Molecularly imprinted polymer

From Wikipedia, the free encyclopedia

 

A molecularly imprinted polymer (MIP) is a polymer that has been processed using the molecular imprinting technique which leaves cavities in the polymer matrix with an affinity for a chosen "template" molecule. The process usually involves initiating the polymerization of monomers in the presence of a template molecule that is extracted afterwards, leaving behind complementary cavities. These polymers have affinity for the original molecule and have been used in applications such as chemical separations, catalysis, or molecular sensors. Published works on the topic date to the 1930s.

Molecular imprinting techniques (state of the art and perspectives)

Molecular imprinting is the process of generating an impression within a solid or a gel, the size, shape and charge distribution of which corresponds to a template molecule (typically present during polymerisation). The result is a synthetic receptor capable of binding to a target molecule, which fits into the binding site with high affinity and specificity. The interactions between the polymer and the template are similar to those between antibodies and antigens, consisting of electrostatic interactions, hydrogen bonds, Van der Waals forces, and hydrophobic interactions. 

One of the greatest advantages of artificial receptors over naturally occurring receptors is freedom of molecular design. Their frameworks are not restricted to proteins, and a variety of skeletons (e.g., carbon chains and fused aromatic rings) can be used. Thus, the stability, flexibility, and other properties are freely modulated according to need. Even functional groups that are not found in nature can be employed in these synthetic compounds. Furthermore, when necessary, the activity in response towards outer stimuli (photo-irradiation, pH change, electric or magnetic field, and others) can be provided by using appropriate functional groups.

In a molecular imprinting processes, one needs a 1) template, 2) functional monomer(s) 3) cross-linker, 4) radical or other polymerization initiator, 5) porogenic solvent and 6) extraction solvent. According to polymerization method and final polymer format one or some of the reagent can be avoided.

There are two main methods for creating these specialized polymers. The first is known as self-assembly, which involves the formation of polymer by combining all elements of the MIP and allowing the molecular interactions to form the cross-linked polymer with the template molecule bound. The second method of formation of MIPs involves covalently linking the imprint molecule to the monomer. After polymerization, the monomer is cleaved from the template molecule. The selectivity is greatly influenced by the kind and amount of cross-linking agent used in the synthesis of the imprinted polymer. The selectivity is also determined by the covalent and non-covalent interactions between the target molecule and monomer functional groups. The careful choice of functional monomer is another important choice to provide complementary interactions with the template and substrates. In an imprinted polymer, the cross-linker fulfills three major functions: First of all, the cross-linker is important in controlling the morphology of the polymer matrix, whether it is gel-type, macroporous or a microgel powder. Secondly, it serves to stabilize the imprinted binding site. Finally, it imparts mechanical stability to the polymer matrix. From a polymerization point of view, high cross-link ratios are generally preferred in order to access permanently porous materials and in order to be able to generate materials with adequate mechanical stability. 

The self-assembly method has advantages in the fact that it forms a more natural binding site, and also offers additional flexibility in the types of monomers that can be polymerized. The covalent method has its advantages in generally offering a high yield of homogeneous binding sites, but first requires the synthesis of a derivatized imprint molecule and may not imitate the "natural" conditions that could be present elsewhere. Over the recent years, interest in the technique of molecular imprinting has increased rapidly, both in the academic community and in the industry. Consequently, significant progress has been made in developing polymerization methods that produce adequate MIP formats with rather good binding properties expecting an enhancement in the performance or in order to suit the desirable final application, such as beads, films or nanoparticles. One of the key issues that have limited the performance of MIPs in practical applications so far is the lack of simple and robust methods to synthesize MIPs in the optimum formats required by the application. Chronologically, the first polymerization method encountered for MIP was based on "bulk" or solution polymerization. This method is the most common technique used by groups working on imprinting especially due to its simplicity and versatility. It is used exclusively with organic solvents mainly with low dielectric constant and consists basically of mixing all the components (template, monomer, solvent and initiator) and subsequently polymerizing them. The resultant polymeric block is then pulverized, freed from the template, crushed and sieved to obtain particles of irregular shape and size between 20 and 50 µm. Depending on the target (template) type and the final application of the MIP, MIPs are appeared in different formats such as nano/micro spherical particles, nanowires and thin film or membranes. They are produced with different polymerization techniques like bulk, precipitation, emulsion, suspension, dispersion, gelation, and multi-step swelling polymerization. Most of investigators in the field of MIP are making MIP with heuristic techniques such as hierarchical imprinting method. The technique for the first time was used for making MIP by Sellergren et al. for imprinting small target molecules. With the same concept, Nematollahzadeh et al. developed a general technique, so-called polymerization packed bed, to obtain hierarchically-structured, high capacity protein imprinted porous polymer beads by using silica porous particles for protein recognition and capture.

Solid-phase synthesis

Solid-phase molecular imprinting has been recently developed as an alternative to traditional bulk imprinting, generating water-soluble nanoparticles. As the name implies, this technique requires the immobilisation of the target molecule on a solid support prior to performing polymerisation. This is analogous to solid-phase synthesis of peptides. The solid phase doubles as an affinity separation matrix, allowing the removal of low-affinity MIPs and overcoming many of the previously described limitations of MIPs:

• Separation of MIPs from the immobilised template molecule is greatly simplified.
• Binding sites are more uniform, and template molecules cannot become trapped within the polymer matrix.
• MIPs can be functionalised post-synthesis (whilst attached to the solid phase) without significantly influencing binding sites.
• The immobilised template can be reused, reducing the cost of MIP synthesis.

MIP nanoparticles synthesised via this approach have found applications in various diagnostic assay and sensors.

Molecular modelling

Molecular modelling has become a convenient choice in MIP design and analysis, allowing rapid selection of monomers and optimisation of polymer composition, with a range of different techniques being applied. The application of molecular modelling in this capacity is commonly attributed to Sergey A. Piletsky, who developed a method of automated screening of a large database of monomers against a given target or template with a molecular mechanics approach. In recent years technological advances have permitted more efficient analysis of monomer-template interactions by quantum mechanical molecular modelling, providing more precise calculations of binding energies. Molecular dynamics has also been applied for more detailed analysis of systems before polymerisation, and of the resulting polymer, which by including more system components (cross-linkers, solvents) provide greater accuracy in predicting successful MIP synthesis than monomer-template interactions alone. Molecular modelling, particular molecular dynamics and the less common coarse-grained techniques, can often also be integrated into greater theoretical models permitting thermodynamic analysis and kinetic data for mesoscopic analysis of imprinted polymer bulk monoliths and MIP nanoparticles.

Applications

Niche areas for application of MIPs are in sensors and separation. Despite the current good health of molecular imprinting in general, one difficulty which appears to remain to this day is the commercialization of molecularly imprinted polymers. Despite this, many patents (1035 patents, up to October 2018, according to the Scifinder data base) on molecular imprinting were held by different groups. Commercial interest is also confirmed by the fact that MIP Technologies, offers a range of commercially available MIP products and Sigma-Aldrich produces SupelMIP for beta-agonists, beta-blockers, pesticides and some drugs of abuse such as amphetamine. Additionally, POLYINTELL designs, manufactures and markets AFFINIMIPSPE products for instance for mycotoxins such as patulin, zearalenone, fumonisins, ochratoxin A, for endocrine disruptors (bisphenol A, estrogen derivatives etc...) or for the purification of radiotracers before their use in positron emission tomography (PET).

Fast and cost-effective molecularly imprinted polymer technique has applications in many fields of chemistry, biology and engineering, particularly as an affinity material for sensors, detection of chemical, antimicrobial, and dye, residues in food, adsorbents for solid phase extraction, binding assays, artificial antibodies, chromatographic stationary phase, catalysis, drug development and screening, and byproduct removal in chemical reaction. Molecular imprinted polymers pose this wide range of capabilities in extraction through highly specific micro-cavity binding sites. Due to the specific binding site created in a MIP this technique is showing promise in analytical chemistry as a useful method for solid phase extraction. The capability for MIPs to be a cheaper easier production of antibody/enzyme like binding sites doubles the use of this technique as a valuable breakthrough in medical research and application. Such possible medical applications include "controlled release drugs, drug monitoring devices, and biological receptor mimetics". Beyond this MIPs show a promising future in the developing knowledge and application in food sciences.

"Plastic antibodies" The binding activity of MIPs can be two magnitudes of activity lower than that of specific antibodies. These binding sites, though not as strong as antibodies, are still highly specific that can be made easily and relatively cheaply. This yields a wide variety of applications for MIPs from efficient extraction to pharmaceutical/medical uses. MIPs offer many advantages over protein binding sites. Proteins are difficult and expensive to purify, denature (pH, heat, proteolysis), and are difficult to immobilize for reuse. Synthetic polymers are cheap, easy to synthesize, and allow for elaborate, synthetic side chains to be incorporated. Unique side chains allow for higher affinity, selectivity, and specificity. 

Molecularly imprinted assays Molecularly imprinted polymers arguably demonstrate their greatest potential as alternative affinity reagents for use in diagnostic applications, due to their comparable (and in some regards superior) performance to antibodies. Many studies have therefore focused on the development of molecularly imprinted assays (MIAs) since the seminal work by Vlatakis et al. in 1993, where the term “molecularly imprinted [sorbet] assay” was first introduced. Initial work on ligand binding assays utilising MIPs in place of antibodies consisted of radio-labelled MIAs, however the field has now evolved to include numerous assay formats such as fluorescence MIAs, enzyme-linked MIAs, and molecularly imprinted nanoparticle assay (MINA).

Molecularly imprinted polymers have also been used to enrich low abundant phosphopeptides from a cell lysate, outperforming titanium dioxide (TiO₂) enrichment- a gold standard to enrich phosphopeptides.

History

In a paper published in 1931, Polyakov reported the effects of presence of different solvents (benzene, toluene and xylene) on the silica pore structure during drying a newly prepared silica. When H₂SO₄ was used as the polymerization initiator (acidifying agent), a positive correlation was found between surface areas, e.g. load capacities, and the molecular weights of the respective solvents. Later on, in 1949 Dickey reported the polymerization of sodium silicate in the presence of four different dyes (namely methyl, ethyl, n-propyl and n-butyl orange). The dyes were subsequently removed, and in rebinding experiments it was found that silica prepared in the presence of any of these "pattern molecules" would bind the pattern molecule in preference to the other three dyes. Shortly after this work had appeared, several research groups pursued the preparation of specific adsorbents using Dickey's method. Some commercial interest was also shown by the fact that Merck patented a nicotine filter, consisting of nicotine imprinted silica, able to adsorb 10.7% more nicotine than non-imprinted silica. The material was intended for use in cigarettes, cigars and pipes filters. Shortly after this work had appeared, molecular imprinting attracted wide interest from the scientific community as reflected in the 4000 original papers published in the field during for the period 1931–2009 (from Scifinder). However, although interest in the technique is new, commonly the molecularly imprinted technique has been shown to be effective when targeting small molecules of molecular weight less than 1000. Therefore, in following subsection molecularly imprinted polymers are reviewed into two categories, for small and big templates.

Production limitations

Production of novel MIPs has implicit challenges unique to this field. These challenges arise chiefly from the fact that all substrates are different and thus require different monomer and cross-linker combinations to adequately form imprinted polymers for that substrate. The first, and lesser, challenge arises from choosing those monomers which will yield adequate binding sites complementary to the functional groups of the substrate molecule. For example, it would be unwise to choose completely hydrophobic monomers to be imprinted with a highly hydrophilic substrate. These considerations need to be taken into account before any new MIP is created. Molecular modelling can be used to predict favourable interactions between templates and monomers, allowing intelligent monomer selection.

Secondly, and more troublesome, the yield of properly created MIPs is limited by the capacity to effectively wash the substrate from the MIP once the polymer has been formed around it. In creating new MIPs, a compromise must be created between full removal of the original template and damaging of the substrate binding cavity. Such damage is generally caused by strong removal methods and includes collapsing of the cavity, distorting the binding points, incomplete removal of the template and rupture of the cavity. 

Challenges of Template Removal for Molecular Imprinted Polymers

Template removal

Most of the developments in MIP production during the last decade have come in the form of new polymerization techniques in an attempt to control the arrangement of monomers and therefore the polymers structure. However, there have been very few advances in the efficient removal of the template from the MIP once it has been polymerized. Due to this neglect, the process of template removal is now the least cost efficient and most time consuming process in MIP production. Furthermore, in order of MIPs to reach their full potential in analytical and biotechnological applications, an efficient removal process must be demonstrated. 

There are several different methods of extraction which are currently being used for template removal. These have been grouped into 3 main categories: Solvent extraction, physically assisted extraction, and subcritical or supercritical solvent extraction.

Solvent extraction

• Soxhlet extraction This has been a standard extraction method with organic solvents since its creation over a century ago. This technique consists of placing the MIP particles into a cartridge inside the extraction chamber, and the extraction solvent in poured into a flask connected to the extractor chamber. The solvent is then heated and condenses inside the cartridge thereby contacting the MIP particles and extracting the template. The main advantages to this technique are the repeated washing of MIP particles with fresh extracting solvent, favors solubilization because it uses hot solvent, no filtration is required upon completion to collect the MIP particles, the equipment is affordable, and it is very versatile and can be applied to nearly any polymer matrix. The main disadvantages are the long extraction time, the large amount of organic solvent used, the possibility or degradation for temperature sensitive polymers, the static nature of the technique does not facilitate solvent flow through MIP, and the automation is difficult.
• Incubation This involves the immersion of the MIPs into solvents that can induce swelling of the polymer network and simultaneously favor the dissociation of the template from the polymer. Generally this method is carried out under mild conditions and the stability of the polymer is not affected. However, much like the Soxhlet extraction technique, this method also is very time consuming.
• Solid-phase template As described above, one benefit of immobilising the template molecule on a solid support such as glass beads is the easy removal of the MIPs from the template. Following a cold wash to remove unreacted monomers and low-affinity polymers, hot solvent can be added to disrupt binding and allow the collection of high affinity MIPs.

Physically-assisted extraction

• Ultrasound-assisted extraction (UAE) This method uses Ultrasound which is a cyclic sound pressure with a frequency greater than 20 kHz. This method works through the process known as cavitation which forms small bubbles in liquids and the mechanical erosion of solid particles. This causes a local increase in temperature and pressure which favor solubility, diffusivity, penetration and transport of solvent and template molecules.
• Microwave-assisted extraction (MAE) This method uses microwaves which directly interact with the molecules causing Ionic conduction and dipole rotation. The use of microwaves for extraction make the extraction of the template occur rapidly, however, one must be careful to avoid excessively high temperatures if the polymers are heat sensitive. This has the best results when the technique is used in concert with strong organic acids, however, this poses another problem because it may cause partial MIP degradation as well. This method does have some benefits in that it significantly reduces the time required to extract the template, decreases the solvent costs, and is considered to be a clean technique.
• Mechanical method A study has shown that the microcontact molecular imprinting method allows mechanical removal of the target (large biomolecules, proteins etc.) from the template. This technology combined with biosensor applications is promising for biotechnological, environmental and medical applications.

Subcritical or supercritical solvent extraction

• Subcritical water (PHWE) This method employs the use of water, which is the cheapest and greenest solvent, under high temperatures (100–374 C) and pressures ( 10–60 bar). This method is based upon the high reduction in polarity that liquid water undergoes when heated to high temperatures. This allows water to solubilize a wide variety of polar, ionic and non-polar compounds. The decreased surface tension and viscosity under these conditions also favor diffusivity. Furthermore, the high thermal energy helps break intermolecular forces such as dipole-dipole interactions, vander Waals forces, and hydrogen bonding between the template and the matrix.
• Supercritical CO₂ (SFE)

Artificial enzyme

From Wikipedia, the free encyclopedia

Schematic drawing of artificial phosphorylase

 

An artificial enzyme is a synthetic, organic molecule or ion that recreate some function of an enzyme. The area promises to deliver catalysis at rates and selectivity observed in many enzymes.

History

Enzyme catalysis of chemical reactions occur with high selectivity and rate. The substrate is activated in a small part of the enzyme's macromolecule called the active site. There, the binding of a substrate close to functional groups in the enzyme causes catalysis by so-called proximity effects. It is possible to create similar catalysts from small molecule by combining substrate-binding with catalytic functional groups. Classically artificial enzymes bind substrates using receptors such as cyclodextrin, crown ethers, and calixarene.

Artificial enzymes based on amino acids or peptides as characteristic molecular moieties have expanded the field of artificial enzymes or enzyme mimics. For instance, scaffolded histidine residues mimics certain metalloproteins and -enzymes such as hemocyanin, tyrosinase, and catechol oxidase).

Artificial enzymes have been designed from scratch via a computational strategy using Rosetta. In December 2014, it was announced that active enzymes had been produced that were made from artificial molecules which do not occur anywhere in nature. In 2017, a book chapter entitled "Artificial Enzymes: The Next Wave" was published.

Nanozymes

Nanozymes are nanomaterials with enzyme-like characteristics. They have been widely explored for various applications, such as biosensing, bioimaging, tumor diagnosis and therapy, antibiofouling.

1990s

In 1996 and 1997, Dugan et al. discovered the superoxide dismutase (SOD) mimicking activities of fullerene derivatives.

2000s

In 2004, the term "nanozymes" was coined by Flavio Manea, Florence Bodar Houillon, Lucia Pasquato, and Paolo Scrimin. In 2006, nanoceria (i.e., CeO2 nanoparticles) was used for preventing retinal degeneration induced by intracellular peroxides. In 2007, Xiyun Yan and coworkers reported that ferromagnetic nanoparticles possessed intrinsic peroxidase-like activity. In 2008, Hui Wei and Erkang Wang developed an iron oxide nanozyme based sensing platform for bioactive molecules (such as hydrogen peroxide and glucose).

2010s

In 2010 and 2011, graphene oxide with peroxidase-like activity was reported. In 2012, recombinant human heavy-chain ferritin coated iron oxide nanoparticle with peroxidase-like activity was prepared and used for targeting and visualizing tumour tissues. In 2012, vanadium pentoxide nanoparticles with vanadium haloperoxidase mimicking activities were used for preventing marine biofouling. In 2014, it was demonstrated that carboxyfullerene could be used to treat neuroprotection postinjury in Parkinsonian nonhuman primates. Peroxidase-like polyoxometalate derivatives were developed as functional anti-amyloid agents for Alzheimer’s disease. V2O5 nanozymes with cytoprotective function was reported. In 2015, a supramolecular regulation strategy was proposed to modulate the activity of gold-based nanozymes for imaging and therapeutic applications. A nanozyme-strip for rapid local diagnosis of Ebola was developed. Nanoceria nanozymes were used for DNA sensing. An integrated nanozyme has been developed for real time monitoring the dynamic changes of cerebral glucose in living brains. Cu(OH)2 nanozymes with peroxidase-like activities were reported. Ionic FePt, Fe3O4, Pd, and CdSe NPs with peroxidase-like activities were reported. A book entitled "Nanozymes: Next Wave of Artificial Enzymes" was published. A book chapter entitled "Nanozymes" in the book of "Enzyme Engineering" was published (in Chinese). Oxidase-like nanoceria has been used for developing self-regulated bioassays. Multi-enzyme mimicking Prussian blue was developed for therapeutics. Histidine was used to modulate iron oxide nanoparticles' peroxidase mimicking activities. Gold nanoparticles' peroxidase mimicking activities were modulated via a supramolecular strategy for cascade reactions. A molecular imprinting strategy was developed to improve the selectivity of Fe3O4 nanozymes with peroxidase-like activity. A new strategy was developed to enhance the peroxidase mimicking activity of gold nanoparticles by using hot electrons. Researchers have designed gold nanoparticles (AuNPs) based integrative nanozymes with both SERS and peroxidase mimicking activities for measuring glucose and lactate in living tissues. Cytochrome c oxidase mimicking activity of Cu2O nanoparticles was modulated by receiving electrons from cytochrome c. Fe3O4 NPs were combined with glucose oxidase for tumor therapeutics. Manganese dioxide nanozymes have been used as cytoprotective shells. Mn3O4 Nanozyme for Parkinson's Disease (cellular model) was reported. Heparin elimination in live rats has been monitored with 2D MOF based peroxidase mimics and AG73 peptide. Glucose oxidase and iron oxide nanozymes were encapsulated within multi-compartmental hydrogels for incompatible tandem reactions. A cascade nanozyme biosensor was developed for detection of viable Enterobacter sakazakii. An integrated nanozyme of GOx@ZIF-8(NiPd) was developed for tandem catalysis. Charge-switchable nanozymes were developed. Site-selective RNA splicing nanozyme was developed. A nanozymes special issue in Progress in Biochemistry and Biophysics was published. Mn3O4 nanozymes with ROS scavenging activities have been developed for in vivo anti-inflammation. A concept entitled "A Step into the Future – Applications of Nanoparticle Enzyme Mimics" was proposed. Facet-dependent oxidase and peroxidase-like activities of Pd nanoparticles were reported. Au@Pt multibranched nanostructures as bifunctional nanozymes were developed. Ferritin coated carbon nanozymes were developed for tumor catalytic therapy. CuO nanozymes were developed to kill bacteria via a light-controlled manner. Enzymatic activity of oxygenated CNT was studied. Nanozymes were used to catalyze the oxidation of l-Tyrosine and l-Phenylalanine to dopachrome. Nanozyme as an emerging alternative to natural enzyme for biosensing and immunoassay was summarized. Standardized assay was proposed for peroxidase-like nanozymes. Semiconductor QDs as nucleases for site-selective photoinduced cleavage of DNA. 2D-MOF nanozyme-based sensor arrays was constructed for detecting phosphates and probing their enzymatic hydrolysis. N-doped carbon nanomaterials as specific peroxidase mimics were reported. Nanozyme sensor arrays were developed to detect analytes from small Molecules to proteins and cells. Copper oxide nanozyme for Parkinson’s Disease was reported. Exosome-like nanozyme vesicles for tumor Imaging was developed. A comprehensive review on nanozymes was published by Chemical Society Reviews. A progress report on nanozymes was published. eg occupancy as an effective descriptor was developed for the catalytic activity of perovskite oxide-based peroxidase mimics. A Chemical Reviews on nanozymes was published. A single-atom strategy was used for developing nanozymes. Nanozyme for metal-free bioinspired cascade photocatalysis was reported.

Conferences

Several conferences have focused on nanozymes. In 2015, a nanozyme workshop for was held at the 9th Asian Biophysics Associatation (ABA) Symposium. In Pittcon 2016, a Networking entitled "Nanozymes in Analytical Chemistry and Beyond" was devoted to nanozymes. An Xiangshan Science Conference was devoted to nanozyme research. A scientific session was devoted to "Biomimetic Nanocatalysis" in 15th Chinese Biophysics Congress. The "Nanozymes for Bioanalysis (Oral)" section was included in the 256th ACS National Meeting (2018 Fall, Boston).

Nanoparticle–biomolecule conjugate

From Wikipedia, the free encyclopedia

Attachments on nanoparticles make them more biocompatible.

 

A nanoparticle–biomolecule conjugate is a nanoparticle with biomolecules attached to its surface. Nanoparticles are minuscule particles, typically measured in nanometers (nm), that are used in nanobiotechnology to explore the functions of biomolecules. Properties of the ultrafine particles are characterized by the components on their surfaces more so than larger structures, such as cells, due to large surface area-to-volume ratios. Large surface area-to-volume-ratios of nanoparticles optimize the potential for interactions with biomolecules.

Characterization

Major characteristics of nanoparticles include volume, structure, and visual properties that make them valuable in nanobiotechnology. Depending on specific properties of size, structure, and luminescence, nanoparticles can be used for different applications. Imaging techniques are used to identify such properties and give more information about the tested sample. Techniques used to characterize nanoparticles are also useful in studying how nanoparticles interact with biomolecules, such as amino acids or DNA, and include magnetic resonance imaging (MRI), denoted by the solubility of the nanoparticles in water and fluorescent. MRI can be applied in the medical field to visualize structures; atomic force microscopy (AFM) that gives a topographic view of the sample on a substrate; transmission electron microscopy (TEM) that gives a top view, but with a different technique then that of atomic force microscopy; Raman spectroscopy or surface enhanced Raman spectroscopy (SERS) gives information about wavelengths and energy in the sample. ultraviolet-visible spectroscopy (UV-Vis) measures the wavelengths where light is absorbed; X-ray diffraction (XRD) generally gives an idea of the chemical composition of the sample.

Chemistry

Physical

Nanomolecules can be created from virtually any element, but the majority produced in today's industry use carbon as the basis upon which the molecules are built around. Carbon can bond with nearly any element, allowing many possibilities when it comes to creating a specific molecule. Scientists can create thousands upon thousands of individual nanomolecules from a simple carbon basis. Some of the most famous nanomolecules currently in existence are solely carbon; these include carbon nanotubes and buckminsterfullerenes. In contrast with nanomolecules, the chemical components of nanoparticles usually consist of metals, such as iron, gold, silver, and platinum.

Interactions between nanoparticles and molecules change depending on the nanoparticle's core. Nanoparticle properties depend not only on the composition of the core material, but also on varying thicknesses of material used. Magnetic properties are particularly useful in molecule manipulation, and thus metals are often used as core material. Metals contain inherent magnetic properties that allow for manipulation of molecular assembly. As nanoparticles interact with molecules via ligand properties, molecular assembly can be controlled by external magnetic fields interacting with magnetic properties in the nanoparticles. Significant problems with producing nanoparticles initially arise once these nanoparticles are generated in solution. Without the use of a stabilizing agent, nanoparticles tend to stick together once the stirring is stopped. In order to counteract this, a certain collidial stabilizer is generally added. These stabilizers bind to the nanoparticles in a way that prevents other particles from bonding with them. Some effective stabilizers found so far include citrate, cellulose, and sodium borohydride.

Application chemistry

Nanoparticles are desirable in today's industry for their high surface area-to-volume ratio in comparison with larger particles of the same elements. Because chemical reactions occur at a rate directly proportional to the available surface area of reactant compounds, nanoparticles can generate reactions at a much faster rate than larger particles of equal mass. Nanoparticles therefore are among the most efficient means of producing reactions and are inherently valuable in the chemical industry. The same property makes them valuable in interactions with molecules.

Applications with biomolecules and biological processes

Nanoparticles have the potential to greatly influence biological processes. The potency of a nanoparticle increases as its surface area-to-volume-ratio does. Attachments of ligands to the surface of nanoparticles allow them to interact with biomolecules.

Identification of biomolecules

Nanoparticles are valuable tools in identification of biomolecules, through the use of bio-tagging or labeling. Attachments of ligands or molecular coatings to the surface of a nanoparticle facilitate nanoparticle-molecule interaction, and make them biocompatible. Conjugation can be achieved through intermolecular attractions between the nanoparticle and biomolecule such as covalent bonding, chemisorption, and noncovalent interactions.

To enhance visualization, nanoparticles can also be made to fluoresce by controlling the size and shape of a nanoparticle probe. Fluorescence increases luminescence by increasing the range of wavelengths the emitted light can reach, allowing for biomarkers with a variety of colors. This technique is used to track the efficacy of protein transfer both in vivo and in vitro in terms of genetic alternations.

Biological process control

Biological processes can be controlled through transcription regulation, gene regulation, and enzyme inhibition processes that can be regulated using nanoparticles. Nanoparticles can play a part in gene regulation through ionic bonding between positively charged cationic ligands on the surfaces of nanoparticles and negatively charged anionic nucleic acids present in DNA. In an experiment, a nanoparticle-DNA complex inhibited transcription by T7 RNA polymerase, signifying strong bonding in the complex. A high affinity of the nanoparticle-DNA complex indicates strong bonding and a favorable use of nanoparticles. Attaching ionic ligands to nanoparticles allows control over enzyme activity. An example of enzyme inhibition is given by binding of a-chymotrypsin (ChT), an enzyme with a largely cationic active site. When a-chymotrypsin is incubated with anionic (negatively charged) nanoparticles, ChT activity is inhibited as anionic nanoparticles bind to the active site. Enzyme activity can be restored by the addition of cationic surfactants. Alkyl surfactants form a bilayer around ChT, whereas thiol and alcohol surfactants alter the surface of ChT such that interactions with nanoparticles are interrupted. Though formation of a protein-nanoparticle complex can inhibit enzyme activity, studies show that it can also stabilize protein structure, and significantly protect the protein from denaturization. Attachments of ligands to segments of nanoparticles selected for functionalization of metallic properties can be used to generate a magnetic nanowire, which generates a magnetic field that allows for the manipulation of cellular assemblies.

Genetic alteration

Nanoparticles can also be used in conjunction with DNA to perform genetic alterations. These are frequently monitored through the use of fluorescent materials, allowing scientists to judge if these tagged proteins have successfully been transmitted—for example green fluorescent protein, or GFP. Nanoparticles are significantly less cytotoxic than currently used organic methods, providing a more efficient method of monitoring genetic alternations. They also do not degrade or bleach with time, as organic dyes do. Suspensions of nanoparticles with the same size and shapes (mono-dispersed) with functional groups attached to their surfaces can also electrostatically bind to DNA, protecting them from several types of degradation. Because the fluorescence of these nanoparticles does not degrade, cellular localization can be tracked without the use of additional tagging, with GFPs or other methods. The 'unpacking' of the DNA can be detected in live cells using luminescence resonance energy transfer (LRET) technology.

Medical implications

Small molecules in vivo have a short retention time, but the use of larger nanoparticles does not. These nanoparticles can be used to avoid immune response, which aids in the treatment of chronic diseases. It has been investigated as a potential cancer therapy and also has the potential to affect the understanding of genetic disorders. Nanoparticles also have the potential to aid in site-specific drug delivery by improving the amount of unmodified drug that is circulated within the system, which also decreases the necessary dosage frequency. The targeted nature of nanoparticles also means that non-targeted organs are much less likely to experience side effects of drugs intended for other areas.

Studying cell interactions

Cellular interactions occur at a microscopic level and cannot be easily observed even with the advanced microscopes available today. Due to difficulties observing reactions at the molecular level, indirect methods are used which greatly limits the scope of the understanding that can be gained by studying these processes essential to life. Advances in the material industry has evolved a new field known as nanobiotechnology, that uses nanoparticles to study interactions at the biomolecular level.

One area of research featuring nanobiotechnology is the extracellular matrices of cells (ECM). The ECM is primarily composed of interwoven fibers of collagen and elastin that have diameters ranging from 10–300 nm. In addition to holding the cell in place, the ECM has a variety of other functions including providing a point of attachment for the ECM of other cells and transmembrane receptors that are essential for life. Until recently it has been nearly impossible to study the physical forces that help cells maintain their functionality, but nanobiotechnology has given us the ability to learn more about these interactions. Using the unique properties of nanoparticles, it is possible to control how the nanoparticles adhere to certain patterns present in the ECM, and as a result can understand how changes in the ECM's shape can affect cell functionality.

Using nanobiotechnology to study the ECM allows scientists to investigate the binding interactions that occur between the ECM and its supporting environment. Investigators were able to study these interactions by utilizing tools such as optical tweezers, which have the ability to trap nano-scale objects with focused light. The tweezers can affect the binding of a substrate to the ECM by attempting to draw the substrate away from it. The light emitted from the tweezers was used to restrain ECM-coated microbeads, and the changes in the force exerted by the ECM onto the substrate were studied by modulating the effect of the optical tweezers. Experiments showed that the force exerted by the ECM on the substrate positively correlated with the force of the tweezers, which led to the subsequent discovery that the ECM and the transmembrane proteins are able to sense external forces, and can adapt to overcome these forces.

Nanotechnology crossing the blood-brain barrier

The blood-brain barrier (BBB) is composed of a system of capillaries that has an especially dense lining of endothelial cells which protects the central nervous system (CNS) against the diffusion of foreign substances into the cerebrospinal fluid. These harmful objects include microscopic bacteria, large hydrophobic molecules, certain hormones and neurotransmitters, and low-lipid-soluble molecules. The BBB prevents these harmful particles from entering the brain via tight junctions between endothelial cells and metabolic barriers. The thoroughness with which the BBB does its job makes it difficult to treat diseases of the brain such as cancer, Alzheimer's, and autism, because it is very difficult to transport drugs across the BBB. Currently, in order to deliver therapeutic molecules into the brain, doctors must use highly invasive techniques such as drilling directly into the brain, or sabotaging the integrity of the BBB through biochemical means. Due to their small size and large surface area, nanoparticles offer a promising solution for neurotherapeutics. 

Nanotechnology is helpful in delivering drugs and other molecules across the blood-brain barrier (BBB). Nanoparticles allow drugs, or other foreign molecules, to efficiently cross the BBB by camouflaging themselves and tricking the brain into providing them with the ability to cross the BBB in a process called the Trojan Horse Method. Using nanotechnology is advantageous because only the engineered complex is necessary whereas in ordinary applications the active compound must carry out the reaction. This allows for maximum efficacy of the active drug. Also, the use of nanoparticles results in the attraction of proteins to the surfaces of cells, giving cell membranes a biological identity. They also use endogenous active transport where transferrin, an iron binding protein, is linked to rod-shaped semiconductor nanocrystals, in order to move across the BBB into the brain. This discovery is a promising development towards designing an efficient nanoparticle-based drug delivery system.

Nanoparticle

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TEM (a, b, and c) images of prepared mesoporous silica nanoparticles with mean outer diameter: (a) 20nm, (b) 45nm, and (c) 80nm. SEM (d) image corresponding to (b). The insets are a high magnification of mesoporous silica particle.

 

Nanoparticles are particles between 1 and 100 nanometres (nm) in size with a surrounding interfacial layer. The interfacial layer is an integral part of nanoscale matter, fundamentally affecting all of its properties. The interfacial layer typically consists of ions, inorganic and organic molecules. Organic molecules coating inorganic nanoparticles are known as stabilizers, capping and surface ligands, or passivating agents. In nanotechnology, a particle is defined as a small object that behaves as a whole unit with respect to its transport and properties. Particles are further classified according to diameter.

Definition

IUPAC definition

 

Particle of any shape with dimensions in the 1 × 10⁻⁹ and 1 × 10⁻⁷ m range.

 Note 1: Modified from definitions of nanoparticle and nanogel.

Note 2: The basis of the 100-nm limit is the fact that novel properties that
differentiate particles from the bulk material typically develop at a critical
length scale of under 100 nm.

Note 3: Because other phenomena (transparency or turbidity, ultrafiltration,
stable dispersion, etc.) that extend the upper limit are occasionally considered,
the use of the prefix nano is accepted for dimensions smaller than 500 nm,
provided reference to the definition is indicated.
 

Note 4: Tubes and fibers with only two dimensions below 100 nm are also
nanoparticles.

The term "nanoparticle" is not usually applied to individual molecules; it usually refers to inorganic materials. 

Ultrafine particles are the same as nanoparticles and between 1 and 100 nm in size, as opposed to fine particles are sized between 100 and 2,500 nm, and coarse particles cover a range between 2,500 and 10,000 nm. The reason for the synonymous definition of nanoparticles and ultrafine particles is that, during the 1970s and 80s, when the first thorough fundamental studies with "nanoparticles" were underway in the USA (by Granqvist and Buhrman) and Japan, (within an ERATO Project) they were called "ultrafine particles" (UFP). However, during the 1990s before the National Nanotechnology Initiative was launched in the USA, the new name, "nanoparticle," had become more common (for example, see the same senior author's paper 20 years later addressing the same issue, lognormal distribution of sizes). Nanoparticles can exhibit size-related properties significantly different from those of either fine particles or bulk materials.

Nanoclusters have at least one dimension between 1 and 10 nanometers and a narrow size distribution. Nanopowders are agglomerates of ultrafine particles, nanoparticles, or nanoclusters. Nanometer-sized single crystals, or single-domain ultrafine particles, are often referred to as nanocrystals. 

According to ISO Technical Specification 80004, a nanoparticle is defined as a nano-object with all three external dimensions in the nanoscale, whose longest and shortest axes do not differ significantly, with a significant difference typically being a factor of at least 3.

The terms colloid and nanoparticle are not interchangeable. A colloid is a mixture which has solid particles dispersed in a liquid medium. The term applies only if the particles are larger than atomic dimensions but small enough to exhibit Brownian motion, with the critical size range (or particle diameter) typically ranging from nanometers (10⁻⁹ m) to micrometers (10⁻⁶ m). Colloids can contain particles too large to be nanoparticles, and nanoparticles can exist in non-colloidal form, for examples as a powder or in a solid matrix.

History

Although nanoparticles are associated with modern science, they have a long history. Nanoparticles were used by artisans as far back as Rome in the fourth century in the famous Lycurgus cup made of dichroic glass as well as the ninth century in Mesopotamia for creating a glittering effect on the surface of pots. In modern times, pottery from the Middle Ages and Renaissance often retains a distinct gold- or copper-colored metallic glitter. This luster is caused by a metallic film that was applied to the transparent surface of a glazing. The luster can still be visible if the film has resisted atmospheric oxidation and other weathering.

The luster originates within the film itself, which contains silver and copper nanoparticles dispersed homogeneously in the glassy matrix of the ceramic glaze. These nanoparticles are created by the artisans by adding copper and silver salts and oxides together with vinegar, ochre, and clay on the surface of previously-glazed pottery. The object is then placed into a kiln and heated to about 600 °C in a reducing atmosphere. In heat the glaze softens, causing the copper and silver ions to migrate into the outer layers of the glaze. There the reducing atmosphere reduced the ions back to metals, which then came together forming the nanoparticles that give the color and optical effects. Luster technique showed that ancient craftsmen had a sophisticated empirical knowledge of materials. The technique originated in the Muslim world. As Muslims were not allowed to use gold in artistic representations, they sought a way to create a similar effect without using real gold. The solution they found was using luster.

Michael Faraday provided the first description, in scientific terms, of the optical properties of nanometer-scale metals in his classic 1857 paper. In a subsequent paper, the author (Turner) points out that: "It is well known that when thin leaves of gold or silver are mounted upon glass and heated to a temperature that is well below a red heat (~500 °C), a remarkable change of properties takes place, whereby the continuity of the metallic film is destroyed. The result is that white light is now freely transmitted, reflection is correspondingly diminished, while the electrical resistivity is enormously increased."

Properties

Silicon nanopowder

 

1 kg of particles of 1 mm³ has the same surface area as 1 mg of particles of 1 nm³

 

Nanoparticles are of great scientific interest as they are, in effect, a bridge between bulk materials and atomic or molecular structures. A bulk material should have constant physical properties regardless of its size, but at the nano-scale size-dependent properties are often observed. Thus, the properties of materials change as their size approaches the nanoscale and as the percentage of the surface in relation to the percentage of the volume of a material becomes significant. For bulk materials larger than one micrometer (or micron), the percentage of the surface is insignificant in relation to the volume in the bulk of the material. The interesting and sometimes unexpected properties of nanoparticles are therefore largely due to the large surface area of the material, which dominates the contributions made by the small bulk of the material. 

Nanoparticles often possess unexpected optical properties as they are small enough to confine their electrons and produce quantum effects. For example, gold nanoparticles appear deep-red to black in solution. Nanoparticles of yellow gold and grey silicon are red in color. Gold nanoparticles melt at much lower temperatures (~300 °C for 2.5 nm size) than the gold slabs (1064 °C);. Absorption of solar radiation is much higher in materials composed of nanoparticles than it is in thin films of continuous sheets of material. In both solar PV and solar thermal applications, controlling the size, shape, and material of the particles, it is possible to control solar absorption. Recently, the core (metal)-shell (dielectric) nanoparticle has demonstrated a zero backward scattering with enhanced forward scattering on Si substrate when surface plasmon is located in front of a solar cell. The core-shell nanoparticles can support simultaneously both electric and magnetic resonances, demonstrating entirely new properties when compared with bare metallic nanoparticles if the resonances are properly engineered. 

Other size-dependent property changes include quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials. What would appear ironic is that the changes in physical properties are not always desirable. Ferromagnetic materials smaller than 10 nm can switch their magnetisation direction using room temperature thermal energy, thus making them unsuitable for memory storage.

Suspensions of nanoparticles are possible since the interaction of the particle surface with the solvent is strong enough to overcome density differences, which otherwise usually result in a material either sinking or floating in a liquid. 

The high surface area to volume ratio of nanoparticles provides a tremendous driving force for diffusion, especially at elevated temperatures. Sintering can take place at lower temperatures, over shorter time scales than for larger particles. In theory, this does not affect the density of the final product, though flow difficulties and the tendency of nanoparticles to agglomerate complicates matters. Moreover, nanoparticles have been found to impart some extra properties to various day to day products. For example, the presence of titanium dioxide nanoparticles imparts what we call the self-cleaning effect, and, the size being nano-range, the particles cannot be observed. Zinc oxide particles have been found to have superior UV blocking properties compared to its bulk substitute. This is one of the reasons why it is often used in the preparation of sunscreen lotions, is completely photostable, and toxic [DJS -- ??].

Clay nanoparticles when incorporated into polymer matrices increase reinforcement, leading to stronger plastics, verifiable by a higher glass transition temperature and other mechanical property tests. These nanoparticles are hard, and impart their properties to the polymer (plastic). Nanoparticles have also been attached to textile fibers in order to create smart and functional clothing.

Metal, dielectric, and semiconductor nanoparticles have been formed, as well as hybrid structures (e.g., core–shell nanoparticles). Nanoparticles made of semiconducting material may also be labeled quantum dots if they are small enough (typically sub 10 nm) that quantization of electronic energy levels occurs. Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents with work being done to try to understand the fluid dynamic properties (e.g. drag forces) in nanoscale applications. This has shown the relationship between the fluid forces on nanoparticles and the fluid Reynolds and Knudsen numbers.

Semiconductor nanoparticle (quantum dot) of lead sulfide with complete passivation by oleic acid, oleyl amine and hydroxyl ligands (size ~5nm)

 

Semi-solid and soft nanoparticles have been manufactured. A prototype nanoparticle of semi-solid nature is the liposome. Various types of liposome nanoparticles are currently used clinically as delivery systems for anticancer drugs and vaccines. 

Nanoparticles with one half hydrophilic and the other half hydrophobic are termed Janus particles and are particularly effective for stabilizing emulsions. They can self-assemble at water/oil interfaces and act as solid surfactants.

Hydrogel nanoparticles made of N-isopropylacrylamide hydrogel core shell can be dyed with affinity baits, internally. These affinity baits allow the nanoparticles to isolate and remove undesirable proteins while enhancing the target analytes.

Variation in properties

The chemical processing and synthesis of high-performance technological components for the private, industrial, and military sectors requires the use of high-purity ceramics (oxide ceramics, such as aluminium oxide or copper(II) oxide), polymers, glass-ceramics, and composite materials, as metal carbides (SiC), nitrides (Aluminum nitrides, Silicon nitride), metals (Al, Cu), non-metals (graphite, carbon nanotubes) and layered (Al + Aluminium carbonate, Cu + C). In condensed bodies formed from fine powders, the irregular particle sizes and shapes in a typical powder often lead to non-uniform packing morphologies that result in packing density variations in the powder compact.

Uncontrolled agglomeration of powders due to attractive van der Waals forces can also give rise to microstructural heterogeneity. Differential stresses that develop as a result of non-uniform drying shrinkage are directly related to the rate at which the solvent can be removed, and thus highly dependent upon the distribution of porosity. Such stresses have been associated with a plastic-to-brittle transition in consolidated bodies, and can yield to crack propagation in the unfired body if not relieved.

In addition, any fluctuations in packing density in the compact as it is prepared for the kiln are often amplified during the sintering process, yielding inhomogeneous densification. Some pores and other structural defects associated with density variations have been shown to play a detrimental role in the sintering process by growing and thus limiting end-point densities. Differential stresses arising from inhomogeneous densification have also been shown to result in the propagation of internal cracks, thus becoming the strength-controlling flaws.

Inert gas evaporation and inert gas deposition are free many of these defects due to the distillation (cf. purification) nature of the process and having enough time to form single crystal particles, however even their non-aggreated deposits have lognormal size distribution, which is typical with nanoparticles. The reason why modern gas evaporation techniques can produce a relatively narrow size distribution is that aggregation can be avoided. However, even in this case, random residence times in the growth zone, due to the combination of drift and diffusion, result in a size distribution appearing lognormal.

It would, therefore, appear desirable to process a material in such a way that it is physically uniform with regard to the distribution of components and porosity, rather than using particle size distributions that will maximize the green density. The containment of a uniformly dispersed assembly of strongly interacting particles in suspension requires total control over interparticle forces. Monodisperse nanoparticles and colloids provide this potential.

Monodisperse powders of colloidal silica, for example, may therefore be stabilized sufficiently to ensure a high degree of order in the colloidal crystal or polycrystalline colloidal solid that results from aggregation. The degree of order appears to be limited by the time and space allowed for longer-range correlations to be established. Such defective polycrystalline colloidal structures would appear to be the basic elements of submicrometer colloidal materials science and, therefore, provide the first step in developing a more rigorous understanding of the mechanisms involved in microstructural evolution in high performance materials and components.

Synthesis

There are several methods for creating nanoparticles, including gas condensation, attrition, chemical precipitation, ion implantation, pyrolysis and hydrothermal synthesis. In attrition, macro- or micro-scale particles are ground in a ball mill, a planetary ball mill, or other size-reducing mechanism. The resulting particles are air classified to recover nanoparticles. In pyrolysis, a vaporous precursor (liquid or gas) is forced through an orifice at high pressure and burned. The resulting solid (a version of soot) is air classified to recover oxide particles from by-product gases. Traditional pyrolysis often results in aggregates and agglomerates rather than single primary particles. Ultrasonic nozzle spray pyrolysis (USP) on the other hand aids in preventing agglomerates from forming.

A thermal plasma can deliver the energy to vaporize small micrometer-size particles. The thermal plasma temperatures are in the order of 10,000 K, so that solid powder easily evaporates. Nanoparticles are formed upon cooling while exiting the plasma region. The main types of the thermal plasma torches used to produce nanoparticles are dc plasma jet, dc arc plasma, and radio frequency (RF) induction plasmas. In the arc plasma reactors, the energy necessary for evaporation and reaction is provided by an electric arc formed between the anode and the cathode. For example, silica sand can be vaporized with an arc plasma at atmospheric pressure, or thin aluminum wires can be vaporized by exploding wire method. The resulting mixture of plasma gas and silica vapour can be rapidly cooled by quenching with oxygen, thus ensuring the quality of the fumed silica produced.

In RF induction plasma torches, energy coupling to the plasma is accomplished through the electromagnetic field generated by the induction coil. The plasma gas does not come in contact with electrodes, thus eliminating possible sources of contamination and allowing the operation of such plasma torches with a wide range of gases including inert, reducing, oxidizing, and other corrosive atmospheres. The working frequency is typically between 200 kHz and 40 MHz. Laboratory units run at power levels in the order of 30–50 kW, whereas the large-scale industrial units have been tested at power levels up to 1 MW. As the residence time of the injected feed droplets in the plasma is very short, it is important that the droplet sizes are small enough in order to obtain complete evaporation. The RF plasma method has been used to synthesize different nanoparticle materials, for example synthesis of various ceramic nanoparticles such as oxides, carbours/carbides, and nitrides of Ti and Si.

Inert gas condensation

Inert-gas condensation is frequently used to produce metallic nanoparticles. The metal is evaporated in a vacuum chamber containing a reduced atmosphere of an inert gas. Condensation of the supersaturated metal vapor results in creation of nanometer-size particles, which can be entrained in the inert gas stream and deposited on a substrate or studied in situ. Early studies were based on thermal evaporation. Using magnetron sputtering to create the metal vapor allows to achieve higher yields. The method can easily be generalized to alloy nanoparticles by choosing appropriate metallic targets. The use of sequential growth schemes, where the particles travel through a second metallic vapor, results in growth of core-shell (CS) structures.

Radiolysis method

Left) Transmission electron microscopy (TEM) image of Hf nanoparticles grown by magnetron-sputtering inert-gas condensation (inset: size distribution) and right) energy dispersive x-ray (EDX) mapping of Ni and Ni@Cu core@shell nanoparticles.

 

Nanoparticles can also be formed using radiation chemistry. Radiolysis from gamma rays can create strongly active free radicals in solution. This relatively simple technique uses a minimum number of chemicals. These including water, a soluble metallic salt, a radical scavenger (often a secondary alcohol), and a surfactant (organic capping agent). High gamma doses on the order of 10⁴ Gray are required. In this process, reducing radicals will drop metallic ions down to the zero-valence state. A scavenger chemical will preferentially interact with oxidizing radicals to prevent the re-oxidation of the metal. Once in the zero-valence state, metal atoms begin to coalesce into particles. A chemical surfactant surrounds the particle during formation and regulates its growth. In sufficient concentrations, the surfactant molecules stay attached to the particle. This prevents it from dissociating or forming clusters with other particles. Formation of nanoparticles using the radiolysis method allows for tailoring of particle size and shape by adjusting precursor concentrations and gamma dose.

Sol–gel

The sol–gel process is a wet-chemical technique (also known as chemical solution deposition) widely used recently in the fields of materials science and ceramic engineering. Such methods are used primarily for the fabrication of materials (typically a metal oxide) starting from a chemical solution (sol, short for solution), which acts as the precursor for an integrated network (or gel) of either discrete particles or network polymers. 

Typical precursors are metal alkoxides and metal chlorides, which undergo hydrolysis and polycondensation reactions to form either a network "elastic solid" or a colloidal suspension (or dispersion) – a system composed of discrete (often amorphous) submicrometer particles dispersed to various degrees in a host fluid. Formation of a metal oxide involves connecting the metal centers with oxo (M-O-M) or hydroxo (M-OH-M) bridges, therefore generating metal-oxo or metal-hydroxo polymers in solution. Thus, the sol evolves toward the formation of a gel-like diphasic system containing both a liquid phase and solid phase whose morphologies range from discrete particles to continuous polymer networks.

In the case of the colloid, the volume fraction of particles (or particle density) may be so low that a significant amount of fluid may need to be removed initially for the gel-like properties to be recognized. This can be accomplished in a number of ways. The most simple method is to allow time for sedimentation to occur, and then pour off the remaining liquid. Centrifugation can also be used to accelerate the process of phase separation.

Removal of the remaining liquid (solvent) phase requires a drying process, which typically causes shrinkage and densification. The rate at which the solvent can be removed is ultimately determined by the distribution of porosity in the gel. The ultimate microstructure of the final component will clearly be strongly influenced by changes implemented during this phase of processing. Afterward, a thermal treatment, or firing process, is often necessary in order to favor further polycondensation and enhance mechanical properties and structural stability via final sintering, densification, and grain growth. One of the distinct advantages of using this methodology as opposed to the more traditional processing techniques is that densification is often achieved at a much lower temperature.

The precursor sol can be either deposited on a substrate to form a film (e.g., by dip-coating or spin-coating), cast into a suitable container with the desired shape (e.g., to obtain a monolithic ceramics, glasses, fibers, membranes, aerogels), or used to synthesize powders (e.g., microspheres, nanospheres). The sol–gel approach is a cheap and low-temperature technique that allows for the fine control of the product’s chemical composition. Even small quantities of dopants, such as organic dyes and rare earth metals, can be introduced in the sol and end up uniformly dispersed in the final product. It can be used in ceramics processing and manufacturing as an investment casting material, or as a means of producing very thin films of metal oxides for various purposes. Sol–gel derived materials have diverse applications in optics, electronics, energy, space, (bio)sensors, medicine (e.g., controlled drug release) and separation (e.g., chromatography) technology.

Ion implantation

Ion implantation may be used to treat the surfaces of dielectric materials such as sapphire and silica to make composites with near-surface dispersions of metal or oxide nanoparticles.

Morphology

Nanostars of vanadium(IV) oxide

 

Scientists have taken to naming their particles after the real-world shapes that they might represent. Nanospheres, nanochains, nanoreefs, nanoboxes, and more have appeared in the literature. These morphologies sometimes arise spontaneously as an effect of a templating or directing agent present in the synthesis such as miscellar emulsions or anodized alumina pores, or from the innate crystallographic growth patterns of the materials themselves. Some of these morphologies may serve a purpose, such as long carbon nanotubes used to bridge an electrical junction, or just a scientific curiosity like the stars shown at right. 

Amorphous particles usually adopt a spherical shape (due to their microstructural isotropy), whereas the shape of anisotropic microcrystalline whiskers corresponds to their particular crystal habit. At the small end of the size range, nanoparticles are often referred to as clusters. Spheres, rods, fibers, and cups are just a few of the shapes that have been grown. The study of fine particles is called micromeritics.

Characterization

Nanoparticles have different analytical requirements than conventional chemicals, for which chemical composition and concentration are sufficient metrics. Nanoparticles have other physical properties that must be measured for a complete description, such as size, shape, surface properties, crystallinity, and dispersion state. Additionally, sampling and laboratory procedures can perturb their dispersion state or bias the distribution of other properties. In environmental contexts, an additional challenge is that many methods cannot detect low concentrations of nanoparticles that may still have an adverse effect. For some applications, nanoparticles may be characterized in complex matrices such as water, soil, food, polymers, inks, complex mixtures of organic liquids such as in cosmetics, or blood.

There are several overall categories of methods used to characterize nanoparticles. Microscopy methods generate images of individual nanoparticles to characterize their shape, size, and location. Electron microscopy and scanning probe microscopy are the dominant methods. Because nanoparticles have a size below the diffraction limit of visible light, conventional optical microscopy is not useful. Electron microscopes can be coupled to spectroscopic methods that can perform elemental analysis. Microscopy methods are destructive, and can be prone to undesirable artifacts from sample preparation, or from probe tip geometry in the case of scanning probe microscopy. Additionally, microscopy is based on single-particle measurements, meaning that large numbers of individual particles must be characterized to estimate their bulk properties.

Spectroscopy, which measures the particles' interaction with electromagnetic radiation as a function of wavelength, is useful for some classes of nanoparticles to characterize concentration, size, and shape. X-ray, ultraviolet–visible, infrared, and nuclear magnetic resonance spectroscopy can be used with nanoparticles. Light scattering methods using laser light, X-rays, or neutron scattering are used to determine particle size, with each method suitable for different size ranges and particle compositions. Some miscellaneous methods are electrophoresis for surface charge, the Brunauer–Emmett–Teller method for surface area, and X-ray diffraction for crystal structure, as well as mass spectrometry for particle mass, and particle counters for particle number. Chromatography, centrifugation, and filtration techniques can be used to separate nanoparticles by size or other physical properties before or during characterization.

Functionalization

Functionalization is the introduction of organic molecules or polymers on the surface of the nanoparticle. The surface coating of nanoparticles determines many of their physical and chemical properties, notably stability, solubility, and targeting. A coating that is multivalent or polymeric confers high stability. Functionalized nanomaterial-based catalysts can be used for catalysis of many known organic reactions.

Surface coating for biological applications

For biological applications, the surface coating should be polar to give high aqueous solubility and prevent nanoparticle aggregation. In serum or on the cell surface, highly charged coatings promote non-specific binding, whereas polyethylene glycol linked to terminal hydroxyl or methoxy groups repel non-specific interactions. Nanoparticles can be linked to biological molecules that can act as address tags, to direct the nanoparticles to specific sites within the body, specific organelles within the cell, or to follow specifically the movement of individual protein or RNA molecules in living cells. Common address tags are monoclonal antibodies, aptamers, streptavidin or peptides. These targeting agents should ideally be covalently linked to the nanoparticle and should be present in a controlled number per nanoparticle. Multivalent nanoparticles, bearing multiple targeting groups, can cluster receptors, which can activate cellular signaling pathways, and give stronger anchoring. Monovalent nanoparticles, bearing a single binding site, avoid clustering and so are preferable for tracking the behavior of individual proteins. 

Red blood cell coatings can help nanoparticles evade the immune system.

Health and safety

Nanoparticles present possible dangers, both medically and environmentally. Most of these are due to the high surface to volume ratio, which can make the particles very reactive or catalytic. They are also able to pass through cell membranes in organisms, and their interactions with biological systems are relatively unknown. However, it is unlikely the particles would enter the cell nucleus, Golgi complex, endoplasmic reticulum or other internal cellular components due to the particle size and intercellular agglomeration. A recent study looking at the effects of ZnO nanoparticles on human immune cells has found varying levels of susceptibility to cytotoxicity. There are concerns that pharmaceutical companies, seeking regulatory approval for nano-reformulations of existing medicines, are relying on safety data produced during clinical studies of the earlier, pre-reformulation version of the medicine. This could result in regulatory bodies, such as the FDA, missing new side effects that are specific to the nano-reformulation.

Whether cosmetics and sunscreens containing nanomaterials pose health risks remains largely unknown at this stage. However considerable research has demonstrated that zinc nanoparticles are not absorbed into the bloodstream in vivo.

Concern has also been raised over the health effects of respirable nanoparticles from certain combustion processes. As of 2013 the U.S. Environmental Protection Agency was investigating the safety of the following nanoparticles:

• Carbon Nanotubes: Carbon materials have a wide range of uses, ranging from composites for use in vehicles and sports equipment to integrated circuits for electronic components. The interactions between nanomaterials such as carbon nanotubes and natural organic matter strongly influence both their aggregation and deposition, which strongly affects their transport, transformation, and exposure in aquatic environments. In past research, carbon nanotubes exhibited some toxicological impacts that will be evaluated in various environmental settings in current EPA chemical safety research. EPA research will provide data, models, test methods, and best practices to discover the acute health effects of carbon nanotubes and identify methods to predict them.
• Cerium oxide: Nanoscale cerium oxide is used in electronics, biomedical supplies, energy, and fuel additives. Many applications of engineered cerium oxide nanoparticles naturally disperse themselves into the environment, which increases the risk of exposure. There is ongoing exposure to new diesel emissions using fuel additives containing CeO₂ nanoparticles, and the environmental and public health impacts of this new technology are unknown. EPA’s chemical safety research is assessing the environmental, ecological, and health implications of nanotechnology-enabled diesel fuel additives.
• Titanium dioxide: Nano titanium dioxide is currently used in many products. Depending on the type of particle, it may be found in sunscreens, cosmetics, and paints and coatings. It is also being investigated for use in removing contaminants from drinking water.
• Nano Silver: Nano silver is being incorporated into textiles, clothing, food packaging, and other materials to eliminate bacteria. EPA and the U.S. Consumer Product Safety Commission are studying certain products to see whether they transfer nano-size silver particles in real-world scenarios. EPA is researching this topic to better understand how much nano-silver children come in contact with in their environments.
• Iron: While nano-scale iron is being investigated for many uses, including “smart fluids” for uses such as optics polishing and as a better-absorbed iron nutrient supplement, one of its more prominent current uses is to remove contamination from groundwater. This use, supported by EPA research, is being piloted at a number of sites across the United States.

Regulation

As of 2016, the U.S. Environmental Protection Agency had conditionally registered, for a period of four years, only two nanomaterial pesticides as ingredients. The EPA differentiates nanoscale ingredients from non-nanoscale forms of the ingredient, but there is little scientific data about potential variation in toxicity. Testing protocols still need to be developed.

Applications

As the most prevalent morphology of nanomaterials used in consumer products, nanoparticles have potential and actual applications in all industries. Table below summarizes the most common nanoparticles used in various product types available on the global markets.

Various nanoparticles which are commonly used in the consumer products by industrial sectors

No.	Industrial sectors	Nanoparticles
1	agriculture	silver, silicon dioxide, potassium, calcium, iron, zinc, phosphorus, boron, zinc oxide and molybdenum
2	automotive	tungsten, disulfidesilicon dioxide, clay, titanium dioxide, diamond, copper, cobalt oxide, zinc oxide, boron nitride, zirconium dioxide, tungsten, γ-aluminium oxide, boron, palladium, platinum, cerium(IV) oxide, carnauba, aluminium oxide, silver, calcium carbonate and calcium sulfonate
3	construction	titanium, dioxidesilicon dioxide, silver, clay, aluminium oxide, calcium carbonate calcium silicate hydrate, carbon, aluminium phosphate cerium(IV) oxide and calcium hydroxide
4	cosmetics	silver, titanium dioxide, gold, carbon, zinc oxide, silicon dioxide, clay, sodium silicate, kojic acid and hydroxy acid
5	electronics	silver, aluminum, silicon dioxide and palladium
6	environment	silver, titanium dioxide, carbonmanganese oxide, clay, gold and selenium
7	food	silver, clay, titanium dioxide, gold, zinc oxide, silicon dioxide, calcium, copper, zinc, platinum, manganese, palladium and carbon
8	home appliance	silver, zinc oxide, silicon dioxide, diamond and titanium dioxide
9	medicine	silver, gold, hydroxyapatite, clay, titanium dioxide, silicon dioxide, zirconium dioxide, carbon, diamond, aluminium oxide and ytterbium trifluoride
10	petroleum	tungsten, disulfidezinc oxide, silicon dioxide, diamond, clay, boron, boron nitride, silver, titanium dioxide, tungsten, γ-aluminium oxide, carbon, molybdenum disulfide and γ-aluminium oxide
11	printing	toner, deposited by a printer onto paper or other substrate
12	renewable energies	titanium, palladium, tungsten disulfide, silicon dioxide, clay, graphite, zirconium(IV) oxide-yttria stabilized, carbon, gd-doped-cerium(IV) oxide, nickel cobalt oxide, nickel(II) oxide, rhodium, sm-doped-cerium(IV) oxide, barium strontium titanate and silver
13	sports and fitness	silver, titanium dioxide, gold, clay and carbon
14	textile	silver, carbon, titanium dioxide, copper sulfide, clay, gold, polyethylene terephthalate and silicon dioxide

Scientific research on nanoparticles is intense as they have many potential applications in medicine, physics, optics, and electronics. The U.S. National Nanotechnology Initiative offers government funding focused on nanoparticle research.|The use of nanoparticles in laser dye-doped poly(methyl methacrylate) (PMMA) laser gain media was demonstrated in 2003 and it has been shown to improve conversion efficiencies and to decrease laser beam divergence. Researchers attribute the reduction in beam divergence to improved dn/dT characteristics of the organic-inorganic dye-doped nanocomposite. The optimum composition reported by these researchers is 30% w/w of SiO₂ (~ 12 nm) in dye-doped PMMA.|Nanoparticles are being investigated as potential drug delivery system. Drugs, growth factors or other biomolecules can be conjugated to nano particles to aid targeted delivery. This nanoparticle-assisted delivery allows for spatial and temporal controls of the loaded drugs to achieve the most desirable biological outcome.|Nanoparticles are also studied for possible applications as dietary supplements for delivery of biologically active substances, for example mineral elements.