WO2002029136A1 - Procede de fabrication de particules colloidales de type tige sous forme de nano codes-barres - Google Patents

Procede de fabrication de particules colloidales de type tige sous forme de nano codes-barres Download PDF

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Publication number
WO2002029136A1
WO2002029136A1 PCT/US2001/030729 US0130729W WO0229136A1 WO 2002029136 A1 WO2002029136 A1 WO 2002029136A1 US 0130729 W US0130729 W US 0130729W WO 0229136 A1 WO0229136 A1 WO 0229136A1
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WIPO (PCT)
Prior art keywords
pores
pattern
nanoparticles
substrate
membrane
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Application number
PCT/US2001/030729
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English (en)
Inventor
Walter Stonas
Louis J. Dietz
Ian Walton
Michael J. Natan
James L. Winkler
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Surromed, Inc.
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Publication date
Priority claimed from US09/677,203 external-priority patent/US7045049B1/en
Application filed by Surromed, Inc. filed Critical Surromed, Inc.
Priority to AU2001296460A priority Critical patent/AU2001296460A1/en
Priority to EP01977334A priority patent/EP1337694A4/fr
Publication of WO2002029136A1 publication Critical patent/WO2002029136A1/fr

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    • 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
    • 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
    • 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
    • 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
    • C25D1/006—Nanostructures, e.g. using aluminium anodic oxidation templates [AAO]
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00502—Particles of irregular geometry
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • B01J2219/00547—Bar codes
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • 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
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00596—Solid-phase processes
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes

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 membranes of the present invention may be used as templates for the synthesis of nanoparticles according to methods provided herein.
  • the membranes include anodized alumina membranes, polycarbonate trach-etched membranes, and membranes made using photolithographic methods. Throughout this application, said membranes may be interchangeably referred to as "porous membranes," “porous templates” and “templates.”
  • Nanoparticles may be formed within the pores by deposition methods including, electrochemical deposition, sequential chemical reaction, and chemical vapor deposition (CVD). Alternatively, the nanoparticles maybe directly manufactured using photolithographic techniques.
  • 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.
  • multiplexing such as those involving immobilized molecular arrays
  • second (or third) information channels such as in 2-D gel electrophoresis or CE-electrospray MS/MS.
  • 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 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.
  • methods of making segmented nanoparticles using a porous template manufactured by standard photolithographic techniques comprising exposing a pattern on a resist-coated substrate or multi-layer stack and then etching the exposed pattern to form pores.
  • 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.
  • Figure 3 is a schematic illustration of a four-layer stack on a silicon wafer substrate (A) before exposure; (B) following exposure and development of the photoresist, and etching to etch stop; (C) following further etching to conductive layer, (D) after formation of the segmented nanoparticle, and (E) the liberated segmented nanoparticles.
  • Figure 4 is an SEM (top view) of a template prepared using photolithographic techniques in which nanoparticles have been formed by electrochemical deposition. The pore diameter is approximately 2.5 to 3 ⁇ m.
  • Figure 5 is an SEM (side view) of a free-standing nanoparticle made by electrodeposition in a template prepared using photolithographic techniques.
  • Figure 6 is an SEM (cross-sectional view) of a template prepared using photolithographic techniques.
  • 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, NanobarcodesTM particles, 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 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).
  • electrochemical deposition can be accomplished using another method of manufacture in which the length or other attribute of the segments can be controlled. While the diameter of the rods and the segment lengths are typically of nanometer dimensions, the overall length is such that in preferred embodiments it can be visualized directly in an optical microscope, exploiting the differential reflectivity of the metal components.
  • 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 in certain embodiments, need not be perpendicular to the length of the particle or a smooth line of transition.
  • composition of one segment may be blended into the composition of the adjacent segment.
  • 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.
  • 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.
  • each of the nanobar codes of the assembly may be functionalized 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. Indeed, certain embodiments of the invention, 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, 9, 1014; Martin, C. R. Chem. Mater. 1996, 8, 1739) on template-directed electrochemical synthesis. See, Example 1 , below.
  • the synthetic method of the present invention differs from previous work in several respects including the following.
  • 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., Pt ⁇ + , Au + ) within the pores of the membranes.
  • the rod resembles a "bar code" on the nanometer scale, with each segment length (and identity) programmable in advance. While 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.
  • 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 2 ) 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.
  • 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 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. In order to produce many thousands of flavors of nanorods, in practical quantities, and to attach molecules to most or all, novel combinatorial or multiplexed synthesis techniques are necessary. Several synthesis embodiments are included within the scope of the invention. Each approach has advantages and disadvantages depending on the specific application and the required number of types and total number of nanorods needed for the application.
  • 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 effect this parallel manufacture are the following:
  • Multi-electrode and Microfluidic 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 nariobarcode 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.
  • Template Dicing A template may be cut into a number of smaller pieces. This may be accomplished, for example, using a dicing saw or by a "scribe and break" procedure where the wafer is cut part of the way through and then broken; the latter may be preferred in some embodiments because it generates less dust and debris.
  • 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 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.
  • a positive photoresist-coated substrate is exposed to an interference pattern of light, using a technique similar to that used for interference-lithography generated diffraction gratings.
  • the substrate is a silicon wafer, with (a) a thin coating of a conductive material, such as titanium nitride, or gold, (b) a thick coating of polymer, such as polymethylmethacrylate (PMMA) or polyimide, (c) an etch stop, such as SiO 2 , aluminum, or nickel, and (d) a photoresist. Exposure and subsequent development yields a two- dimensional array of pores in the photoresist. Reactive ion etching may then be used to transfer the pore pattern down through the polymer layer. The photoresist layer is removed, and the conductive layer under the polymer becomes the cathode for electroplating into the pores.
  • a conductive material such as titanium nitride, or gold
  • PMMA polymethylmethacrylate
  • etch stop such as SiO 2
  • Al aluminum
  • nickel nickel
  • the shape and diameter of the nanorods can be controlled by the mask or by adjusting the light source and the resultant standing wave pattern. For most applications, a conventional mask is preferred. However, interference lithography techniques may be preferred when the desired pore diameter is lower than the resolution limit available from state of the art projection lithography tools. Achieving smaller pore size may also benefit from the use of x-ray or e-beam etching.
  • the template thickness which may be the same as pore length, can be tailored to the length of the rods, which may improve uniformity of electroplating across the membrane.
  • 10 10 to 10 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 an 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.
  • this could result in 10 to 10 6 separate flavors of nanorods synthesized on a single wafer.
  • 10 6 to 10 8 nanorods of each flavor could be synthesized.
  • Membranes with extremely high densities of uniform pores can be created by photolithographic techniques and the resulting nanoparticles are of very uniform size and length.
  • a 4-inch silicon wafer can serve as the substrate for the formation of, for example, 50 billion pores of diameter 200 nm and period 400 nm. Pores of smaller diameter and lower period are readily achievable. Unlike the pores formed in anodized alumina membranes or polycarbonate trach-etched membranes, pores formed by photolithographic techniques have a very tight diameter distribution, do not overlap or branch, and are straight and parallel.
  • membrane templates are formed from resist-coated substrates or multi-layer stacks by means of interference lithography (also known as “holographic” or “interferometric” lithography).
  • Interference lithography is well known in the semiconductor and microfabrication arts as a technique capable of patterning grids and gratings over a large area of resist (up to 10 cm diameter) without using a mask.
  • IL involves forming an optical standing wave through the intersection of two laser beams. The standing wave creates a line of alternating exposed and unexposed regions on the resist.
  • a "grid" is patterned on the resist. This pattern can be transferred into material that lies underneath the resist, thereby forming pores, by developing the resist and then performing an etch.
  • the resist and/or the underlying material form the walls of the membrane pores within which nanoparticle can subsequently be formed.
  • Interference lithography is best performed with wavelengths longer than 248 nm; this corresponds to a period of approximately 200 nm.
  • shorter wavelength laser light is required.
  • lasers that provide shorter wavelength light generally do not produce sufficiently monochromatic light to generate robust interference patterns.
  • achromatic interference lithography uses a first phase grating to generate two first-order light beams from an incident light source. Two further phase gratings recombine these divergent light beams by second-order diffraction.
  • each phase grating has a period of 200 nm and each is fabricated by interference lithography and reactive ion etching.
  • the resulting light beam takes the form of a standing optical wave of 100 nm period which can extend over a 10 cm diameter area.
  • Orthogonal exposure of a resist-coated substrate to the standing optical wave can form an array of pores in the same way as described above for interference lithography.
  • IL or AIL is performed on multi-layer stack, comprising a substrate on which has been deposited a conductive material layer, a polymer layer, an etch stop layer, and a photoresist.
  • the resist can be developed by techniques well known in the art.
  • the grid pattern in the developed resist can then be transferred down into the etch mask layer, and the polymer layer by any of the etching techniques known in the art, including wet etching, dry etching, reactive ion etching, electron beam and laser writing; reactive ion etching is preferred.
  • each pore passes through the resist layer, the etch mask layer, and the polymer layer.
  • the resist layer can be completely removed following etching so that the pores are formed solely within the polymer layer. The depth of the pores, and hence the length of nanoparticles that can be formed in the pores, is determined by the thickness of the relevant layers of the stack.
  • the conductive material may be a metal, a metal-containing compound, or a metal alloy, including without limitation titanium nitride, nickel, copper, zinc, silver and gold; titanium nitride and gold are preferred.
  • the conductive layer may be deposited by any suitable means, including sputtering.
  • a layer of adhesion promoting material may be deposited on the substrate before deposition of the conductive layer.
  • Adhesion promoting materials include titanium and cromium; titanium is preferred where titanium nitride is the conductive material; cromium is preferred where gold is the conductive material.
  • the polymer may be polyimide, polymethylmethacrylate (PMMA), photoresist, or other suitable polymer known in the art.
  • PMMA polymethylmethacrylate
  • the "polymer” layer includes materials that can be etched according to the methods of the present invention to form pores even if those materials are not polymeric (e.g., polysilicon, SiO 2 ).
  • the etch stop layer may be SiO 2 , aluminum, and nickel, or other etch stop know in the art.
  • Suitable resists include both positive and negative photoresists known in the art. Positive photoresists are preferred for features less than 3 ⁇ m in size.
  • resists including positive and negative resists
  • etch stops and polymers that can be patterned into grids using IL and AIL.
  • Any stack that can be patterned by IL or by AIL to yield pores suitable for the formation of nanoparticles is contemplated by the present invention.
  • silicon wafers are the preferred substrates of the invention, many other suitable substrates are known in the art.
  • An antireflective coating may be included in the stack. Such a coating acts to prevent the reflection of light by the underlying substrate, thereby assisting the integrity of the standing optical wave.
  • the etch stop layer may be omitted from the stack.
  • the conductive layer may also be omitted if the substrate is sufficiently conductive (e.g., if it has been doped) or if the nanoparticles are to be made by a process other than electrodeposition (e.g., CVD), and therefore do not require an electrode. Indeed, in the most basic embodiments of the invention, even the polymer layer may be omitted, so that the photoresist will form the walls of the pores.
  • Membrane templates for the formation of nanoparticles also may be formed by conventional mask-based photolithography techniques well-known in the semiconductor and microfabrication arts.
  • masks with a grid pattern generated by standard methods known in the art e.g., e-beam writing and laser writing
  • the substrates and multi-layer stacks, as well as the techniques for development and etching thereof, are preferably based on those described above (e.g., a substrate overlaid first with a polymer layer, an etch stop material, and a photoresist).
  • An advantage of using masks is that each mask can be used a number of times, thereby obviating the need to use the AIL or IL optical configuration every time a membrane template is required.
  • the use of any type of mask known in the art is contemplated by the invention.
  • the mask itself may be formed by IL or AIL.
  • the mask is a grating
  • two orthogonal exposures of the resist are necessary to pattern the resist with a grid
  • a single resist exposure can be used to pattern a grid.
  • Methods for forming free-standing grating and grid masks by IL and AIL are described in, for example, Wolf and Tauber, Silicon Processing for the VLSI Era, Vol. 1 Process Technology (2nd Ed.) Lattice Press, California (2000), incorporated herein by reference in its entirety.
  • the membrane templates produced by the methods of the present invention can be used to form nanoparticles via a number of techniques.
  • electrochemical deposition is used, requiring that the membrane template have a conductive material in communication with the pores. This may be achieved, for example, by depositing a layer of conductive material overlying the substrate, as described above, doping the substrate so that it can act as the electrode, or both.
  • material can be deposited within pores by chemical vapor deposition (e.g., organic-metallic vapor deposition) or evaporation.
  • chemical vapor deposition e.g., organic-metallic vapor deposition
  • evaporation electron- beam evaporation has been used to deposit metal within pores formed by AIL. Savas et al., J. Applied Physics 1999, 85 . 6160, incorporated herein by reference in its entirety. Methods for the formation of nanoparticles in membrane template pores by evaporative techniques are discussed further herein.
  • the substrate may first be coated with one or more conductive layers before the stack is built. The photoresist is then exposed and developed, as described above. When the stack is etched down to the conductive layer, the resulting pores comprise a layer of conductive material at their base. By applying a current to the substrate, the conductive layer acts as an electrode at the base of each pore, thereby allowing charged material to be electrodeposited within the pore. In this way, segmented nanoparticles can be built through sequential electrochemical deposition according to the methods provided herein.
  • the conductive layer comprises a layer of Ti overlaid with a layer of TiN, or Cr overlaid with a layer of Au.
  • Ti or Cr layer is about 5 nm thick and the TiN or Au layer is about 20 nm thick.
  • the material that forms the walls of the pore e.g., PMMA
  • the material that forms the walls of the pore can be removed, exposing the nanoparticles.
  • the nanoparticles can be released from the silicon wafer by a number of methods.
  • the nanoparticles can be liberated by physically breaking the linkage between the wafer and the nanoparticles using, for example, sonication or high-pressure water.
  • the nanoparticles also may be liberated by etching the silicon wafer, for example using HF acid. All of the aforementioned techniques for liberating nanoparticles are equally applicable in embodiments where nanoparticles are formed in pores through techniques other than electrochemical deposition.
  • the nanoparticles may be released by dissolving the conductive layer.
  • areas of sacrificial conductive material may be deposited on the conductive layer such that they lie at the bottom of the pores. Because it is conductive, the material can transmit the current to the growing nanoparticles. Selected so that it is easily dissolved or otherwise removed, the sacrificial conductive material may be useful in liberating the nanoparticles formed in the pores.
  • a number of materials may be used as sacrificial conductive materials, including without limitation Ag, Cu, and Zn.
  • FIG. 3 illustrates schematically an embodiment of the invention using a four-layer stack on a silicon wafer substrate 101. In Figure 3A, the stack is shown before exposure to radiation.
  • Substrate 101 is overlaid with conductive layer 102, then with polymer layer 103, then with a etch stop layer 104, and finally with photoresist layer 105.
  • the stack is shown following exposure and development of the photoresist, followed by etching down to etch stop 104, thereby forming pores 106. Exposure may be performed using IL or AIL (with two orthogonal exposures), or using conventional mask-based photolithography with a grid mask.
  • FIG 3C further etching down through polymer layer 103 to conductive layer 102 results in the formation of pores 107.
  • nanoparticles 108 are formed within pores 107 by electrochemical deposition using the conductive layer 102 as the plating electrode.
  • free-standing nanoparticles 109 are liberated by dissolving the conductive layer 102.
  • the membrane template created using photolithographic techniques is re-usable. This can be achieved in the following way.
  • Step 1 a layer of polysilicon is deposited on a silicon wafer using either CVD or PECVD deposition.
  • Step 2 A layer of photoresist is spun on the silicon wafer.
  • Step 3 The resist is exposed using a mask, IL, or AIL, to pattern a grid.
  • Step 4 The resist is developed and the polysilicon is etched, revealing an array of pores in the polysilicon.
  • a sacrificial layer of conductive metal is deposited, electrochemically or by CVD, inside the pores that were etched into the polysilicon.
  • Step 6 A layer of silicon dioxide is then deposited on the surface of the stack, followed by a hydrogen bake to remove metal oxide formed in the silicon deposition process.
  • Step 7 Nanoparticles may be formed inside the pores using CVD or electrochemical deposition; in the latter case, the Zn may participate as an electrode.
  • Step 8 the silicon dioxide deposited in step 7 is dissolved using HF.
  • Step 9 The Zn deposited in step 6 is dissolved, thereby liberating the nanoparticles.
  • the membrane template can be re-used by returning to step 5.
  • Photolithographic Formation of Nanoparticles By Etching a Pre-formed Film Stack The aforementioned embodiments are all directed to the formation nanoparticles in porous membrane templates made by photolithographic techniques.
  • photolithographic techniques are used to etch nanoparticles from a pre-formed stack of material, wherein each layer of the stack corresponds to a particular segment of the subsequent nanoparticle.
  • layers of material such as metal films, are deposited onto a silicon wafer to form a stack.
  • a layer of photoresist is then spun on the material stack.
  • the stack is then exposed to radiation (e.g., UV light) by conventional mask-based photolithography (or by IL or by AIL) to pattern a grid on the resist.
  • the entire film stack is then etched revealing many cylindrical film stacks.
  • the nanoparticles can be liberated by one of the methods described above (e.g., physically, or by dissolving a sacrificial base layer).
  • a layer of material is depositied on a silicon wafer, via electrochemical deposition or CVD, to form Film 1 (corresponding to the first segment of the nanoparticle).
  • Photoresist is then spun on top of Film 1.
  • the resist is exposed, e.g., using a mask or by IL or AIL, to pattern an array of cylindrical posts (i.e., the opposite resist pattern to a pore pattern).
  • the film is etched with an appropriate wet or dry etch method to leave cyclindrical posts of the Film 1 material.
  • the preceding steps are repeated n times, depositing and etching Films 2 through n, to form the segments in the nanoparticle.
  • the nanoparticles can be liberated by one of the methods described above.
  • One example of many are bundles of optical fibers in which the cores are etchable under conditions where the claddings are not. Carrying out this etching, followed by slicing across the bundle, yields a membrane with hole diameters the size of the fiber cores. Note that fibers can be drawn out (using heat) to submicron diameters. Note also that fiber bundles with collections of greater than 1,000,000 fibers are commercially available; this could easily be extended to 10 million. Another group of materials that could be used, for example, are molecular sieve materials with well-defined cavities such as zeolites.
  • templates or membranes can be prepared from a variety of different methods. 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 shrunk 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, the temperature of which is controlled by recirculation through a temperature-controlled bath.
  • an ultrasonic transducer 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.
  • the membranes are removed from the flow cell, and individually postprocessed to free the nanobar codes from the template pores.
  • 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.
  • the membranes or templates may be moved from one plating solution to another.
  • FIG. 1 and 2 An apparatus for performing such manufacture of 25 types or flavors of nanobar codes is depicted in Figures 1 and 2.
  • 25 separate membrane templates are placed in a common solution environment, and deposition is controlled by the application of current to the individual membranes.
  • 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. Referring to Figure 1, 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 11 .
  • 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 electroforming 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.
  • the number of a single type of particles could be increased by growing multiple copies of a single rod within the same reaction vessel. It should likewise be realized that, rather than introduction of one plating solution to a collection of membranes, it is straightforward to employ microfluidics to address templates individually. In other words, a different plating solution could simultaneously be delivered to two or more locations. Thus, in principle, one could be making stripes of 5 or 10 or more compositions, and with 5 or 10 or more segment widths, at the same time, but in different, pre-programmed locations.
  • the materials chosen for this synthesis are meant to be illustrative, and in no way limiting. There are numerous materials that can be electrodeposited in this fashion, including metals, metal oxides, polymers, and so forth, that are amenable to multiplexed synthesis.
  • 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. This expands the possibilities for multiplexed nanoparticle synthesis to include all oxides, semiconductors, and metals.
  • 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.
  • 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.
  • 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.
  • known techniques are adequate and can simply be scaled up to provide the necessary number.
  • 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.
  • Flavor #1 is 4 microns long gold
  • Flavor #2 is 2 microns gold followed by 1 micron silver, followed by
  • Flavor #4 A detailed description of the synthesis of Flavor #4 follows. (All other flavors were synthesized by minor and obvious changes to this protocol.)
  • 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.
  • the synthesis of 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.
  • 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 4 and SeO 2 .
  • Mechanical stability problems have been encountered with the metakCdSe 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 CoSO 4 /Citrate 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. 1. Materials 200 nm pore diameter Whatman Anoporedisks (Al 2 O 3 -membranes) were used for template directed diode synthesis.
  • Electrochemical metal deposition was carried out using commercially available gold (Technic Orotemp 24), platinum (Technic TP), and silver plating solutions. Titanium tetraisopropoxide[Ti(ipro) 4 ], mercaptoethylamine hydrochloride(MEA),ethyltriethoxy silane, chlorotrimethyl silane were purchased from Aldrich. All the reagents were used without further purification. All other chemicals were reagent grade and obtained from commercial sources.
  • 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 HC1 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 2 /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.
  • a membrane was successively soaked in absolute ethanol andanhydrous toluene or dichlorethane for 1 h, after which it was immersed in a ethyltriethoxy silane solution in anhydrous toluene (2.5% vol) or a chlorotrimethyl silane solution in anhydrous dichlorethane (2.5% vol) for 15 h. Then 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 Transmission electron microscope
  • JEOL 1200 EXII at 120 kV of accelerating voltage and 80mA of filament cunent.
  • OM Optical microscope
  • Transmission IR spectra were recorded using a Specord M-80 CareZeiss Jena spectrometer. I-V characteristics for rod- shaped diodes were measured in air at ambient temperature.
  • hydrophobization of Al 2 O 3 -terminated surface of pore walls with propionic acid or alkylsilane derivatives, such as ethyltriethoxy silaneor chlorotrimethyl silane, was tried to smooth down the top rod end surface by reducing the metal adso ⁇ tion on the pore walls.
  • the hydrophobization of pore walls may also be expected to prevent TiO 2 particles from adso ⁇ tion on the wall surface rather than on metal electrode surface situated in the depth ( ⁇ 65 ⁇ m) of the pore. It was shown that the TiO 2 particles readily formed a densely packed layer on a plane AI/AI 2 O 3 substrate.
  • a typical higher resolution image of rod's upper part confirmed that the cup-like ends are situated at the top of the rods, and showed that the wall passivation to some extent resulted in smoothing of the surface of rod ends.
  • Au/(TiO 2 /PAN) 6 rod taken in the first several seconds did not reveal any particles.
  • gold melted revealing nanoparticle film on the rod's top.
  • the upper contour line of the film is very close to that of Au rod before melting. This fact is consistent with the cup-shaped top of the metal rods.
  • the multilayer film grows on the surface both of cup bottom and cup walls and approximately retains cup shape after the thin walls have melted. This explanation is consistent with observed film height of -100 nm, which allows estimating rather gold cup depth than (TiO 2 /PAN) 6 film thickness.
  • Ellipsometric thickness of TiO 2 /PAN) 6 film self-assembled on a plane Au(MEA) substrate is estimated at about lOnm.
  • I-V characteristic of the Pt/( TiO 2 /PAN) 3 TiO 2 /Au rod-shaped device reveals current rectifying behavior.
  • the forward and reverse bias turn-on potentials are- -0.2 and -0.9 V, respectively.
  • EXAMPLE 4 Segmented nanoparticles can be synthesized from membranes produced using photolithographic techniques as follows: A silicon wafer is spin coated with a the photoresist AZ ® 4620 (Clariant Co ⁇ ., Somerville, N.J.). The spin coating is conducted at 1000 ⁇ m for 40 seconds. The photoresist-coated substrate is then baked for about 200 seconds on a hot plate coater at 110 °C. Outgassing to remove volatile materials is conducted by allowing the material to sit out at room temperature for at least 24 hours. The photoresist-coated substrate is then exposed to radiation for about 3100 msec using a mask to pattern the resist.
  • the photoresist is then developed using AZ ® 400K (potassium based buffered developer) (Clariant Co ⁇ .) for about 15 minutes to reveal cylindrical pores.
  • AZ ® 400K potassium based buffered developer
  • the porous membrane is spin rinsed and dried.
  • the membrane is then evacuated for about an hour using a high vacuum.
  • the pores of the membrane can be filled with alternating bands of metals to form segmented nanoparticles as follows: copper is plated into the pores using 1.0 mA for about 5 minutes. Gold is plated into the pores using 1.0 mA for about 120 minutes. Silver is plated into the pores using 1.0 mA for about 30 minutes. Gold is again plated into the pores using 1.0 mA for about 30 minutes. The photoresist is then dissolved using acetone. An SEM (top view) of the template after plating is complete and the photoresist has been dissolved is shown in Figure 4. The tops of the nanoparticles, having diameter approximately 2.5 to 3 ⁇ m are visible. The segmented nanoparticles may then be separated from the membrane using acetic acid for about 60 minutes.
  • segmented nanoparticles can be synthesized from membranes produced using photolithographic techniques as follows: A silicon wafer is initially sputtered with chromium and then gold, to form layers of about 200 A and 1000 A in thickness, respectively. A wafer singe is then performed to remove water vapor and/or residual organics by heating at a temperature of about 150°C for 30 minutes. The conductive substrate is then spin coated first with 50% hexamethyldisilazane (HMDS), and then with SPR 220 (Shipley Co ⁇ ., Marlborough, MA). The spin coating is conducted at 3500 ⁇ m for about 40 seconds.
  • HMDS hexamethyldisilazane
  • SPR 220 Chipley Co ⁇ ., Marlborough, MA
  • the photoresist-coated stack is then baked for about 200 seconds at 90 °C on an SVG coater (Silicon Valley Group, San Jose, CA).
  • This "soft bake” step is recognized in the art to reduce solvent concentrations in the photoresist and improve adhesion by relieving film stresses.
  • Outgassing to remove volatile materials is then conducted by allowing the material to sit out at room temperature for at least 24 hours.
  • the photoresist- coated stack is exposed to radiation for about 1600 msec using an appropriate mask to pattern the surface.
  • the photoresist is developed using LDD26W for about 100 seconds.
  • the developing step is repeated three times to reveal cylindrical pores.
  • Oxygen plasma is applied at 65 W for about 4 minutes, removing any photoresist debris.
  • the porous membrane is evacuated for about an hour using high vacuum.
  • the pores of the membrane can be filled with alternating bands of metals to form nanoparticles as follows: copper is plated into the pores using 1.0 mA for about 5 minutes. Gold is plated into the pores using 1.0 mA for about 115 minutes. After plating is complete, the photoresist is dissolved using acetone. The segmented particles are separated from the substrate using acetic acid for about 60 minutes. An SEM (side view) of a nanoparticle made according to the above procedure is shown in Figure 5.
  • segmented nanoparticles can be synthesized from membranes produced using photolithographic techniques as follows: Cr and then Au, are sputtered onto a silicon wafer to a thickness of about 200 A and about 1000 A, respectively. The wafer is heated at a temperature of about 150°C for 30 minutes and then spin coated with 50% HMDS to promote adhesion. The stack is then spin coated with polyimide, to a thickness of about 10 ⁇ m followed by a soft bake to remove solvent. Aluminum is then sputtered on the stack to form an etch stop layer of about 3000 A in thickness.
  • the stack is spin coated with Shipley 3612 (5,500 ⁇ m for 30 min.) resulting in a layer about 1 ⁇ m in thickness, and then heated at a temperature of about 90 °C for about 60 seconds. Outgassing to remove volatile materials is conducted by allowing the material to sit out at room temperature for at least 24 hours.
  • the stack is exposed to radiation which has traveled through a mask to transfer a pattern which will leave cylindrical holes in the photoresist.
  • the photoresist is developed using LDD26W for 60 seconds. Deep reactive ion etching is used to transfer the pattern in the photoresist to the aluminum etch stop (450 W, 200 mTorr, 60 sec. BC1 3 40sccm, Cl 2 30 seem, N 2 40 seem).
  • the stack is then placed in water to remove any residual choloride, and then spin rinsed and dried.
  • the polyimide is then etched via deep reactive ion etching using oxygen plasma (500 W, 250 mTorr, 300 sec, O 2 50 seem) to reveal cylindrical pores in the polyimide.
  • the resulting membrane is evacuated for one hour using high vacuum.
  • An SEM (cross-sectional view) of a template prepared according to the above procedure is shown in Figure 6.
  • the cylindrical pores can subsequently be filled with alternating bands of metals as set forth described above.

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Abstract

L'invention concerne un procédé permettant de fabriquer des particules colloïdales de type tige sous forme de nano codes-barres. La figure 3 illustre un mode de réalisation de cette invention, à l'aide d'un empilage de quatre couches sur un substrat de plaque de silicium (101). Ce substrat (101) est recouvert d'une couche conductrice (102), d'une couche polymère (103), d'une couche d'arrêt de gravure (104) et d'une couche photosensible (105). Des pores (106) sont formés après exposition et développement du film photosensible et gravure jusqu'à la couche d'arrêt de gravure. Des pores (107) sont formés par une gravure ultérieure à travers la couche polymère (103). Des nanoparticules (108) sont formées dans les pores (107) par dépôt électrochimique au moyen de la couche conductrice (102) en tant qu'électrode de dépôt. Les nanoparticules autonomes (109) sont formées par dissolution subséquente de la couche conductrice (102), formant des nano codes-barres.
PCT/US2001/030729 2000-10-02 2001-10-02 Procede de fabrication de particules colloidales de type tige sous forme de nano codes-barres WO2002029136A1 (fr)

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AU2001296460A AU2001296460A1 (en) 2000-10-02 2001-10-02 Method of manufacture of colloidal rod particles as nanobarcodes
EP01977334A EP1337694A4 (fr) 2000-10-02 2001-10-02 Procede de fabrication de particules colloidales de type tige sous forme de nano codes-barres

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US09/677,203 US7045049B1 (en) 1999-10-01 2000-10-02 Method of manufacture of colloidal rod particles as nanobar codes
US60/237,322 2000-10-02
US28501701P 2001-04-19 2001-04-19
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US7443489B2 (en) 1999-10-06 2008-10-28 Oxonica, Inc. Surface enhanced spectroscopy-active composite nanoparticles
WO2011044708A1 (fr) * 2009-10-14 2011-04-21 Biocartis Sa Procédé de production de microparticules
WO2011094672A3 (fr) * 2010-01-29 2011-10-27 Molecular Imprints, Inc. Procédés de lithographie par nano-impression pour former des nanoparticules
EP2635522A2 (fr) * 2010-11-05 2013-09-11 Molecular Imprints, Inc. Formation de nanoparticules par lithographie nanométrique à l'aide de doubles couches anti-adhésives
US8918161B2 (en) 1999-10-06 2014-12-23 Becton, Dickinson And Company Methods of use for surface enhanced spectroscopy-active composite nanoparticles
US8961800B2 (en) 2009-08-26 2015-02-24 Board Of Regents, The University Of Texas System Functional nanoparticles
US9297766B2 (en) 2001-01-26 2016-03-29 Becton, Dickinson And Company Method of tagging materials with surface-enhanced spectroscopy-active sandwich particles

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Cited By (14)

* Cited by examiner, † Cited by third party
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US8918161B2 (en) 1999-10-06 2014-12-23 Becton, Dickinson And Company Methods of use for surface enhanced spectroscopy-active composite nanoparticles
US9201013B2 (en) 1999-10-06 2015-12-01 Becton, Dickinson And Company Method for tagging material with surface-enhanced spectroscopy (SES)-active composite nanoparticles
US7443489B2 (en) 1999-10-06 2008-10-28 Oxonica, Inc. Surface enhanced spectroscopy-active composite nanoparticles
US9297766B2 (en) 2001-01-26 2016-03-29 Becton, Dickinson And Company Method of tagging materials with surface-enhanced spectroscopy-active sandwich particles
US8961800B2 (en) 2009-08-26 2015-02-24 Board Of Regents, The University Of Texas System Functional nanoparticles
US8802747B2 (en) 2009-08-26 2014-08-12 Molecular Imprints, Inc. Nanoimprint lithography processes for forming nanoparticles
CN102597875A (zh) * 2009-10-14 2012-07-18 比奥卡尔齐什股份有限公司 用于生产微颗粒的方法
US9162518B2 (en) 2009-10-14 2015-10-20 Mycartis Nv Method for producing microparticles
WO2011044708A1 (fr) * 2009-10-14 2011-04-21 Biocartis Sa Procédé de production de microparticules
CN102597875B (zh) * 2009-10-14 2016-06-01 麦卡提斯股份有限公司 用于生产微颗粒的方法
WO2011094672A3 (fr) * 2010-01-29 2011-10-27 Molecular Imprints, Inc. Procédés de lithographie par nano-impression pour former des nanoparticules
EP2635522A4 (fr) * 2010-11-05 2014-06-11 Molecular Imprints Inc Formation de nanoparticules par lithographie nanométrique à l'aide de doubles couches anti-adhésives
EP2635522A2 (fr) * 2010-11-05 2013-09-11 Molecular Imprints, Inc. Formation de nanoparticules par lithographie nanométrique à l'aide de doubles couches anti-adhésives
US8916200B2 (en) 2010-11-05 2014-12-23 Molecular Imprints, Inc. Nanoimprint lithography formation of functional nanoparticles using dual release layers

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