The design and fabrication of particles with dimensions in the colloidal size scale (< 10 µm) has become an area of great and continually growing interest for many applications. Particles have been researched and developed for such varied applications as catalysis, microelectronics, photovoltaics, coatings, cosmetics, smart fluids and nanomedicine, among others. These small particles are of fundamental interest not only because of the changes in optical, electrical and other material properties which occur when the material is reduced to the nanometer size scale, but also from other factors such as improved solubility properties or the capability of encapsulating bioactive materials, such as therepeutics or imaging agents, which can be poorly soluble or toxic lacking the protection of the particle. Anisotropic colloidal particles can assemble to form structures which are distinct from the hexagonal close packed arrangements favored by spherical particles and are of interest in the fields of memory storage, optical electronics, photonics and sensors.1
Considerable effort has been devoted to the development of fabrication methods which can mass produce colloidal particles with fine control of size, shape, composition, cargo and surface chemistry. We submit Particle Replication In Non-wetting Templates (PRINT) as a readily scalable method for the fabrication of such monodisperse colloids with precise control over size and shape and with broad capabilities with regards to material composition and chemical anisotropy. In addition to PRINT, we will present several other top-down particle fabrication methods which have excellent potential for scalable production of monodisperse, shape-specific particles on the colloidal size scale.
Two broad approaches are amenable for the fabrication of anisotropic particles; bottom-up and top-down techniques. Bottom-up approaches begin at the atomic or molecular scale and build up to the desired particle size, while top-down methods process a material on the desired size scale. The most commonly employed methods for the production of mass quantities of particles on the colloidal length scale are bottom-up synthetic approaches such as emulsion polymerization. In a typical process, a monomer is emulsified via rapid stirring in a mobile phase which contains an initiator and a surfactant. Upon heating to activate the initiator, spherical particles are nucleated in the surfactant micelles and grow to the desired size. Particles obtained by emulsion methods are typically spherical and can vary in size from tens of nanometers to as large as several microns in diameter. The particle size and the molecular weight of the polymers formed in emulsions are controlled with parameters such as the surfactant concentration and reaction temperature. Surfactant adsorbed onto the surface of these particles can be difficult to remove if undesired. While this method is extremely scalable, the particles fabricated in this way are typically spherical in shape and are fairly polydisperse.
There is a growing need to generate particles with a diversity of non-spherical shapes. Complex particle shapes are desirable for a range of applications, including self-assembly2
, photonic materials3
, and microelectromechanical systems (MEMS).4
Particles with non-spherical shape are of increasing interest for biomedical applications such as drug delivery, where the rod-like or corkscrew morphologies possessed by many viruses and bacteria are suspected to have derived an evolutionary advantage from their specific shapes.5
For many applications, the ability to control particle size and shape is of vital importance, and the ability to manufacture large quantities of such size and shape-specific particles is a crucial factor in the utility of the fabrication method. For a particle fabrication method to prove industrially useful, it must be scalable and capable of producing usefully large quantities of particles. For example, a particle tested for efficacy as a drug carrier will have very different production needs in the laboratory setting compared to the industrial scale. The fabrication of milligram quantities of particles suffices for testing in the lab, while commercialization of this technology would require production of gram and kilogram quantities to satisfy the needs of phase 1 or 2 clinical trials.
While the focus of this paper is on top-down methods, a brief review of bottom-up particle fabrication methods may be instructive by way of comparison. Bottom-up approaches are readily scalable, but can lack fine control of particle size and dispersity, and can be limited in the variety of shapes which can be produced. Crystals of many metals and metal-oxides can be grown into both spherical and anisotropic shapes such as cubes, rods, discs and faceted polyhedra using nucleation and arrested growth strategies.1
More complex branched structures can be formed by sequential growth of dots and rods of different materials.6
Selective crystallization and deposition methods have been developed to produce prisms, rods, arrows and teardrop shaped crystals of gold, silver and cadmium selenide, respectively.7–9
Such nucleation and growth methods are limited to inorganics and the shape selectivity is highly dependent on the material and its crystal structure. Further, these inorganic materials often lack the capability to encapsulate a cargo or undergo surface modification.
Bottom-up approaches for the fabrication of organic particles have received a great deal of attention for use in biomedical applications such as imaging, gene or drug delivery. These methods chiefly rely on self-assembly to create hollow particles such as micelles, vesicles, liposomes, and polymersomes which are able to encapsulate a cargo in their otherwise hollow interior. In a typical preparation, molecules are synthesized which possess both hydrophilic and hydrophobic domains. Upon exposure to water, the molecules orient themselves to present their hydrophilic portion to the water, while the hydrophobic domains orient inward, resulting in a sphere with a hydrophobic pocket. The hydrophobic interior is able to encapsulate a hydrophobic cargo. While spherical particles have been the standard, increasing attention has been directed towards higher aspect ratio particles which are achievable with control of the relative length of hydrophobic and hydrophilic domains.5, 10
Recently, Discher, et. al
. explored filamentous polymersomes called filomicelles for their circulation persistence and ability to encapsulate and deliver chemotherepeutics. The filomicelles were prepared from block copolymers with lipid-like amphiphilicity, but a more symmetric ratio of hydrophilic to hydrophobic blocks than is found in lipids. Filomicelles were prepared with a hydrophilic block of poly(ethylene oxide) and hydrophobic block of either poly(ethylethylene) or poly(caprolactone). These filamentous particles persisted in the circulation about ten times longer than spheres with similar surface chemistry, and were successful in encapsulating and delivering a hydrophobic chemotherapeutic to tumored mice.10
One criticism of these self-assembled systems is the dynamic nature of the particles so assembled. With membrane components held together with attractive forces rather than with covalent bonds, the structures generated can add or lose components, making their size and shape more fluid than may be desired. The dynamic nature of these self-assembled systems has been addressed by Wooley et al
. with shell-cross linked knedel-like particles (SCKs).11
These block copolymer micelles are modified with reactive groups on the surface which can be chemically cross-linked after self-assembly, giving superior stability to their structure.