Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
  • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
  • G01N33/54346—Nanoparticles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
  • B01J13/0004—Preparation of sols
  • B01J13/0047—Preparation of sols containing a metal oxide
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
  • B01J13/0091—Preparation of aerogels, e.g. xerogels
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
  • B01J19/10—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing sonic or ultrasonic vibrations
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B22—CASTING; POWDER METALLURGY
  • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
  • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
  • B22F1/06—Metallic powder characterised by the shape of the particles
  • B22F1/062—Fibrous particles
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
• • C—CHEMISTRY; METALLURGY
  • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
  • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
  • C25D1/00—Electroforming
  • C25D1/04—Wires; Strips; Foils
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
  • H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
  • H01F1/0036—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties showing low dimensional magnetism, i.e. spin rearrangements due to a restriction of dimensions, e.g. showing giant magnetoresistivity
  • H01F1/0072—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties showing low dimensional magnetism, i.e. spin rearrangements due to a restriction of dimensions, e.g. showing giant magnetoresistivity one dimensional, i.e. linear or dendritic nanostructures
  • H01F1/0081—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties showing low dimensional magnetism, i.e. spin rearrangements due to a restriction of dimensions, e.g. showing giant magnetoresistivity one dimensional, i.e. linear or dendritic nanostructures in a non-magnetic matrix, e.g. Fe-nanowires in a nanoporous membrane
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B22—CASTING; POWDER METALLURGY
  • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
  • B22F2999/00—Aspects linked to processes or compositions used in powder metallurgy

Definitions

• the present invention is directed to methods of manufacture of nanoparticles and approaches for such manufacture.
• the nanoparticles may be used to encode information and thereby serve as molecular (or cellular) tags, labels and substrates.
• the present invention relates to methods of manufacture of segmented particles and assemblies of differentiable particles (which may or may not be segmented). Without a doubt, there has been a paradigm change in what is traditionally defined as bioanalytical chemistry. A major focus of these new technologies is to generate what could be called “increased per volume information content". This term encompasses several approaches, from reduction in the volume of sample required to carry out an assay, to highly parallel measurements ("multiplexing"), such as those involving immobilized molecular arrays, to incorporation of second (or third) information channels, such as in 2-D gel electrophoresis or CE-electrospray MS/MS. Unfortunately, many of these seemingly revolutionary technologies are limited by a reliance on relatively pedestrian materials, methods, and analyses.
• beads are chemically modified with a ratio of fluorescent dyes intended to uniquely identify the beads, which are then further modified with a unique chemistry (e.g. a different antibody or enzyme).
• a unique chemistry e.g. a different antibody or enzyme.
• the beads are then randomly dispersed on an etched fiber array so that one bead associates with each fiber.
• the identity of the bead is ascertained by its fluorescence readout, and the analyte is detected by fluorescence readout at the same fiber in a different spectral region.
• the particle flavor is determined by fluorescence, and once the biochemistry is put onto the bead, any spectrally distinct fluorescence generated due to the presence of analyte can be read out. Note that as currently configured, it is necessary to use one color of laser to interrogate the particle flavor, and another, separate laser to excite the bioassay fluorophores.
• particle-based bioanalysis would become exceptionally attractive, insofar as a single technology platform could then be considered for the multiple high-information content research areas; including combinatorial chemistry, genomics, and proteomics (via multiplexed immunoassays).
• Rod-shaped nanoparticles have been prepared whose composition is varied along the length of the rod. These particles are referred to as nanoparticles or nanobar codes, though in reality some or all dimensions may be in the micron size range.
• the present invention is directed to methods of manufacture of such nanoparticles.
• the present invention includes methods of manufacture of free-standing particles comprising a plurality of segments, wherein the particle length is from 10 nm to 50 ⁇ m and particle width is from 5 nm to 50 ⁇ m.
• the segments of the particles of the present invention may be comprised of any material. Included among the possible materials are a metal, any metal chalcogenide, a metal oxide, a metal sulfide, a metal selenide, a metal telluride, a metal 4 alloy, a metal nitride, a metal phosphide, a metal antimonide, a semiconductor, a semi-metal, any organic compound or material, any inorganic compound or material, a particulate layer of material or a composite material.
• the segments of the particles of the present invention may be comprised of polymeric materials, crystalline or non-crystalline materials, amorphous materials or glasses.
• the particles are "functionalized" (e.g., have their surface coated with IgG antibody).
• functionalization may be attached on selected or all segments, on the body or one or both tips of the particle.
• the functionalization may actually coat segments or the entire particle.
• Such functionalization may include organic compounds, such as an antibody, an antibody fragment, or an oligonucleotide, inorganic compounds, and combinations thereof.
• Such functionalization may also be a detectable tag or comprise a species that will bind a detectable tag.
• the particle types are differentiable based on differences in the length, width or shape of the particles and/or the number, composition, length or pattern of said segments.
• the particles are differentiable based on the nature of their functionalization or physical properties (e.g., as measured by mass spectrometry or light scattering).
• the present invention includes the manufacture of nanobar codes by the electrochemical deposition of metals inside a template wherein the process is improved, separately and collectively, by i) electroplating in an ultrasonication bath; and ii) controlling the temperature of the deposition environment, preferably by using a recirculating temperature bath.
• a plurality of templates are held in a common solution chamber and electrochemical deposition is accomplished by controlling deposition at each membrane by applying current selectively to predetermined electrodes associated with each such membrane.
• an apparatus for the manufacture of nanobar codes comprising: a plating solution cell, a defined pore size template, means for applying a current to cause electrochemical deposition of a metal into said template, means for agitation of the plating solution, such as an ultrasonic transducer, and temperature control means.
• an apparatus for the simultaneous manufacture of a plurality of different types of nanobar codes comprises: a solution chamber, a plurality of templates, means for selectively applying a current to each of said templates, and control means for operating said apparatus.
• Figure 1 is a perspective view of an apparatus for manufacturing a plurality of different types of nanobar codes.
• Figure 2 is a cross-sectional elevation view of the apparatus of Figure 1.
• the present application is directed to methods of manufacture of nanoparticles. Such nanoparticles and their uses are described in detail in United States Utility Application Serial No. 09/598,395, filed June 20, 2000, entitled “Colloidal Rod Particles as Nanobar Codes,” incorporated hereby in its entirety by reference. Filed concurrently with the present application, and also incorporated herein in their entirety by reference, are two United States Utility Applications entitled “Methods of Imaging Colloidal Rod Particles as Nanobarcodes" and “Colloidal Rod Particles as Nanobar Codes.” The present application is filed as a Continuation-in-Part of the 09/598,395 application.
• bar codes based on analysis of open reading frames
• bar codes based on isotopic mass variations bar codes based on strings of chemical or physical reporter beads
• bar codes based on electrophoretic patterns of restriction-enzyme cleaved mRNA bar codes based on electrophoretic patterns of restriction-enzyme cleaved mRNA
• bar-coded surfaces for repeatable imaging of biological molecules using scanning probe microscopies
• chromosomal bar codes a.k.a. chromosome painting
• the particles to be manufactured according to the present invention are alternately referred to as nanoparticles, nanobar codes, rods, nanorods, nanobar codes, and rod shaped particles.
• the label applied should be ignored.
• the particle's composition contains informational content, this is not true for all embodiments of the invention.
• nanometer-sized particles fall within the scope of the invention, not all of the particles of the invention fall within such size range.
• the nanobar code particles are manufactured by electrochemical deposition in an alumina or polycarbonate template, followed by template dissolution, and typically, they are prepared by alternating electrochemical reduction of metal ions, though they may easily be prepared by other means, both with or without a template material.
• the nanobar codes have widths between 30 nm and 1,000 nanometers, though they can have widths of several microns.
• the lengths (i.e. the long dimension) of the materials are typically on the order of 1 to 15 microns, they can easily be prepared in lengths as long as 50 microns, and in lengths as short as 20 nanometers.
• the nanobar codes comprise two or more different materials alternated along the length, although in principle as many as dozens of different materials could be used.
• the segments could consist of non-metallic material, including but not limited to polymers, oxides, sulfides, semiconductors, insulators, plastics, and even thin (i.e., monolayer) films of organic or inorganic species.
• the length of the segments (as well as their density and porosity) can be adjusted by controlling the amount of current (or electrochemical potential) passed in each electroplating step; as a result, the rod resembles a "bar code" on the nanometer scale, with each segment length (and identity) programmable in advance.
• Other forms of deposition can also yield the same results.
• deposition can be accomplished via electroless processes and in electrochemical deposition by controlling the area of the electrode, the heterogenous rate constant, the concentration of the plating material, and the potential and combinations thereof (collectively referred to herein as electrochemical deposition). The same result could be achieved using another method of manufacture in which the length or other attribute of the segments can be controlled.
• the particles of this embodiment of the present invention are defined in part by their size and by the existence of at least 2 segments.
• the length of the particles can be from 10 nm up to 50 ⁇ m. In preferred embodiments the particle is 500 nm - 30 ⁇ m in length. In the most preferred embodiments, the length of the particles of this invention is 1-15 ⁇ m.
• the width, or diameter, of the particles of the invention is within the range of 5 nm - 50 ⁇ m. In preferred embodiments the width is 10 nm - 1 ⁇ m, and in the most preferred embodiments the width or cross-sectional dimension is 30 nm - 500 nm.
• the particles of the present invention are characterized by the presence of at least two segments.
• a segment represents a region of the particle that is distinguishable, by any means, from adjacent regions of the particle. Segments of the particle bisect the length of the particle to form regions that have the same cross-section (generally) and width as the whole particle, while representing a portion of the length of the whole particle.
• a segment is composed of different materials from its adjacent segments. However, not every segment needs to be distinguishable from all other segments of the particle.
• a particle could be composed of 2 types of segments, e.g., gold and platinum, while having 10 or even 20 different segments, simply by alternating segments of gold and platinum.
• a particle of the present invention contains at least two segments, and as many as 50.
• the particles of the invention preferably have from 2-30 segments and most preferably from 3-20 segments.
• the particles may have from 2-10 different types of segments, preferably 2 to 5 different types of segments.
• a segment of the particle of the present invention is defined by its being distinguishable from adjacent segments of the particle.
• the ability to distinguish between segments includes distinguishing by any physical or chemical means of interrogation, including but not limited to electromagnetic, magnetic, optical, spectrometric, spectroscopic and mechanical.
• the method of interrogating between segments is optical (reflectivity).
• Adjacent segments may even be of the same material, as long as they are distinguishable by some means. For example, different phases of the same elemental material, or enantiomers of organic polymer materials can make up adjacent segments.
• a rod comprised of a single material could be considered to fall within the scope of the invention if segments could be distinguished from others, for example, by functionalization on the surface, or having varying diameters. Also particles comprising organic polymer materials could have segments defined by the inclusion of dyes that would change the relative optical properties of the segments.
• composition of the particles of the present invention is best defined by describing the compositions of the segments that make up the particles.
• a particle may contain segments with extremely different compositions.
• a single particle could be comprised of one segment that is a metal, and a segment that is an organic polymer material.
• the segments of the present invention may be comprised of any material.
• the segments comprise a metal (e.g., silver, gold, copper, nickel, palladium, platinum, cobalt, rhodium, iridium); any metal chalcognide; a metal oxide (e.g., cupric oxide, titanium dioxide); a metal sulfide; a metal selenide; a metal telluride; a metal alloy; a metal nitride; a metal phosphide; a metal antimonide; a semiconductor; a semi-metal.
• a segment may also be comprised of an organic mono- or bilayer such as a molecular film. For example, monolayers of organic molecules or self assembled, controlled layers of molecules can be associated with a variety of metal surfaces.
• a segment may be comprised of any organic compound or material, or inorganic compound or material or organic polymeric materials, including the large body of mono and copolymers known to those skilled in the art.
• Biological polymers such as peptides, oligonucleotides and polysaccharides may also be the major components of a segment.
• Segments may be comprised of particulate materials, e.g., metals, metal oxide or organic particulate materials; or composite materials, e.g., metal in polyacrylamide, dye in polymeric material, porous metals.
• the segments of the particles of the present invention may be comprised of polymeric materials, crystalline or non-crystalline materials, amorphous materials or glasses.
• Segments may be defined by notches on the surface of the particle, or by the presence of dents, divits, holes, vesicles, bubbles, pores or tunnels that may or may not contact the surface of the particle. Segments may also be defined by a discernable change in the angle, shape, or density of such physical attributes or in the contour of the surface. In embodiments of the invention where the particle is coated, for example with a polymer or glass, the segment may consist of a void between other materials.
• the length of each segment may be from 10 nm to 50 ⁇ m. In preferred embodiments the length of each segment is 50 nm to 20 ⁇ m.
• the interface between segments need not be perpendicular to the length of the particle or a smooth line of transition.
• the composition of one segment may be blended into the composition of the adjacent segment. For example, between segments of gold and platinum, there may be a 5 nm to 5 ⁇ m region that is comprised of both gold and platinum. This type of transition is acceptable so long as the segments are distinguishable. For any given particle the segments may be of any length relative to the length of the segments of the rest of the particle.
• the particles of the present invention can have any cross-sectional shape.
• the particles are generally straight along the lengthwise axis.
• the particles may be curved or helical.
• the ends of the particles of the present invention may be flat, convex or concave.
• the ends may be spiked or pencil tipped. Sharp-tipped embodiments of the invention may be preferred when the particles are used in Raman spectroscopy applications or others in which energy field effects are important.
• the ends of any given particle may be the same or different.
• the contour of the particle may be advantageously selected to contribute to the sensitivity or specificity of the assays (e.g., an undulating contour will be expected to enhance "quenching" of fluorophores located in the troughs).
• an assembly or collection of particles is prepared.
• the members of the assembly are identical, while in other embodiments, the assembly is comprised of a plurality of different types of particles.
• the length of substantially all of the particles for particles in the 1 ⁇ m - 15 ⁇ m range may vary up to 50%. Segments of 10 nm in length will vary ⁇ 5 nm while segments in 1 ⁇ m range may vary up to 50%).
• the width of substantially all of the particles may vary between 10 and 100% preferably less than 50%> and most preferably less than 10% .
• the present invention includes assemblies or collections of nanobar codes made up of a plurality of particles that are differentiable from each other.
• Assembly or collection does not mean that the nanoparticles that make up such an assembly or collection are ordered or organized in any particular manner. Such an assembly is considered to be made up of a plurality of different types or "flavors" of particles. In some such assemblies, each of the nanobar codes of the assembly may be funcfionalized in some manner. In many applications, the functionalization is different and specific to the specific flavor of nanoparticle.
• the assemblies of the present invention can include from 2 to 10 different and identifiable nanoparticles. Preferred assemblies include more than 10, more than 100, more than 1,000 and, in some cases, more than 10,000 different flavors of nanoparticles.
• the particles that make up the assemblies or collections of the present invention are segmented in most embodiments. However, in certain embodiments of the invention the particles of an assembly of particles do not necessarily contain a plurality of segments.
• the particles of the present invention may include mono-molecular layers. Such mono-molecular layers may be found at the tips or ends of the particle, or between segments. Examples of the use of mono-molecular layers between segments are described in the section entitled ELECTRONIC DEVICES in United States Utility Application Serial No. 09/598,395, filed June 20, 2000.
• the present invention is directed to the manufacture of freestanding nanobar codes.
• freestanding it is meant that nanobar codes that are produced by some form of deposition or growth within a template have been released from the template. Such nanobar codes are typically freely dispensable in a liquid and not permanently associated with a stationary phase. Nanobar codes that are not produced by some form of deposition or growth within a template (e.g., self-assembled nanobar codes) may be considered freestanding even though they have not been released from a template.
• the term “free standing” does not imply that such nanoparticles must be in solution (although they may be) or that the nanobar codes can not be bound to, incorporated in, or a part of a macro structure.
• the nanoparticles may be dispersed in a solution, e.g., paint, or incorporated within a polymeric composition.
• the particles of the present invention may be prepared by a variety of processes. The preferred process for the manufacture of a particular particle can often be a function of the nature of the segments comprising the particle.
• a template or mold is utilized into which the materials that constitute the various segments are introduced.
• defined pore materials are the preferred templates for many of the preferred particles of the present invention. Al 2 O 3 membranes containing consistently sized pores are among the preferred templates, while photolithographically prepared templates, porous polycarbonate membranes, zeolites and block co-polymers may also be used.
• Methods for forming segments of particles include electrodeposition, chemical deposition, evaporation, chemical self assembly, solid phase manufacturing techniques and photolithography techniques.
• Chemical self assembly is a method of forming particles from preformed segments whereby the segments are derivatized and a chemical reaction between species on different segments create a juncture between segments.
• Chemically self-assembled nanoparticles have the unique ability of being controllably separated between segments by reversing the chemical bond formation process.
• One of the preferred synthetic protocols used to prepare metallic nanobar codes according to the embodiments of the present invention is an extension of the work of Al- Mawlawi et al. (Al-Mawlawi, D.; Liu, C. Z.; Moskovits, M. J. Mater. Res. 1994, £, 1014; Martin, C. R. Chem. Mater. 1996, £, 1739) on template-directed electrochemical synthesis. See, Example 1, below. In this approach, metals are deposited electrochemically inside a porous membrane.
• the synthetic method of the present invention differs from previous work in several respects including the following. First, the electroplating is done with agitation, such as in an ultrasonication bath.
• the temperature is controlled, for example, by using a recirculating temperature bath.
• These first two modifications increase the reproducibility and monodispersity of rod samples by facilitating the mass transport of ions and gases through the pores of the membrane.
• rods with multiple stripes are prepared by sequential electrochemical reduction of metal ions (e.g., Pt2 + , Au + ) within the pores of the membranes. Because the length of the segments can be adjusted by controlling the amount of current passed in each electroplating step, the rod resembles a "bar code" on the nanometer scale, with each segment length (and identity) programmable in advance.
• the width of the rods and the segment lengths are generally of nanometer dimensions, the overall length is generally such that it can be visualized directly in an optical microscope, exploiting the differential reflectivity of the metal components.
• the nanorod synthesis There are many parameters in the nanorod synthesis that are tunable, such that it is theoretically possible to generate many millions of different patterns, uniquely identifiable by using conventional optical microscopy or other methods.
• the most important characteristic that can be changed is the composition of the striped rods.
• the simplest form of a nanoparticle is one with only one segment. To this end, several different types of these solid bar codes have been prepared. By simply using only one plating solution during the preparation, a solid nanoparticle is produced.
• two metals e.g., Au, Ag, Pd, Cu, etc.
• Nanobar codes can also be generated using 3 different metals.
• Synthesis of a Au-/Pt-/Au rod may be accomplished with 1 C of Au, 8 C Pt, and 1 C of Au.
• the nominal dimensions of the segments are 1 ⁇ m of Au, 3 ⁇ m of Pt, 1 ⁇ m of Au.
• the 5-segment nanobar codes, Ag-/Au-/Ag-/Au-/Ag were generated by sequentially plating the appropriate metal. In some embodiments it is possible to include all metals in solution but control deposition by varying the charge potential current.
• a nine-segment nanobar code, Au-/Ag-/Au-/Ag-/Au-/Ag-/Au-/Ag-/Au has also been prepared. The number of segments can be altered to desired specifications.
• the next controllable factor is diameter (sometimes referred to herein as width) of the individual rods.
• Many of the nanobar codes described were synthesized using membranes with a pore diameter of 200 nm. By altering the pore diameter, rods of differing diameter can be made.
• Au rods have been synthesized in a membrane that has 10 nm diameter pores, 40 nm pores and pores in the range of 200-300 nm.
• the ends of the rods typically have rounded ends or flat ends.
• a TEM image of an Au rod that was made by reversing the current flow (from reduction at -0.55 mA cm to oxidation at +0.55 mA/cm ) and removing some of the gold from the tip of the rod generated a spike extending from the tip of the rod.
• branched ends can be generated. This can be typically controlled by controlling the amount of metal that is plated into the membrane. The edges of the membrane pores have a tendency to be branched which lead to this type of structure.
• An additional way to alter the ends of the rods is to control the rate of deposition.
• Gold rods (2 C total, 3 ⁇ m) were plated at a current density of 0.55 mA/cm 2 . Then the current density was reduced to 0.055 mA/cm 2 and 0.1 C of Au was plated. The last segment of gold deposits is a hollow tube along the walls of the membrane.
• Example 1 describes the manufacture of single flavors of nanoparticles according to one embodiment of the invention.
• the present invention includes methods of manufacture of nanoparticles that allow for the simultaneous or parallel manufacture of a plurality of different flavors of nanobar codes.
• no system or apparatus has been described whereby it was possible to prepare more than one type of nanobar code simultaneously or in parallel.
• such method for the simultaneous manufacture of nanobar codes allows for the manufacture of 2 or more, more than 5, more than the 10 and preferably more than 25 different flavors of nanobar codes.
• simultaneous or parallel it is meant that common elements are employed in the manufacture of the more than one nanobar code.
• the separate membranes may have a common electrode, but separately controllable solution access.
• the simultaneous manufacture of different types of nanoparticles is commonly controlled. Any system or apparatus whereby a plurality of different flavors of nanoparticles (e.g, particles having a plurality of segments, that are 10 nm to 50 ⁇ m in length, and have a width from 5 nm to 50 ⁇ m that are differentiable from each other) can be prepared in parallel is included within the scope of this invention. Among the options that can be employed to affect this parallel manufacture are the following:
• Multi-electrode and Micro fluidic Synthesis To synthesize many flavors of nanorods on a single membrane, the membrane can be divided into separate electrical zones, with each zone using a different plating recipe. Of course, several smaller membranes could be used, one for each separate zone, as opposed to a single membrane with multiple zones.
• the electrical zone approach can be achieved by patterning the Ag evaporation that initially seals one side of the membrane into many separate islands. Each island would have its own electrode, and control circuitry can activate each island separately for plating.
• the microfluidic approach utilizes a single evaporated Ag electrode, but would divide the opposite side of the membrane into separate fluidic regions, and control the flow of plating solutions to each region.
• Patterned front-side insulation This approach applies insulating patterned coatings (e.g., photoresist) to the front-side (electrodeposition side) of a membrane. Where the membrane is coated, electroplating is inhibited. The coating can be removed and reapplied with different pattern between electroplating steps to achieve synthesis of many flavors of nanobarcode within one membrane.
• insulating patterned coatings e.g., photoresist
• Patterned back-side insulation This approach applies insulating patterned coatings (e.g., photoresist) to the back-side (electrode side) of a membrane, which is divided into many separate electrical contacts. Where the electrode is coated, electroplating is inhibited. The coating can be removed and reapplied with different patterns between electroplating steps to achieve synthesis of many flavors of nanobarcode within one membrane.
• insulating patterned coatings e.g., photoresist
• Lithography vertical or horizontal This technique, that offers increased design flexibility in the size and shape of nanorods, utilizes lithographic processes to pattern the deposition of multiple layers of metals on a silicon substrate. This approach takes advantage of the tremendous capabilities developed in microelectronics and MEMS, and promises very high quality nanorods with greater design flexibility in the size and shape of nanorods than membrane-based techniques. Each of these synthetic approaches must be mated to complementary well arrays to allow nanobar release into separate vessels.
• Light-addressable electroplating A further technique that could produce thousands of flavors in one synthesis step also utilizes membrane-based synthesis, but includes light-directed control of the electroplating process.
• a light-addressable semiconductor device is used to spatially modify the electrical potentials in the vicinity of the membrane, and thus spatially modulate electroplating currents.
• the membrane is optically subdivided into many different zones, each of which produces a different flavor of nanorod.
• each island would be plated with unique combinations of metal types and thicknesses. In this manner, each island would produce rods of different lengths, different numbers of stripes, and different material combinations, allowing ultimate design flexibility, (ii) The above approach will be limited in the number of types of rods that can be synthesized by the reliability and packing density of the bed-of-nails apparatus.
• the bed-of-nails apparatus can be replaced by a liquid metal contact.
• the backside of the membrane may be patterned with a nonconductive coating.
• the pattern would be removed and replaced with a different pattern between electroplating steps. This approach will enable a much higher density of isolated islands, and therefore more types of rods to be synthesized. With island spacing of 100 microns, which would be trivial to achieve using lithographical patterning, up to 10 5 types of rods could be synthesized.
• pore matrices may be constructed using photolithography techniques, which will give ultimate control over the pore dimensions and lengths, and increase the design flexibility and quality of the resulting nanorods.
• photolithography techniques which will give ultimate control over the pore dimensions and lengths, and increase the design flexibility and quality of the resulting nanorods.
• a positive photoresist-coated wafer is exposed to an interference pattern of light, using a technique similar to that used for interference-lithography generated diffraction gratings.
• the wafer is typically silicon, with a thin coating of titanium and gold, a thick coating of polymethylmethacrylate (PMMA), and a photoresist.
• PMMA polymethylmethacrylate
• Two exposures at right angles and subsequent development yields a two-dimensional array of holes in the photoresist.
• Reactive ion etching is then used to transfer the hole pattern down through the PMMA layer, which becomes the template.
• the photoresist layer is removed, and the gold layer under the PMMA becomes the cathods for electroplating into the PMMA pores.
• the shape and diameter of the nanorods can be controlled by adjusting the light source and the resultant standing wave pattern.
• an advantage to this technique is that the template thickness, which is the same as pore length, can be tailored to the length of the rods, which improves uniformity of electroplating across the membrane.
• 10 10 to IO 12 nanorods can be constructed on a single substrate.
• the two approaches described above can be utilized to synthesize many types of nanobar code from a single wafer, (iv)
• a further approach uses the customized lithographically-defined pores from above, and achieves the ultimate in design flexibility by using novel light-directed electroplating.
• the template pores are constructed just as in the third approach, but on top of a photosensitive semiconductor wafer. The pore- side of the wafer is immersed in electroplating reagent, and the other side is illuminated with patterns of light.
• Light exposure is used to generate photocurrent in the wafer, and switch the plating current on or off for each conductive zone within the wafer.
• a computer-controlled spatial light modulator selectively illuminates different zones at different times, so that each zone will be subjected to a different computer-controlled plating recipe. Depending on the resolution of the optical system that exposes the wafer, this could result in IO 4 to IO 6 separate flavors of nanorods synthesized on a single wafer. With IO 12 total pores per wafer, 10° to 10 8 nanorods of each flavor could be synthesized.
• Such methods include but are not limited to: MEMS, electron beam lithography, x-ray lithography, uv lithography, deep lithography, projection lithography, standing wave lithography, interference lithography, and microcontact printing.
• Chemical self-assembly/deassembly methods may also be used. For example, formation of an infinite, close-packed, 2-dimensional hexagonal layer of latex balls on a planar surface has been demonstrated. Such particles could be slrrunk by 10%) in size, e.g., by cooling the temperature. Then a polymer may be grown in the spaces between the infinite 2-D array (that is no longer close packed). Then the balls are selectively dissolved, leaving behind a polymeric material with well defined holes equal to the final diameter of the latex balls.
• the particles of the present invention may also be prepared in large scale by automating the basic electroplating process that is described in Example 1.
• an apparatus containing a series of membranes and separate electrodes can be used to make a large number of different flavors of nanoparticles in an efficient computer controlled manner.
• An example of this type of apparatus is depicted in Figures 1 and 2.
• each membrane is silver-coated on one side (which is the branched-pore side of the membrane) in a vacuum evaporator. Then each membrane is immersed in a silver plating solution with electrodes on both sides, and additional silver is electroplated onto the evaporated silver coating and into the pores (at 4 mA for about 30 minutes), to completely close all of the membrane pores. Each membrane is then mounted with its silver-coated side in contact with an electrode in the flow cell.
• the flow cell is about 1.5 mm thick, containing about 30 ml of liquid.
• Opposite the membranes is a platinum mesh electrode with surface area slightly larger than the entire 5x5 array of membranes.
• the flow cell can be filled (by computer control) with water, nitrogen gas, gold plating solution (e.g., Technics), silver plating solution (e.g.,Technics Silver Streak and/or additional plating solutions).
• the flow cell is in thermal contact with a coolant water tank, l o the temperature of which is controlled by recirculation through a temperature-controlled bath.
• a coolant water tank In the coolant tank opposite the flow cell is an ultrasonic transducer (Crest, 250 Watt), which is turned on during electroplating operations to facilitate mass transport of ions and gases through the membrane pores.
• Control software is used to automatically flow the appropriate solutions through the flow cell, and individually control the electroplating currents or potentials at each separate membrane.
• the software also measures temperature at various locations in the apparatus, and controls the sonicator and peristaltic pump.
• the software allows the user to define recipes describing the desired stripe pattern for each nanobar code in the 5x5 array.
• the software reads the recipe, and then automatically executes all fluidic and electrical steps to synthesize different types of nanobar codes in each membrane.
• each membrane is immersed in approximately 2M HN (nitric acid) for about 30 minutes to dissolve the backside silver coating. Then the membrane is immersed in NaOH to dissolve the alumina membrane, and release the rods into solution. The rods are then allowed to settle under gravity, and the NaOH is washed out and replaced with H 2 0 or Ethanol for storage.
• HN nitric acid
• moving the membranes or templates may be moved from one plating solution to another.
• membranes 1-10 may begin with the deposition of a layer of gold that is 50 nm thick
• membranes 11-20 may begin with the deposition of gold that is 100 nm thick
• membranes 21-25 may not have an initial layer of gold.
• This deposition step can be easily accomplished in the apparatus of this embodiment by filling the solution reservoir with a gold plating solution and applying current to membranes 1-10 for the predetermined length of time, membranes 11-20 for twice as long and not at all to membranes 21-25. The gold plating solution is then removed from the chamber and the chamber rinsed before introducing the next plating solution.
• the apparatus of this embodiment has been designed to be rotatable around a pivot point for ease of access to the solution chamber and the electric and plumbing controls on the back of the apparatus.
• the apparatus rests upon a base 101.
• the pivoting mechanism is comprised of the pivoting support 103, the pivot locking pin handle 105, and the pivot pin 107.
• the apparatus is equipped with a halogen light, contained in the box 108, and a sonicator, located at 109, in fluid communication with a solution chamber.
• the flow cell is defined by the rear cell assembly 111 and the front cell assembly 113.
• the electrical connectors 115 are on the tops of the rear and front assemblies.
• the assemblies are held in place by clamping bolts 117 to maintain a sealed solution chamber.
• the 25 templates 119 for nanoparticle growth are held between front and rear assemblies, and the front assembly has an electro forming cell front window 121.
• Figure 2 is a cross-sectional view of the apparatus shown in Figure 1. Many of the same elements can be seen in Figure 2 that were defined with respect to Figure 1, and they have been numbered the same. Figure 2 also allows visualization of cell partitioning gaskets 123 between front and rear assemblies and gasket alignment pin 125. Figure 2 also shows rear assembly glass window 127. The water tank 129 for temperature control is found adjacent to the rear assembly, and the halogen lamp 131 is shown.
• the ultrasonic apparatus is comprised of the ultrasonic transducer 133 and the ultrasonic tank 135.
• multiplexed synthesis of nanoparticles need not be confined to electrochemical deposition into a host.
• the materials described herein could likewise be prepared by sequential evaporation, or by sequential chemical reaction.
• a final critical step is required to separate each unique type of nanorod and release all the nanorods into solution, for surface preparation or denaturation. In the preferred embodiments of the invention this is done by chemical dissolution of the membrane and electrode backing, using a series of solvents.
• solvents could be acids, bases, organic or aqueous solutions, at one or more temperature or pressures, with one or more treatment times.
• Two additional release techniques are: (i) Following synthesis, whether on membrane or planar substrate, die separation techniques from the semiconductor industry can be utilized. The substrate will be mated to a flexible adhesive material. A dicing saw cuts through the substrate, leaving the adhesive intact. The adhesive is then uniformly stretched to provide physical separation between each island, each of which is then picked up automatically by robot and placed into a separate microwell.
• An automated fluidics station is used to introduce the necessary etching solutions to release each rod into solution
• An alternative embodiment is a matching microwell substrate that contains wells in the same pattern as the individual islands in the membrane, and a matching array of channels through which flow etching solutions.
• the membrane or wafer can be sandwiched between the microwell substrate and the channel array.
• Etching fluid is then introduced into the channels which dissolves the Ag backing and carries the nanorods into the corresponding well.
• Other means for removing the particles from the membrane are also possible, including but not limited to laser ablation, heating, cooling, and other physical methods.
• the membrane-based template-directed synthesis techniques are preferred because they are capable of making a very large number of very small nanorods.
• the electroplating conditions can be adequately controlled to produce many types of nanorod bar codes.
• applications such as multiplexed immunoassays, where tens to many hundreds of types are required, known techniques are adequate and can simply be scaled up to provide the necessary number.
• applications such as proteomic signatures, where from dozens to many thousands of types are required, higher throughput synthesis techniques and the ability to uniquely identify each of thousands of different bar codes are required.
• One embodiment of the present invention is directed to the template-directed synthesis of multiple flavors of nanobar codes for the purpose of multiplexed assays.
• 10 different flavors of nanobar codes were individually synthesized according to the table below, using gold and silver segments. Note that the description field of the table indicates the composition of each nanobar code by segment material and length (in microns) in parentheses. For example, Flavor #1 is 4 microns long gold, and Flavor #2 is 2 microns gold followed by 1 micron silver, followed by 2 microns gold.
• Electrochemical metal deposition was carried out using commercially available gold (Technic Orotemp 24), and silver (Technic ACR 1025 SilverStreak Bath) plating solutions. All of the electroplating steps described below were carried out in an electrochemical cell immersed in a sonication bath, which was temperature controlled to 25°C.
• nanobar code Flavor #4 was carried out as follows.
• the membrane was pretreated by evaporating -500 nm of silver on its branched side. To completely fill the pores on this side, approximately 1 C of silver was electroplated onto the evaporated silver, using 1.7 mA of plating current for approximately 15 minutes. Then an additional 1 C of silver was electroplated into the pores of the membrane from the side opposite the evaporated silver, using 1.7 mA of plating current for approximately 15 minutes. This silver layer is used to fill up the several micron thick "branched-pore" region of the membrane. The silver plating solution was removed by serial dilutions with water, and was replaced by the gold plating solution.
• the 2 micron long gold segments were then deposited using 1.7 mA of plating current for approximately 30 minutes.
• the gold plating solution was removed by serial dilutions with water, and was replaced by the silver plating solution.
• the final 2 micron long silver segment was then deposited using 1.7 mA of plating current for approximately 30 minutes.
• the membrane was removed from the apparatus, and the evaporated silver layer (and the electrodeposited silver in the branched pores) was removed by dissolution in 6 M nitric acid, being careful to expose only the branched-pore side of the membrane to the acid.
• the nanobar codes were released from the alumina membrane by dissolving the membrane in 0.5 M NaOH. The resulting suspension of nanobar codes were then repeatedly centrifuged and washed with water.
• rod structures formed by electrochemical deposition into a membrane template include Ag, Au, Pt, Pd, Cu, Ni, CdSe, and Co.
• alumina or track etch polycarbonate alumina or track etch polycarbonate
• the 200-nm pore diameter alumina membranes have been used for convenience.
• Many of the materials are now also being used in the smaller diameter polycarbonate membranes.
• CdSe is currently plated via a potential sweep method from a solution of CdSO and SeO 2 .
• Mechanical stability problems have been encountered with the metahCdSe interface; i.e. they break when sonicated during the process of removing them from the membrane. This has been remedied with the addition of a 1,6-hexanedithiol layer between each surface.
• the Cu and Ni are plated using a commercially available plating solution. By running under similar conditions as the Ag and Au solutions, it was found that these metals plate at roughly the same rate, -3 ⁇ m hr.
• the Co is plated from a CoSOVCitrate solution. These rods seems to grow fairly monodispersely, however they grow comparatively slowly, -1.5 ⁇ m hr.
• One embodiment of the present invention is directed to the template-directed synthesis of nanoscale electronic devices, in particular diodes.
• One approach combines the membrane replication electrochemical plating of rod-shaped metal electrodes with the electroless layer-by-layer self-assembly of nanoparticle semiconductor/polymer films sandwiched between the electrodes. Described below, is the wet layer-by-layer self-assembly of multilayer TiO 2 /polyaniline film on the top of a metal nanorod inside 200 nm pores of an alumina membrane.
• XRD investigations of the titania xerogel allowed estimating average size of the colloidal anatase crystals at 6 nm, TEM image of the stock TiO 2 sol shows particles of 4-13 nm in diameter.
• the emmeraldine base (EB) form of polyaniline (PAN) was also prepared.
• a dark blue solution of PAN in dimethyl formamide (0.006% wt) was used as a stock solution for the film synthesis.
• the synthesis of rod-shaped diodes was carried out as follows. Metal electrodes were grown electrochemically inside porous membrane. Briefly, the membrane was pretreated by evaporating -150 nm of silver on its branched side. To completely fill the pores on this side 1 C of silver was electroplated onto the evaporated silver. These Ag “plugs" were used as foundations onto which a bottom electrode was electrochemically grown. The bottom gold electrode of desired length was electroplated sonicating. The plating solution was removed by soaking the membrane in water and drying in Ar stream. Priming the bottom electrode surface with MEA preceded depositing multilayer TiO 2 /PAN film. This was achieved by 24 hour adsorption from MEA(5%>) ethanolic solution.
• the multilayer film was grown by repeating successive immersing the membrane in the TiO 2 aqueous solution and PAN solution in DMF for 1 h. Each adsorption step was followed by removing the excess of reagents by soaking the membrane in several portions of an appropriate solvent (0.01 M aqueous HCl or DMF) for 1 h, and drying in Ar stream. Finally, a top electrode (Ag or Pt) of desired length was electroplated at the top of TiO /PAN multilayer without sonicating. Then the evaporated silver, "plugs" and alumina membrane were removed by dissolving in 6 M nitric acid and 0.5M NaOH, respectively.
• the membrane was successively soaked for 1 h in the appropriate anhydrous solvent, a mixture (1 :1) of the solvent and absolute ethanol, the absolute ethanol, and finally was dried in Ar stream.
• Wetting so treated membranes with water revealed hydrophobic properties of their external surface.
• Transmission IR spectra of the membrane treated with ethyltriethoxy silane or propionic acid showed the appearance of weak bands at 2940, 2865, 2800 cm-1, which can be assigned to C-H stretching vibrations of alkyl and alkoxy groups.
• TEM images were obtained with a JEOL 1200 EXII at 120 kV of accelerating voltage and 80mA of filament current.
• Optical microscope (OM)images were recorded. Transmission IR spectra were recorded using a Specord M-80 CareZeiss Jena spectrometer. I-N characteristics for rod- shaped diodes were measured in air at ambient temperature.
• I-V characteristic of the Pt/( TiO 2 /PAN) 3 TiO /Au rod-shaped device reveals current rectifying behavior.
• the forward and reverse bias turn-on potentials are- -0.2 and -0.9 V, respectively.

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