setup [209]. Similar approaches have been adapted by other groups to increase sensitivity to growth hormones [210] and inhibit tumor metastasis [211].

1.6 Nanofabrication Many technologies have been developed to produce nanomaterials, nanospheres, and nanostructures. These techniques can be divided into several groups according to the reaction media, the form of products, the way of nanostructure formation, the properties of nanomaterials, etc. as follows: vapor-phase nucleation and growth, liquid phase nucleation and growth, solid phase formation, colloidal process, solution-liquid-solid growth, thin film formation, self-assembly of small particles, top-down and bottom-up approaches, etc. The so-called bottom-up approach to the fabrication of nanostructures from stable building blocks has become a popular theme in current science and engineering. This construction principle mimics biological systems by exploiting the orderinducing factors that are immanent to the system rather than imposing order top-down from an external source. However, the fabrication techniques of current commercial importance such as lithography fall practically without exception into the top-down category. The main disadvantage of the top-down approach is the imperfection of the performed nanostructures. The top-down lithography approach can be accompanied with

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the significant crystallographic damage to the processes spheres [212]. This includes experimental simplicity down to the atomic size scale and the potential for inexpensive mass fabrication. Bottom-up fabrication refers, on the contrary, to the building up of nanomaterials or nanospheres from the bottom to top: atom by atom or molecule by molecule. In the colloidal chemistry and polymer chemistry, the polymer-based nanospheres can be produced by the radical polymerization of unsaturated monomers in the direct or inverse micellar solutions. The reduction of metal salts by radicals and reducing agents in the micellar systems leads to the formation of metal or composite nanoparticles. This method can in the future offer a number of potentially very attractive advantages. The bottom-up approach promises the best chance to obtain the regular spherical particles with less or minimum defects. The bottom-up approach to the fabrication of nanostructures from stable building blocks has become a popular theme in current science and engineering. While the fabrication techniques of current commercial importance such as lithography fall practically without exception into the top-down category, bottom-up fabrication may in the future offer a number of potentially very attractive advantages. These include experimental simplicity down to the atomic size scale, the possibility of three-dimensional assembly, and the potential for inexpensive mass fabrication. A prerequisite for nanostructure preparation via this self-assembly route is the availability of sufficiently stable building blocks which have to well-characterized and uniform in size and shape. A range of interesting self-assembled structures can be obtained from ligand-stabilized metal nanoparticles, which likewise show a fascinating wealth of size-related electronic and optical properties. The synthetic methods can be divided into chemical and physical (molecular beam epitaxy, sputter deposition, electron beam lithography, etc.) methods. Chemical methods include a large variety of different chemical techniques with the common property of using reactions in solutions to produce particles of different sizes and materials. In order to control the size and shape of the particles, the synthesis is based on the appropriate control of the parameters that influence nucleation and growth. The use of ligands (stabilizing agents) such as surfactants and polymers (or oligomers) is very common in the specific control of growth and in the prevention of agglomeration of the particles once they have been synthesized [213–217]. Besides the many advantages there are also disadvantages of the traditional routes to nanomaterials: -

The large interface area costs a lot of energy and requires large amounts of stabilizer or embedded surface units. The simple nucleation-and-growth route demands very low in situ concentrations of the formed colloids, i.e., the mass output is rather low. Concentrating the products or harsh reaction conditions usually leads to the failure of stabilization and the formation of larger aggregates.

For these reasons, some modern techniques developed to control the uniformity in size and shape make use of synthesis in mesoscopically confined geometries, such as in vesicles [218], reverse micelles [219, 220], sol-gel processing [221], zeolites, [222],

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Langmuir-Blodgett (LB) films [223, 224], microporous glass [225], organic or inorganic gels, etc. Nanoparticle formation in block-copolymer aggregates can be considered to be a further advancement of these techniques. Research and development are focused on the development of science and technology at the right size—and that size may range from nanometers to millimeters (for the technologies of small things). Associated with these developments, nanostructures offer a new paradigm for materials manufacture by submicron-scale self-organization and selfassembly to create entities from the “bottom up” rather than the “top down” method. However, we are just beginning to understand some of the principles to use to create “by design” nanostructures and how to economically fabricate nanodevices. Each significant advance in understanding the physical/chemical/biological properties and fabrication principles, as well as in development of predictive methods to control them, is likely to lead to major advances in our ability to design, fabricate, and assemble the nanostructures and nanodevices into a working system. “Bottom-up” approaches, closely linked as they are to the field of molecular electronics, are elegant, cheap, and possibly enormously powerful techniques for future mass replication, but their applicability remains limited until total control over the emerging structures in terms of wiring and interconnections can be obtained. It is clear that new architectures are required for such bottom-up fabrication approaches [226]. Nanoparticle, crystal, and nanolayer manufacturing processes aim to take advantage of four kinds of effects: -

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New physical, chemical, or biological properties are caused by size scaling. Smaller particle size determines larger interfacial area, an increased number of molecules on the particle interfaces, quantum electromagnetic interactions, increased surface tension, and size confinement effects (from electronic and optic to confined crystallization and flow structures). The wave-like properties of the electrons inside matter are affected by shape and volume variations on the nanometer scale. Quantum effects become significant for organizational structures under 50 nm, and they manifest even at room temperature if their size is under 10 nm. New phenomena are due to size reduction to the point where interaction length scales of physical, chemical, and biological phenomena (for instance, the magnetic, laser, photonic, and heat radiation wavelengths) become comparable to the size of the particle, crystal, or respective microstructure grain. Examples are unusual optoelectronic and magnetic properties of nanostructured materials, changes of color of suspensions with particle size, and placing artificial components inside cells. Generation of new atomic, molecular, and macromolecular structures of materials by using various routes: chemistry (three-dimensional macromolecular structures, chemical self-assembling), nanofabrication (creating nanostructures on surfaces, manipulation of three-dimensional structures), or biotechnology (evolutionary approach, bio-templating, and three-dimensional molecular folding).

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Significant increase of the degree of complexity and speed of processes in particulate systems. Timescales change because of smaller distances and the increased spectrum of forces with intrinsically short timescales (electrostatic, magnetic, electrophoresis, radiation pressure, others). Nanoscale phenomena and processes are yet to be understood and the resulting structures to be controlled and manipulated. Critical length and time scales and surface and interface phenomena are essential aspects to be defined. Novel mechanical, optical, electric, magnetic, thermal, chemical, and biological properties occur as compared to bulk behavior because of the small structure size and short timescale, but only a small part of these properties have been fully identified and quantified.

Several industrial domains have been identified as essential for future applications of nanotechnologies. They include materials as nanostructured materials, nanoelectronics, optoelectronics, magnetics, and advances in healthcare, therapeutics, diagnostics, environment, and energy. We intend to design and fabricate stronger, lighter, harder, self-repairing, and safer nanostructured materials. Nanocomposites and nanoparticles reinforced by polymers could for instance be used for automotive applications. It is foreseeable that nanometer structures (nanoelectronics, optoelectronics, and magnetics) foster a revolution in information technology hardware rivaling the microelectronics revolution 30 years ago. Advances in healthcare, therapeutics, and diagnostics via nanotechnology will contribute to significant advances through the development of biosensors and improved imaging technologies. Drug production and delivery are expected to be drastically change in the next decade. A major issue in nanoscale research is how scientific paradigm changes will translate into novel technological processes. Nanoparticle systems, including nanoclusters, nanowires, nanobelts, nanotubes, nanorods, nanostructured particles, and other three-dimensional nanostructures in the size range between 1 and about 50 nm, are seen as tailored precursors for nanostructure materials and devices. Particle processing (sintering, extrusion, plasma activation, self-assembling, etc.) is the most general method of preparation of nanostructured materials and devices. Research on nanomaterials has been stimulated by the interest for their technological applications, such as catalysts, ceramics, battery materials, color imaging, drug delivery systems, pigments in pains, magnetic tapes, ferrofluids, magnetic refrigerants, giant magnetoresistance, etc. [227, 228]. The ability to fabricate nanomaterials and to exploit their special properties is gaining widespread attention. Important areas of relevance for nanoparticles and nanotechnology are advanced materials, electronics, biotechnology, catalysis, pharmaceutics, and sensors. These include hard disks in computers, photographic systems, dispersions with novel optoelectronic properties, information recording layers, biodetectors, advanced drug delivery systems, chemical-mechanical polishing, a new generation of lasers, chemical catalysts, nanoparticle-reinforced materials, inkjet systems, colorants, and nanosystems on a chip, to name some of the most important. Organic (synthetic and nature polymer) and metal nanoparticles, thus, may serve as efficient catalyst in chemical and photographic processes [229]. Metal clusters and nanoparticles

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immobilized in polymer films give metallopolymer materials that prove to be useful for technical purposes due to their specific physicochemical properties [230]. In addition, some small smart particles demonstrate a distinct biological activity and may be applied in ecology and medicine; for example, a significant antimicrobial activity of silver nanoparticles allowed the improvement of the water purification in some water-filtering apparatus [231]. The demand for smaller materials for use in high-density storage media is one of the fundamental motivations for the fabrication of nanoscale magnetic materials. The development of a high-density magnetic memory device may be more readily achieved by patterning metal nanoparticles into organized assemblies on the surface of a substrate. Since these assemblies usually exhibit unusual electronic, optical, magnetic, and chemical properties significantly different from those of the bulk materials, they have various potential applications such as electronic, optical, and mechanical devices, magnetic recording media, superconductors, high-performance engineering materials, dyes, adhesives, photographic suspensions, drug delivery, and so on [42, 232, 233]. In this connection, catalysis represents one of the single most important applications of nanotechnology. Traditionally, supported catalysts have been produced by wet impregnation using watersoluble metal salts, which results in well-dispersed catalysts with high activity and good stability. The particle size of the activated phase is usually in the nanometer range but with a quite broad size distribution and a low degree of control over the particle size. This renders the interpretation of, for example, size-dependent mechanistic phenomena of the catalyst impossible. Another route to prepare nanosized particles is use a water-in-oil (w/o) microemulsion where a metal (platinum) precursor is reduced to metallic platinum in water pools. Oil-in-water (o/w) microemulsions are used to prepare the polymer nanoparticles. With these methods of preparation, particles with relatively narrow size distribution down to an average of a few nanometers can be obtained [234]. At least in some systems it has been found that not only the size but also the shape of the particles can be controlled [235]. Novel ideas have been proposed in laser ablation of materials to generate nanoparticles used in nanoelectronics, production of polymer/metal composites for development of nonlinear optics for waveguides, molecular and nanostructure self-assembly techniques, high-performance catalysts, control of nanoparticles resulted from combustion and plasma processes, and special sensors applied in chemical plants and the environment. Nanoparticle manufacturing is an essential component of nanotechnology because the specific properties are realized at the nanoparticle, nanocrystal, or nanolayer level, and assembling of precursor particles and related structures is the most generic route to generate nanostructured materials. Nanoparticles realized at the nanoparticle or nanocrystal/ grain level, and the use of precursor nanoparticles as building blocks of tailored properties for nanostructured materials and nanocomponents processes include nanotechnology [236]. Nanoparticle manufacturing processes may be separated into the following groups: -

Processing and conversion of nanoparticles into nanostructured materials (such as advanced ceramics), nanocomponents (such as thin layers), and nanodevices (such as sensors and transistors). Examples of processing methods include sintering,

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generation of nanostructures on surfaces, evolutionary biotechnology, and molecular self-organization techniques. Research challenges include continuous particle synthesis and processing into functional nanostructures and devices. Utilization of nanoparticles in order to produce or enhance a process or a phenomenon of mechanical, chemical, electrical, magnetic, and biological nature. Examples of the more frequently used manufacturing processes are particle contamination control, chemical vapor deposition, use of particles as agents of surface modification, filtration, mass spectroscopy, bioseparation, combustion pollution control, drug delivery and health diagnostics, and use of nanoparticles as catalysts and pigments in chemical plants. Process control and instrumentation aspects. Important problems include off- and on-line measuring techniques for fine particles and their structures. In parallel with the better established characterization methods for particle size, shape, and composition, new instruments are needed to measure particle interaction forces, their roughness, electric, optic, and thermal properties.

Progress in nanotechnology demands the capability to fabricate nanostructures in a variety of materials with an accuracy in the nanometer scale and sometimes in the atomic scale. Stringent nanofabrication specifications have to be met in industrially relevant processes due to manufacturability and costs considerations as, for example, in the electronics industry. However, less demanding conditions are needed for developments in optics, sensors, and biological applications. In a laboratory environment, at the level of enabling nanofabrication techniques as tools for experiments to understand the underlying science and engineering in the nanometer scale, easily accessible and flexible nanofabrication approaches are required for investigations in, e.g., materials science, organic optoelectronics, nano-optics, and life sciences. Alternative techniques to cost-intensive or limited-access fabrication methods with nanometer resolution have been under development for nearly two decades. One clear example is the evolving set of scanning probe techniques, which has become ubiquitous in many research areas. If one considers planar structures, that is, where nanostructuring is carried out on a surface, as distinct from a three-dimensional nanofabrication or multilayer self-assembly, then several emerging nanofabrication techniques can be discussed. Their classification depends on whether the nature of the patterning is chemical or physical, or its modality in time is parallel or sequential, or a hard or a soft mold or stamp is used, etc. The literature on the subject is increasing very rapidly; for example, progress in micro-contact printing [103], scanning probe-based techniques [104], and NIL technique [105] have been published. Recent developments in nanopatterning include dip pen lithography [237] and nanoplotting [238], as well as stencelling [239]. The chemical industry faces particularly interesting choices, since taking full advantage of the opportunities of nanotechnology will require it to behave in new ways. A few nanomaterials will be commodities, and a few processes for making nanofabricated structures will be carried out in facilities having the scale of those used in the production

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of commodity chemicals. The value of nanomaterials and nanostructures will come in their function, and in the systems in which they are embedded. Time will tell whether chemical companies will choose to make photonic devices in order to exploit their ability to produce photonic bandgap (PBG) materials, or whether telecommunications companies will choose to make PBG materials in order to exploit the functions that they provide in their devices and systems. Regardless, it seems inevitable that chemical companies active in nanotechnology will find themselves competing with their customers in the areas of high-valued, functional materials, components, and systems. Since there are few new, high-margin markets open to the chemical industry, it may need to move downstream— uncomfortable though it may be to do so—in nanotechnology (or other emerging areas) if it is not to stagnate technically and financially. Competition in new markets requires agility, and the ability to move quickly to capture new opportunities is always a difficult trick. It will be particularly difficult for an industry that, for some decades, has not been rewarded for embracing new ideas or for accomplishing new tricks, and that, through lack of practice, has become unaccustomed to doing so [22]. Nanotechnology offers the industry several particular opportunities: -

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Production of new tools and equipment for research. Production of new materials of nano- and microstructures. Examples include structural and electrically/magnetically/optically functional polymers, particles, and metal/polymer composites for a range of applications [240]. Development of new processes to make new materials for fabrication in the chemical industry. Development of new photoresists and processes with which to fabricate structures with the sub-50 nm dimensions required by nanoelectronics will present opportunities for materials science and chemistry [241]. Nanoparticle technology will become important in a wide range of applications—from hydrophobic drugs generated and formulated in nanoparticulate form to improve bioavailability, to electrodes and lumiphores for new kinds of graphic displays. Development of revolutionary nanomaterials or nanoobjects such as nano-CDs, quantum and molecular computers, biocompatible nanoparticles, etc.

The chemical industry has used phase-separated statistic and block copolymers and blends for many years to optimize properties of additive saturated polymeric materials. Nanoscience is beginning to produce new methods of characterizing the structures of the phase-separated regions (which are often of nanometer dimensions), and thus provide ways of engineering these regions (and the properties of the polymeric materials) in rational ways [242]. Understanding these relationships between the composition of the polymer, and the properties of the materials made from it, will provide a new approach to engineered materials. Nanoscale, phase-separated block copolymers are also finding uses as materials in microelectronics and photonics. For applications in PLEDs, light-emitting polymers have attracted much attention because of their unique properties. They appear able to fulfill functions such as charge

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injection, charge transport, and emission of light in one active layer in a PLED. Therefore, the complete construction of a PLED can be much simpler than that of a SMOLED. Wetchemistry fabrication processes are used for applying polymers. They permit coverage of larger areas, which becomes important for applications such as computer displays and television screens [243]. For PLEDs, the organic layers can be deposited by spin-coating (resulting in monochrome devices) or inkjet printing (used for full-color devices). A lowwork-function metal cathode is applied by vacuum deposition. Even though in the case of solution-processable polymers, fluorescent PLEDs with good efficiencies have been reported, the search for solution-processable materials that allow full-color applications with high brightness and increased efficiencies is ongoing. A new class of materials has become prominent in OLEDs, namely, dendrimers [244]. Such light-emitting dendrimers contain surface groups, dendrons, and cores. These materials can be classified as either fully conjugated dendrimers [245] or materials where the fluorophore is attached to dendrons that contain nonconjugated moieties [246]. When comparing conjugated polymers with conjugated dendrimers, a number of potential advantages become apparent. The controlled molecular synthesis of dendrimers would provide greater freedom and a better control of the material properties [247]. Optimization of electronic and processing properties can be tuned and optimized independently. Moreover, the dendrimer generation provides molecular control over the intermolecular interaction.

1.7 Investigative tools Search of effective ways for controlling the morphology of nanophase materials is of principal importance for nanotechnology and for development of advanced nanostructured materials. It is known that the method of nanoparticle synthesis often influences the properties of the product; in particularly, synthesis of nanoparticles in confined geometries and structured reaction media can result in anisotropic and size-controlled nanoparticles [248]. The nanostructures are difficult to characterize because they are much smaller than visible light wavelengths and significantly larger than individual molecules. Likewise, simulation at the nanoscale is equally difficult, as the structures are mostly too small for continuum treatments and too large for simulations involving individual atoms and molecules. Investigative tools have played a critical role in the advancement of the entire nanofield. The main research areas and design tools may be grouped as: -

Modeling and simulation of the connection between structure, properties, functions, and processing using atom-based quantum mechanics, molecular dynamics, and macromolecular approaches. Simulations aims to incorporate phenomena at scales from quantum (0.1 nm), molecular (1 nm), and nanoscale macromolecular (10 nm) dimensions, to mesoscale molecular assemblies (100 nm), microscale (1 μm), and macroscale (>1 μm). A critical aspect is bridging the spatial and temporal scales.

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A wide range of instruments and techniques, from scanning tunneling mapping of surfaces to atomic force chemistry, nuclear chemistry, and near-field visualization for testing and measurements. Scanning probes and optical and laser-based diagnostic techniques are the most widely applied experimental tools. Information technology, including pattern recognition, molecular organization mechanisms, and nanorobotics. Information on surfaces play a key role in selforganization and self-assembling. Techniques such as reaction pathways and process control. These can be used in order to obtain a predetermined structure or function, and integrate the operation of nanosystems with complex architectures. Unique size-dependent properties, phenomena, and processes of nanoparticle, droplet, bubble, tube, fiber, and layer systems. Fundamental physical (mechanical, thermal, optical, electronic, etc.), chemical, and biological characterization of nanoparticles and their interfaces, and development of in-situ and ex-situ instrumentation based on new principles for probing properties and phenomena not well understood at the nanometer scale. Synthesis and processing of nanoparticles and related nanoprecursor structures, including clusters, aerosol and colloid particles, nanotubes, nanolayers, biological structures, and self-assembled systems. Approaches may include gas-, liquid-, solid-, and vacuum-based processes, size reduction, and chemical and bio-self-assembly. Utilization of nanoparticle systems for enhancing a phenomenon or process, such as chemical reactions, nano-electronics, nano-ionics, magnetic processes, optical processes, heat transfer, bioseparation, and bio- and chemical reactivity. Utilization of nanoparticles for generating one- to three-dimensional hierarchical structures by assembling, including functional nanostructures in dispersions, structural materials, and electronic devices. Utilization of nanoparticles for the formulation and the administration of drugs, including drug and gene delivery systems, transport of molecules in biotechnology, and the use of nanoparticles in the field of the diagnosis. The promise of nanotechnology is being realized through the confluence of advances in scientific discovery that has enabled the atomic and molecular control of material building blocks, and engineering that has provided the means to assemble and utilize these tailored building blocks for new processes and devices in a wide variety of applications. Control over molecular-level organization of amphiphiles and ions that may be exercised at the air-water interface. The degree of control can result in its extensive use in the organization of large inorganic ions [249] and biological macromolecules [250].

The direct observation of atoms and molecules was initiated more than 20 years ago by scanning tunneling microscopy (STM) [251]. It keeps providing us with fresh insight into structure and dynamics at nanometer scales. However, besides the many varieties of scanning-probe techniques derived from tunneling microscopy, single-molecule sensitivity

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can also be reached by purely optical methods, in the far field. To select a single molecule in a diffraction-limited light spot, one strongly dilutes the active molecules in a nonabsorbing medium, until at most one of them absorbs the exciting laser at any given spot. A detected signal, usually fluorescence, will then necessarily arise from a single molecule. Singlemolecule spectroscopy (SMS) that is, the study of single nano-objects (molecules, nanocrystals, metal colloids, etc.), in the focus of an optical microscope, has brought its share of recent surprises. Widespread blinking or flickering, for example, has become a hallmark of singlemolecule signals [252] and the routine criterion for reaching the single molecule level. STM relies on measuring the tunneling current between an atomic-sized tip and the sample, which resides on a conductive substrate. The imaging of atomic surfaces is possible by scanning the tip over the sample and registering the interaction for each position. The property that sets STM apart from most other sensitive techniques is its ability to resolve structures and dynamics of surfaces on an atom-by-atom scale. The impact of STM in other fields besides surface science, such as material science and biology, is growing steadily. Since its invention in the early 1980s, scanning probe microscopy (SPM) has been continuously developed to become a versatile and key tool for researchers, particular in the field of materials science and technology. Over the years the basic principle of SPM of measuring a specific interaction between a probe with an ultrasharp tip and a material’s surface to collect, for example, topographic information with atomic resolution, has generated a complete family of scanning probe microscopy techniques (Scheme 5) [253], such as STM [255], as its very first member, AFM [256], and scanning near-field optical Scanning Tunneling Microscopy (STM) Spin-polarized Scanning Tunneling Microscopy (SP-STM) Magnetic Force Scanning Tunneling (MF-STM) Scanning Tunneling Spectroscopy (STS) Inelastic Electron Tunneling Spectroscopy (IETS) Atomic Force Microscopy (AFM) Tapping Mode Atomic Force Microscopy (TM-AFM) Chemical Force Microscopy (CFM) Magnetic Force Microscopy (MFM) Electrical Force Microscopy (EFM) Current Sensing Atomic Force Microscopy (CS-AFM) Atomic Force Acoustic Microscopy (AFAM) Lateral Force Microscopy (LFM) Friction Force Microscopy (FFM) Force Spectroscopy Shear Force Microscopy (SFM) Scanning Near-field Optical Microscopy (SNOM) Scanning Probe Lithography (SPL) Din-Pen Nanolithography (DPN) Mechanical Lithography, Indenting, Ploughing, Scribing Tip-induced Oxidation SCHEME 5 General classification of SPM techniques; indicated are main SPM classes and some of their modifications (see more in [253, 254]).

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microscopy (SNOM) [257]. The development of new techniques and operating modes to collect more and more information from the nanoworld is continuously in progress. Besides enabling the organization of matter to be imaged with subnanometer resolution, the basic operating principle of SPM provides the power to measure, analyze, and even quantify properties of matter on the nanometer length scale. Using specific probes and measuring conditions, adhesion, elasticity, conductivity, and capacitance data can be obtained, to quote but a few. These data reflect local properties, possibly even of single molecules and atoms and offer new insights into structure-property relations in the nanoworld of matter. Moreover, because of its unique potential to manipulate the organization of atoms, molecules, assemblies, or particles and to structure surfaces in a controlled fashion, SPM has become one of the most powerful tools in the fields of nanoscience and nanotechnology for the preparation and analysis of nanostructures and their functionality. The power of scanning probe methods also plays an important role in nanostructured magnetic materials for data storage applications and spintronic devices. Spin-polarized scanning tunneling microscopy and spectroscopy utilizes nonmagnetic probe tips that are coated by a thin (typically less than 10 atomic layers) film of magnetic material, which allows the measurement of both the in-plane and out-of-plane magnetization component of the sample. Thus, the smallest magnetic features, such as domain walls in ferromagnetic iron films in W (110) with a width of 0.6 nm and the atomic-scale antiferromagnetic structure of a manganese monolayer, can be analyzed. In addition, the shape-dependent thermal switching behavior of superparamagnetic nanoislands was explained. The unique resolving power of STM can provide important new information on the atomic-scale realm and on the dynamics of nanostructures. For example, the mobility of defects such as oxygen vacancies on TiO2 surfaces (which become mobile after O2 exposure) can be explored. For the diffusion of O2 molecules on rutile TiO2 (110) surfaces (which plays an important role in understanding (photo)catalytic activity), a chargetransfer-induced diffusion mechanism for the adsorbed O2 molecules was observed. AFM is a method that quantifies the involved forces arising between a sharp atomicsized tip and molecules attached to surfaces. Through the scanning of a tip across the surface, AFM can image these forces with submolecular resolution. The ability to perform such experiments under physiological conditions makes it a tool of immense value for the study of biological samples. The forces required revealed the electrostatic, van der Waals, or hydrogen-bond forces involved in structural organization. This method introduced a remarkable increase in sensitivity and force resolution. Similar to STM or AFM, SNOM measures the light induced very close to an atomicsized tip. Current SNOM microscopes are either operated in the aperture or scattering mode. The first technique is based on a metal-coated, tapered glass fiber, which squeezes the light through an aperture of 50–100-nm diameter, while the latter technique exploits the effect of field enhancement when illuminating close to an atomic-sized metal tip. In surface-enhanced Raman scattering (SERS), silver or gold nanoparticles, with a regular rather than periodic motif, interact with an electromagnetic field to yield site-specific

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increments of that field [258]. This in turn allows obtaining the Raman signature of biological molecules with unprecedented sensitivity and thus to diagnose a disease at the very early stages of its progression. SERS effect occurs because of the collective/resonant oscillations of electrons on the surface of a rough metal, where the roughness of the surface has to be a fraction of the wavelength of the incident electromagnetic (EM) field [259]. Similar oscillations are named localized surface plasmons (LSPs) and the study of the generation, propagation, and dependence of LSPs on the geometry of a metal substrate is at the basis of a new revolution in optics. For certain combinations of physical characteristics of the metal, wavelength, and nanotopography, LSPs are responsible for enhanced EM absorption in lieu of EM scattering. Enhanced EM absorption in turn generates heat and the nanomaterial itself may be regarded as a nano-heat generator remotely controlled by light [260]. Differently from SERS, the described thermo-plasmonics effect depends on the square (and not to the power of four) of the EM field intensity [260]. Thus the EM distribution on a metal substrate indicates how power density propagates on that substrate. A similar thermos-plasmonic effect has been used in a variety of applications including drug delivery, plasmonic photo-thermal therapy, nano-surgery, photo-thermal imaging, plasmon-assisted nano-chemistry, and plasmon-assisted opto-fluidics [261]. Similar unique techniques are summarized more in detail in [254, 262].

1.8 Nanoarchitectures There is a growing interest in the organization of nanoparticles in two- and threedimensional structures. The main challenge in this area is to develop approaches for the organization of arrays of nanoparticles wherein both the size and separation between the nanoparticles in the arrays can be tailored. Applications based on the collective properties of the organized particles require flexibility in controlling the nanoarchitecture of the materials [45]. Attempts have been made to assemble nanoparticles in twodimensional structures by a variety of methods that include self-assembly of the particles during solvent evaporation [263], immobilization of covalent attachment at the surface of the self-assembled monolayers [264] or surface-modified polymers [265], electrophoretic assembly onto suitable substrates [266], electrostatic attachment to Langmuir monolayers at the air-water interface [267] and air-organic solvent interface [268], and by diffusion into ignitable fatty lipid films [269]. The organization of the metal nanoparticles at the air-water interface can be followed by surface pressure-area isotherm measurements while the formation of multilayer films of the nanoparticles by the Langmuir-Blodgett technique can be monitored by quartz crystal microgravimetry, UV-vis spectroscopy, Fourier transform infrared spectroscopy, and transmission electron microscopy. The simple and primary step toward more complex structures is the controlled linkage of particles to each other or to the surface of an already existing structure, which acts as a template. The simplest approach to such systems is to allow the particles to react with bifunctional molecules which can attach to the surface of two particles and link them together. This has been demonstrated for alkane dithiols, which can be used, for example,

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to precipitate cross-linked networks of gold particles from solution [270] or to assemble spherical ultramicroelectrodes by immersion of dithiol-filled micropipettes in solutions of gold particles [271]. An appealing “brick and mortar” approach to the controlled fabrication of nanoparticle aggregates has been developed by Boal et al. [272], who prepared gold nanoparticles, which contained molecular recognition elements in the ligand (organic) shell. These particles aggregated in the presence of specifically designed complementary polymers which acted as a molecular “mortar.” The size of the aggregates prepared in this way depended on the temperature in a controllable way. Thiol-stabilized gold nanoparticles have not only been used as building blocks for larger structures comprising hundreds or thousands of particles but are also of interest as individual large molecules, that is, so-called monolayer protected clusters (MPCs) [273]. They represent nanoscopic metal surfaces and can be regarded as threedimensional analogs of two-dimensional macroscopic surfaces. This notion has been promoted chiefly by the groups of Murray [273, 274] and Lennox [275, 276], who carried out extensive spectroscopic studies including NMR investigations which are not possible with self-assembled monolayers (SAMs) of thiols on macroscopic surfaces. Murray and coworkers further explored new routes to functionalized MPCs by ligand place exchange reactions [277–279]. Simple alkane thiol ligands can be partially or completely exchanged by more complex functional thiols in order to introduce, for example, electrochemically active [280–282] or photoluminescent [175] moieties into the ligand shell. This has opened up a new field of preparative chemistry which is still in a very early stage of development. A particularly elegant study by Boal and Rotello [283] describes the evolution of an optimized flavin binding site on an MPC surface containing two different thiols functionalized with pyrene and diaminopyridine moieties, respectively, diluted by a matrix monolayer of octanethiol. The binding of flavin to diaminopyridine by hydrogen bonding is enhanced by the proximity of a pyrene unit, which can provide an additional binding interaction by aromatic stacking. It also confirms that MPCs are quite dynamic systems that do not only readily undergo ligand place exchange reactions but are also capable of remarkable re-organization processes in their ligand shell. Many technologies including electronics, separations, and coatings will be enhanced by the ability to control the structure of materials on a nanometer-length scale. Furthermore, the unique properties of nanoscale materials may give rise to entirely new technologies. One approach for constructing mesoscopic structures is to use solution-phase nanocrystals as “building blocks” [42, 284, 285]. Because nanocrystal diameters can range between 2 and 10 nm, these structures would have characteristic dimensions much smaller than those possible using current lithographic technology. One obvious goal for electronic applications is to achieve the capability to position nanocrystals with a high degree of accuracy. A periodic nanocrystal array, for example, requires the precise positioning of nanocrystals with respect to their neighbors. Encouragingly, this architecture is experimentally attainable and it has been found that hydrophobic, sterically stabilized nanocrystals can be organized into close packed arrays simply by evaporating the solvent from a dispersion, provided that the size distribution is sufficiently tight. This general

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experimental approach to quantum dot superlattice formation has been shown to apply to a variety of materials, such as Au [286], CdSe [287, 288], Ag [289], Ag2S [290], and γ-Fe2O3 [291] nanocrystals. Up to this point, however, superlattice formation remains highly empirical. Because these arrays could provide the possibility of: -

implementing the unique size-dependent physical properties of individual nanocrystals in a device and eliciting electronic and optical properties due to “electronic overlap” resulting from the relative positioning of the nanocrystals in the array [45] there is great interest in developing a fundamental understanding of the intrinsic forces that direct superlattice formation. For example, applications of NIL to realize two-dimensional photonic crystals have been reported [292].

A major motivation for research in the field of assemblies of nano-particles, droplets, bubbles, fibers, and tubes remains the challenge to understand how ordered or complex structures form spontaneously by self-assembly, and how such processes can be controlled in order to prepare structures with a predetermined geometry. For this purpose it is important to build up a broad experimental database, from which a better fundamental understanding of self-organization processes and eventually predictive power can be developed. A prerequisite for nanostructure preparation via this self-assembly route is the availability of sufficiently stable building blocks which have to be well characterized and uniform in size and shape [293]. They should ideally also be chemically versatile enough to undergo a range of reactions allowing them to fulfill various structural and/or functional roles within the final system. Examples of such materials include large organic molecules [294], fullerenes and carbon nanotubes [295] and inorganic nanoparticles of insulators [296], metals [297], or semiconductors [151]. Impressive progress has been made, particularly in the assembly of semiconductor quantum dot solids. This is due to the possibility of obtaining certain nanoparticles, as highly monodisperse and stable products. These can crystallize from solution into materials, the electronic characteristics of which reflect the quantum confinement properties of the individual building blocks [288]. Similar materials and a range of interesting self-assembled structures can be obtained from ligand-stabilized metal nanoparticles, which likewise show a fascinating wealth of size-related electronic and optical properties. The materials known as “SAMs” are formed by allowing appropriate surfactants to assemble on surfaces [298]. They provide synthetic routes to nanometer-thick, highly structured films on surfaces that provide biocompatibility, control of corrosion, friction, wetting, and adhesion, and may offer routes to possible nanometer-scale devices for use in “organic microelectronics.” They have also changed the face of surface science as a research enterprise, moving it from the study of metals and metal oxides in high vacuum to the study of organic materials in circumstances more closely approximating the real world. Selfassembly—a strategy best understood and most highly developed in chemistry—also offers an appealing strategy for fusing “bottom-up” and “top-down” fabrication, and leading to hierarchical structures of the types so widely found in nature [299, 300].

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An alternative strategy for the formation of ordered nanoparticle arrays is the selforganization method based on biomolecular templates by direct or synergistic templating techniques. The template-directed synthesis of nanoparticle arrays in mesostructured silica, as well as helical nanostructures in unusual shaped materials such as chiral lipid tubules, were developed. Another strategy is to utilize the advantages of self-organization processes by means of noncovalent interactions. The self-assembly of grid-type metal ion architectures can generate 1D, 2D, and 3D functional metallosupramolecular arrays. Such arrays combine the properties of their constituent metal ions and ligands, and show unique optical, electrochemical, and magnetic behavior. Successful self-organization is based on the interplay of steric, enthalpic, and entropic factors, in terms of both the ligands and the metal ions. The multitude of different transition metal cations and organic ligand combinations results in a multitude of different grids with a broad variation of properties. The beauty of such grid-type systems is their geometrical simplicity and their small size, which is about 1000 times smaller than quantum dot arrays, thus opening up plenty of room for complexity at the bottom. The progress has also been attained in the characterization and application of nanostructured materials using block copolymers. Nanostructure fabrication from block copolymers involves polymer design, synthesis, self-assembly, and derivatization. Block copolymers self-assembled into micelle afford a powerful means of manipulating the characteristics of surfaces and interfaces, and therefore, are expected to have novel structures, properties, and applications. For example, nanoparticle fabrication using heterobifunctional poly(ethylene glycol) (PEG) and their block copolymer is explored to construct functionalized PEG layers on surfaces, achieving the bio-specific adsorption of a target protein through an appropriate ligand tethered on PEG layers without nonspecific adsorption of other proteins. The properties of polymeric micelles formed through the multimolecular assembly of block copolymers are highly useful as novel core@shell-type colloidal carriers for drug and gene targeting. Surface organization of block copolymer micelles with a cross-linking core can exhibit nonfouling properties. The surfaces of these aggregates can work as the reservoir for hydrophobic reagents and can be used in diverse fields of medicine and biology to construct high-performance medical devices and drugdelivery systems. Furthermore, by controlling metal and semiconductor structure precisely through the concept to construct functionalized PEG layers, one can modify the nanostructures to better suit their integration with biological systems; for example, modifying their surface layer for enhanced aqueous solubility, biocompatibility, and more importantly biorecognition. The use of the exquisite recognition properties of biomolecules in organizing nonbiological inorganic objects into functional materials led to new applications including ultrasensitive bioassays and multicolor fluorescent labels for high-throughput detection and imaging. Another intriguing route to complex nanostructures is the use of templates onto which the particles can assemble in a predetermined fashion. An example of this approach is the selective decoration of phase-separated diblock copolymers with thiol-protected gold nanoparticles [301]. Such polymers exhibit complex patterns of microphases of the two

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different components that can have very different affinities for the adsorption of particles. In the case of poly(styrene-block-methyl methacrylate), for example, only the polystyrene phases are decorated with gold particles, which results in the formation of complex gold nanostructures with the shape and size of the polystyrene microphases [301]. Fitzmaurice and coworkers [300] have discovered the use of a particularly interesting template that allowed them to create continuous tubular gold nanostructures in a two-step process. Following the notion that C60 fullerene molecules attach spontaneously to the surface of certain gold particles in organic solution [301] they readily achieved the decoration of bundles of carbon nanotubes by such particles.

1.9 Nanobiotechnology Nanoparticles (NPs) are key to the application of nanotechnology in medicine, defined as nanomedicine, and are effective in multifunctionality for theranostic strategies. The goal of theranostic nanomedicine is to tailor therapies to a patient’s specific diagnosis and improve treatment outcomes with fewer side effects in a shorter amount of time than current trial-and-error treatment regimens. Nanoparticles have significant advantages in theranostics because of their targetability and multifunctionality [302]. By passive and/ or active targeting, NPs can target the disease site. Once there, theranostic NPs may diagnose the disease by reporting on the location of the disease, the stage of disease, or the response to treatment [303]. Finally, nanoparticles can deliver a therapeutic agent to the targeted site at necessary concentrations, potentially in response to molecular signals or external stimuli. Overall, theranostic nanomedicine can be used to monitor drug delivery, drug release, and drug efficacy. Theranostics is the integration of therapeutics and diagnostics, which can be administered simultaneously or sequentially. Nanomedicines are a large field of nanosized systems that can be divided in two categories: (i) nanocarriers, which include polymeric nanoparticles, micelles, liposomes, and solid lipid nanoparticles and (ii) drug conjugates, which include dendrimers and polymer conjugates (Scheme 6). The sizes of these systems range from a few nanometers to 1 μm [305]. Nanomedicines are of the same size as biological entities and can readily interact with biomolecules on both the cell surface and within the cell [306]. The combination of this attractive feature with interesting drug delivery properties has led to the development of a wide array of nanomedicines. New applications will become available for diagnosis, treatment, monitoring, and prevention of disease [307]. Together they can contribute to solving some of the grand challenges in healthcare. Over the past decades, significant progress has been made in the field of nanomedicine, resulting in a number of products, including therapeutics and imaging agents, enabling more effective and less toxic therapeutic and diagnostic interventions [308]. These products are new or existing products in formulations at the nanometer scale. They may consist of nanoparticle forms of the active pharmaceutical ingredient, nanoporous materials engineered to achieve a controlled release of their payload or nanoparticles used as a carrier material for drug delivery, either with the drug encapsulated inside or

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SCHEME 6 The different types of nanomedicine structures. (A) Polymeric nanoparticles. (B) Micelles. (C) Liposomes. (D) Solid lipid nanoparticles. (E) Dendrimers. (F) AuNP PEGylated conjugates [304].

attached onto the surface. The nanoparticles may contain all kinds of active pharmaceutical ingredients, for example, chemical substances, proteins, or genetic material. Not only are an increasing range of nanostructures being applied, including well-known examples like liposomes [309], micelles [57], nanosilver [310, 311], and iron oxide nanoparticles [312], but also more novel structures like dendrimers [313] and block-copolymer micelles [314]. The in vivo biological behavior of such nanostructures depends on their physicochemical characteristics, which can be engineered to obtain the optimal effect. It is expected that nanomedicinal products will provide novel solutions for diseases like cancer, infections, auto-immune diseases, and inflammations. Therapies with drugs that produce considerable side effects can especially be expected to benefit from nanotechnological solutions. The active pharmaceutical ingredient can be targeted more accurately, and it can be shielded until reaching the target where a controlled release takes place. These features lead to a higher efficacy and a decrease in side effects. Application of nanostructures also provides new options for drugs with solubility problems and increases their bioavailability, enabling more efficient dosing [313]. In addition, they are instrumental in transporting drugs to targets that are difficult to reach, for example, by enabling passage through the blood-brain barrier [315]. While the above-listed potential advantages are obviously highly desirable, the emergence of nanomedicinal products also gives rise to questions of whether currently used

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and newly developed characterization and testing methods as well as assessment strategies provide a sound scientific basis for an adequate evaluation of the quality, safety, and efficacy of these products within the current regulatory frameworks [316, 317]. The safety evaluation of nanomedicinal products poses specific challenges associated with the particulate character of their formulations. Especially the toxicokinetic profile of nanoparticles is quite different from that of dissolved chemicals. The greatest regulatory challenges, as identified by Ehmann et al. [316], are associated with the novel, “next-generation” nanomedicinal products, for example, based on dendrimers, and the generic versions of first-generation products, for example, based on liposomes or iron oxide nanoparticles, which have been indicated by the term “nanosimilars.” It is important to have clear insights into the state of affairs with regard to the availability of nanomedicinal products and their specific properties, not only for regulators and the pharmaceutical industry, but also for physicians and pharmacists. The terms studied were: nanomedicine, nanotechnology, nanodrug, nanoparticle, drugs, therapeutics, vaccines, biologicals, diagnostics, pharmaceutics, horizon scan(ning), overview, roadmap, foresight, forecast, future, clinical trials, randomized controlled trials, cohort studies, case reports, human, drug delivery (systems), drug carrier, drug targeting, gene therapy, drug discovery, drug encapsulation, liposomes, micelles, dendrimer, fleximer, hard NP, soft NP, nanodispersion, polymeric NP, protein NP, emulsion, virosome, and any combination of the mentioned terms. The uses for each of the products can be grouped into several application areas based on the approved or intended use: cancer treatment, infectious diseases, cardiac/vascular disorders, degenerative disorders, inflammatory/immune disorders, endocrine/exocrine disorders, kidney diseases, neurological diseases, imaging, and others. Looking at the type of products, it is clear that the overwhelming majority are therapeutic products. This may partly be explained by the fact that medicinal products in general are mostly therapeutic products, while the total number of diagnostic products is rather small. For vaccines, the identified number of products is relatively low. Several tens of vaccines are registered for human use. Vaccines with adjuvants are regarded to be nanoformulations. It needs to be confirmed whether we have indeed identified all vaccines that incorporate adjuvants. A possible explanation for the low numbers of diagnostics and vaccines might be the potential uncertainty in the benefit-risk evaluations that have to be performed for medicinal products. For the risk assessment of nanomaterials in general, there are currently still a number of uncertainties. Consequently, it can be expected that applications with the larger benefit-risk ratios would be more attractive for development of nano-applications than products with a smaller benefit-risk ratio. Such products can be expected more often in the category of therapeutic products. This explanation can also be applied to the observation that by far the highest number of product per application area is intended for cancer treatment. Not only does this imply a high benefit given the prognosis of cancer without treatment, the treatment options currently available are generally products with severe side effects. Lagging behind in frequency of the number of products for cancer treatments are products indicated for infectious diseases, followed by immune disorders and degenerative disorders.

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With regard to the type of structures being applied for nanomedicinal products, the first result that stands out is the high number of protein nanoparticles in the list. These products are practically all monoclonal antibodies. They are often excluded from the field of nanomedicinal products, since they are biological products, although in some way manipulated. It depends on the interpretation of the description of nanomedicinal products whether these products should be included in the list of nanomedicinal products or not. Strictly speaking, all of these products comply with the description: although their sizes are generally not available, it can be assumed that they are particulate substances of less than 1000 nm. In addition, they have been designed to have specific properties in order to obtain the intended functionality. The polymer conjugate products are mostly products with PEG. PEG is well known for its effect to shield a product from the immune system, sometimes referred to as the “stealth effect.” Therefore, it has also been applied as a coating on other particle types and thus prolongs the circulation time of nanomaterials [318]. Another result that stands out is the high number of liposomal and polymer nanoparticle products that are currently under investigation. Surface properties may be imparted to nanoparticles by coating them with various substances. PEG, for example, enables the nanoparticles to avoid immune recognition following intravenous administration or resist enzyme degradation following oral administration [319]. Moreover, coating with polymers or antibodies, which bind specifically to a particular cell, can help to better achieve targeted drug delivery [320]. The penetrating capability of a NP across a biologic surface depends also on the contact area and the curvature of the particle at the contact point. Thus, the geometrical shape represents an important characteristic for NP performance. Disk-shaped or road-shaped NPs have the largest adhesion probability mainly due to the larger surface area available for contact and multivalent interactions [321] giving rise to a larger drug flux per unit volume [322]. Nanopharmacology has been defined as the application of nanotechnologies to drug design and drug delivery [323]. The usual course of a drug after administration follows the kinetic processes of absorption, distribution, metabolism, and elimination. Several kinds of nanosized carrier systems can be considered: water-soluble polymer, emulsion (dispersion), nanosphere, liposome, polymeric micelle, PNP, MNP, etc. The water-soluble polymeric carriers include both naturally occurring and synthetic polymers (including antibodies). Emulsions comprise small oil droplets stabilized with an outer amphiphilic layer. Nanospheres are solid, small particles made from natural or synthetic polymers. The difference between emulsions and nanospheres is the status of the interior, liquid for emulsions and solid for nanospheres. The liposome is a vesicle consisting of a lipid bi-layer that mimics cellular membranes. Polymeric micelles are the newest type of drug carrier systems. They are macromolecular assemblies of amphiphilic block copolymers with a spherical inner core and an outer shell [324]. In general a carrier must be produced from materials that are biodegradable or, if not, residual material after drug delivery should be nontoxic [61]. We can consider also porous materials that possess vast amounts of nanopores that allow the inclusion and retention of drugs, modulating their release in order to obtain controlled and sustained drug-delivery systems [325].

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Two main strategies are used to load the drug polymer nanoparticle carriers: (1) covalent linkage to a polymer matrix and (2) encapsulation in a hollow coat. Presently, both strategies are realized using water-soluble polymeric carriers, the same used in the pioneer study aimed to evaluate the targeting of intestinal inflammation by nanoparticles. This approach can be conducted using poly(lactic-co-glycolic acid) (PLGA), to encapsulate rolipram, a drug with antitumor necrosis factor (TNF)-α effects. Either the rolipram solution or the rolipram carrying NPs were able to decrease inflammation in a trinitrobenzene sulfonic acid (TNBS) colitis. However, while the effect of free solution vanished after a few days, the effect of rolipram NPs was significantly prolonged as drug release in the NP system was found to be sustained over 1 week. This was the first observation that this nanosized polymer allows a sustained drug release due to the retention of the carrier system in the targeted inflamed area [326]. Most of the subsequent studies on experimental models of intestinal inflammation were performed using three kinds of polymers: chitosan, PLGA, and Eudragit [327]. Chitosan is a naturally occurring polysaccharide with excellent mucoadhesive properties. PLGA, a biodegradable polymer able to act as a sustained drug delivery system, is degraded in the body through hydrolysis to lactic and glycolic acids, that are further metabolized in the citric acid cycle. Eudragit, a pH-sensitive material, is the same polymer adopted for conventional bulk preparations. Some polymers can be used also in combination to realize the “polymeric micelle” system of carriers. In this system, the drug is firstly incorporated into a matrix by both chemical conjugation and physical entrapment to realize the inner core. Secondly the core is entrapped in an outer shell composed by another polymer with other characteristics [324]. For example, in order to minimize early drug release in the proximal intestine, an inner core composed by a polymeric matrix entrapping budesonide, was encapsulated within an enteric pH-sensitive polymer (Eudragit) conferring to the drug a significant enhancement of antiinflammatory activity [328]. Polymer micelles are assemblies of amphiphilic block copolymers forming a core@shell structure that is well suited for drug delivery, where hydrophobic molecules are segregated to the core. These 50
100 nm clusters of surfactant molecules are formed in water when the concentration is above the critical micelle concentration (CMC) [329]. Traditional surfactant micelles are unstable below the CMC; so, an approach to produce a stable polymer micelle typically includes crosslinking of the micelle “shell” or “core” using ester, amide, disulfide, or radical chemistries [330]. Polymer or liposomal self-assembly without crosslinking typically results in reduced stability in circulation and premature drug release. Core and shell stabilization has achieved varying degrees of success, but concerns remain regarding drug-loading effectiveness, stability, drug release, and preparation. A less common approach to core crosslinking involves a triblock copolymer specifically designed to address the inherent micelle instability. Triblock copolymer production incorporates a middle block in addition to the standard hydrophobic and hydrophilic blocks, which imparts micelle stability. Previously this approach was utilized with vinyl-based polymers prepared from radical polymerization techniques [331]. The researchers have developed a micelle forming triblock copolymer specifically designed to address the

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inherent stability of nanoparticles. This polymer contains a hydroxamic acid block that can chelate with iron atoms. The addition of iron to the triblock copolymer micelle results in the formation of dative bonds among the polymer chains, providing stability at neutral pH. At low pH, such as conditions found in the tumor environment, the iron-hydroxamic bonds dissociate, reducing particle stability, and subsequently release the drug [332]. Bakewell et al. have prepared a triblock copolymer comprised of a PEG hydrophilic block, a central glutamic acid hydroxamate stabilizing block, and a hydrophobic polypeptide block (Scheme 7) [333]. The hydroxamic acid-containing block interacts with iron atoms to form dative bonds among the polymer chains to stabilize the micelle. Iron chelation imparts transient stability to the nanoparticle in neutral pH environments. These iron-hydroxamic acid dative bonds are unstable at low pH, providing a mechanism for environment-dependent micelle stability and subsequent drug release (Scheme 7C). Drug-loaded, iron-stabilized micelles self-assemble during formulation to form nanoparticles composed of an amphiphilic poly(ethylene glycol) corona, hydroxamic acid stabilizing middle block, and hydrophobic core block for drug (nano)encapsulation. Hydrophobic amino acids sequester drugs in the core of the micelle without the need for covalent attachment, which requires chemical or enzymatic cleavage for release. Iron chelates with the hydroxamic acid moieties forming dative bonds among polymer strands to stabilize the micelle for intravenous administration and subsequent dilution. The final drug product is a lyophilized powder for reconstitution in saline for administration [333]. Application of the discussed technology has produced formulations of stable micelles that encapsulate hydrophobic anticancer agents to include SN-38, daunorubicin, epothilone D, panobinostat, paclitaxel, and aminopterin. In all cases, loading active pharmaceutical ingredient (API) averaged more than 80% efficiency with API weight loading ranging from 3.0% to 7.4%. Average micelle diameters range between 58 and 120 nm as verified by electron microscopy and by dynamic light scattering. The polymer micelles, thus, encapsulated the following drugs: SN-38 (IT-141), daunorubicin (IT-143), and epothilone D (IT-147). Polymer nanoparticles being able to inhibit TNFα have been realized through both nano-antibodies (nanobodies) and gene silencing. Nanobodies are formatted anti-TNFα

SCHEME 7 Encapsulation of drugs via self-assembling of amphiphilic copolymers and iron-complexation: (A) Solution of amphiphilic copolymer molecules, (B) self-assembling of amphiphilic copolymers and drug loading, and (C) iron-stabilized micelles during formulation of composite nanoparticles [334].

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single-domain antibody fragments derived from heavy-chain camelid antibodies. Gene silencing via RNA interference (RNAi) represents another promising treatment strategy for intestinal inflammation. RNAi obtained by means of orally delivered small (or short) interfering RNA (siRNA), usually composed of double-stranded 20–25 nucleotides, is a powerful tool for post-transcriptionally silencing gene expression, interfering with the expression of a specific gene, e.g., one that is overexpressed in certain diseases. TNFαsiRNA was loaded into polylactide (PLA) (NP matrix) and then covered with polyvinyl alcohol (PVA) (NP shell). The resulting NPs were efficiently taken up by inflamed macrophages and, interestingly, gene silencing was not found in the liver confirming the low systemic bio-availability [334]. An alternative way to obtain gene silencing is that of synthetic double-stranded antisense oligonucleotide using plasmid DNA. Oligonucleotide directed toward nuclear factor-κB (NF-κB) gene was encapsulated into PNPs consisting of chitosan-modified PLGA nanospheres. PNPs were specifically deposited and adsorbed on the inflamed mucosal tissue of the UC model rat [335]. Although all these nanotechnology applications to biologic therapies are highly promising, many challenges still need to be addressed when using RNAi or plasmid DNA to manipulate inflammation in vivo. Among these challenges are immune toxicity and deposition of the oligonucleotides and the PNPs at the cellular level, which needs to be carefully evaluated [336]. A clodronate-loaded polymer nanoparticle based on a cationic polymethacrylate (Eudragit RL) with particle diameter around 120 nm was studied in murine experimental colitis in vivo. This formulation was able to decrease inflammatory activity in TNBS-colitis and oxazolone-colitis models while free clodronate did not show a mitigating effect. Cell culture experiments indicated that intracellular delivery of clodronate was necessary to obtain an antiinflammatory effect [337]. A microsized drug-delivery system composed of a pH-sensitive material was used to incorporate low molecular-weight heparin in the attempt to reduce the risk of severe hemorrhagic adverse effects. To this purpose, enoxaparin was entrapped into pH-sensitive microspheres (100–400 μm) using Eudragit P4135F. This NP-drug complex showed a selective oral delivery of heparin into the colon, proving its efficacy as a new therapeutic strategy in inflammatory bowel disease (IBD) [338]. The PNPs were of spherical shape, composed of PLGA, with average sizes of 250 nm and 3.0 μm, respectively. Microscopy revealed no mucosal binding of either NPs or MiPs in the healthy controls, whereas bindings of both were found in areas of epithelial lesions, suggesting persorption through cellular voids of the inflamed mucosa. Interestingly, a clear size-dependent difference regarding the accumulation of particles within inflamed mucosa was observed, NPs prevailing in the deeper regions with the larger microparticles confined to the more superficial areas. This phenomenon probably reflects a size-dependent limitation of the persorptive capacity of particles in general. Another interesting observation was that accumulation of particles turned out to be strictly related to the severity of the lesions, with no particles found in normal IBD mucosa, minor amounts in cases of mild-to-moderate disease, and marked accumulation in cases of severe disease.

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Overall, MiPs exhibit accumulation and bioadhesion to the inflamed mucosal wall with no absorption of these particles across the normal epithelial barrier, whereas NPs are able to translocate to the serosal compartment suggesting that the choice of size can determine the extent of penetration in the intestinal wall [66]. The same group of investigators studied the impact of the modification of the surface chemical composition of the particles on their uptake into the mucosa of IBD patients. NPs sized 300 nm and MiPs sized 3.0 μm were used. Three different types of surfaces were used for NPs. The first type was the nonfunctionalized PLGA surface, the same used in the previous study. Chitosan- and PEG-functionalized surfaces were the other two types. The chitosan surface confers a positive charge to the particles with a consequent electrostatic affinity to negatively charged surfaces. PEG confers a hydrophilic surface to the particles with an increased transport through the mucus. The study demonstrated the superiority of PEG-functionalized drug carriers in particle translocation and deposition in inflamed mucosal tissues compared to chitosan- and nonfunctionalized particles. PEGfunctionalized MiPs demonstrated a low translocation into healthy tissues but a significantly increased translocation into inflamed mucosal tissues. The hydrophilic surface provides an accelerated translocation into the leaky epithelium, and then into the core of the intestinal inflammation [339]. It can therefore be hypothesized that MiPs could be useful in the cure of active disease where the mechanism of persorption permits the passage of the large particles, whereas NPs could be more effective under conditions of remission or minor inflammation where the mucosal barrier is less permeable and absorption through epithelial cells prevails with respect to persorption. Finally, functionalization of the particles’ surface using PEG could ameliorate the affinity to intestinal inflammation. It is found that geometry of the particles, the third feature affecting nanoparticle kinetics and dynamics together with size and composition, might influence and further ameliorate their uptake in inflammatory tissue [340]. The idealized goal for chemotherapy is to provide a highly efficacious treatment with minimal toxicity. Side effects are the result of off-target effects on healthy tissue and for this reason site-specific delivery of oncology drugs has been a decades-long goal. Nanoparticle drug carriers offer a promising solution to this goal by overcoming inherent biological barriers. Due to their unique size range (20–150 nm), nanocarriers can evade the mononuclear phagocyte system [341] uptake by the liver, and avoid renal clearance. Increased circulation time enhanced by micelle stability in plasma allows nanoparticles to preferentially accumulate in solid tumors via the enhanced permeation and retention (EPR) effect [342], thereby improving treatment efficacy [343]. Magnetic nanoparticles possess unique properties that make them an attractive contrast agent for magnetic resonance imaging [344]. Iron oxide nanoparticles such as magnetite (Fe3O4), maghemite (Fe2O3), ferumoxides, and ferucarbotran demonstrate superparamagnetic properties [345] with a mean particle diameter of approximately 50 nm and have been widely investigated for magnetic resonance imaging (MRI) application. Superparamagnetic iron oxide (SPIO) nanoparticles are already an established tool in

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diagnostic radiology and serve as contrast agents in MRI. They can also be used as triggers and for hyperthermia-based tumor ablation. The combination of magnetic nanoparticles, noble metal nanoparticles or other contrast media with nanoparticle drug carriers has resulted in dual-purpose nanoparticles often referred to as “theranostics.” This approach enables the nanoparticle platform to carry both a therapeutic agent in addition to a diagnostic agent to reveal spatial location within the patient. Approaches to theranostics include the encapsulation of iron-oxide nanoparticles in cross-linked diblock copolymers [346]; oxaliplatin and gadolinium complexes in diblock copolymer micelles [347]; and doxorubicin and iron oxide nanoparticles in folate-targeted polymer micelles [348]. Contrary to these theranostic nanoparticles that co-encapsulate the imaging agent and the drug, the researchers have discovered that their drug-loaded hydroxamic-acid micelles inherently function as an MRI contrast agent through the clustering of the ironstabilizing atoms. Some of the pioneers in nano-oncology equipped their polymer and noble metal NPs with “targeting” devices trying to direct the therapy to the malignant cells [254, 262]. A number of ligands have been utilized, including antibodies, aptamers, and lectins among others [349]. Receptors on the cell surface of the cancer cells have included transferrin receptors, folic acid receptors, somatostatin receptors, and receptors for melanocyte stimulating hormones among others. Furthermore, AuNPs and AgNPs can be used with lasers to achieve localized thermal ablation. Coupling of gold nanoparticles to targeting ligands may allow for localization to cell-surface structures. If the gold particles are also coupled to an isotope, the conjugate can be used as a biological tracer, and if the gold particle is coupled to a cytotoxic drug it can act as a theranostic. Considerable attention has been focused on the development of gene therapy to treat diseases such as cancer caused by faulty genes. Gene therapy is one of the most serious challenges in nanotechnology and biomedicine. In recent years, nonviral vectors have become an alternative therapeutic strategy, which has taken the place of the usual approaches of viruses as gene carriers. The development of carriers is the first step that must be addressed to transfer the gene of therapeutic interest to the site of action in the cells [350]. In general, the inherent ability of virus to deliver genes inspired scientists to use them for tumor therapy. However, the end result was met with drastic consequences that paved the way for other alternatives [351]. Meanwhile the realization of merging nanotechnology with medicine gave a significant boost for research in this direction and led to the invention of nonviral delivery systems. Nanotechnology has been employed to modify polymers and bring them down to colloidal carriers of nanosizes that would enable gene delivery for cellular therapeutic application [352]. In terms of efficiency, polymer-based colloidal systems are capable of allowing chemical modifications and also have the capacity to carry large inserts of genetic material, which make them an attractive choice to yield nanoparticles [353]. Silver nanoparticles have been known to exhibit powerful antimicrobial activity and are widely applied in medicine owing to its high and wide spectrum of antimicrobial activities [354]. Therefore, some strategies have been developed to maximize the toxicity of

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silver nanoparticles to pathogenic organisms while minimizing the toxic effects on mammalian cells. Liu et al. reported cell-penetrating peptide-conjugated AgNPs, which demonstrated a distinctly enhanced biocidal effect toward bacteria (Gram-positive Bacillus subtilis, Gram-negative Escherichia coli) and pathogenic yeast and satisfactory biocompatibility [355]. Collagen-stabilized silver nanoparticles show high biocompatibility while retaining potent antibacterial properties [356]. A nanocomposite composed of silver nanoparticles decorated on the surface of the monodisperse polystyrene (PSt) spheres was prepared by Cong et al. These PSt/Ag nanocomposites can enhance antibacterial activities against E. coli (Gram-negative bacteria) and Staphylococcus aureus (Grampositive bacteria), while they do not show significant in vitro cytotoxicity against HEK293T human embryonic kidney cells [357]. Silver nanoparticle-decorated biodegradable polymer vesicles with excellent antibacterial efficacy were reported to solve agglomeration of silver nanoparticles and the metabolization of polymer micelles [358]. It is well accepted that the bactericidal activity of silver nanoparticles depends on their size, shape, stability, and their surface properties [359]. Chen et al. demonstrated that the smaller particles possess higher hemolytic activity than that of the larger particles [360]. Therefore, to be larger or to be smaller is a dilemma for AgNPs used as an antibacterial agent in the medical field. Smaller nanocarriers can penetrate tumors, but very small particles have short-lived blood circulation. Shen et al. accommodated the opposing functions using a dendrimer-lipid nanoassembly, which accomplishes the mission of blood circulation and tumor accumulation. After accumulation in the tumor, the nanoassembly explodes and releases the smaller dendrimers, which act as “bomblets” and accomplish the mission of tumor penetration and cell internalization as well as drug release [361]. Su et al. prepared a novel nanocomposite composed of silver nanoparticles decorated lipase-sensitive polyurethane micelles (PUM-Ag) with MPEG brush on the surface [362]. As is shown in Scheme 8, at the absence of bacteria, the nanoassembly remained intact (be a larger aggregate) and the silver nanoparticles were protected by the polymer matrix and PEG brush which show good cytocompatibility [363]. However, in the presence of bacteria, the polymer matrix of nanocomposites is subject to degradation by the activity of bacterial lipases, which are abundant in microbial flora since these enzymes are involved in bacterial lipid metabolism [364]. Afterwards, smaller silver nanoparticles were released, which show enhanced toxicity to microorganisms. Therefore, the nanocomposites are biocompatible to mammalian cells and this can also lead to activated smaller silver nanoparticles release at the presence of bacteria and subsequently enhanced inhibition of bacteria growth. All initial ligand-receptor binding experiments were performed in vitro where viscosity was low (all work was done in a fluid medium) and where mechanical obstacles were absent. In vivo, however, the situation is much more complex and includes high viscosity, rigid barriers, stiff matrices, and long distances. There are fundamental laws of physics and chemistry governing in vivo diffusion, adsorption, adhesion, hemodynamics, and metabolism that cannot be avoided: First, the forces attracting the ligand to its target are utterly weak (van der Waal’s forces and hydrogen bonds), and the targeting ligand and the receptor must be very close

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SCHEME 8 Schematic illustration of silver nanoparticles decorated PU micelles (PUM-Ag), the release of small silver nanoparticles in the presence of lipase and their interaction with the bacteria and mammalian cells [362].

(<0.5 nm) before any interaction can occur [365]. In practice, this means that targeting is very difficult if not impossible in solid tumors in humans. Second, passive diffusion is a time-consuming process. The time required for an NP to traverse one single normal cell is estimated to be a few hours [365]. If the distance from the afferent blood capillary to the tumor target is a few cell layers, it might take a day or two for the NP to diffuse toward the nearest cancer cell. It is not likely that the ligand will remain intact after such a journey. Even stealth liposomes have been shown to still remain within 50 nm of the blood vessel 2 days after intravenous injection [366]. Third, the more multifunctional (complicated) the NP becomes, the less effective it will become [367], and the production costs will increase steeply. Fourth, the ligand cannot distinguish between the receptor on a malignant cell from the same receptor on a normal cell. In the patient’s body there might be a thousand times as many receptors on normal cells compared the malignant cell population, and there is a good chance that the therapeutic will be hijacked by normal structures on its way to its target [368]. Fifth, ligand-functionalized NPs lose their targeting capacities when a biocorona is formed [369]. Sixth, tumor cells in the center are shielded by their dead but still protective siblings. Finally, the ligand on the nanoparticle is directed against receptors considered to be “overexpressed” by proliferating tumor cells. However, the stem cells in the tumor population are not proliferating and are, therefore, not “overexpressing” the receptors. The stem cells will evade the therapeutic and

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can cause a recurrence of the cancer. Results based on in vitro experiments have not always proven to be transferrable to in vivo situations and they have created false promises based on false premises [370]. Reaching cancer cells in humans with targeted NPs has not been very efficient and binding fractions as low as 0.01% of the total dose administered have been recorded. This means that all particles that reach the target (e.g., tumor cells) do so via passive diffusion, and adding ligands to the particles does not typically increase the amount that reaches the target. There are still no targeted NPs on the market for oncologic treatment, but several are under clinical phase testing. One such example is BIND-014, a polymer NP system that delivers docetaxel utilizing prostate-specific membrane antigen as a targeting agent (PSMA) [371]. One of the reasons why results based on studies in experimental animals have not been transferrable to humans is that the growth conditions for experimental malignancies are very different from those in humans. Experimental cancers have been selected for fast growth rates (in order to obtain fast and thus less expensive results). However, fast-growing cancers create a phenomenon termed the EPR effect, which may not exist in all human tumors. Despite the limitations mentioned above, nanoparticles may provide several advantages, including: – – – – –

New drug formulations; New administrative routes; Incorporation of new therapeutics; Revival of previously discarded drugs; New targets in the patient’s body.

The currently approved nanomedical systems that aim to deliver a therapeutic cargo, and are in clinical use, are mostly based on controlling the release of the pharmaceutically active component via passive diffusion. These drug-delivery systems are constructed to impose a diffusion barrier through their physical construction, such as the core-shell morphology of micelles and the lipid bilayer of liposomes, and sometimes with the aid of secondary interactions for further diffusion control. In the research world, there is a great interest in further advancing these systems so that the active components can be released on cue at a specific location. Most systems utilize the following principles: -

pH

Tumors usually have a lower pH (<7.0) than normal tissue (pH 7.2–7.4). This can be taken advantage of if the nanoparticle is constructed in such a manner that it dissolves in acidic environments. To achieve such a behavior, polymers are often used to construct the NPs. -

Temperature

The vector can be constructed in such a way that it dissolves at temperatures above normal (i.e., at 43°C). Such a locally elevated temperature can be achieved by either oscillating magnetic fields (for magnetic particles) or plasmon resonance (for gold NPs) [372].

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Light

The particle can designed to be dissolved by light (photodegradation) [373]. In this way, only NPs in the exposed volume/area subjected to that wavelength will dissolve. This has been used with laser therapy for visible tumors that are seen by the naked eye and are accessible (ENT, esophagus, urinary bladder, and colon, among others). For deeper lying tissues, the use of near-infrared light is being investigated [374]. Designing of controlled drug delivery systems is a promising and rapidly developing area. The main advantage of using drug-delivery systems is that drug concentration in a patient’s blood and/or tissues can be maintained at a target level for an extended time [375]. The basic requirements of a good drug-delivery system is availability of an appropriate material, which must be absolutely harmless to an organism and possess the necessary physical–mechanical and biomedical properties, including degradability in biological media. Considering the toxic effects of various other nonbiopolymer-based nanoparticle carrier systems; now the focus is extensively driven toward fabrication of nontoxic benign bioinspired nanoparticles, which perhaps are new-generation controlled drug-delivery systems [376]. Biolabeling with fluorescent dyes has many biomedical applications like fluorescent immunoassays for diagnostics and imaging in commercial and institutional setups. Fluorescent immunoassays (FIAs) increase the high throughput efficiency and sensitivity [377, 378]. The traditionally used organic fluorophores like fluorescein isothiocyanate (FITC) suffer from lack of photostability in addition to being relatively less fluorescent. The new improved Alexa series though have high intensity but have the disadvantages of low labeling efficiency and photostability. Advances in nanotechnology have facilitated the engineering of nanoassemblies for various analytical and biological applications. The past decade witnessed the emergence of silica (Si) nanoparticles, gold nanoparticles, QDs, and florescent polymeric nanoparticles as the new-generation markers [379]. Various QDs have been utilized to image many cancer cell lines such as human mammary epithelial tumor, human breast cancer, human prostate cancer, and lung tumor [380, 381]. However, QDs are difficult to synthesize requiring extreme temperature-pressure conditions along with a water-free environment. Furthermore, the utilization of QDs is restricted owing to their cytotoxicity and water incompatibility. Surface modifications are also necessary to make them water dispersible [382, 383]. Extensive research work is ongoing regarding dye-doped silica nanoparticles in bioimaging and bio-analysis applications for the detection of various analytes including tumor necrosis factor-α, enterotoxins, bacteria, and cancer cells [380, 381, 384]. Zhao et al. have developed a rapid test for the analysis of the bacterial cell E. coli O157:H7 using bioconjugated Si nanoparticles [385]. An indirect homogeneous solution-based immunofluorescence microscopic method was developed for the detection of Mycobacterium tuberculosis using SiNPs [386]. However, reports suggest that the dye molecules doped inside the Si shell have high chances of leaching because of the porous nature of Si. They also require multistep reactions for the generation of functionality for the attachment of biological moieties [382, 383].

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1.10 Conclusion Technology is the main driving force for the progress of mankind since it provides a wealth of novel materials, devices, and machines capable of improving the quality of life. The term “nanotechnology” was included to describe the manufacturing of products with tolerances much less than 1 μm. It deals with the materials with the size range from 1 nm (molecular scale) to about 50 nm. They appear at the interface between condensed matter and isolated atoms/molecules. The essence of nanotechnology is the ability to work at the molecular level, atom by atom, to create large structures with fundamentally new molecular organization. Nanotechnologies are multidisciplinary by nature. Experimental sciences are converging toward the “nanoworld”: nanosciences, nanotechnology, nanostructures, nanomaterials, and nanoelectronics. Basic research in nanotechnology and obtained results say that “the possibilities of nanotechnology are endless.” Entirely new classes of incredibly strong, extremely light, and environmentally benign materials could be “created” and went on to discuss inexpensive nanostructures for broad applications. Feynman introduced the concept of building with molecules, “bottom-up” manufacturing, in contrast with the “topdown” manufacturing, we are familiar with. He suggested that almost any chemically stable structure, that can be specified, can in fact be built. Nanomaterials and ultrathin functional coatings of nanoparticles will determine the utility of many products in the future: superhard materials and superfast computers, dirt-repellent surfaces and new cancer treatments, scratchproof coatings, and environmentally friendly fuel cells with highly effective catalysts. Highly developed synthetic strategies to such nanoparticles or nanomaterials provide a well-defined geometry, core-shell thickness, and composition, and therefore give controllable properties. Nanoscience and nanotechnology belong to the broad interdisciplinary area comprising polymer and metal nanoparticles, nanoelectrics, supramolecular and colloid chemistry, nanostructured materials, biochemistry, and biology. Science is the most powerful means that mankind has to understand the working principles of the material world, as well as to change the world. Nanomaterials are implicated in several domains such as chemistry, electronics, high-density magnetic recording media, sensors, biotechnology, etc. Nano-sized materials have now emerged as one of the focal points of modern research. The most active nanoparticle research activities in the world include fundamental studies for generation, processing, characterization, and modeling; studies on metallic and composite particles; studies on particle colloidal properties of metal, metal/polymer and synthetic and natural polymer particles, and self-assembling techniques. Due to their extremely small size and large specific surface area, nanoparticles usually exhibit unusual physical and chemical properties compared to that of bulk materials. The “top-down approach miniaturization” is based on a progressive reduction of dimensions. These technologies are mostly based on lithography and pattern transfer, and address dimensions down to 10 nm. The “bottom-up approach” on the contrary relies on the atom per atom, or molecule per molecule building of functionalized elements and their self-organization.

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A self-organization process includes self-ordering, self-assembly, and self-limiting phenomena through which a huge number of nanostructures can fabricate in parallel processing, with atomic accuracies and within a practically acceptable time. Nanotechnology can be defined as the ability of taking advantage of the progress of science to create novel opportunities for practical applications. The essence of nanotechnology is the ability to work at the molecular level, atom by atom, to create large structures with fundamentally new molecular organization. Nanotechnology is a multidisciplinary field bringing together chemists, physicists, biologists, pharmacologists, physicians, clinicians, veterinarians and many other specialists. This is because of the scientific convergence of physics, chemistry, biology, materials, and engineering at nanoscale, and of the importance of the control of matter at nanoscale on almost all technologies. In chemistry, the range of sizes from a few nanometers to much less than 100 nm has historically been associated with colloids, micelles, polymer molecules, phase-separated regions in block copolymers, and similar structures—typically, very large molecules, or aggregates of many molecules. More recently, structures such as nanotubes, nanorods, nanowells, and compound semiconductor QDs have emerged as particularly interesting classes of nanostructures. In physics and electrical engineering, nanoscience is most often associated with quantum behavior, and the behavior of electrons and photons in nanoscale structures. Biology and biochemistry also have a deep interest in nanostructures as components of the cell; many of the most interesting structures in biology—from DNA and viruses to subcellular organelles and gap junctions—can be considered as nanostructures. Nanobiotechnology consists of two closely related sides; one focuses on developing nanotechnology with biologically related approaches while the other applies nanotechnology in biomedical studies. Biological systems such as cells and viruses are structured at the nanometer scale and function at the same scale. In that sense, they are natural, proven nanotechnology systems. It can deal, for example, with protein- and DNA-based nanostructures or devices. Proteins and DNA can self-assemble into various structures with nanometer-scale features. Such biological structures can be used as templates or scaffolds to prepare nanoconjugates with magnetic, plasmonic, semiconductive, polymer, inorganic, and composite nanoparticles. In chemistry, the range of sizes from a few nanometers to much less than 100 nm has historically been associated with colloids, micelles, polymer molecules, phase-separated regions in block copolymers, and similar structures—typically, very large molecules, or aggregates of many molecules. More recently, structures such as nanotubes, nanorods, nanowells, and compound semiconductor QDs have emerged as particularly interesting classes of nanostructures. In physics and electrical engineering, nanoscience is most often associated with quantum behavior, and the behavior of electrons and photons in nanoscale structures. Biology and biochemistry also have a deep interest in nanostructures as components of the cell; many of the most interesting structures in biology—from DNA and viruses to subcellular organelles and gap junctions—can be considered as nanostructures. Chemists can make new forms of matter by joining atoms and groups of atoms together with bonds. They carry out this subnanometer-scale activity—chemical synthesis—on megaton scales.

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Nanoparticles are seen either as agents of change of various phenomena and processes, or as building blocks of materials and devices with tailored characteristics. Use of nanoparticles aims to take advantage of properties that are caused by the confinement effects, larger surface area, interactions at length scales where wave phenomena have comparable features to the structural features, and the possibility of generating new atomic and macromolecular structures. Important applications of nanoparticles are in dispersions and coatings, functional nanostructures, consolidated materials, biological systems, and the environment. Preparation of nanoparticles enables the systematic characterization of the structural, physical, electronic, and optical properties of materials as they evolve from atom form or molecular to bulk via the nanometer size regime. In recent times, new methods of synthesis (inert gas condensation, layer deposition, ultrarapid quenching, mechanical attrition, aerosol, etc.) have been used to fabricate magnetic systems with characteristic dimensions on a nanometer scale. An ultimate goal of nanoparticle and nanocrystal research is to develop the ability to manipulate the size, morphology, and arrangement of these “superatoms” in such a fashion that their unique optical, electrical, and magnetic properties can be utilized for different applications. They have a characteristic high surface-to-volume ratio, providing sites for the efficient adsorption of the reacting substrates leading to unusual size dependent chemical reactivity. Atoms and molecules on the air/solid or liquid/solid surfaces have fewer neighbors than those in the subsurface or solid matrix. In many cases, the properties of these nanostructures change in an abrupt manner below a certain particle size, for example, the electrical conductivity or the type of magnetism. Small, single-domain particles exhibit an exotic magnetic behavior that allows them to reach a limiting magnetism (superparamagnetism) and excited states (light absorption, scattering and emitting, heat emitting). Because of confinement and quantum-size effect, a reduction in the dimension of metal domains produces dramatic changes in the behavior of the massive metal properties. A unique property of semiconductor nanoparticles, known as QD and metal nanoshell, is that they absorb and scatter light of the near infrared, a spectrum region where tissues are essentially transparent. QDs are highly light-absorbable and luminescent with absorbance onset and emission maximum shift to higher energy with decreasing particle size due to quantum confinement effects. These nanoparticles are in the size range of 2–8 nm in diameter. Unlike molecular fluorophores, which typically have very narrow excitation spectra, semiconductor QDs absorb light over a very broad spectral range. This makes it possible to optically excite a broad spectrum of QD colors using a single polyexcitation laser wavelength, which enables one to simultaneously probe several markers. Research into the use of nanoparticles in drug delivery is in progress, especially nanoparticulate and nanoporous materials for catalytic and biomaterials applications. This includes stimuli-responsive drug-delivery systems, which, for example, release insulin only when glucose concentration is high. The potential risks of nanoparticles are well known and broadly discussed. Health issues arise from the altered properties of nanomaterials. Questions concerning the inhalation or disposition of nanoparticles still remain

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open. A roadmap to safe nanotechnology should include the development and validation of testing methods and increased awareness of the potential environmental and biological hazards of nanoparticles and nanotechnology. Moreover, after in vivo administration NPs can differ considerably in size compared to the situation in vitro. In vivo, the particle’s surface can be covered by lipids and proteins (a so-called “biocorona”) depending on the particle’s material, electrical charge, and hydrophilicity, among others. Some NPs such as lipid-based nanocarriers (liposomes, stealth liposomes, solid lipid NPs, …), polymer-based nanocarriers (PNPs, polymeric micelles, …), metal, silica and inorganic nanoparticles, composite NPs, viral NPs, dendrimers, etc. can be loaded with drugs, bioactive agents, and diagnostic tools that can be absorbed on the surface, entrapped inside or dissolved within the matrix of the polymer or NP. For instance, the size of orally assumed NPs could somehow determine its fate addressing the kind of cell to interact with (i.e., epithelial or phagocytic cell), or the depth level in the intestinal tissue. Nowadays, experimental studies have mostly been conducted with spherical (liposomes, emulsions, capsules, spheres) or tubular (nanotubes) NPs, due in part to fabrication technology limitations in controlling their shape. Composition of nanoparticles may be of biologic or chemical origin. Biologic materials include phospholipids, lipids, lactic acid, dextran, chitosan, and albumin. Chemical materials include polymers, carbon, silica, and metals. Polymers, in turn, may have different chemical compositions. Chemistry is of crucial importance in safety issues as some nanosized constituents can result toxic. Green synthesis provides advancement over chemical and physical methods as it is cost effective, environment friendly, and easily scaled up for large-scale synthesis, where there is no need to use high pressure, energy, temperature, and toxic chemicals. The miniaturization of components for the construction of useful nanodevices and nanomachines can be pursued by the top-down and bottom-up approaches. The promising route for the fabrication of nanodevices is the use of metal, polymer, and composite nanoparticles as the building blocks. Efforts have been made to assemble nanoparticles into various nanostructures, such as one-, two-, and three-dimensional nanoparticle arrangements (1D, 2D, and 3D). In addition to the size and composition, the morphology and orientation of the nanoparticles play an important role in modulating the electronic and chemical properties. Million-fold fluorescence enhancement in gold nanorods and distinct quadruple plasmon resonances in silver nanoprisms are some exciting shapedependent properties that have already been reported. By using different functional nanoparticles and nanomaterials, it should be possible to give micro-/nanostructures, i.e., micro-/nanodevices and micro-/nanomachines, unique properties, which may allow for various applications. The single most important fabrication technology of our time is micro- and/or nanolithography. Applications of nanolithography include among others: multigate devices such as field effect transistors (FETs), QDs, nanowires, gratings, zone plates and photomasks, NEMS, or semiconductor integrated circuits (nanocircuitry).

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A particularly exciting class of such hybrid devices utilizes biomolecular motors, which can add active, chemically powered force generation and movement to the functionality of the device. Applications of devices based on biomolecular motors have been explored for nanoscale transport systems (molecular shuttles), surface imaging, force measurements, single molecule manipulation, and lab-on-a-chip systems. Different nanotechnologies have developed devices for continuous drug delivery over an extended period of time. Implantable devices with percutaneous components such as ambulatory peritoneal dialysis, catheters, intravenous catheters, and orthopedic implants are often associated with different failure modes. A nanochannel filter nanodevice offers good control of channel size and pore distribution, making it possible to control the release rate. Many efforts in the field of OLEDs have been made during recent years motivated by their potential for applications in display technology, for instance, to replace LCDs, which are currently used in computer and television screens. Within the science of nanomaterials, there has been some focus on novel methods for engineering thermoelectric microand nanodevices. In particular, thermoelectric devices were fabricated and evaluated for power generation and cooling performance. Thermoelectrics convert heat into electricity (Seebeck effect) and vice versa (Peltier effect). BME is raising increasing interest worldwide, due to the appealing possibility of realizing cheap and easy-to-fabricate devices exploiting the natural self-assembling, self-recognition, and self-repairing capability of biological matter. For any artificial molecular DNA-based device aimed for in vivo applications, a primary requirement is stability and biocompatibility. The nucleic acid structures must remain structurally intact during the functional relevant time period when exposed to bodily fluids. At the same time the devices should be sufficiently biocompatible such that they can be excreted from, or naturally degraded in, the human body to avoid toxicity. Furthermore, the devices must be able to evade immune recognition to avoid rapid clearance and reduce the risk of acute anaphylaxis shock. DNA nanostructures hold tremendous structural powers. Upon hybridization with its target, the device shifts conformation from a fluorescently quenched hairpin-like structure to a fluorescence linear state. The original design could detect specific nucleic acid sequences, e.g., miRNAs, SNP products of realtime PCR reactions. Several types of nucleic acid-based biosensors have been constructed throughout the years with a wide range of sensor capabilities usually leading to structural rearrangements. Many DNA-based devices with various abilities to detect, for instance, ions, small molecules, proteins and peptides, nucleic acid sequences, and pH have been designed. One of the most impressive therapeutic DNA nanodevices is the logic-gated DNA nanorobot. Instead of relying on delivery of a therapeutic cargo to the interior of targeted cells, the researchers induced cell-signaling pathways through binding of exterior receptors yielding a desired therapeutic response. The used origami was of a hexagonal barrelshaped design.

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Many technologies including electronics, separations, and coatings will be enhanced by the ability to control the structure of materials on a nanometer-length scale. Furthermore, the unique properties of nanoscale materials may give rise to entirely new technologies. One approach for constructing mesoscopic structures is to use solution-phase nanocrystals as “building blocks.” An alternative strategy for the formation of ordered nanoparticle arrays is the selforganization method based on biomolecular templates by direct or synergistic templating techniques. The template-directed synthesis of nanoparticle arrays in mesostructured silica, as well as helical nanostructures in unusual-shaped materials such as chiral lipid tubules were developed. Another strategy to utilize the advantages of self-organization processes by means of noncovalent interactions. Nanostructure fabrication from block copolymers involves polymer design, synthesis, self-assembly, and derivatization. Block copolymers self-assembled into micelle afford a powerful means of manipulating the characteristics of surfaces and interfaces, and therefore, are expected to have novel structures, properties, and applications. Surface properties may be imparted to PNPs by coating them with various substances. Moreover, coating with polymers or antibodies that bind specifically to a particular cell can help to better achieve targeted drug delivery. The usual course of a drug after administration follows the kinetic processes of absorption, distribution, metabolism, and elimination. Several kinds of nanosized carrier systems can be considered: water-soluble polymer, emulsion (dispersion), nanosphere, liposome, PNP, polymeric micelle. In general a carrier must be produced from materials that are biodegradable or, if not, residual material after drug delivery should be nontoxic. We can consider also porous materials that possess vast amounts of nanopores that allow the inclusion and retention of drugs, modulating their release in order to obtain controlled and sustained drug-delivery systems. Some polymers can be used also in combination to realize the “polymeric micelle” system of carriers. In this system drug is firstly incorporated into a matrix by both chemical conjugation and physical entrapment to realize the inner core. Secondly the core is entrapped in an outer shell composed by another polymer with other characteristics. The combination of polymer, magnetic and/or noble metal nanoparticles or other contrast media with nanoparticle drug carriers has resulted in dual-purpose (therapeutic and diagnostic) nanoparticles often referred to as “theranostics.” Drug-loaded polymer micelles self-assemble during formulation to form nanoparticles composed of an amphiphilic poly(ethylene glycol) corona, hydroxamic acid stabilizing middle block, and hydrophobic core block for drug encapsulation. Hydrophobic amino acids sequester drugs in the core of the micelle without the need for covalent attachment, which requires chemical or enzymatic cleavage for release. The development of a stable in vivo molecular DNA, polysaccharide, peptide, etc. device carrying the above-described characteristics could open up a new frontier in medical treatment. By combining these ideas, researchers could build injectable macromolecular devices capable of sensing diseased tissue followed by therapeutic intervention

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at the subcellular level. As an interesting prospect, future molecular machines could incorporate functional domains to perform active locomotion. Instead of relying on passive diffusion, the device could thus traffic its way around the body. Coupled with a sensing functionality, the devices could move in response to a chemical stimulus, seek out their specific target and initiate a relevant action when in reach (similarly to chemotaxis) yielding a highly sophisticated nanorobot. The realization of such devices would enable us to treat diseases or molecular dysfunctions at an entire new level, which would lead to great improvement to human health. As summarized above, DNA nanotechnology holds many of the properties required for the realization of such devices. Throughout the past three decades, researchers have succeeded in addressing key challenges and developed both dynamic and therapeutic DNA devices capable of responding to external stimuli. The modularity of DNA nanostructures will enable researchers to build even more complex multifunctional devices as already demonstrated. Although challenges still lie ahead, research continue to push the technological limits beyond what anyone would have imagined possible just a few years ago. DNA nanodevices have become established as one of the most promising multifunctional gadgets and will undoubtedly become even more widespread in the future.

Abbreviations 1D 2D 3D AFAM AFM AgNP API AuNP BME CFM CMC CNS CpG CS-AFM DNA DPN dsDNA E. coli E-beam EFM EM EPR EVOH Fab’ FET

one dimensional two dimensional three dimensional atomic force acoustic microscopy atomic force microscopes silver nanoparticle active pharmaceutical ingredient gold nanoparticle biomolecular electronics chemical force microscopy critical micelle concentration central nervous system oligodeoxynucleotides current sensing atomic force microscopy deoxyribonucleic acid din-pen nanolithography double-stranded DNA Escherichia coli electron beam electrical force microscopy electromagnetic enhanced permeation and retention ethylene-vinyl alcohol copolymer antibody fragment field effect transistor

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FFM FIA FIB FITC GOx HRP HTL IBD IETS ITO LB LCD LEC LED LFM LSP MEMS MFM MF-STM MiP miRNA MNP MPC MPEG MRI MST MTs NAD+ nDSs NEMS NF-κB NIL NP OLED PBG PCR PDMS PEDOT PEG PLA PLED PLGA PMMA PNP PSMA PSt PStS PU PUM

friction force microscopy fluorescent immunoassays focused ion beam fluorescein isothiocyanate glucose oxidase horseradish peroxidase hole-transporting layer inflammatory bowel disease inelastic electron tunneling spectroscopy indium tin oxide Langmuir-Blodgett liquid-crystal display light-emitting electrochemical cell light-emitting diode lateral force microscopy localized surface plasmons micro-electrical-mechanical systems magnetic force microscopy magnetic force scanning tunneling microparticle microRNA metal nanoparticle monolayer protected cluster methoxy PEG magnetic resonance imaging microsystems technologies, as known in Europe microtubules nicotinamide adenine dinucleotide nanochannel delivery systems nanoelectromechanical system nuclear factor-κB nanoimprint-based lithography nanoparticle organic light-emitting diode produce photonic bandgap polymerase chain reaction poly(dimethylsiloxane) poly(3,4-ethylenedioxythiophene) poly(ethylene glycol) polylactide polymer-based LED poly(lactic-co-glycolic acid) poly(methyl methacrylate) polymer NP prostate-specific membrane antigen as a targeting agent polystyrene poly(styrene sullonate) poly(urethane) polyurethane micelles

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PVA QD R&D RNA RNAi RTG SAM SEM SERS SFM SiNP siRNA SMOLED SMS SNOM SNP SPIO SPL SPM SP-STM SSIL STM STS TEM TEs TM-AFM TNBS TNF TPA UHV VEGF w/o

polyvinyl alcohol quantum dots research and development ribonucleic acid RNA interference radioisotope thermoelectric generators self-assembled monolayer scanning electron microscopy surface-enhanced Raman scattering shear force microscopy silica NP small (or short) interfering RNA small-molecule OLED single-molecule spectroscopy scanning near-field optical microscopy single-nucleotide polymorphism superparamagnetic iron oxide scanning probe lithography scanning probe microscopy spin-polarized scanning tunneling microscopy step-and-stamp imprint lithography scanning tunneling microscopes scanning tunneling spectroscopy transmission electron microscopy thermoelectrics tapping mode atomic force microscopy trinitrobenzene sulfonic acid antitumor necrosis factor two-photon absorption ultra-high vacuum vascular endothelial growth factor water-in-oil

References [1] Tartaj P, Morales M, Veintemillas-Verdaguer S, Gonzalez Carreno T, Serna C. The preparation of magnetic nanoparticles for applications in biomedicine. J Phys 2003;36:R182–97. [2] Mirkin CA. The beginning of a small revolution. Small 2005;1:14–9. [3] Wang DC. An example in the curriculum development of nanotechnology. In: International conference on engineering education, August 6-10, Oslo, Norway, Session 8B2; 2001. p. 12. pin A, Chen Y, Mejias M, Lebib A, et al. Appl Surf Sci 2000;164:111–7. [4] Vieu C, Carcenac F, Pe [5] Daniel MC, Astruc D. Gold nanoparticles: assembly, supramolecular chemistry, quantum-sizerelated properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev 2004;104:293–346. [6] Roco MC, Li BC, Fissan HJ, Schoonman J, Hayashi C, Oda M. Reviews of national research programs in nanoparticle and nanotechnology research. J Aerosol Sci 1998;29:749–60.

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