WO1997006468A2 - Formation, reproduction, fabrication d'un motif et dispositifs ainsi obtenus - Google Patents

Formation, reproduction, fabrication d'un motif et dispositifs ainsi obtenus Download PDF

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Publication number
WO1997006468A2
WO1997006468A2 PCT/IB1996/000912 IB9600912W WO9706468A2 WO 1997006468 A2 WO1997006468 A2 WO 1997006468A2 IB 9600912 W IB9600912 W IB 9600912W WO 9706468 A2 WO9706468 A2 WO 9706468A2
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Prior art keywords
εaid
relief
molecular
array
patterned
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PCT/IB1996/000912
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WO1997006468A3 (fr
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Ely Michael Rabani
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Ely Michael Rabani
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Priority to AU67524/96A priority Critical patent/AU6752496A/en
Publication of WO1997006468A2 publication Critical patent/WO1997006468A2/fr
Publication of WO1997006468A3 publication Critical patent/WO1997006468A3/fr

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    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/0035—Multiple processes, e.g. applying a further resist layer on an already in a previously step, processed pattern or textured surface
    • 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
    • B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/0002—Lithographic processes using patterning methods other than those involving the exposure to radiation, e.g. by stamping
    • 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
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00382—Stamping
    • 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
    • B01J2219/00527—Sheets
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00614—Delimitation of the attachment areas
    • B01J2219/00617—Delimitation of the attachment areas by chemical means
    • B01J2219/00619—Delimitation of the attachment areas by chemical means using hydrophilic or hydrophobic regions
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00623—Immobilisation or binding
    • B01J2219/0063—Other, e.g. van der Waals forces, hydrogen bonding
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00632—Introduction of reactive groups to the surface
    • B01J2219/00637—Introduction of reactive groups to the surface by coating it with another layer
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00639—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium
    • B01J2219/00641—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium the porous medium being continuous, e.g. porous oxide substrates
    • 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
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional 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
    • 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
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • 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
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides
    • 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
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00725—Peptides
    • 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
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

  • the invention relates to the fabrication of two- and three- dimensional patterns and the production of devices thereby; the present invention finds application in the areas of microelectronics, micromechanics, microfluidics, scanning probe microscopy, mass data storage, scientific instrumentation, clinical diagnostics, molecular assembly, and other area ⁇ .
  • metal layers may h ⁇ ched to form wiring patterns and regions of a semiconductint .bstrate may be doped to form electronic components in an integrated device.
  • Metal layers may also be patterned by lift-off processes involving the local dissolution of a pre-patterned resist underlayer-, which carries away with it the immediately overlying regions of the metal layer.
  • Fault Tolerant Circuit Designs One approach that has been applied in the field of microelectronics to increasing the tolerable physical defect rate arising from a particular fabrication process involves fault tolerant circuit design. This is a category of methods which includes redundancy of functions or components, self-testing or quality checking during the fabrication process, and rerouting of connections between functional blocks to serve functions lost to defect ⁇ . For example, such methods have been applied to dynamic RAM fabrication, where the memory bit array is divided into a number of blocks, the total capacity of which is larger than the device specification. All blocks are checked for defects or functionality, and where defects are found, the involved blocks are deactivated. Functional blocks are then reconfigured, as needed, to contiguously fill the device addre ⁇ s space. Analogous methods have been applied in the design of gate arrays, field programmable gate arrays, memory devices and other microelectronic devices.
  • J.L. Nistler has disclosed a method for the reduction of defects in lithographic phase shift masks.
  • the es ⁇ ence of this method is to form a resist pattern, use it to etch the underlying quartz surface only partially, remove said resist pattern and any defects it may include, form a substantially identical pattern of resi ⁇ t on said quartz surface again, partially etch again and remove said substantially identical pattern of resist again, in repetitive cycles.
  • etch resistant region ⁇ appearing in all resist patterns will be reproduced in the final patterned quartz article at the fully etched depth.
  • this method checks one pattern, which may contain random defects, against other patterns which may also contain random defects which are not likely to appear at the ⁇ ame location a ⁇ those random defect ⁇ in any other pattern.
  • the ca ⁇ e of the pha ⁇ e ⁇ hifting reticles produced by that invention only regions etched such that the tran ⁇ mitted light i ⁇ shifted by 180 degree ⁇ exposes the lithographic resi ⁇ t the ⁇ e reticle ⁇ are u ⁇ ed to expose.
  • correspondence between multiple source patterns is required for a feature to be represented in the final product mask produced therefrom.
  • Thi ⁇ method form ⁇ lithographic plate ⁇ by expo ⁇ ing materials similar or identical to those used as resists in conventional microfabrication, such that exposed regions have affinity or repel ink or other liquids, such that a pattern of differential retention of ink or ⁇ aid other liquid ⁇ may be u ⁇ ed to form a pattern of ⁇ aid ink or other liquids on said lithographic plates and then transfer this pattern to the sub ⁇ trate. While thi ⁇ method reduce ⁇ the extent to which photolithographic equipment i ⁇ needed for patterning, production of micropatterned articles by this method still requires routine acces ⁇ to ⁇ uch photolithographic equipment for lithographic plate production.
  • a relief is produced by selectively exposing regions of a photoresist coated onto a first surface and mechanically transferring either the exposed or non- exposed regions to a polymeric foil second surface by juxtaposing said second surface to the image-expo ⁇ ed polymeric re ⁇ ist and relying on the differential adhesion properties resulting from expo ⁇ ure. Thu ⁇ , a po ⁇ itive image i ⁇ produced on one ⁇ urface while the other ⁇ urface retains the corresponding negative pattern.
  • Such relief patterns may provide differential wetting or liquid-retention properties differing from tho ⁇ e of the underlying ⁇ urface ⁇ , and thus be used as offset lithographic plates.
  • G. Gal has, in U.S. Patent Number 5,310,623, taught a method whereby microlens array ⁇ are formed.
  • grey ⁇ cale expo ⁇ ure of a resist material may be used to cause the differential etching (in the preferred case by ion milling) of the underlying substrate, to produce a correspondingly curved surface.
  • Microelectromechanical Systems Microfabrication technique ⁇ have been applied to multilayered substrates comprising sacrificial layers which permit under-etching. Under-etching permit ⁇ the fabrication of ⁇ tructures with suspended or overhanging members and freely moving microscale mechanical part ⁇ . Such a proce ⁇ may be combined with conventional microfabrication ⁇ tep ⁇ or applied to ⁇ ub ⁇ trate ⁇ comprising microelectronic device ⁇ to integrate both electronic and mechanical components of micron and submicron dimen ⁇ ion. Such integrated devices have been termed microelectromechanical sy ⁇ tems (MEMS) 5 .
  • MEMS microelectromechanical sy ⁇ tems
  • Data is recorded in the form of pit ⁇ on ⁇ aid ⁇ urface.
  • a la ⁇ er is used to heat said polycarbonate above the glas ⁇ tran ⁇ ition temperature, and the AFM tip impre ⁇ e ⁇ a pit into the locally heated region.
  • the size of the resulting pit corresponds to the apical geometry of said AFM tip.
  • Readout is accomplished by conventional contact-mode AFM detection of said pits.
  • a relief pattern is formed which encodes the corresponding, stored data.
  • Scanning Probe Pattern Formation Scanning Resist Patterning: Scanning Tunneling Micro ⁇ cope ⁇ (STM) 11 ' 12 , Atomic Force Microscopes (AFM) and Near Field Scanning Optical Microscopes (NFSOM) 13 have been used to selectively form patterns in surfaces on the nanometer scale. These include patterns in materials or layers which mask the underlying sub ⁇ trate from the action of etchant ⁇ when not modified by the micro ⁇ copic probe u ⁇ ed.
  • STM Scanning Tunneling Micro ⁇ cope ⁇
  • AFM Atomic Force Microscopes
  • NFSOM Near Field Scanning Optical Microscopes
  • B.J. Mclntyre, M. Salmeron and G.A. Somorjai 15 have ⁇ i ilarly effected po ⁇ itional control of metallic ⁇ urface cataly ⁇ is using a platinum- rhodium STM tip in an atmo ⁇ pheric-pressure chemical reactor to catalyze the rehydrogenation of molecules comprising alkyne functionalities on (111) platinum surfaces.
  • M.A. Voelker 16 has proposed a method for the patterning of chemical moietie ⁇ on ⁇ urface ⁇ , and the formation of patterns in multicomponent Langmuir-Blodgett (L-B) film ⁇ according to the interaction of affinity groups of molecules in said L-B films with complementary affinity moieties on ⁇ aid surfaces.
  • Such a method would entail that the molecules of which said L-B film is composed have good mobility in the as-formed L-B film prior to any polymerization, and that transport permits good segregation of molecular species within ⁇ aid L-B film without any congestion problems or other hindrance to the proper assortment of specie ⁇ to match the pattern on the underlying ⁇ urface.
  • Integrated optical devices and other micro ⁇ cale optical components have been fabricated by the replication of relief patterns into polymeric material ⁇ 17 .
  • the optical propertie ⁇ of the ⁇ e materials and the structure ⁇ resulting from pattern replication determine device function and characteristics.
  • Replication methods used include injection molding and casting into polymeric, elastiomeric or metallic molds or mold inserts, and hot embos ⁇ ing with relief ⁇ , for example, metal relief ⁇ .
  • Multiple cycle ⁇ of replication may be performed to yield a large number of relief ⁇ for the rapid ma ⁇ production of devices, according to the fidelity of replication and acceptable device tolerances.
  • This first generation mold may then be as a mold for the casting or microinjection molding of a second polymeric relief nearly identical to the first relief.
  • the molding or casting proces ⁇ may be repeated with the fir ⁇ t generation mold, and the electroforming proce ⁇ may be repeated with ⁇ econd or subsequent generation polymeric relief structures produced with said molds by appropriate methods.
  • polymeric object ⁇ and metallic objects with sub-micron patterns may be economically reproduced.
  • Gale et al., 20 extend method ⁇ from the embo ⁇ ed diffractive foil and compact di ⁇ k (CD) industries by the replication of an original (e.g. microfabricated) microrelief on the surface of a replication shim through electroforming, followed by replication of this first shim by surface passivation followed again by electroforming.
  • the ⁇ e workers find that the shim replication proce ⁇ occur ⁇ with only slight ( ⁇ 2nm) increases in surface roughne ⁇ per generation, thus enabling the reproduction of nanoscale relief features, with corresponding cost advantages.
  • Related injection molding methods are described by A. Neyer et al., 21 and R. Klein and A. Neyer. 22
  • micropatterned reliefs may be used to micromold ceramic pattern ⁇ .
  • these workers used a polyimide relief, prepared by reactive ion etching through a Ti mask, was used as a "cookie cutter" which was impressed into a chemically softened ethyl-methacrylate tape comprising powdered ceramic particles (ceria-zirconia) of average size 0.3 micron ⁇ . After embos ⁇ ing, the tape was dried, removed from the micromold, heated at 600 degrees centigrade to remove the EMA binder and then sintered at 1500 degrees centigrade. Features as small as 4 micron ⁇ could be thu ⁇ produced. The ⁇ e workers have developed this method for the fabrication of piezoelectric ceramics.
  • Self-Assembling Monolayers and Resists Therefrom A paradigmatic example of self-a ⁇ sembling monolayers is provided by the self assembly into monolayer ⁇ of alkanethiols onto gold ⁇ urface ⁇ , according to the strong affinity of thiol groups for gold ⁇ urface ⁇ .
  • the ⁇ e ⁇ elf-assembling monolayer ⁇ y ⁇ tem ⁇ also include organosilanes and derivatives thereof (e.g. RSiX 3 , R2 ⁇ iX2 or R3SiX where R groups may be identical or distinct) , which form covalent linkages to surface hydroxyl groups (e.g.
  • monolayers thus formed may be modified such that the molecules of said monolayers thus formed bear terminal hydroxyl groups, which may then serve as donors for the succe ⁇ ive, covalent addition of monolayer ⁇ , forming cro ⁇ slinked multilayered structures on said surface ⁇ .
  • the organic chains of such monolayers may additionally comprise polymerizable or photopolymerizable groups such as alkynes. 25 Further, such monolayers may be used to render surfaces hydrophobic, such that they are protected from a solution with which said surfaces are contacted, ⁇ uch a ⁇ an aqueou ⁇ etchant solution.
  • SAMs homogenous ⁇ elf-a ⁇ sembling monolayers
  • metal films generally gold films
  • SAMs homogenous ⁇ elf-a ⁇ sembling monolayers
  • These methods include scraping with sharpened tools 26 to produce the desired pattern as well as applying increased force to an AFM tip during scanning operation ⁇ or increa ⁇ ing the ⁇ etpoint current to cause physical contact of an STM tip so said metal surface with increased local force ⁇ re ⁇ ulting.
  • Whitesides and co-workers 27 have also produced a rapidograph- like micropen for the application of organothiol compounds to specified surface regions, and used this writing instrument to produce organothiol patterns on gold surface ⁇ .
  • the underlying ⁇ urface i ⁇ exposed; where said underlying surface is, for example, cry ⁇ talline ⁇ ilicon, it may be wet etched to produce a relief pattern corre ⁇ ponding to the mirror image of the relief surface used in said printing.
  • the ⁇ e method ⁇ are found by these workers to yield a defect rate (of over 1/mm 2 per mask-etch cycle) 28 which they deem unacceptably high to make these methods competitive with conventional lithographic techniques for the production of microelectronic devices. They speculate that these defects primarily owe to microcrystallite ⁇ in ⁇ aid gold film ⁇ , ari ⁇ ing from incomplete coverage of said microcrystallites by said organothiol molecules.
  • Pattern ⁇ of organothiol SAM ⁇ by the ⁇ e method ⁇ have reproducible resolution of features smaller than lOOnm. Such patterns have also been formed on the surfaces of glas ⁇ cylinders and fibers, which have been used ⁇ ubsequently to replicate the corresponding pattern on flat surfaces by a rolling technique, analogous to that u ⁇ ed in the printing of hologram ⁇ in metallized polymeric film ⁇ but on a smaller scale.
  • said first organothiol may have a terminal methyl group such that regions with a SAM of said first organothiol composition are wetted well by organic liquid ⁇ and poorly by aqueous or polar solutions
  • said second organothiol may have a polar terminal group, such a ⁇ a hydroxyl group ⁇ uch that region ⁇ with a SAM of ⁇ aid second organothiol are wetted well by aqueous or polar liquids and poorly by organic liquid ⁇ .
  • ⁇ urface-ten ⁇ ion defined ⁇ tructure ⁇ such as a microlens array 29 from solutions comprising optically clear polymerizable compound ⁇ .
  • Wetting may be conducted, for example, by vapor condensation or dipping into solutions.
  • S.P.A. Fodor et al. 30 have disclosed methods for the spatially directed synthesis of copolymers including biopolymers such a ⁇ oligonucleotides and polypeptide ⁇ . These worker ⁇ bind initiator chemical group ⁇ protected with photolabile protecting groups to a ⁇ ub ⁇ trate. Spatially ma ⁇ ked exposure to appropriate wavelength actinic radiation removes said photolabile protecting groups from expo ⁇ ed region ⁇ , where the extent of ⁇ aid exposed regions is delimited by an exposure mask having a de ⁇ ired radiation ma ⁇ king pattern.
  • Said masked exposure step, said protected monomer contacting steps and said washing ⁇ tep ⁇ are repeated ⁇ o a ⁇ to synthesize desired oligomers at desired locations on said surface ⁇ uch that an array of diver ⁇ e oligomer ⁇ ⁇ ituated on said surface i ⁇ produced and the location of an array element comprising oligomers bears a predetermined relationship to the sequence composition of said oligomer copolymer located at said array element.
  • Such copolymer arrays may be used, depending on the compositions of said copolymer, to detect affinity binding to members of a population of molecules (comprised within the compo ⁇ ition of ⁇ aid array) of a ⁇ ample, which method ⁇ are u ⁇ eful to ⁇ creen antibody specificity, to detect the presence of polynucleotide sequence ⁇ in a ⁇ ample or mixture, and for ⁇ equencing by hybridization method ⁇ .
  • Array Fabrication by Masking for Materials Screening X.-D. Xiang et al. 31 have recently described a method for the ⁇ creening of material ⁇ compri ⁇ ing the repetitive evaporation of different material ⁇ onto a ⁇ urface occluded by a ma ⁇ k, ⁇ uch that an array is formed comprising elements of different compo ⁇ ition, which array i ⁇ then ⁇ intered. Array elements thus prepared may then be subjected to ⁇ creening for de ⁇ ired propertie ⁇ in analogy to the methods of the field of combinatorial chemistry.
  • Whitesides and co-workers 32 have used elastiomeric patterned relief ⁇ urfaces to produce surfaces with correspondingly patterned depo ⁇ it ⁇ of protein ⁇ .
  • thi ⁇ method a gold ⁇ urface i ⁇ patterned with an organothiol, and then expo ⁇ ed to and organothiol comprising terminal hydrophilic moieties are then adsorbed to unpattemed region ⁇ .
  • Such a surface is then contacted with a solution of the de ⁇ ired protein or protein ⁇ , which ad ⁇ orb to the hydrophobic ⁇ urface region ⁇ .
  • Such a method does not provide for the formation of pattern ⁇ of variation ⁇ of combinations of protein ⁇ from one region to the next.
  • Various workers 33 , 34 , 35 have de ⁇ cribed method ⁇ for the stepwise addition of monolayers or bilayers to a surface, such that a multilayer ⁇ tructure compri ⁇ ing a predetermined number of layer ⁇ of only a few nanometer ⁇ in thicknes ⁇ may be formed.
  • a monolayer or bilayer i ⁇ thu ⁇ deposited on a surface including surfaces comprising monolayers, bilayers or multilayers
  • said monolayer or bilayer remains situated upon said surface.
  • S.I. Stupp et al. 36 have ⁇ hown that ⁇ ub ⁇ tantially linear molecule ⁇ compri ⁇ ing extended linear region ⁇ along their length, a polar enantiomeric ordering center and two polymerizable reactive groups of distinct polymerization chemi ⁇ try at a ⁇ pecific positions along their length spontaneously assemble into layered meso ⁇ cale structures which may then be polymerized to yield two dimensional polymer ⁇ .
  • Thi ⁇ work continue ⁇ the teachings of S.I. Stupp disclosed in U.S. Patent Number 5,229,474.
  • M. Kotera, J.-M. Lenh, and J.-P. Vigneron 37 have disclo ⁇ ed compound ⁇ comprising rigid rod molecular segment ⁇ with ⁇ ingle terminal nucleoba ⁇ e moietie ⁇ . Said compounds self as ⁇ emble in organic ⁇ olvent ⁇ to form supramolecular rods according to well-known Watson-Crick pairing rules. The re ⁇ ulting rods self-organize into meso ⁇ cale ⁇ tructures.
  • oligonucleotides were ⁇ ynthesized to comprise a thiol group which was cros ⁇ linked to an amine functionalized organosilane derivatized silica AFM tip. Disruption of association of complementary oligonucleotides was shown to be reversible.
  • Musgrave ha ⁇ undertaken theoretical analyses of factors related to the assembly of diamondoid structures from reactive carbon specie ⁇ under mechanical or po ⁇ itional control and force ⁇ exerted on reactants thereby (referred to a ⁇ mechano ⁇ ynthe ⁇ i ⁇ ) .
  • Objects of the Invention It i ⁇ an object of the pre ⁇ ent invention to reduce the capital co ⁇ ts of microscale and submicron patterning in the fields of microelectronics, micromechanics and MEMS. It i ⁇ a further object to reduce the minimum feature ⁇ ize below that attainable with vi ⁇ ible light in certain embodiment ⁇ . It is an object of further embodiments to facilitate the inexpensive prototyping and low-volume production of such device ⁇ . It i ⁇ a yet further object of the present invention to provide for the inexpensive production of miniaturized ⁇ canned probe device ⁇ . It i ⁇ a further object of the pre ⁇ ent invention to provide for the used of said miniaturized scanned probe devices in the parallel positional synthe ⁇ i ⁇ of complex molecule ⁇ and ⁇ upramolecular assemblages.
  • an object of the pre ⁇ ent invention to provide an inexpen ⁇ ive method for the ⁇ ynthe ⁇ i ⁇ of complex copolymer array ⁇ without exten ⁇ ive u ⁇ e of lithography. It i ⁇ a further object to extend the methods of use of ⁇ uch complex copolymer array ⁇ to provide enhanced capabilitiesitie ⁇ and refinement of discrimination.
  • the present invention employs either contact printing , contact molding, or devices produced thereby, in combination with pattern replication, and applies these to the fabrication of numerous device ⁇ .
  • An initial or master relief pattern or pattern of surface composition is produced by prior art methods or by method ⁇ of the pre ⁇ ent invention.
  • Final generation templates are used in device production.
  • Macroscale to nanoscale features may be achieved by the ⁇ e methods, including within the same fabrication proces ⁇ and article of manufacture.
  • Preferred embodiment ⁇ include the generation of masking patterns for etch control and diffusion barrier formation in semiconductor fabrication, microfluidics fabrication, MEMS fabrication and the like, patterned chemical synthesis and copolymer synthe ⁇ i ⁇ , the formation of patterned molecular monolayer ⁇ and multilayer ⁇ , replication of chemical patterns, fabrication of microstructured and nano ⁇ tructured materials and combinations of any of the foregoing.
  • patterned relief ⁇ urface ⁇ are compo ⁇ ed of materials that are either unreactive to any chemical species which are applied to them or may be pretreated to render them similarly unreactive, or otherwise that any reactivity to said chemical species which are applied to said patterned relief surfaces occurs or may be caused to occur to only a negligible extent.
  • precaution ⁇ must be taken to avoid microscopic contaminants, which cause defects at micron and submicron scales; such precautions include ultrafiltration of solutions, and protection from atmospheric contaminants.
  • adhe ⁇ ion layer ⁇ , re ⁇ i ⁇ t layer ⁇ and ⁇ acrificial layer ⁇ may be used as needed without departing from the scope of the present invention.
  • a re ⁇ i ⁇ t or ma ⁇ king re ⁇ i ⁇ t pattern may be formed upon a ⁇ urface by molding an appropriate material in the de ⁇ ired pattern on ⁇ aid ⁇ urface or by analogou ⁇ technique ⁇ ⁇ uch a ⁇ casting, injection molding, or alternatively by a method comprising the step ⁇ of ⁇ heet stamping followed by a brief pre- etch to eliminate protecting material in reduced thicknes ⁇ region ⁇ formed by ⁇ aid ⁇ heet stamping step.
  • a fir ⁇ t relief pattern i ⁇ replicated in a convenient material, ⁇ uch a ⁇ by the polymerization of a prepolymer (preferably an ela ⁇ tiomer) on ⁇ aid surface, ca ⁇ ting a plastic, polymeric or other appropriate solidifiable liquid material with ⁇ aid fir ⁇ t relief ⁇ urface, plating with one or more metal ⁇ by known art technique ⁇ , or, ⁇ tamping into a melted material such as is practiced in hot-foil technology and CD replication, to define a mold.
  • a prepolymer preferably an ela ⁇ tiomer
  • a mold is thu ⁇ formed with a pattern defined by ⁇ aid fir ⁇ t relief pattern, and has surface features corresponding to the negative pattern formed by ⁇ aid first relief (defined a ⁇ the po ⁇ itive pattern) .
  • ⁇ aid fir ⁇ t relief pattern may be fabricated ⁇ o a ⁇ to it ⁇ elf be the negative pattern, from which further negative pattern ⁇ are generated in even numbered replication generation ⁇ .
  • Said fir ⁇ t relief pattern i ⁇ fabricated either by prior art mean ⁇ or by method ⁇ di ⁇ clo ⁇ ed within the pre ⁇ ent invention.
  • Relief feature height (or depth) is predefined so as to permit reliable pattern formation, reliable cast or molded material self-cohe ⁇ ion and substrate surface adhesion, and also reliable release of said cast or molded material from said from ⁇ aid negative replicated relief.
  • Optimal feature ⁇ izes will vary according to the materials and materials combination ⁇ cho ⁇ en, and ⁇ pecifics of any particular embodiment of this category of methods.
  • Said initial pattern may be used repetitively to form the opposite pattern on a replica surface such that high quality first generation replicas are formed in a quantity increasing arithmetically with each replication cycle.
  • First generation replicas formed by said first relief pattern may be used in turn to generate ⁇ ub ⁇ equent generation replica ⁇ , with multiplicative increa ⁇ e in replica quantity per replication generation.
  • Thu ⁇ tradeoff ⁇ will exist between the quantity of replicas formed in a particular length of time and the quality of replicas thu ⁇ formed.
  • High fidelity replication method ⁇ such a ⁇ are used in the fabrication of integrated optical devices and component ⁇ thu ⁇ permit the rapid production of replica ⁇ ; negative replica ⁇ are then u ⁇ ed to mold a re ⁇ i ⁇ t pattern onto a ⁇ urface.
  • a prototype ma ⁇ ter is used repetitively to create negative replicas neighboring each other on a first generation replica ⁇ urface, which i ⁇ then in turn u ⁇ ed repetitively to create replica ⁇ of the entire adjacent group of first generation replicas, again in an adjacent configuration.
  • a single pattern is repeated an increasing number of times on the surface generated by each generation of replication.
  • advantageous tradeoffs between relief life, rapidity of pattern production, and pattern fidelity may be attained according to the demands (e.g. time, volume, quality) of production. Calculations relating the ⁇ e will be obviou ⁇ from the nece ⁇ ary empirical data and production con ⁇ traints.
  • ⁇ e methods exclude masking material from regions contacted by the highest extent of ⁇ aid negative replicated relief, which, if of elastiomeric composition, will conform to the contours of the sub ⁇ trate ⁇ urface when juxtaposed to said surface under sufficient normal force.
  • molded resist layers may favorably be formed on the ⁇ urface ⁇ of adhesion layers which have first been deposited or coated onto said ⁇ ub ⁇ trate ⁇ urface without departing from the above a ⁇ pect of the present invention.
  • an ultra-thin, uniform adhesion layer which i ⁇ ⁇ ensitive to an etching solution or procedure comprising polymerizable chemical functional groups may first be ⁇ ituated upon a ⁇ ubstrate, which is then, for example, coated uniformly with a photopolymerizable polymeric re ⁇ ist, which i ⁇ then patterned under pre ⁇ ure with a clear relief ⁇ urface and then photopolymerized by expo ⁇ ure to appropriate wavelength light, with the re ⁇ ulting polymeric re ⁇ i ⁇ t material covalently linked to ⁇ aid polymerizable chemical functional groups of said adhesion layer.
  • Said adhe ⁇ ion layer is chosen to not protect the underlying sub ⁇ trate surface from etching treatments or procedures, and is formed at a thickness sufficiently small to prevent the significant under-etch of the overlying resi ⁇ t material (due to the ⁇ mall cro ⁇ - ⁇ ectional area and correspondingly small diffusion rate through such an area) .
  • an underlayer may, when po ⁇ ses ⁇ ed of sufficient elasticity, alternatively permit the u ⁇ e of a metal relief replica a ⁇ said negative replicated relief because ⁇ aid ela ⁇ ticity ⁇ erve ⁇ the ⁇ ame function a ⁇ the ela ⁇ ticity of an ela ⁇ tiomeric mold, i.e.
  • a yet further variation involves the u ⁇ e of metal or other rugged relief ⁇ a ⁇ "cookie-cutter ⁇ " which mechanically exclude a ⁇ oftened re ⁇ i ⁇ t precur ⁇ or such as a melt or sol-gel from surface regions underlying outermost exten ⁇ ion ⁇ of the applied relief ⁇ tructure.
  • a ⁇ oftened re ⁇ i ⁇ t precur ⁇ or such as a melt or sol-gel from surface regions underlying outermost exten ⁇ ion ⁇ of the applied relief ⁇ tructure.
  • Fabrication by Layered Molding of Patterned Article Material and Sacrificial Material Technique ⁇ ⁇ uch a ⁇ tho ⁇ e de ⁇ cribed above for molding of ⁇ tructure ⁇ u ⁇ ing relief masters may be used recur ⁇ ively where each repetition add ⁇ another patterned layer (i.e. a portion of a layer in a predetermined pattern which may additionally have ⁇ urface feature ⁇ or height contour ⁇ ) of material for the de ⁇ ired final article or another patterned layer of ⁇ acrificial material u ⁇ eful in the production of un ⁇ upported or overhanging ⁇ tructure ⁇ .
  • another patterned layer i.e. a portion of a layer in a predetermined pattern which may additionally have ⁇ urface feature ⁇ or height contour ⁇
  • ⁇ acrificial material ⁇ may include waxe ⁇ which are melted away at elevated temperature ⁇ or di ⁇ olved in solvents such as alcohols.
  • the ⁇ e would mo ⁇ t favorably be u ⁇ ed as sacrificial material with polymers that polymerize in aqueous solution or other solution ⁇ in which said wax i ⁇ ⁇ ubstantially insoluble.
  • Sacrificial material may also be used to flatten intermediate surface ⁇ of article material a ⁇ an article i ⁇ being built up by this method.
  • article material is patterned by molding, ca ⁇ ting or ⁇ tamping, and when hardened (if hardening i ⁇ required,) the article under fabrication is juxtaposingly contacted to a flat ⁇ urface which i ⁇ coated with ⁇ oftened or liquefied sacrificial material (where a ⁇ nece ⁇ ary a relea ⁇ e agent i ⁇ u ⁇ ed between said flat surface and ⁇ aid ⁇ acrificial material to facilitate removal of ⁇ aid flat ⁇ urface after ⁇ aid flattened material has set or hardened.)
  • This method is advantageous where an article is conveniently built up in layers with ⁇ ub ⁇ tantially flat border ⁇ .
  • article material i ⁇ preferably cho ⁇ en ⁇ uch that where article precur ⁇ or material ( ⁇ uch a ⁇ a prepolymer) i ⁇ overlaid onto polymerized or hardened article material, chemical cro ⁇ link ⁇ will form between the ⁇ e region ⁇ of two such juxtaposed layers.
  • This will be the ca ⁇ e, for example, for polymers where polymerization occur ⁇ via ⁇ ide-group ⁇ or where there i ⁇ an exce ⁇ of one of the two chemical functionalitie ⁇ which are involved in polymerization, such that a plurality of unreacted functional groups are available on the surface of ⁇ uch article material after polymerization of that portion of article material ha ⁇ proceeded to completion.
  • i. Metal Film Annealing The defects encountered by Whiteside ⁇ and co-worker ⁇ are attributed by the ⁇ e workers to crystallite ⁇ arising in the gold film depo ⁇ ition process. It has been determined 45 that an acetylene flame annealing step yields atomically flat terraces extending hundreds of nanometers. STM shows these surfaces to be better coated with an organothiol derivative (dimethylaminoethanethiol) than the unannealed film.
  • M.D. Ward and co-workers 46 have previously found that annealing a gold wire with a hydrogen flame yield ⁇ atomically flat terraces extending over hundreds of microns.
  • thermal annealing ⁇ tep ⁇ will thu ⁇ reduce the occurrence of defect ⁇ when added, before the formation of the patterned organothiol SAM, to the procedure of White ⁇ ide ⁇ and co-worker ⁇ . It i ⁇ , of cour ⁇ e, nece ⁇ ary that the annealed film be permitted to cool (i.e. thermally equilibrate with the temperature of the relief and applied ⁇ olution) before application of the SAM forming material, becau ⁇ e thermal contraction will otherwi ⁇ e di ⁇ tort the de ⁇ ired pattern.
  • Multilayer Vetoing Defect ⁇ which are ⁇ mall and occur approximately randomly, a ⁇ i ⁇ the ca ⁇ e as the gold-organothiol re ⁇ i ⁇ t ma ⁇ king method of Whitesides et al. , may be prevented from appearing in the etched final product by a vetoing method which bears analogy to the reticle voting method de ⁇ cribed in U.S. Patent Number 5,308,722 by J.L. Ni ⁇ tler.
  • An elastiomeric relief may be prepared by related art methods or as otherwise disclo ⁇ ed in the pre ⁇ ent invention, and then coated with an organothiol ⁇ olution.
  • a thin layer of gold is deposited by suitable means onto a substrate.
  • the pattern of ⁇ aid relief are thu ⁇ tran ⁇ ferred, in the form of a SAM of said organothiol, to the surface of ⁇ aid gold film, in a first printing step.
  • the patterned ⁇ urface thu ⁇ produced i ⁇ then coated again with gold, forming a ⁇ econd gold film layer, and again patterned in a ⁇ econd printing ⁇ tep with the same relief surface coated either with the same or a different organothiol compound ⁇ olution.
  • the uncoated regions of said second gold film layer are then etched by appropriate ⁇ olution ⁇ , ⁇ uch a ⁇ ⁇ trong acid ⁇ , such that the underlying sub ⁇ trate i ⁇ expo ⁇ ed in these unprotected regions and thu ⁇ ⁇ u ⁇ ceptible to etching and impurity diffu ⁇ ion.
  • ⁇ ub ⁇ trate i ⁇ compo ⁇ ed of ⁇ emiconductive material ⁇ electronic, microelectronic, MEMS and other device ⁇ may be produced through processe ⁇ compri ⁇ ing the above method.
  • a ⁇ uming a defect 1 ⁇ quare micron in ⁇ ize occur ⁇ on average once, randomly, in an area of 1mm 2 , the relative defect area of 10 ⁇ ° yields a defect rate per two-layer mask of 10 ⁇ 12 , which should be tolerably low for most applications.
  • Such a defect rate may be reduced further by three or more repetition of the above coating and printing step ⁇ .
  • reliefs may favorably incorporate features which facilitate alignment between succe ⁇ ively applied relief pattern ⁇ , such as features, favorably placed at borders which generate Moire patterns under appropriate illumination and imaging (which may include electron microscopy) due to the overlap of pattern ⁇ in ⁇ aid ⁇ ub ⁇ trate and said negative relief.
  • the methods of the present a ⁇ pect of the present invention very directly also permit accurate tactile alignment, where ⁇ aid feature ⁇ compri ⁇ e interlocking relief ⁇ which only fit together when ⁇ aid relief and ⁇ aid substrate are in precise registry with each other.
  • Such tactile alignment methods may thu ⁇ permit repeatable accuracy to within a few nanometer ⁇ with appropriately de ⁇ igned pattern ⁇ and sufficiently resilient materials.
  • Initiator Polymerization A further approach to defect reduction i ⁇ applicable to defect ⁇ arising from incomplete SAM formation in relief contacted regions.
  • the chemical composition of said SAM is chosen such that the exposed surface of said SAM comprises chemical functional groups which serve as initiators for ⁇ ome polymerizable material.
  • compounds which do not form SAMs may also be used, provided these are reliably deposited on said sub ⁇ trate and do not diffuse; compounds used need only suitably form patterned initiator compound region ⁇ .
  • a quantity of material of ⁇ aid chemical compo ⁇ ition (for example, dissolved in a first solution) i ⁇ applied in ⁇ ufficient but not exce ⁇ ive quantity to a de ⁇ ired patterned ⁇ urface, which i ⁇ then contacted with a ⁇ ub ⁇ trate to tran ⁇ fer ⁇ aid material of ⁇ aid chemical composition to ⁇ aid surface in a pattern determined by the pattern of said patterned ⁇ urface. Said ⁇ urface i ⁇ then washed to remove any exces ⁇ reactant ⁇ or reagent ⁇ .
  • Said material of said desired chemical compo ⁇ ition now ⁇ ituated in a patterned manner on ⁇ aid ⁇ urface, is then contacted with a second solution comprising monomer reactant species which are capable of reacting with said chemical functional groups which serve a ⁇ initiator ⁇ .
  • Said ⁇ econd solution preferably contain ⁇ ⁇ aid monomer reactant species at low concentrations such that molecules of said monomer reactant ⁇ pecies are more likely to react with said chemical functional groups which serve a ⁇ initiator ⁇ , or oligomers or polymers therefrom, rather than with other said molecule ⁇ of said monomer reactant species.
  • the limit on the concentration of said monomer reactant species are those po ⁇ ed by non-specific polymerization, i.e.
  • the term ⁇ ignificant here refer ⁇ to the quality of the overlayer ⁇ thu ⁇ produced and the non-coating of ⁇ ub ⁇ trate region ⁇ not compri ⁇ ing ⁇ aid chemical functional group which ⁇ erve ⁇ a ⁇ initiators, i.e. reduction of resolution in non-resi ⁇ t coated regions.
  • Said second solution may further comprise multimeric monomers or other cro ⁇ linking reagent ⁇ which serve to cause branching of polymer chains during a polymerization proces ⁇ .
  • the concentration of said monomer reactant specie ⁇ , and the proportion or ⁇ urface density of said chemical functional groups are chosen such that the polymer coating formed will be substantially limited to the regions of ⁇ aid ⁇ urface originally contacted by ⁇ aid patterned ⁇ urface, i.e. not extending far from any of ⁇ aid chemical functional groups which serve a ⁇ initiator ⁇ .
  • monomeric species may be added at a limiting quantity, or at a concentration sufficiently low that exces ⁇ ive polymerization does not occur within some conveniently short period of time.
  • Thi ⁇ method of ⁇ urface coating patterning followed by coating thickening (which may be termed overlayer formation) ⁇ erve ⁇ to enclose any small resi ⁇ t layer defect ⁇ without ⁇ ignificantly compromi ⁇ ing patterning re ⁇ olution.
  • Such enclo ⁇ ure reduce ⁇ or prevents transport of etching agents to defect site ⁇ and etching products from said defect sites.
  • this method requires that overlayer thicknes ⁇ be increa ⁇ ed corre ⁇ pondingly to ensure enclosure or encap ⁇ ulation of defect ⁇ of ⁇ aid defect ⁇ ize.
  • said chemical composition of said SAM may be chosen to comprise an alkanethiol moiety and a methacrylate moiety.
  • a solution compri ⁇ ing a quantity of ⁇ aid chemical composition is applied to a gold film situated on a substrate, such that a SAM is formed according to the pattern of said patterned ⁇ urface. Said gold film and substrate is then wa ⁇ hed to remove any exce ⁇ unbound material.
  • Resist Formation by Wettability Control The methods of G.M. Whiteside ⁇ and co-worker ⁇ involving the wetting of patterned surface regions, which these worker ⁇ have used to form microlen ⁇ array ⁇ from polymer ⁇ olution ⁇ , may al ⁇ o be applied to the elimination of small defects.
  • patterns of resist are formed by fir ⁇ t patterning a SAM which i ⁇ preferentially wet by a re ⁇ i ⁇ t monomer ⁇ olution or precursor solution on a surface which is poorly wet by said solution. Said patterning is accomplished by one or more of the methods described herein, such as microcontact printing, and the patterned said surface is then contacted with a resi ⁇ t precursor ⁇ olution, which i ⁇ then withdrawn.
  • Portions of said resist precursor solution retained on said surface are then caused or permitted to polymerize, such that a developed resi ⁇ t layer i ⁇ formed.
  • defect ⁇ related to incomplete ma ⁇ king may be eliminated by their enclosure by the overlying resi ⁇ t precur ⁇ or ⁇ olution and hence the re ⁇ ulting developed resi ⁇ t.
  • Etch ⁇ tep ⁇ are then performed a ⁇ in conventional microfabrication practice.
  • resi ⁇ t depth-dependent etching in analogy to that described by G. Gal in U.S. Patent Number 5,310,623, may be performed, for example by reactive ion etching, to replicate the self-a ⁇ embled resist structure in the underlying solid sub ⁇ trate material.
  • Patterned Metallization for example, for the formation of electrical contact ⁇ , may be accompli ⁇ hed according to the patterning method ⁇ of the present invention and corresponding exten ⁇ ion ⁇ of related art methods, as well as by the application of related art method ⁇ to article ⁇ produced by the method ⁇ of the present invention (e.g. formation of alkanethiol patterns by microcontact printing on gold films, employing, as neces ⁇ ary, the defect reduction method ⁇ disclosed herein) .
  • Molded materials such a ⁇ those used above for resi ⁇ t purposes may, with appropriate solvent ⁇ , be u ⁇ ed a ⁇ lift-off layers which eliminate any metallic film ⁇ ituated on the surface of ⁇ aid molded material ⁇ upon expo ⁇ ure of the ⁇ urface compri ⁇ ing the ⁇ e to said appropriate solvent. Patterns of said metallic film remain in regions which were not covered by said molded materials.
  • metal film ⁇ may be accomplished by vacuum evaporation of the corre ⁇ ponding metallic material onto the ⁇ urface of the article under production.
  • ⁇ uch lift-off patterning may be applied to thin electroformed (e.g. electrodepo ⁇ ited or electrole ⁇ plated) metallization layers.
  • metallization may be accomplished by the hot embos ⁇ ing of a first ⁇ urface with a metallized polymeric foil with the metallized ⁇ urface juxtapo ⁇ ed to ⁇ aid fir ⁇ t ⁇ urface, under ⁇ ufficient pre ⁇ ure and at ⁇ ufficient temperature to en ⁇ ure good electrical contact with expo ⁇ ed region ⁇ of said first ⁇ urface, followed by di ⁇ olution of ⁇ aid polymeric foil and underlying lift-off region ⁇ .
  • Such transferred film ⁇ may be ⁇ ubjected to brief electrodepo ⁇ ition steps to ensure good electrical contact, though care.mu ⁇ t be taken to avoid the formation of ⁇ hort circuits.
  • the foregoing fabrication methods compri ⁇ ing the u ⁇ e of relief pattern ⁇ u ⁇ ed to pattern re ⁇ ist or masking layers may be u ⁇ ed to control the etching and doping (impuritie ⁇ diffu ⁇ ion) of ⁇ emiconductor materials and overlying dielectric layer ⁇ , as well as the formation of metallization layers for electrical interconnection. These methods serve all of the patterning functions required in microelectronic ⁇ fabrication.
  • re ⁇ i ⁇ t molding and ca ⁇ ting methods may similarly be applied to conductive polymers compo ⁇ itions such a ⁇ tho ⁇ e comprising polyparaphenylene and derivatives thereof, polypyrrole and derivatives thereof, polythiophene and derivatives thereof, or other such conducting or electroactive polymer ⁇ , ⁇ o a ⁇ to directly form polymeric device ⁇ rather than re ⁇ i ⁇ t patterns.
  • the ⁇ e material ⁇ and devices based thereupon may further be combined with more conventional microelectronic device ⁇ fabricated by the method ⁇ of the pre ⁇ ent invention.
  • Initial relief pattern ⁇ may be formed in, for example, gla ⁇ or ⁇ ilicon ⁇ urface ⁇ by known art method ⁇ including photolithography, or may be formed by appropriate scanning probe based patterning method ⁇ of related art, or combination ⁇ thereof.
  • a gla ⁇ ⁇ urface may be coated with a gold film, upon which an organothiol SAM i ⁇ formed, which i ⁇ then patterned by STM or field emi ⁇ sion mode STM, followed by an acid etch to remove exposed gold regions and a base etch to remove thus exposed gla ⁇ region ⁇ .
  • a large patterned area may be formed by the replication of a ⁇ maller pattern from an initial relief acro ⁇ ⁇ aid large patterned area, a ⁇ , for example, a ⁇ ingle integrated electronic device pattern layer (e.g. corre ⁇ ponding to a ma ⁇ k layer) repeated many time ⁇ acro ⁇ the ⁇ urface area corre ⁇ ponding to a wafer diameter.
  • the replication methods of the present invention may be applied both to expand the number of occurrences of a pattern on a single surface a ⁇ well a ⁇ the number of ⁇ urface ⁇ thu ⁇ patterned.
  • a relief patterned surface preferably of elastiomeric compo ⁇ ition, may be used to spatially control the pattern of addition of monomer or macromonomer reactant ⁇ to a ⁇ ub ⁇ et of appropriate chemical reactive ⁇ ite ⁇ on a ⁇ ub ⁇ trate ⁇ urface.
  • reactant ⁇ are added to region ⁇ of the ⁇ urface of ⁇ aid ⁇ ub ⁇ trate according to the pattern of ⁇ aid patterned ⁇ urface, permitted or cau ⁇ ed to react, and unreacted or unbound ⁇ pecies are then washed away.
  • said sub ⁇ trate will comprise one or more sub ⁇ tantially flat surface region ⁇ and be prepared by the reaction or ad ⁇ orption of ⁇ ome chemical ⁇ pecie ⁇ to ⁇ aid ⁇ urface ⁇ uch that chemical ⁇ pecie ⁇ having desired reactivitie ⁇ are bound to ⁇ aid ⁇ ubstrate, which is thus capable of being reacted with desired reactant specie ⁇ .
  • ⁇ aid a ⁇ olution may further compri ⁇ e inert compounds which increase the visco ⁇ ity of ⁇ aid ⁇ olutions.
  • Said relief patterned surface is then contacted, in a contacting step, with said substrate to transfer ⁇ aid de ⁇ ired reactant to one or more predetermined regions of said ⁇ ub ⁇ trate.
  • said desired reactant is applied only to the desired region ⁇ , according to the predetermined pattern of said relief patterned surface.
  • the control of precise copolymer sequence thu ⁇ ⁇ ynthe ⁇ ized is favorably achieved, for example, through the u ⁇ e of protection/deprotection or activation chemi ⁇ trie ⁇ to effect ⁇ tep control over reactant addition to the monomer or copolymer ⁇ pecie ⁇ with which said desired reactants are reacted.
  • reactants added will generally comprise a protecting group or an activatable reactive group, which serve to prevent multiple monomer or macromonomer addition to the ⁇ ame molecule.
  • different patterned relief surface ⁇ are u ⁇ ed at different ⁇ tep ⁇ , and may optionally be ⁇ hifted in location from one ⁇ tep to the next; similarly, different desired reactant species may be used during different cycles.
  • This is in analogy to multiple masking step ⁇ in related art microfabrication, and directly related to the multiple masking method ⁇ of other a ⁇ pects of the present invention.
  • arrays of copolymer ⁇ of predetermined ⁇ equence, ⁇ uch a ⁇ oligonucleotide ⁇ , polypeptide ⁇ , biomimetic copolymer ⁇ and non- biological copolymer ⁇ may be produced at a resolution equal to that with which a relief master may be fabricated.
  • Pattern ⁇ having feature ⁇ many time ⁇ ⁇ maller than one micron are thu ⁇ achievable, and corre ⁇ pondingly high den ⁇ itie ⁇ (such as 10° to 10 10 array elements per cm 2 ) may be achieved without extensive use of costly lithographic equipment.
  • Such methods thus carry several advantages over the methods of S.P.A. Fodor et al. in that protection/deprotection chemi ⁇ trie ⁇ (and the corre ⁇ ponding reactant compounds or protected/deactivated) need not be limited to those respon ⁇ ive to actinic radiation or other energetic beam ⁇ .
  • reactant ⁇ useful for ordinary (e.g. not light controlled) stepwi ⁇ e ⁇ ynthe ⁇ es are u ⁇ eful with the ⁇ e methods. Further, these methods are ⁇ uitable for the synthesis of copolymer of compositions which might be or are desired to be sen ⁇ itive to photochemical or other energy induced degradation.
  • ⁇ uch a ⁇ aid patterned ⁇ urface may be u ⁇ ed to control the ⁇ patially controlled activation or deprotection of copolymer ⁇ or copolymer precur ⁇ or ⁇ , ⁇ uch that only the copolymer ⁇ or copolymer precursor ⁇ located at predetermined region ⁇ of ⁇ aid surface are prepared for subsequent reaction with a monomer or macromonomer, which is thereby added only to said copolymers or copolymer precursor ⁇ located at said predetermined region ⁇ .
  • a relief is for example coated with solution ⁇ comprising deprotection or activation reagents at sufficient concentrations (and preferably also inert constituents increasing the viscosity of said solutions) and contacted with said surface to effect the spatially controlled deprotection of the product precursor copolymer ⁇ ⁇ ituated thereupon.
  • a ⁇ olution compri ⁇ ing ⁇ aid monomer or macromonomer i ⁇ then contacted with said s.ub ⁇ trate ⁇ uch that the ⁇ e specie ⁇ may react with any available corresponding reactive groups.
  • the methods of this aspect of the present invention thus permit the synthe ⁇ i ⁇ of a potentially large array of diver ⁇ e copolymer ⁇ pecie ⁇ ⁇ ituated on a ⁇ urface according to a predetermined pattern, ⁇ uch that compo ⁇ ition of the copolymer ⁇ at a particular region of said surface correspond in a known fashion to the location of said region.
  • the copolymer sequence composition respon ⁇ ible for ⁇ aid activitie ⁇ may directly be deduced from information about the spatial location of said particular region ⁇ .
  • thi ⁇ method may be u ⁇ ed to synthesize or otherwise target copolymer ⁇ , affinity groups or other molecular functionalities or decorations to predefined region ⁇ of the surfaces of microreliefs, micromolded component ⁇ and component ⁇ of micromechanical or microelectromechai-ical systems.
  • the reliefs used for pattern formation are produced from master structures which are identical to the molded surfaces in regions to which said reliefs are to contact ⁇ aid microrelief ⁇ , ⁇ aid micromolded component ⁇ , etc., and thus situate reactant monomers or other reactive compounds, but which have surfaces or surface features of increased height at regions not to be targeted by ⁇ aid reactant monomers or other reactive compounds.
  • the reliefs used to target reactant ⁇ to predetermined region ⁇ of contoured ⁇ urface ⁇ conform to the geometry of tho ⁇ e ⁇ urface ⁇ in region ⁇ to be targeted or modified, but do not contact regions to not be affected due to clearance within said relief that prevent ⁇ contact of the ⁇ urface of said relief with regions of ⁇ aid contoured ⁇ urface ⁇ not targeted.
  • reliefs may be mounted on a roller apparatus, in analogy to arrangements used in holograph stamping processes, to facilitate rapid patterned deposition of reactants.
  • rin ⁇ e ⁇ teps may favorably be performed with reagent ⁇ that react with unreacted monomer reactants to inactivate said unreacted reactants such that these will not, upon washing, react with specie ⁇ bound to region ⁇ onto which ⁇ aid unreacted reactant ⁇ were not contacted by ⁇ aid relief.
  • alcoholic ⁇ olution ⁇ may be u ⁇ ed to inactivate and wash away unreacted phosphoramidite monomers, which will react with the hydroxyls of alcohol molecules.
  • a first surface such as a glass surface, is patterned with a first alkyl ⁇ ilane compound compri ⁇ ing an extended methylene or polyethylene glycol linker, or other substantially linear linker chosen to be well solvated or wetted by oligonucleotide synthesis solvents or chosen to be readily modified so as to be well ⁇ olvated or wetted by oligonucleotide synthesis solvent, and an esterified terminal hydroxyl group by use of an elastiomeric relief with a square grid pattern such that ⁇ uare regions of said fir ⁇ t ⁇ urface are modified by said first alkyl ⁇ ilane compound with di ⁇ tinct unmodified border ⁇ (which are hydroxylated) remaining.
  • a first alkyl ⁇ ilane compound compri ⁇ ing an extended methylene or polyethylene glycol linker, or other substantially linear linker chosen to be well solvated or wetted by oligonucleotide synthesis solvents or chosen to be readily modified so as to be well
  • Untreated region ⁇ of ⁇ aid ⁇ urface may then optionally be permitted to react with a ⁇ econd alkyl ⁇ ilane compound compri ⁇ ing a terminal functionality which will be poorly wetted by the ⁇ olvent ⁇ containing oligonucleotide ⁇ ynthe ⁇ i ⁇ reactant monomer ⁇ .
  • Said fir ⁇ t surface is then treated with appropriate reagents such as bases to hydrolyze the terminal ester group of said first alkylsilane and thu ⁇ deprotect the terminal hydroxyl group.
  • a ⁇ olution of 3' or 5' protected oligonucleotide synthesis reactant monomers of one nucleoba ⁇ e type is then coated onto a second ⁇ urface, onto which an ela ⁇ tiomeric relief i ⁇ impre ⁇ ed to tran ⁇ fer ⁇ ome of ⁇ aid reactant to the surface of high regions of said ela ⁇ tiomeric relief (with raised square regions corresponding to a subset of the raised ⁇ quare region ⁇ of the relief u ⁇ ed to form the regular array of said fir ⁇ t alkyl ⁇ ilane) , or the entire ⁇ urface of said elastiomeric relief is directly coated with a solution of ⁇ aid reactant monomer.
  • Such a proce ⁇ s is carried out with different relief pattern ⁇ and the remaining three nucleotide monomers, such that all array elements experience the positionally controlled addition of exactly one of the four nucleotide precur ⁇ or ⁇ pecie ⁇ .
  • ⁇ aid fir ⁇ t ⁇ urface region ⁇ which may have optionally been treated to be poorly wetted by said reactant ⁇ olutions will serve as borders impeding the spreading of these reactants beyond targeted array elements; said well solvated linker moieties are drawn into the solution ⁇ with which they are contacted, even where the ⁇ e are ⁇ ituated on surfaces which are poorly wetted by said solutions with which they are contacted (in which case undesirable spreading of reactants to inappropriate surface regions i ⁇ prevented while ⁇ ynthe ⁇ is is not frustrated) .
  • Said first surface is then thoroughly rinsed.
  • Capping reagents ( ⁇ uch a ⁇ acylating reagent ⁇ ) may optionally be applied to all of ⁇ aid first surface to prevent any further elongation of unreacted hydroxyl groups.
  • Other standard oligonucleotide ⁇ ynthe ⁇ i ⁇ ⁇ tep ⁇ , ⁇ uch a ⁇ oxidation, may then be performed as required by the particular chemistry u ⁇ ed.
  • the entire array i ⁇ then treated with reagents to deprotect the reactant monomers added during the previou ⁇ cycle (e.g.
  • Such cycle ⁇ are repeated until the array thu ⁇ ⁇ ynthesized sub ⁇ tantially consists of oligonucleotides of the de ⁇ ired length (i.e. n cycle ⁇ total to produce an array of n-mer ⁇ ) and de ⁇ ired element ⁇ equence according to po ⁇ ition within ⁇ aid array.
  • ⁇ tep ⁇ deprotecting nucleobase moieties and, where applicable, deprotecting the phosphate backbone are performed to yield the desired final molecular structure, a ⁇ in conventional oligonucleotide synthesis methods, excepting support removal step ⁇ .
  • Alternative copolymer array patterned synthesis methods may be used to produce a stencil capable of masking surface regions from exposure to reactants.
  • a substrate is first coated uniformly with a sacrificial layer, which is hardened or set.
  • an ela ⁇ tiomer precursor i ⁇ applied to the surface of said sacrificial layer and then molded by a negative relief.
  • analogous ca ⁇ ting or injection molding may be utilized, or embo ⁇ ing of a polymeric film with brief po ⁇ t-etching of the embossed film may be used.
  • Said sacrificial layer is then di ⁇ olved to free the patterned elastiomeric stencil.
  • Such a stencil is used in combination with an array of microfabricated columns, said columns being of uniform height, and with a pitch smaller than the smallest stencil feature.
  • Said stencil may either be combined with said array of microfabricated columns into one ⁇ tenciling body, or said stencil and said columns may merely be fu ⁇ ed together. In either case, said stencil is juxtaposed to the substrate which is to be subjected to patterned copolymer synthesis, and said array of microfabricated columns i ⁇ pre ⁇ ed onto ⁇ aid stencil, such that said columns force the ⁇ tencil ⁇ urface into good ma ⁇ king contact with ⁇ aid ⁇ ub ⁇ trate.
  • Solution ⁇ containing reactants e.g.
  • deprotection reagents or monomer reactants are then cau ⁇ ed to flow through said array of microfabricated columns, such that areas not masked by said stencil are exposed to said ⁇ olution ⁇ .
  • ⁇ tencil i ⁇ released from said sub ⁇ trate thorough wa ⁇ h ⁇ tep ⁇ are performed to remove re ⁇ idual reactant ⁇ or reagent ⁇ .
  • Differently patterned ⁇ tencil ⁇ are used in predetermines sequence with different monomer type ⁇ to produce the desired diverse copolymer array with sequence correlated to location in a predetermined manner.
  • said array microfabricated columns is to form one body with said stencil, these may be joined together, e.g. by coating the upper surface of said stencil with an adhesive or cro ⁇ linking agent which will react with both the material of ⁇ aid columns and the material of said stencil.
  • Compounds used for such joining mu ⁇ t be selected so as to be inert to the reagents and solvents which will be pas ⁇ ed over them.
  • said array of microfabricated columns may favorably be produced by LIGA methods or other replication methods including those of the present invention, and may favorably be composed of metals, e.g. formed by electrodeposition or electroless plating methods.
  • a ⁇ pect of the present invention may be used in a variety of ways including for sequencing by hybridization (where said copolymers are oligonucleotide ⁇ or oligonucleotide analogs) , sequence confirmation by hybridization, for the ⁇ creening of small peptides and the determination of affinity interactions (a ⁇ described by Fodor et al., referenced elsewhere herein), for the detection or determination of antibodies, in clinical medical as ⁇ ays, and in the screening of organic material for desired propertie ⁇ according to known method ⁇ in combinatorial chemi ⁇ try.
  • Sequencing by hybridization, a ⁇ well a ⁇ other technique ⁇ involving binding determination may favorably be performed by contacting ⁇ ample ⁇ with such an array, where sample molecule ⁇ binding to said array is monitored by any of se ral known art techniques, while physical or chemical condition ⁇ are changed and binding is recorded (e.g. by capture of signal ⁇ detected by ⁇ uch monitoring and recorded electronically) a ⁇ a function of condition ⁇ .
  • the condition dependent propertie ⁇ of set ⁇ of array elements (i.e. copolymer sequences) of interest are determined by observation of condition dependent binding of known samples, and information thus obtained i ⁇ used to further refine the discrimination of correct (i.e. most highly matched) or most specific binding from incorrect or relaxed specificity binding.
  • condition ⁇ which may be varied include temperature, ionic ⁇ trength, divalent cation concentration, pre ⁇ ence and/or concentration of tetramethylamonium chloride, pre ⁇ ence and/or concentration of denaturant compound ⁇ ⁇ uch a ⁇ formamide or dimethylformamide, pH, and other factors known to affect the hybridization specificity and stringency of oligonucleotides or polynucleotides, may be varied individually or in combination.
  • the binding, and also di ⁇ ociation of a particular ⁇ equence with the complementary n-mer oligonucleotide will occur at a characteri ⁇ tic temperature (i.e. having a characteri ⁇ tic T m melting temperature at which half of all homoduplex complexes dis ⁇ ociate) , and thi ⁇ property verifie ⁇ the correctne ⁇ of ba ⁇ e pairing.
  • Such array ⁇ may be used to detect very low quantities, approaching single molecules, of complementary molecules in samples by a few distinct methods.
  • an oligonucleotide array is produce by forming first square regions, subdivided into four square region ⁇ each containing one of adenosine, guanosine, cyto ⁇ ine or thymidine nucleotide ⁇ (e.g.
  • each ⁇ tep adding one nucleotide to one subdivision region) .
  • succe ⁇ ive synthesi ⁇ ⁇ tep ⁇ identical ⁇ quare ⁇ with ⁇ ides one half that of those of the preceding ⁇ tep and area one quarter that of the preceding ⁇ tep are formed, again ⁇ ubdivided into four square regions each containing one of the four nucleotide ⁇ , preferably in the same relative configuration as that of the preceding set of ⁇ tep ⁇ , are added, ⁇ uch that one subdivi ⁇ ion ⁇ quare of the previou ⁇ step is thus subdivided into four subdivisions.
  • a set of array ⁇ of oligonucleotide ⁇ of increa ⁇ ing length e.g. ⁇ (n-m) , (n-m+1) ... (n-l) , n ⁇ -mers in the case of single nucleotide increments, is produced as above.
  • This set of array ⁇ i ⁇ designed such that each successive ⁇ ive array in the series is in the mirror image of the preceding array of said series, with at least one further ⁇ ynthe ⁇ i ⁇ cycle (set of synthesi ⁇ steps) further subdividing the region ⁇ oppo ⁇ ed to the smallest array elements of the preceding array.
  • ⁇ aid sample is bound first to the array consisting of the smalle ⁇ t number of elements.
  • the sample is divided such that each oligonucleotide targets a region of some ⁇ ub ⁇ et of molecule ⁇ in ⁇ aid sample.
  • Hybridization to such a lower density array by rare species will be more accurate under appropriate conditions in that fewer array elements of larger area present more molecular target ⁇ and fewer degree ⁇ of freedom.
  • the kinetic limitation on binding depends mainly on the diffu ⁇ ional transit time from across said array.
  • Conditions are changed to denature the as ⁇ ociation of ⁇ ample molecules with said fir ⁇ t array, and then to binding conditions sufficiently stringent that ⁇ aid ⁇ ample molecule ⁇ will favorably bind to their target oligonucleotide ⁇ on said second array in preference to forming the lower energy association with their shorter targets on said first array.
  • This proce ⁇ s result ⁇ in ⁇ uccessive subdivision of said sample, such that each subdivision step ⁇ ucce ⁇ ively narrow ⁇ the volume which mu ⁇ t be traver ⁇ ed by a ⁇ ample molecule in order to find it ⁇ correct binding target, and further correspondingly reduces the chances that a molecule will find an incorrect target.
  • An analogous method within the scope of this fir ⁇ t method may be applied where an array is designed, as above, such that array elements are similar (but not identical) in sequence to most of their nearest neighbors, such that spatial proximity is related to ordered sequence ⁇ imilarity.
  • This similarity may be used to serve a ⁇ imilar "narrowing down" function accompli ⁇ hed above by juxtapo ⁇ ition of hierarchially related mirror image array ⁇ .
  • condition ⁇ affecting binding ⁇ tringency are varied ⁇ uch that after a sample is first applied, only a few contiguous base pairs are sufficient for binding.
  • the regions bound by a sample molecule comprising a specific sequence may either be within the contiguous region compri ⁇ ing many array element ⁇ having m of the total n monomer ⁇ in common ( ⁇ tarting from the fir ⁇ t variable nonomer added during the fir ⁇ t cycle of array synthe ⁇ is), or with m contiguous monomers off ⁇ et from the copolymer terminal from which ⁇ ynthesis began, in which ca ⁇ e, for each cla ⁇ s of array elements with said m monomers in common, contiguou ⁇ region ⁇ of element ⁇ compri ⁇ ing said m monomer ⁇ equence complementary to said specific sequence, where cla ⁇ ses are di ⁇ tingui ⁇ hed according to the number of monomer ⁇ by which ⁇ aid m monomer ⁇ equence i ⁇ off ⁇ et from ⁇ aid fir ⁇ t variable monomer, become increasingly small and increasingly di ⁇ tant from each other.
  • Stringency i.e. the condition ⁇ affecting ⁇ tringency
  • Stringency may be o ⁇ cillated in an increa ⁇ ing trend, such that sample molecules are mo ⁇ t likely to home in on their final target oligonucleotide ⁇ .
  • sample molecules which do not initially bind sufficiently near their targets will enjoy increased diffusional mobility as those sample molecules which have bound to said array are less likely to impede their diffusional transport through the sample ⁇ olution, e.g. after they no longer bind m-mer comprising elements further from their correct targets under more stringent condition ⁇ .
  • Generalizing thi ⁇ method to any copolymer with sequence dependent binding properties, phy ⁇ ical and chemical condition ⁇ may be varied to examine the characteri ⁇ tic ⁇ of, or detect the pre ⁇ ence of, binding activitie ⁇ corresponding to respective ⁇ et ⁇ of condition ⁇ , or ⁇ patial or temporal gradient ⁇ thereof.
  • a second method, applicable to polynucleotide ⁇ ample ⁇ involve ⁇ the amplification of rare specie ⁇ , or ⁇ equence fragments thereof.
  • e ⁇ tablished art methods such as the polymerase chain reaction (e.g. with PCR primers flanking the diverse target sequence) or the ligase chain reaction (e.g. for an 8-mer array, involving all 4-mer oligos under conditions ⁇ ufficiently ⁇ tringent to preclude any mi ⁇ match within said 4-mer ⁇ equence ⁇ for binding) are used to amplify the sample target sequence ⁇ , which may be a diverse sequence in a conserved sequence context.
  • Amplification reagent ⁇ e.g. primer ⁇ or nucleotide ⁇ for PCR or oligonucleotides for LCR
  • Amplification reagent ⁇ may be labeled, for example, with one or more affinity moieties (e.g. biotin, digoxigenin, etc.,) or one or more fluorescent dye moietie ⁇ (e.g. Texa ⁇ red, rhodamine, fluoroe ⁇ cien, etc.,) or one or more other reporter group ⁇ or portion ⁇ .
  • affinity moieties e.g. biotin, digoxigenin, etc.,
  • fluorescent dye moietie ⁇ e.g. Texa ⁇ red, rhodamine, fluoroe ⁇ cien, etc.
  • amplification will produce a geometrically increasing quantity of sequences matching the amplified sequences but also a related quantity (which may be biased by such known art methods as asymmetric PCR)
  • Similar operations as used to synthesize copolymers on a ⁇ urface in a ⁇ patially predetermined manner de ⁇ cribed above may similarly be used to collocalize multiple distinct macromolecule or macromolecule type ⁇ to predetermined ⁇ urface regions.
  • such methods may be u ⁇ ed to generate a very large number of po ⁇ itionally predetermined combination ⁇ , ⁇ hapes and/or patterns of large numbers of adhesion proteins which may be used , for example, to test the effect on cell adhe ⁇ ion, cell motility, cell ⁇ hape or cell phy ⁇ iology in biological and clinical a ⁇ ay ⁇ , as shown by Whiteside ⁇ and co-workers for patterns consisting of a single protein specie ⁇ , as well as in other biotechnological uses, including the interfacing of cells to microelectronic device ⁇ and sensors.
  • the pre ⁇ ent a ⁇ pect of thi ⁇ invention thus depends on the u ⁇ e of a relief pattern compri ⁇ ing raised surface elements to contact a solution containing one or more protein or polypeptide to portions of a fir ⁇ t ⁇ urface to which ⁇ aid protein or polypeptide will adsorb, wherein contact only occurs between said rai ⁇ ed surface elements of said relief pattern and said fir ⁇ t surface, such that a pattern of said protein or polypeptide is depo ⁇ ited in the pattern corre ⁇ ponding to ⁇ aid rai ⁇ ed surface elements onto said first surface, wherein such patterning step ⁇ are repeated to yield depo ⁇ it ⁇ of plural different proteins or polypeptide ⁇ at different region ⁇ of ⁇ aid fir ⁇ t ⁇ urface, ⁇ uch that different combination ⁇ result in a spatially predetermined manner.
  • Patterned Combinatorial Materials Deposition :
  • X.-D. Xiang et al. 49 have recently de ⁇ cribed a method for the production of array ⁇ of combination ⁇ of material, which are then ⁇ creened to di ⁇ cover combinations with useful properties.
  • the patterning methods de ⁇ cribed herein may be extended to the production of such arrays but further permitting the rapid, selective deposition of materials which are not conveniently evaporated or without the use of evaporation equipment.
  • a su ⁇ pen ⁇ ion of very fine particle ⁇ of a material is applied to the surface of a wettable relief, which i ⁇ preferably of ela ⁇ tiomeric compo ⁇ ition.
  • said flat ⁇ urface mu ⁇ t be that of a porous filter, so that negative pressure may be used to draw the suspen ⁇ ion solution through said filter, depositing suspended material onto said filter surface.
  • Template Patterned Synthesis of Sheet-like Complexes and Copolymers permits the use of ⁇ uch chemically patterned ⁇ urfaces as templates for the production of patterned molecular complexes and copolymers, which themselves may be used as templates for co plementarily patterned molecular complexes and copolymers.
  • This aspect of the present invention i ⁇ analogous with other aspects of the present invention in that spatially patterned surface ⁇ may be replicated from an initial pattern and thereafter from each other.
  • patterned compositions of sheet-like molecules serve as molecular template ⁇ for the definition of patterns in thus complementarily patterned ⁇ heet- like molecules in a molecular replication process analogous to the polymerase chain reaction invented by K. Mulli ⁇ for the amplification of polynucleotide molecule ⁇ .
  • a ⁇ well as scanning probe based patterning methods 50 ' 51 ' 52 may be used to perform the patterned chemical derivatization of surfaces.
  • modifications may cause the preferential binding of molecular or macromolecular species to predetermined regions of said surface ⁇ , which are demarcated by said patterned chemical derivatization.
  • Such surface modifications may be used, for example with the methods of G.M. Whitesides et. al. or those of W.T. Muller, P.G. Schultz, et al., to bind specific fir ⁇ t affinity group ⁇ or species to predetermined regions of said surface.
  • Said affinity group ⁇ or ⁇ pecie ⁇ are chosen so as to bind affinity derivatized layer forming molecules comprising a second set of affinity groups or species which are in communication with a layer forming precursor moiety (such as a polymethylene chain, or rigid rod oligomer or polymer) .
  • the affinity moiety of ⁇ aid second ⁇ et of affinity group ⁇ i ⁇ preferably located at one terminu ⁇ of ⁇ aid affinity derivatized layer forming molecule ⁇ , which are preferably ⁇ ub ⁇ tantially linear in ⁇ tructure.
  • Said affinity derivatized layer forming molecule ⁇ preferably but not nece ⁇ arily further compri ⁇ e a moiety of third affinity group or ⁇ pecie ⁇ , which i ⁇ preferably located at the terminus opposite that at which said affinity moiety of said ⁇ econd ⁇ et of affinity group ⁇ i ⁇ located;
  • ⁇ aid affinity derivatized layer forming molecules may also comprise one or more (preferably two or more) distinct reactive, cross-linkable or photopolymerizable chemical functional groups, situated along said layer forming molecules such that each of said distinct reactive, cro ⁇ -linkable or photopolymerizable chemical functional group ⁇ occur ⁇ at a particular po ⁇ ition along the length of said layer forming molecules, and may, after a layered structure ha ⁇ been formed by a ⁇ ociation of moieties ⁇ elected from said second set of affinity groups with said fir ⁇ t affinity group ⁇ pattered on ⁇ aid ⁇ urface, be cau ⁇ ed to react to form a covalently linked network joining said layer forming
  • Said first affinity groups and said second affinity groups are preferably chosen such that the interaction between them i ⁇ ⁇ ufficiently ⁇ trong and ⁇ pecific under a first set of condition ⁇ but i ⁇ substantially weakened or neutralized under a second set of conditions; thus, under said first said of conditions, layer forming molecules assemble at surface ⁇ comprising regions of said fir ⁇ t affinity group in pattern ⁇ corre ⁇ ponding to the pattern of ⁇ aid region ⁇ , while ⁇ aid ⁇ econd ⁇ et of condition ⁇ serve ⁇ to ⁇ eparate layer ⁇ compri ⁇ ing said affinity group ⁇ chosen from among ⁇ aid second set of affinity groups from surfaces (including surfaces of layers) comprising said first affinity groups.
  • Said third affinity group or species is chosen such that it does not bind to either of ⁇ aid fir ⁇ t affinity group ⁇ or ⁇ aid second set of affinity groups, but will bind to affinity groups selected from a fourth set of affinity groups, which in turn will not bind to said first affinity groups, other affinity groups selected from said fourth set of affinity groups, nor to said second affinity group ⁇ (i.e. ⁇ aid fir ⁇ t affinity group ⁇ and affinity groups of said second ⁇ et of affinity groups bind only to each other and not to identical affinity group ⁇ ; said affinity groups cho ⁇ en from ⁇ aid third ⁇ et of affinity groups and said affinity groups chosen from said fourth set of affinity groups bind only to each other and not to them ⁇ elves; e.g.
  • sets of affinity groups may each consist of one of adenine, thymine, cytosine or guanosine nucleobases) .
  • the composition of said surface in unpattemed (or differently derivatized region ⁇ ) i ⁇ cho ⁇ en to not bind ⁇ aid affinity derivatized layer forming molecule ⁇ .
  • a solution containing ⁇ aid affinity derivatized layer forming molecules is contacted with said surface under appropriate conditions and for sufficient time to permit the binding of ⁇ aid affinity derivatized layer forming molecules to all available ⁇ ite ⁇ on ⁇ aid ⁇ urface. Unbound species are washed from said surface.
  • said layer forming molecules comprising affinity groups from said ⁇ econd set of affinity group ⁇ are bound to ⁇ aid ⁇ urface in a pattern replicating the pattern of said fir ⁇ t affinity group ⁇ on said surface. These may then be cros ⁇ -linked via said reactive group ⁇ , for example by the addition of suitable cros ⁇ -linking agent ⁇ , photopolymerized, or cau ⁇ ed to react together by e ⁇ tabli ⁇ hing appropriate phy ⁇ ical or chemical conditions such that a covalent network is formed.
  • said affinity group chosen from said third set of affinity group ⁇ may be initially caged or protected to ⁇ uppress the formation of association ⁇ until a deprotection step is performed.
  • affinity group ⁇ chosen from said fourth set of affinity group may be reacted with regions of said surface not containing said fir ⁇ t affinity group, in direct analogy to the complementarily patterned two component monolayers disclo ⁇ ed by G.M. White ⁇ ide ⁇ and co-workers, formed by patterning a first component monolayer and then permitting a second component compound to self-assemble into a monolayer on remaining uncoated regions.
  • pattern ⁇ composed of domains of multiple distinct affinity moietie ⁇ may be formed by multiple relief contacting ⁇ tep ⁇ , or by multiple spatially selective activation ⁇ tep ⁇ (example ⁇ include: light directed, for photodeprotectable or photoactivatable compound derivated surface ⁇ ; ⁇ canning probe controlled surface cataly ⁇ i ⁇ such a ⁇ the method ⁇ of W.T. Muller, P.G. Schultz et al., or of B.J. Mclntyre, M. Salmeron and G.A.
  • Somorjai, or other ⁇ canning probe based patterning methods capable of directing the adsorption or reaction of molecules comprising the desired affinity moieties to the selected regions of patterned surfaces; and, the replication methods of related art or of the present invention, e.g. involving microcontact printing) .
  • Multiple distinct molecular ⁇ pecie ⁇ comprising multiple distinct affinity moiety types or clas ⁇ e ⁇ and type ⁇ may be patterned onto the ⁇ ame ⁇ urface by repetitive cycle ⁇ of patterned activation or patterned masking followed by deposition of the respective compound (e.g. by contacting a solution of said respective compound to said patterned activated or patterned ma ⁇ ked ⁇ urface) ⁇ uch that deposition occurs at all available site ⁇ .
  • a fir ⁇ t pattern may be formed, and the region ⁇ thu ⁇ ⁇ pecified cau ⁇ ed to react with a first chemical compound by contacting ⁇ aid surface with ⁇ aid fir ⁇ t chemical compound or ⁇ olution ⁇ thereof, a ⁇ econd pattern may be formed and the regions thus specified cau ⁇ ed to react with a second chemical compound by contacting said surface with said second chemical compound or solution ⁇ thereof, and so on, until patterns of all de ⁇ ired pattern ⁇ of all de ⁇ ired chemical compound ⁇ (comprising the corresponding di ⁇ tinct affinity moietie ⁇ ) are formed.
  • affinity groups on each side of said sheet-like polymer may then be used, by similar steps as those used to produce said sheet-like polymer, as a template for the formation of complementarily patterned ⁇ heet-like polymer ⁇ by expo ⁇ ure to appropriate affinity group terminally functionalized layer forming monomer ⁇ .
  • Repetition of ⁇ uch layer forming ⁇ tep ⁇ thus provides geometric amplification (here for fabrication purpose ⁇ ) of the patterned ⁇ heet-like polymer, in analogy to PCR, provided that the sheet-like polymer produced at each step is freed, as above, from the template surface which directed its formation.
  • Pattern ⁇ thu ⁇ generated may be designed to facilitate orderly binding together of such layers under appropriate conditions (e.g. thermal annealing) into bi-layer or multilayer ⁇ tructure ⁇ , in analogy to the hybridization of DNA molecule ⁇ .
  • Such design will favorably include pattern elements that ensure proper sheet-like alignment with proper registry before bulk or random associations between surface regions of said layers are permitted to occur.
  • one corner of each of two sheet-like structures to be juxtaposed may comprise thiol groups, which thus target the ⁇ e corners to each other before affinity interactions are permitted to occur.
  • a second set of corner ⁇ may compri ⁇ e primary hydroxyl ⁇ , which are then cro ⁇ linked by an appropriate crosslinking agent, such as a bifunctional acid anhydride compound.
  • an appropriate crosslinking agent such as a bifunctional acid anhydride compound.
  • Dissolving such a substrate permits the overlying layer to be situated at a phase boundary, and i ⁇ favorably accomplished by slowly lowering said ⁇ ub ⁇ trate into ⁇ aid ⁇ olution which di ⁇ olve ⁇ it, such that once it is dis ⁇ olved, said overlying layer is situated at ⁇ aid pha ⁇ e boundary. After the preceding ⁇ tep ⁇ , there would be two stacked monolayer ⁇ at thi ⁇ point. Condition ⁇ (e.g. temperature, compo ⁇ ition, etc.,) are adjusted such that a dissoluble solid may again be pas ⁇ ed through said ⁇ olution without di ⁇ solution, to capture said overlying layer previously situated at said phase boundary.
  • Condition ⁇ e.g. temperature, compo ⁇ ition, etc.
  • ⁇ uch a method comprises the steps of: forming an interfacial layer, e.g.
  • a ⁇ ub ⁇ trate used with this embodiment may be of a polymeric composition comprising photolabile linkages.
  • Said polymeric composition comprising photolabile linkages is preferably chosen such that the photodegradation products will be soluble in the ⁇ olution u ⁇ ed to form interfacial film ⁇ or to support thus liberated films, and to not bind with or otherwise interfere with these films.
  • compo ⁇ ition ⁇ are suitable for substrates.
  • sub ⁇ trate ⁇ are of polymeric compo ⁇ ition
  • the ⁇ e are mo ⁇ t preferably ca ⁇ t with a highly flat surface, simple examples of which include glass and freshly cleaved mica.
  • substrate ⁇ are floated or otherwise held at the surface of the solution to support the overlying film supported by said substrate after dissolution of said substrate, and the substrate is exposed to a sufficient intensity of light of a frequency chosen to cau ⁇ e the degradation of said photolabile linkages for a sufficient length of time to effect complete di ⁇ olution of ⁇ aid ⁇ ub ⁇ trate, with further time being allowed a ⁇ nece ⁇ sary for degradation products to diffuse away in thi ⁇ solution from the interfacial layer.
  • a proce ⁇ may alternatively avail a release layer, which may be produced a ⁇ a ⁇ elf-as ⁇ embling monolayer, for example compri ⁇ ing photolabile or thermolabile linkage ⁇ situated on the surface of an insoluble ⁇ ub ⁇ trate.
  • composition of said relea ⁇ e layer is preferably chosen ⁇ o that the di ⁇ rupted layer sub ⁇ equently produced is well wetted by the solution ⁇ u ⁇ ed, and such that the free degradation product ⁇ (tho ⁇ e not bound to the sub ⁇ trate ⁇ urface) are well solvated by the solution ⁇ u ⁇ ed.
  • This embodiment describes first device ⁇ for the parallel po ⁇ itional ⁇ ynthe ⁇ i ⁇ of molecular and ⁇ upramolecular object ⁇ or article ⁇ (termed workpiece ⁇ or workpiece precursors) which may also be devices, method ⁇ for the fabrication of ⁇ aid fir ⁇ t device ⁇ according to the general microfabrication method ⁇ of the pre ⁇ ent invention, and method ⁇ for the use of said fir ⁇ t devices to effect positionally controlled molecular and supramolecular synthe ⁇ i ⁇ .
  • Terminology u ⁇ ed will include terminology from the field of art of ⁇ canning probe micro ⁇ copy.
  • a capacitance based actuator is produced by forming electrodes on a surface which serves as a first plate of a parallel plate capacitor. Two categories of capacitive actuators are possible: unfilled (i.e.
  • capacitors where the coulombic force between capacitor plates ari ⁇ ing from the charge separation due to applied voltage difference is opposed by force ⁇ associated with mechanical flexure of a second capacitor plate partially or completely ⁇ uspended over said first plate ⁇ uch that a cantilever arrangement results; and filled capacitors wherein ⁇ aid fir ⁇ t plate i ⁇ coated with an ela ⁇ tiomeric or other compre ⁇ sible substance, according to the molding or casting methods of the present invention, upon which a second plate of a parallel plate capacitor is formed, where compre ⁇ ion of ⁇ aid ela ⁇ tiomeric or other compressible substance oppose ⁇ the coulombic force ⁇ resulting from charge separation acros ⁇ the gap of ⁇ aid parallel plate capacitor.
  • compo ⁇ ition of the ⁇ ubstance between capacitor plates may further be chosen according to dielectric properties in addition to mechanical propertie ⁇ .
  • the functional characteri ⁇ tic ⁇ of both leg ⁇ of actuator ⁇ will be highly dependent on geometrical factor ⁇ and on material ⁇ properties, providing a large range of realizable device characteri ⁇ tics according to tradeoffs elected in design and fabrication.
  • Each such capacitive actuator may be placed under control of a different voltage signal, under electronic control, favorably with the electronic circuitry effecting thi ⁇ control integrated into the same array device, according to conventional electronic device integration de ⁇ ign practice ⁇ and, for example, the microfabrication method ⁇ of the pre ⁇ ent invention, such that each capacitive actuator may be tran ⁇ lated to a position independently of other capacitive actuators in the same array.
  • the direction normal or perpendicular to the ⁇ urface upon which said array of actuator ⁇ i ⁇ formed shall be denoted as the Z-axi ⁇ , which is also the axis ⁇ ub ⁇ tantially perpendicular to the plane of the plate ⁇ of ⁇ aid parallel plate capacitor actuator ⁇ .
  • the portions of said Z-actuators furthe ⁇ t from the subatrate may further compri ⁇ e or be in communication with a small cantilever, the purpose of which i ⁇ to facilitate the mea ⁇ urement of force ⁇ acting upon any tips associated with said cantilever.
  • Said forces may conveniently be measured by reflecting a laser beam from the bottom surface (i.e. the surface nearer to said substrate, which in this instance is chosen to be transparent) and monitoring and changes in the reflected angle of said la ⁇ er beam (e.g. with a split photodiode arrangement as is commonly used as detection means in AFM ⁇ ), or by other mean ⁇ which have been employed in the design of AFM cantilever deflection monitoring means (e.g. capacitive detection, tunneling detection, piezore ⁇ i ⁇ tivity change detection, etc.,.)
  • the extent (proximity) of said tunneling contact to said conductive layer on said cantilever may be self-aligned by electroplating at said tunneling contact until a desired current is observed between ⁇ aid conductive layer and ⁇ aid tunneling contact, while ⁇ aid cantilever i ⁇ at it ⁇ equilibrium (undeflected) po ⁇ ition, optionally followed by a brief rever ⁇ ed potential to di ⁇ olve a very ⁇ mall portion of the depo ⁇ ited metal from the ⁇ urface of said tunneling contact to establi ⁇ h a predetermined gap ⁇ ize.
  • Detection methods relying on ⁇ uch ⁇ tructure ⁇ may additionally rely on detection of variation in field emitted current between ⁇ aid conductive layer and the conductive ⁇ tructure termed a tunneling contact above in the ca ⁇ e of tunneling current ba ⁇ ed deflection detection.
  • the signals corresponding to the deflections thus detected may, as in conventional AFM sy ⁇ tem ⁇ , be u ⁇ ed to adjust the position of said Z- actuators to restore a desired set point value.
  • other regimes of AFM and SPM will be pos ⁇ ible with the appropriate modification ⁇ or exten ⁇ ions of the present array format.
  • the externally exposed surface of the topmost plate of said parallel plate capacitor, or layers formed upon ⁇ aid externally expo ⁇ ed ⁇ urface may be further patterned ⁇ uch that a confined ⁇ urface region, of predetermined ⁇ ize and ⁇ urface elemental or chemical compo ⁇ ition i ⁇ produced in communication with the moving portion of ⁇ aid capacitor actuator.
  • a ma ⁇ king pattern may be formed on the exposed surface of a gold said topmost plate ⁇ uch that only a ⁇ mall region, for example ⁇ maller than lOOnm by lOOnm ⁇ quare of bare gold remain ⁇ exposed.
  • ⁇ aid square of bare gold may be u ⁇ ed a ⁇ a target for the random ad ⁇ orption of organothiol molecule ⁇ or molecular complexes.
  • adsorption i ⁇ preferably carried out ⁇ uch that depo ⁇ ition of ⁇ aid organothiol molecule ⁇ or molecular complexes occurs at a rate of one per pad or region, i.e. preferably exactly one per actuator, but at least on average one per actuator in the case of random deposition.
  • small objects may be ⁇ ubstituted for said organothiol molecules or molecular complexe ⁇ , in which case the ⁇ aid externally expo ⁇ ed ⁇ urface or coating ⁇ thereupon are cho ⁇ en so as to ⁇ tably bind the corre ⁇ ponding ⁇ aid ⁇ mall objects selected.
  • Said small object ⁇ may be ⁇ elected from among: macromolecules, enzymes and conjugates thereof, biological receptors, immunoglobulins or fragment ⁇ thereof or conjugate ⁇ thereof, colloids, nanocrystallite ⁇ , polymeric bead ⁇ , dendrimers, fullerene derivatives, nanotube derivatives, mesoscopically structured single objects or other small objects of predetermined geometries or geometrical place ⁇ .
  • the ⁇ e molecule ⁇ , molecular complexe ⁇ or other small objects serve as an extremities or projections in communication with actuator pad ⁇ ; the ⁇ e will be generically referred to herein a ⁇ tip ⁇ .
  • tips include any of the above small objects in communication via a flexible molecular linker to a chemical functional group which binds stably to said pads, such that ⁇ aid small object i ⁇ po ⁇ itionally con ⁇ trained according to the flexibility and tethering of ⁇ aid linker, but not precisely po ⁇ itioned.
  • another type of tip may be formed by electron beam depo ⁇ ition of vaporized ⁇ ub ⁇ tance ⁇ onto ⁇ aid pad ⁇ .
  • actuator array ⁇ may homogeneously consi ⁇ t of a ⁇ ingle pad type decorated by a ⁇ ingle type of tip, multiple pad type ⁇ (i.e. multiple pads of each type where each of said types has a different ⁇ urface chemical composition) decorated on a one-to-one composition basis by corresponding multiple small object types, or may comprise different pads decorated, according to foregoing spatially predetermined copolymer ⁇ ynthesis method ⁇ , with di ⁇ tinct oligonucleotides, polypeptides or other copolymers with di ⁇ tinct binding propertie .
  • Array ⁇ of workpiece pad ⁇ are produced by forming small exposed regions of a ⁇ urface of a convenient composition on a substrate surface, such that said workpiece pads may line up with actuator pads and/or tips of the above actuator arrays.
  • Workpiece pad ⁇ may al ⁇ o comprise or overlie actuators, which may for example serve to tilt ⁇ aid workpiece pad ⁇ relative to ⁇ aid tip ⁇ , or may merely compri ⁇ e pad array ⁇ which facilitate the colocalization of tip and workpiece, depending on the de ⁇ ign of the article of fabrication and the tip or tip ⁇ u ⁇ ed.
  • molecular tips within tip array ⁇ (tip flat ⁇ ) ⁇ uch a ⁇ tho ⁇ e de ⁇ cribed by Drexler 53 may be ⁇ elected according to the tilt of ⁇ aid workpiece pad effected by one or more actuator ⁇ which adju ⁇ t the angle of the plane of ⁇ aid workpiece pad relative to the normal defined by the Z-actuator of the tip pad.
  • the tip arrays described by Drexler pertain to conventional atomic force microscopes and cantilevers u ⁇ ed therewith, ⁇ aid cantilever ⁇ modified to further comprise ⁇ aid tip flat ⁇ .
  • the pre ⁇ ent invention provide ⁇ that an array of actuator ⁇ po ⁇ ition ⁇ molecular tip ⁇ or array ⁇ thereof along the Z-axi ⁇ , while one or more actuators associated with each workpiece pad orients said workpiece pad to orient said workpiece pad such that one molecular tip of the opposed array is selected according to the orientation dependent proximity.
  • Such molecular tip array ⁇ may, following Drexler, be ⁇ ituated on a curved ⁇ urface, here each in communication with one of ⁇ aid Z- actuators, where the approach of a particular molecular tip in one of said arrays is selected according to the tilt of the workpiece relative to said one of said arrays which selects a distinct normal to said curved surface, thus selecting said molecular tip situated on said curved surface at the locus of the line normal to both said curved surface and said workpiece pad (i.e.
  • provi ⁇ ion of workpiece pads comprising one or more actuator ⁇ effecting tilted orientation of said workpiece pads relative to the Z-axis translation of said Z-actuators of said tip pad arrays permits the use of array ⁇ of tip arrays in the parallel modification of arrays of workpieces.
  • the particular advantage of being able to ⁇ elect individual tip ⁇ from an array of tip ⁇ in the modification of a workpiece accrues from the ability thereby to selectively interact ⁇ aid workpiece with a different, predetermined chemical functionality or compo ⁇ ition of ⁇ aid individual tip ⁇ , while maintaining a determini ⁇ tic relation ⁇ hip between the spatial location of said tip array with said workpiece (i.e. eliminating the need to locate a workpiece upon changeover of tip ⁇ .)
  • An array of tilt actuator ⁇ permit ⁇ ⁇ uch advantage to be availed in coinbination with the advantage ⁇ of paralleli ⁇ m accruing from the simultaneous positionally controlled modification of workpieces situated upon said workpiece pad array comprising said array of tilt actuator ⁇ .
  • ⁇ aid X-Y positioning means is a piezoelectric tube ⁇ canner
  • additional care mu ⁇ t be taken in calibration and scanning voltage waveform generation to en ⁇ ure that deviation ⁇ from planar orientation of the tube opening do not cause a rocking motion of the array mounted thereupon (i.e.
  • Placement of ⁇ aid molecular precur ⁇ or ⁇ of workpieces or said workpiece ⁇ on ⁇ aid workpiece pad ⁇ of ⁇ aid workpiece pad array by said molecular tip ⁇ or other molecular po ⁇ itioning member ⁇ en ⁇ ure ⁇ correct relative po ⁇ itioning of said workpiece precursors or workpieces relative to said molecular tips or other molecular positioning members and the reactants later carried thereupon.
  • a molecular workpiece precursor comprising a thiol group
  • a molecular workpiece precursor may be deposited onto a workpiece pad comprising an exposed gold surface by a molecular tip, such that the resulting position of as ⁇ ociation of ⁇ aid thiol with said gold surface corresponds to the position on said tip pad or cantilever of said molecular tip.
  • said workpiece precursor may additionally comprise a cleavable linkage susceptible to a particular predetermined physical or chemical treatment, and a first reactive group, for example a hydroxyl.
  • a ⁇ econd molecular workpiece precursor molecule for example of identical composition, may be depo ⁇ ited by the ⁇ ame proce ⁇ at a second location on said workpiece pad.
  • two predetermined reactive groups are placed in a predetermined arrangement on ⁇ aid workpiece pad.
  • a third molecular precur ⁇ or molecule may ⁇ imilarly be positioned at a third point, in which ca ⁇ e the three positioned reactive groups thu ⁇ fix a coordinate system admitting no gros ⁇ rotations (i.e.
  • molecular component ⁇ may be reacted with the reactive groups of said workpiece precursor ⁇ according to the method ⁇ de ⁇ cribed below.
  • neces ⁇ ity of ⁇ uch ⁇ teps in practice will depend on the ⁇ ize of such surface ⁇ and the ability to obtain or fabricate ideally flat sub ⁇ trate ⁇ urface ⁇ as materials for the production of tip pad arrays and workpiece pad arrays.
  • Constraint-Based Simplification of Positional Synthesis A more immediately practical approach to the positional synthesi ⁇ propo ⁇ ed by Drexler fabricate ⁇ structure ⁇ from structure ⁇ larger than single atoms, and avails conventional solution and solid-phase chemistry where positional control is not essential. These methods permit the synthetic fabrication of extended, complex heterogeneous structure ⁇ which would be difficult or impo ⁇ sible to produce by known art chemical methods.
  • the size of molecular components or reactant ⁇ and the linker ⁇ which hold the ⁇ e in communication with said molecular tips or molecular positioning means are chosen to be of a sufficiently great size that angstrom positioning accuracy is not ⁇ trictly required to exert po ⁇ itional control over ⁇ ynthe ⁇ i ⁇ .
  • ⁇ aid linkers which may for example be composed of a polymethylene (polyethylene) polymer chain or other preferably straight chain flexible polymer chain, which are attached via ⁇ ome cleavable linkage to said molecular components or reactant ⁇ , con ⁇ train ⁇ ⁇ aid molecular component ⁇ or reaction ⁇ to a volume defined by the linear length of ⁇ aid linker ⁇ (and the ⁇ ize of ⁇ aid molecular component ⁇ or reactant ⁇ ) with a probability di ⁇ tribution (or effective concentration a ⁇ a function of position within said volume) which may be predicted u ⁇ ing Flory theory.
  • Said volume to which ⁇ aid molecular components or reactant may be termed a con ⁇ traint volume.
  • control over translation of said constraint volumes i ⁇ u ⁇ ed to ⁇ elect which reactive sites of said workpieces are reacted.
  • the re ⁇ olution of ⁇ uch a method is limited by the extent of said constraint volume, and workpiece ⁇ are preferably de ⁇ igned according to ⁇ aid re ⁇ olution (otherwi ⁇ e re ⁇ ultant workpieces will obey the corresponding probability distribution related to the number of pos ⁇ ible ⁇ ite ⁇ within an approached con ⁇ traint volume and the effective concentration di ⁇ tribution at each of said pos ⁇ ible sites.)
  • such a linker may alternatively have a large central portion of their length composed of a rigid polymeric member (with terminal flexible polymeric linkages), in which case the attached molecular components or reactants are confined rather to a shell, which may be termed a constraint shell.
  • the configuration of said constraint shell is determined by the structure of the partially rigid said linker, i.e. defining a volume beyond which the terminally situated said molecular components or reactant ⁇ may not extend and also a closest point of approach to the point on said tip pad at which said partially rigid said linker is attached beyond which said molecular components or reactants may not approach.
  • Thi ⁇ may be accompli ⁇ hed by monitoring any forces exerted by said communication as said tip pad array i ⁇ withdrawn from ⁇ aid workpiece pad array or, alternatively, a ⁇ ⁇ aid Z-actuator ⁇ of ⁇ aid tip pad ⁇ are tran ⁇ lated away from ⁇ aid workpiece ⁇ .
  • Said force ⁇ may be monitored conveniently if each of ⁇ aid molecular tip (or said linker) is in communication with a cantilever, the position of which i ⁇ tracked by any known art method ⁇ uch as optical beam deflection, monitoring of a tunneling current between said cantilever (coated by a metal) and a tunneling tip, change ⁇ in piezore ⁇ i ⁇ tivity, changes is capacitance where an electrode situated on said cantilever forms one plate of a capacitor, etc.,.
  • a linker is preferably of elastiomeric compo ⁇ ition such that tension i ⁇ gradually applied to ⁇ aid workpiece a ⁇ deflection of ⁇ aid cantilever occur ⁇ during ⁇ aid withdrawal.
  • tension i ⁇ gradually applied to ⁇ aid workpiece a ⁇ deflection of ⁇ aid cantilever occur ⁇ during ⁇ aid withdrawal.
  • gross severing of linkage ⁇ which would be expected with applied ten ⁇ ion ⁇ of less than 10 nN for single bonded linkages, are avoided. Otherwise care must be taken to ensure that applied tensions remain under a tolerable maximum to prevent such severing.
  • the tip once a reaction between said molecular component and said workpiece has occurred, the tip remain ⁇ in communication with ⁇ aid workpiece, until chemical or phy ⁇ ical treatment severs the resulting linkage.
  • Linkages i.e.
  • linkage composition is chosen according to the de ⁇ ired method ⁇ of linker cleavage.
  • linker ⁇ may compri ⁇ e bond ⁇ ⁇ u ⁇ ceptible to cleavage by particular chemical reagents, may be heat labile or may be photocleavable, e.g. comprising esters to compounds such as nitroveratryloxycarbonyl compounds, such that said ester linkages are cleaved by exposure to appropriate wavelength actinic radiation.
  • reactant molecular components are situated on ⁇ aid molecular tip ⁇ or tip pads by contacting said tip pad array with a solution comprising the said reactant molecular components to be added to said workpieces during the subsequent reaction step and permitted to bind to the available ⁇ ites on said tip pad array, i.e. to molecular tips or to the affinity groups thereupon.
  • a molecular component will generally be bound to a workpiece at more than one location, i.e. will generally have greater than one point of connectivity with ⁇ aid workpiece.
  • a positionally controlled reaction links ⁇ uch a reactant molecular component to a fir ⁇ t reactive ⁇ ite on a workpiece, and the ⁇ tructure of said reactant molecular component and said workpiece are such that the reactive groups on ⁇ aid reactant molecular component and ⁇ aid workpiece will react together for only one relative topological orientation of ⁇ aid reactant molecular component and ⁇ aid workpiece.
  • rigid ⁇ tructure i.e.
  • those comprising rigid polymeric ⁇ tructure ⁇ ) ⁇ imple de ⁇ ign rules may yield such a result, namely, that the pairwise distances of all similar reactive group ⁇ are different and that once a fir ⁇ t bond i ⁇ formed, under po ⁇ itional constraint imposed by linkage to said tip, no incorrect second bonds to reactive group ⁇ on ⁇ aid workpiece may form after release of said reactant molecular component from said tip.
  • no rotation of said reactant molecular component about the first bond formed under positional con ⁇ traint by ⁇ aid tip will yield proximity of reactive group ⁇ situated on said reactant molecular component to correspondingly reactive groups of said workpiece except that rotation which permits the de ⁇ ired reaction and hence the desired connectivity.
  • flexible components may al ⁇ o be employed according to ⁇ uch constraint-ba ⁇ ed de ⁇ ign method ⁇ , but here flexibility entail ⁇ that the positional constraints on reactions of these components obtaining after a first bond or linkage is formed between such flexible component ⁇ and a workpiece will concern the maximum possible reach of other reactive groups on ⁇ aid flexible component ⁇ .
  • the selection of rigid or flexible components for different parts of a workpiece structure will be according to considerations concerning both the de ⁇ ired structure and the preferred molecular as ⁇ emble strategy.
  • component ⁇ et ⁇ may be synthesized comprising different topologie ⁇ ⁇ uch as different degrees of branching, different length ⁇ of branch arms, different chemical functionalization of regions or location of said branch arms, etc.,.
  • workpiece ⁇ may be treated with other reactant ⁇ or chemical modifying reagent ⁇ from bulk ⁇ olution.
  • reactive group ⁇ on molecular components may all be primary hydroxyl group ⁇ .
  • each such cross-linking agent molecule will react with each hydroxyl on said workpiece, while the second such functional group ⁇ of each such cros ⁇ -linking agent molecule, now a reactive group on said workpiece, will only react with approaching hydroxyls of new molecular components.
  • thi ⁇ entails that no two hydroxyls available on a workpiece may be clo ⁇ er together than the length ⁇ panned by the reactive functionalitie ⁇ of ⁇ uch cross-linking groups.
  • molecular components may carry protected functional groups, which, once ⁇ aid molecular component ⁇ are reacted onto said workpieces and relea ⁇ ed from said tips, are deprotected by contacting ⁇ aid workpiece pad array, a ⁇ in the ca ⁇ e of activation with cross-linking agents, in this case with deprotection reagents.
  • function groups which were held inert with respect to each other to prevent unwanted reactions between molecular component ⁇ a ⁇ the ⁇ e are prepared and bound to said tip ⁇ , are activated once on ⁇ aid workpiece.
  • inert ⁇ olvent media mu ⁇ t be chosen.
  • control over the step ⁇ at which functional group ⁇ on ⁇ aid workpiece ⁇ are activated or deprotected provides another method of control over synthesis, i.e. a method by which a sub ⁇ et of functional group ⁇ are held inert until a de ⁇ ired a ⁇ embly step, whereupon they are deprotected or activated by treatment with appropriate reagents.
  • a method by which a sub ⁇ et of functional group ⁇ are held inert until a de ⁇ ired a ⁇ embly step, whereupon they are deprotected or activated by treatment with appropriate reagents It will be obviou ⁇ to those ⁇ killed in organic ⁇ ynthe ⁇ i ⁇ that other reactive chemi ⁇ trie ⁇ , as will a ⁇ multiple, concurrently u ⁇ ed chemi ⁇ trie ⁇ will be po ⁇ ible and often preferably advantageou ⁇ over the ⁇ imple example pre ⁇ ented here merely for purpo ⁇ e ⁇ of illustration.
  • molecular tips and any affinity group ⁇ thereupon may thu ⁇ be ⁇ pared from expo ⁇ ure to highly reactive group ⁇ (e.g. oligonucleotide moietie ⁇ of molecular tip ⁇ need never be expo ⁇ ed to acid chloride containing compounds, which would inactivate said oligonucleotides for proper binding) .
  • reactive groups may be primary hydroxyls on alkyl chain linkers
  • rigid structural members may compri ⁇ e polyparaphenylene derivative ⁇ 57 or the phenylacetylene polymer ⁇ di ⁇ clo ⁇ ed by J. Zhang, J.S. Moore et al. 58 , in either ca ⁇ e comprising component ⁇ with ⁇ tructures synthetically acces ⁇ ible, for example, by the methods of J. Zhang, J.S. Moore et al.,.
  • Affinity members for reversibly binding these components to molecular tips may comprise oligonucleotide ⁇ , oligopeptide ⁇ , peptide nucleic acid oligomer ⁇ or ⁇ mall molecule hapten ⁇ joined to ⁇ aid component ⁇ (e.g. via methylene linker ⁇ ), according to the complementary affinity members on ⁇ aid molecular tip ⁇ .
  • Other molecular component structures of interest in the construction of molecular devices by such as ⁇ embly method ⁇ include rotaxane ⁇ comprising macrocycles which themselves comprise reactive group ⁇ , and catenane ⁇ .
  • Molecular component ⁇ ba ⁇ ed on the ⁇ e topological compounds provide structure ⁇ u ⁇ eful a ⁇ moving part ⁇ in object ⁇ and device ⁇ fabricated by the ⁇ e synthesis method ⁇ .
  • Affinity groups such as oligonucleotides may be included within the structure ⁇ of ⁇ aid molecular component ⁇ or may be po ⁇ itioned by tip ⁇ into proximity with proximity ⁇ elected reactive group ⁇ on said workpieces which will react with linkers (e.g. at terminal hydroxyls) attached to said affinity group ⁇ .
  • linkers e.g. at terminal hydroxyls
  • Said affinity groups used to bind reactant molecular component ⁇ to said molecular tips or molecular positioning means may be in communication with the remainder of the structure of the reactant molecular component which they serve to target to said molecular tip ⁇ or molecular po ⁇ itioning mean ⁇ via linker ⁇ cleavable by predetermined phy ⁇ ical and/or chemical treatment ⁇ (e.g.
  • hydroly ⁇ is of an ester linkage
  • chemical functional groups may be primary amine ⁇ , which may be protected by esterification.
  • a molecular tip may comprise or may be linked (e.g. by known art conjugate chemistry) to a protease enzyme molecule, such as Proteinase K. Only tho ⁇ e primary amine ⁇ within the reach of such enzyme molecules tethered to a molecular tip or tip pad are su ⁇ ceptible to enzymatic deprotection, and hence only the ⁇ ub ⁇ et of such amines on said workpieces will be deprotected.
  • Other catalysts such a ⁇ ribozymes, metal tip surface ⁇ , or metallic colloid ⁇ partially embedded in polymer matrices may similarly be used, as may tethered molecule ⁇ which effect deprotection by non-catalytic reaction ⁇ .
  • the large data capacitie ⁇ realizable with the variou ⁇ data storage methods comprising the use of scanning probe technology based data readout are not accompanied by a commensurate increase in the rate of data recording except where large numbers of scanned probes are used to record a data pattern onto a storage medium surface. Because one particular advantage of such storage technologies is in application ⁇ related to data publishing, a rapid method for the duplication of predefined bit patters readable with such readout technologies would be de ⁇ irable, a ⁇ ha ⁇ been the ca ⁇ e with read-only optical data ⁇ torage technologie ⁇ .
  • the method ⁇ of the pre ⁇ ent invention are well ⁇ uited to the fabrication of ⁇ urface ⁇ with in ⁇ cribed nano ⁇ cale data pattern ⁇ readable with variou ⁇ scanning probe readout mean ⁇ .
  • the ⁇ e include near-field photon transfer (corresponding to NFSOM), electron tunneling and electron field emis ⁇ ion (corre ⁇ ponding to STM and field emis ⁇ ion mode STM) , and surface profile detection (corresponding to AFM and variation ⁇ thereon) .
  • a transparent surface such as glas ⁇ or polycarbonate i ⁇ coated with a metal film, which i ⁇ patterned by the foregoing method ⁇ of the pre ⁇ ent invention for the ⁇ patially predetermined protection or ma ⁇ king of metallic film ⁇ urface ⁇ from etchant ⁇ such that the desired bit pattern is formed compri ⁇ ing apertures in said metallic film and intact regions in ⁇ aid metallic film which reduce or eliminate the local tran ⁇ mi ⁇ ion of light.
  • Such a bit pattern may be read out by conventional NFSOM apparatu ⁇ or variations thereupon, or the near-field detection means described below.
  • the patterned said metal layer may mask the local transmi ⁇ ion of photon ⁇ to a probe aperture which conduct ⁇ received photon ⁇ to a detector, ⁇ aid photon ⁇ originating from a source on the oppo ⁇ ite ⁇ ide of the tran ⁇ parent material comprising said transparent surface, in which case said metal layer serves as a photon tran ⁇ mi ⁇ ion ma ⁇ k.
  • ⁇ aid pattern in said metal layer may ma ⁇ k the tran ⁇ mi ⁇ sion of photons emitted due to the fluore ⁇ cence of compound ⁇ in said transparent material excited by photons either emanating from an NFSOM tip aperture which may be the same aperture used for the detection of fluorescentiy emitted photons or emanating from a source on the other side of ⁇ aid tran ⁇ parent ⁇ urface.
  • a metallization pattern may similarly be formed, here on an insulator, or alternatively a relief pattern may be formed in one or more metal layer ⁇ with all expo ⁇ ed ⁇ urface ⁇ having conductive propertie ⁇ .
  • a bit pattern which may be replicated by the methods of the pre ⁇ ent invention i ⁇ encoded in ⁇ uch a ⁇ urface relief pattern.
  • Such a bit pattern may be read out with instruments such as STMs, microfabricated STM ⁇ or the array device ⁇ di ⁇ clo ⁇ ed herein comprising plural Z-actuators each a ⁇ ociated with a tip, which entire array i ⁇ ⁇ canned acro ⁇ a juxtaposed surface by an X-Y po ⁇ itioning mean ⁇ and wherein data pattern ⁇ are detected by monitoring, with electronic mean ⁇ , voltage, current or height of each tip either ⁇ ingly or in the various po ⁇ ible combination ⁇ and where ⁇ aid current may be either a tunneling current or a field emi ⁇ ion current according to particular implementation .
  • relief surfaces comprising surface patterns are replicated by casting, injection molding or embos ⁇ ing method ⁇ .
  • an original relief comprising the desired bit patterns may be formed by scanning probe technology based patterning methods such as those of related art reviewed above.
  • a CCD array fabricated by methods of the present invention or by conventional methods may be modified to serve as a highly parallel detection means for optical data readout relying on near-field photon transmission through a small aperture.
  • An array of waveguide elements for example compo ⁇ ed of PMMA, i ⁇ molded onto the ⁇ urface of said CCD array such that each photodiode of said CCD array will capture photons conducted by each of ⁇ aid waveguide element ⁇ .
  • the array comprising said waveguide elements must therefore be aligned with the photodiode array of ⁇ aid CCD.
  • Gap ⁇ between ⁇ aid waveguide ⁇ are filled in with, for example, an opaque polymeric material, or may be electroplated provided thi ⁇ will not cau ⁇ e short circuits in said CCD, which may be designed to prevent such problems.
  • Said waveguide element array and any material filling said gaps are formed such that a substantially flat surface result ⁇ .
  • an array of pinhole ⁇ of predetermined size and location is fabricated with as ⁇ ociated waveguide ⁇ , which conduct any photon ⁇ received at the aperture formed by ⁇ aid pinhole ⁇ to the photodiode ⁇ of ⁇ aid CCD in a one-to-one manner.
  • Such an array of pinholes with associated waveguides may al ⁇ o be fabricated by LIGA method ⁇ and variation ⁇ thereupon, and then ⁇ ituated in an appropriately aligned manner onto a CCD array ⁇ urface.
  • the ⁇ ame type of structure comprising an array of pinhole ⁇ with associated waveguides may be fabricated by other molding and electroforming method ⁇ de ⁇ cribed herein and then, ⁇ imilarly, ⁇ ituated in an aligned manner onto a CCD array.
  • Such an array may be termed an aperture limited CCD array (ALCCD) .
  • the CCD array device ⁇ u ⁇ ed in thi ⁇ a ⁇ pect of the present invention are preferably of high sensitivity, ⁇ uch that a reduced number of photon ⁇ must be received by each photodiode to register a signal.
  • Such an ALCCD may be used for data readout by juxtaposing the ⁇ urface of said ALCCD comprising ⁇ aid pinhole array to a patterned metal film surface of a transparent material such glas ⁇ , such a ⁇ that described above which pattern may be replicated as described above.
  • Said pattern metal film surface is held parallel to the ⁇ urface of ⁇ aid ALCCD compri ⁇ ing ⁇ aid pinhole array, at a di ⁇ tance of le ⁇ than one half the wavelength of the light employed and preferably at a distance of le ⁇ than one-quarter of thi ⁇ wavelength. Smaller ⁇ eparation ⁇ are further preferred.
  • the region of ⁇ aid patterned metal film oppo ⁇ ite each pinhole on the ⁇ urface of said ALCCD is either be coated with ⁇ aid metal film or may expose the underlying said transparent material, which distinction provides for the detection of the corresponding data pattern.
  • the den ⁇ ity achievable with thi ⁇ data readout apparatu ⁇ and method is primarily determined by the dimension ⁇ of ⁇ aid pinhole, which limit ⁇ the photons thus received to tho ⁇ e originating from narrow expo ⁇ ed regions.
  • Said patterned metal film surface is ⁇ canned, in a manner maintaining parallel alignment with the pinhole array surface of ⁇ aid ALCCD, ⁇ uch that an area corre ⁇ ponding to the ⁇ ize of each CCD array element pa ⁇ e ⁇ opposite each pinhole, by repeatable positioning mean ⁇ ⁇ uch a ⁇ piezoelectric or capacitor actuator ⁇ .
  • said patterned metal film ⁇ urface i ⁇ ⁇ canned in the X and Y while maintaining a ⁇ ub ⁇ tantially con ⁇ tant Z ⁇ eparation, such that the ⁇ ignal received by each photodiode of each CCD element correlate ⁇ , according to ⁇ can timing, with a particular po ⁇ ition on ⁇ aid patterned metal film surface.
  • Scanning is conducted slowly, such that said CCD captures the bit image corresponding to a particular position of said patterned metal film surface, which is then read out from said CCD according to conventional methods associated with the use of such electronic imaging or memory devices.
  • data rates will primarily depend on the device characteristics of the CCD used.
  • the X-Y location of said patterned metal film surface relative to said ALCCD are then translated by incremental ⁇ canning motion of said actuator, and the bit pattern as ⁇ ociated with this sub ⁇ equent po ⁇ ition i ⁇ then ⁇ imilarly collected.
  • photons originate from a source on the opposite side of said patterned metal film than said ALCCD, with transmis ⁇ ion occurring through exposed regions of said transparent surface as it is masked by said patterned metal film.
  • the number of photons received by each CCD element are limited by the relative size of said pinhole to the area of each CCD element.
  • ⁇ aid patterned metal film surface is situated between said microlen ⁇ array and ⁇ aid ALCCD, and remain ⁇ in a fixed po ⁇ ition relative to ⁇ aid ALCCD a ⁇ ⁇ aid patterned metal film ⁇ urface i ⁇ ⁇ canned between ⁇ aid microlen ⁇ array and ⁇ aid ALCCD surface.
  • a relief is formed by replication methods at the ⁇ urface of an elastiomer polymer composition, comprising a pattern of parallel lines comprising narrow raised regions generally of le ⁇ than 200nm in width and wider ⁇ unken regions preferably of greater than 1 micron in width.
  • the aspect ratio of said narrow raised regions may be reduced by sloping the surface of said wider sunken regions in proximity to ⁇ aid narrow rai ⁇ ed region ⁇ .
  • Said polymer compo ⁇ ition is chosen such that the re ⁇ ulting molecular network compri ⁇ e ⁇ chemical functional groups which may be reacted with cross-linking reagents to attach molecule ⁇ to the ⁇ urface of ⁇ aid relief.
  • An appropriate cro ⁇ -linking agent compri ⁇ ing a central linker of predetermined length, preferably shorter than 50nm is coupled to a nuclease enzyme (such as DNase I or a type II re ⁇ triction endonuclease, preferably recognizing a 4 base restriction site) according to known art conjugate chemistry.
  • Said cross-linking agent is chosen so as to link said nuclease to ⁇ aid elastiomer polymer compri ⁇ ing ⁇ aid chemical functional groups.
  • a small volume of a solution of ⁇ aid cro ⁇ s-linking agent conjugated to said nuclease is spread on a surface as a thin layer in the pattern of a single stripe, preferably of les ⁇ than a few millimeters in width.
  • Said relief is contacted with said stripe of said conjugate on said surface, oriented with said parallel lines perpendicular to said stripe, such that nuclease molecules are linked to the ⁇ urfaces of said narrow raised regions along the region juxtaposed with ⁇ aid ⁇ tripe.
  • the solution used to form said strip may favorably contain a dye or pigment to facilitate identification of the enzyme modified region, or other marking methods may be used to accomplish ⁇ uch identification.
  • a relief comprising parallel lines and trenches of predefined size and location is produced with a predefined region of rai ⁇ ed feature ⁇ upon which nuclea ⁇ e molecules are ⁇ ituated.
  • Linear or linearized DNA molecule ⁇ or chromatin are treated ⁇ o a ⁇ to be immobilized at ⁇ pecific region ⁇ along their length, preferably near to one distinct terminus, and optionally derivatized with bead ⁇ at the opposite terminus.
  • these may be hybridized with an oligonucleotide compri ⁇ ing a fir ⁇ t affinity moiety ⁇ uch a ⁇ biotin moiety and one or more p ⁇ oralen group ⁇ (where plural group ⁇ are preferred to favor the formation of covalent linkage ⁇ with both ⁇ trand ⁇ of the DNA double helix) .
  • ⁇ aid p ⁇ oralen group ⁇ are cau ⁇ ed to react with ⁇ aid DNA to form a covalent linkage ⁇ .
  • Streptavidin is bound to a glass surface in a narrow stripe ( ⁇ 1 micron in width) ⁇ horter in length than the width of ⁇ aid ⁇ trip of ⁇ aid conjugate above.
  • Said DNA terminally linked to said biotin is then contacted with said narrow stripe of streptavidin and affinity binding i ⁇ permitted to occur.
  • the immobilized DNA sample is optionally then briefly subjected to degradation by a 5' to 3' exonuclease, followed by treatment with a polymerase and second affinity group modified nucleotide triphosphate ⁇ to terminally decorate ⁇ aid linearized DNA molecule ⁇ with said second affinity group.
  • said immobilized DNA sample is.then contacted with a ⁇ olution comprising microscopic or sub-micron diameter beads, which may be fluore ⁇ cently labeled, ⁇ urface modified with receptor ⁇ (e.g. immunoglobulins, etc.) according to known art conjugate chemistry. Alignment of the immobilized DNA molecules is then performed by known art technique ⁇ .
  • Straightening of terminally immobilized molecule ⁇ may alternatively be accompli ⁇ hed, where said molecules underwent the optional addition of terminal beads as above, by methods such as those of T.T. Perkins et al. 62 whereby bead ⁇ ⁇ ituated on DNA molecule ⁇ are manipulated u ⁇ ing an optical trap (also known as la ⁇ er tweezer ⁇ ) , or, where ⁇ aid beads are of paramagnetic compo ⁇ ition, by the application of an appropriately directed magnetic field of sufficient strength to straighten, but not so large as to disrupt, the sample molecular and supramolecular ⁇ tructure.
  • an optical trap also known as la ⁇ er tweezer ⁇
  • ⁇ ample molecule ⁇ are end-immobilized to a preci ⁇ e, predetermined region, oriented and extended by mean ⁇ ⁇ uch as those above, the relief prepared above with rai ⁇ ed narrow line ⁇ modified with nuclea ⁇ e molecules i ⁇ then contacted with ⁇ aid gla ⁇ s surface on which said sample molecules have been straightened and aligned, in an orientation such that the parallel lines of said relief are perpendicular to ⁇ aid sample molecules, where said contacting i ⁇ performed under ⁇ light pre ⁇ ure to en ⁇ ure ⁇ ealing of the channel ⁇ thu ⁇ temporarily formed.
  • a gentle fluid flow is immediately established in said channel ⁇ , such that once a molecular region is freed at both ends by cleavage by said nuclease molecule ⁇ , it is carried down said channel away from said nuclease molecules, which might otherwise further degrade it.
  • Said flow then carrie ⁇ the cleaved molecule fragment ⁇ to collection volumes formed in said relief structure ⁇ at the ends of ⁇ aid channels, which are arranged such that the location of the channel in which a fragment was cleaved may be determined or inferred from the location of said collection volume.
  • the collection volumes forms a linearly ordered set, which set comprise ⁇ an ordered arrangement of fragment ⁇ of a well defined physical length and precise ordering with respect to their original location in the in-tact sample molecules.
  • Such a method may be repeated, as desired, with a slightly different offset of said relief with respect to said narrow stripe of streptavidin, such that different regions are occluded from the collected sample ⁇ et, to the extent that retention under ⁇ aid narrow rai ⁇ ed line ⁇ po ⁇ e ⁇ any difficultie ⁇ . Note that in all ⁇ teps, care is taken to avoid shearing sample molecules.
  • Nonethele ⁇ , thi ⁇ ⁇ imple proce ⁇ yield ⁇ ordered fragment populations u ⁇ eful for e ⁇ tabli ⁇ hing phy ⁇ ical map ⁇ of genetic material and producing ordered ⁇ ample ⁇ therefrom for purpo ⁇ e ⁇ such as library cloning or subcloning or other analysi ⁇ techniques, and particularly useful in genome sequencing projects.
  • Two alternative genetic material di ⁇ ection method ⁇ availing ..-lcropatterned relief ⁇ are al ⁇ o po ⁇ ible.
  • a relief compri ⁇ ing parallel rai ⁇ ed narrow line ⁇ and trenche ⁇ such as that described above, is formed.
  • This relief is then contacted with a first surface on which are coated particles ⁇ uch a ⁇ metallic or glass colloids or hard microcrystallite ⁇ , which are coated with chemical ⁇ pecies capable of cros ⁇ linking ⁇ aid particle ⁇ to ⁇ aid relief. Thu ⁇ , said particles are bound to the rai ⁇ ed narrow region ⁇ of said relief.
  • Genetic material is immobilized on a second ⁇ urface and aligned a ⁇ above, and the relief of the pre ⁇ ent alternative i ⁇ oriented a ⁇ above with said parallel lines perpendicular to the direction of alignment of said genetic material on said second surface and contacted with said second surface under an applied normal force. Liquid is caused to flow through the channel ⁇ formed by said trenches and said second surface as a result of the preceding contacting ⁇ tep. The relief i ⁇ then translated in the direction of said parallel lines as said normal force i ⁇ maintained and said liquid flow is maintained.
  • the genetic material i ⁇ abraded and therefore cut by said particles, and once cut, fragments are freed from communication with said second surface and said relief, such that said fragment ⁇ are carried by ⁇ aid liquid flow down said channels to collection volumes.
  • the cutting action availed in the present alternative of this embodiment is in direct analogy to the cutting of DNA molecules by an atomic force microscope tip.
  • Said second surface may be hard, such a ⁇ gla ⁇ , may be ela ⁇ tiomeric; ⁇ aid second surface may comprise bonded particles similar or identical to those used on said raised regions of said relief, in which case the cutting action may be compared to a ⁇ ci ⁇ oring action.
  • a relief compo ⁇ ed of opaque material ⁇ compri ⁇ ing parallel lines of narrow raised regions and trenche ⁇ i ⁇ u ⁇ ed, a ⁇ above, to define flow channel ⁇ when contacted under normal force with a ⁇ econd ⁇ urface, here of a ⁇ heet-like or flat material.
  • said second surface i ⁇ tran ⁇ parent to radiation of the appropriate frequency range but i ⁇ coated (preferably on said second surface, or instead on the surface not contacted with said relief) with material ⁇ which mask ⁇ aid radiation.
  • ⁇ aid flat material may be quartz coated with metallic mask materials and said radiation may be X-radiation, or said flat material may be glas ⁇ coated with any material opaque to vi ⁇ ible or ultraviolet light, which i ⁇ u ⁇ ed for irradiation.
  • X-irradiation genetic material expo ⁇ ed will be cleave directly due to double stranded breaks.
  • the masking pattern used is de ⁇ igned such that when said relief is contacted to ⁇ aid ⁇ econd ⁇ urface, the line ⁇ of narrow rai ⁇ ed region ⁇ are juxtapo ⁇ ed directly to unma ⁇ ked region ⁇ of said second surface.
  • said irradiation cause ⁇ break ⁇ of ⁇ aid genetic material at the loci of said narrow raised region ⁇ , which are in contact with ⁇ aid second surface, ⁇ uch that the fragment ⁇ thu ⁇ produced will be freed within the channel ⁇ formed by said second ⁇ urface and said trenches and carried away, by a fluid flow applied in said channels, to a collection volume corre ⁇ ponding to the re ⁇ pective channel.
  • Articles produced by the methods of the present invention may be used to facilitate the analysis of polynucleotide librarie ⁇ such as plasmid libraries, bacteriophage librarie ⁇ , co ⁇ mid librarie ⁇ , yea ⁇ t autonomou ⁇ chromosome (YAC) based libraries and the like.
  • polynucleotide librarie ⁇ such as plasmid libraries, bacteriophage librarie ⁇ , co ⁇ mid librarie ⁇ , yea ⁇ t autonomou ⁇ chromosome (YAC) based libraries and the like.
  • YAC yea ⁇ t autonomou ⁇ chromosome
  • transcripts are transcribed with radiolabeled ribonucleotides, and the RNA thus obtained is used to probe said arrays or replicas; those array elements or colonies or plaque ⁇ which hybridize the radiolabeled RNA tran ⁇ cript ⁇ thu ⁇ share common sequence ⁇ with the fragments from which said transcripts were obtained.
  • these methods determine which clonal isolates contain common sequence ⁇ , and by repetition identify ⁇ erie ⁇ of clonal i ⁇ olate ⁇ which are of contiguou ⁇ origin. Because such librarie ⁇ may contain well over 10 4 di ⁇ tinct chimera, ⁇ uch information is rarely if ever exhaustively determined for any given library, and i ⁇ u ⁇ ually only applied to small fraction ⁇ of such librarie ⁇ .
  • Copolymer array ⁇ such as those disclosed in related art or produced by the methods of the present invention may gainfully be applied to the ta ⁇ k of determining the linkage relation ⁇ hip between the individual chimera of a library and al ⁇ o to chromosomal mapping thereby.
  • each replicon must be rendered uniquely distinguishable, for example by the incorporation of a sufficiently long random nucleotide sequence (e.g.
  • variable base pair ⁇ (which need not all be contiguou ⁇ ] in a replicon de ⁇ igned for u ⁇ e in preparing librarie ⁇ of which ⁇ 10 ⁇ clones will be used.)
  • tag sequence Such a sequence will be referred to as a tag sequence, but it will be understood by those skilled in the relevant arts that different tagging and discrimination methods (e.g. the use of epitope library fused terminal-protein replicated viral or bacteriophage [e.g. PRD1, phi29, adenovirus], probed with peptide or antibody arrays) are po ⁇ sible, although nucleotide sequence based tagging with oligo array discrimination i ⁇ favorably convenient, and will therefore be empha ⁇ ized here.
  • the tag sequence is favorably placed ⁇ uch that it is transcribed under the influence of a promoter in the replicon sequence and the appropriate purified RNA polymera ⁇ e.
  • each cla ⁇ ifying oligo with a ⁇ ample molecule may be regarded as a positive result from a clas ⁇ ification test; each fragment is te ⁇ ted by the full ⁇ et of cla ⁇ ifying oligo ⁇ (i.e. all line ⁇ ), ⁇ uch that for n such lines such an array will be capable of discriminating up to 2 n different classification results.
  • Clas ⁇ ifying ⁇ equence ⁇ are therefore optimally cho ⁇ en to have about a 50% chance of probing any given ⁇ ample fragment or tran ⁇ cript, however large number ⁇ of cla ⁇ ifying ⁇ equence ⁇ (line ⁇ ) may obviate thi ⁇ effort.
  • Corre ⁇ pondence between tag identity and the regions of said lines of said cla ⁇ sifying oligos is enforced at the appropriate step with a relief (preferably of elastiomeric composition) of parallel raised lines and trenche ⁇ , of ⁇ ufficient spacing to accommodate both the tag probing oligo array element ⁇ and the length of the polynucleotide fragment ⁇ , juxtapo ⁇ ed to the detection oligo array compri ⁇ ing ⁇ aid one dimensional array compri ⁇ ing all sequences complementary to all pos ⁇ ible tag ⁇ equence ⁇ and ⁇ aid line ⁇ of ⁇ aid cla ⁇ sifying oligos, oriented such that said parallel raised line ⁇ and trenche ⁇ are perpendicular to ⁇ aid line ⁇ of said clas ⁇ ifying oligo ⁇ .
  • a relief preferably of elastiomeric composition
  • a library of said chimera, in mixture form, is either transcribed or fragmented, such that for each chimera, a first fragment type comprising a tag ⁇ equence and a ⁇ ufficient length of ⁇ ample fragment derived ⁇ equence i ⁇ obtained.
  • Such fragment ⁇ are either produced in labeled form (affinity, fluore ⁇ cent, radioactive or other label) or otherwi ⁇ e labeled before application to said array.
  • Said lines of said clas ⁇ ifying oligo ⁇ are covered to prevent contact with ⁇ aid first fragment type as a ⁇ olution containing ⁇ aid first fragment type i ⁇ contacted with a region of ⁇ aid array compri ⁇ ing ⁇ aid one dimensional array compri ⁇ ing all ⁇ equence ⁇ complementary to all po ⁇ ible tag ⁇ equences, to which the molecule ⁇ of ⁇ aid first fragment type are permitted to hybridize under sufficiently ⁇ tringent conditions to en ⁇ ure high ⁇ pecificity and accuracy of tag identification. Unbound ⁇ ample molecule ⁇ are washed away. Said relief is then juxtaposed to said array in said perpendicular orientation.
  • the hybrids formed comprising said sequences complementary to all possible tag sequences are then denatured and a flow of buffer solution is applied along the channels formed by the trenches of said relief and the surface of the substrate of said two dimensional array, and conditions permitting ⁇ tringent hybridization are then quickly re-e ⁇ tablished.
  • the molecules of said first fragment type which have been confined to particular channels according to the tag sequence which they comprise are swept by said flow acros ⁇ said lines of said cla ⁇ ifying oligos and which they thus have the opportunity to hybridize with if and only if they comprise sequence ⁇ complementary to the sequence ⁇ of any of said clas ⁇ ifying oligo ⁇ . Unbound molecules are then washed away.
  • Hybridization of sample molecules to ⁇ aid array is then detected by means which correspond to the labeling method used, and the corresponding data favorably recorded by digital computer.
  • Combination of data derived from en ⁇ emble ⁇ of ⁇ uch overlap information permit the reconstruction of maps of larger contiguou ⁇ region ⁇ ( ⁇ uch a ⁇ chromosomal material) from which sample fragments derive, and simultaneously yield information about which chimeras (as identified by tag sequences) are derived from particular regions of said maps.
  • Molecules of said first fragment type preferably consi ⁇ t of material from one extremity of the ⁇ ample fragment incorporated into the re ⁇ pective chimera.
  • Thi ⁇ minimize ⁇ the degree of overlap between two chimera ⁇ classified as contiguou ⁇ and thu ⁇ minimize ⁇ the number of chimera ⁇ nece ⁇ sary to represent the original linear ⁇ ample, reducing the work nece ⁇ ary for analy ⁇ i ⁇ . Note, however, that more redundant information may be obtained by permitting a greater degree of overlap, for example, by producing and then analyzing longer molecule ⁇ of ⁇ aid first fragment type.
  • two extreme case ⁇ are po ⁇ ible: said first fragment type comprising most all of a chimera; and said fir ⁇ t fragment type con ⁇ isting of a minimal length of ⁇ equence to permit useful clas ⁇ ification.
  • tradeoff ⁇ exi ⁇ t between these extremes, and intermediate cases are probably preferable according to the specific library and sample.
  • each of ⁇ aid molecule ⁇ of said fir ⁇ t fragment type mu ⁇ t compri ⁇ e ⁇ aid tag ⁇ equence and ⁇ equence from ⁇ aid original sample from which ⁇ aid library wa ⁇ derived.
  • ⁇ aid molecules of said fir ⁇ t fragment type are limited to one terminu ⁇ of the ⁇ ample fragment ⁇ equence (i.e. one ⁇ ample fragment sequence region adjacent to one arm of the replicon vector used to construct the library)
  • the method of preparation of said first fragment type must ensure that the tag sequence associated with one terminus may be correlated with the tag ⁇ equence a ⁇ sociated with the other terminus. At lea ⁇ t two instances conforming to this requirement are pos ⁇ ible.
  • ⁇ aid molecule ⁇ of ⁇ aid fir ⁇ t fragment type may be prepared by re ⁇ tricting aliquot ⁇ of the library of said chimera differently.
  • a the vector from which ⁇ aid library wa ⁇ prepared comprises a first unique restriction enzyme ⁇ ite, which may be cho ⁇ en according to infrequent occurrence in the ⁇ ubject genome or original ⁇ ample, on one ⁇ ide of a tag ⁇ equence, and a ⁇ econd unique re ⁇ triction enzyme site, which may be chosen according to infrequent occurrence in the subject genome or original sample, on the other side of a tag sequence.
  • fragments may be shortened by any convenient method ⁇ uch a ⁇ ⁇ hearing, random nuclea ⁇ e treatment, etc., to re ⁇ trict the length of polynucleotide fragment ⁇ captured by tag probe oligo ⁇ and ⁇ ubsequently analyzed to convenient length ⁇ .
  • each aliquot i ⁇ analyzed ⁇ eparately according to thi ⁇ aspect of the present invention, and result ⁇ are u ⁇ ed to correlate similarly cla ⁇ ed fragment ⁇ equence ⁇ found in said first aliquot with tho ⁇ e found in ⁇ aid ⁇ econd aliquot.
  • each molecule of ⁇ aid vector from which ⁇ aid library wa ⁇ prepared compri ⁇ e ⁇ two different, unique tag ⁇ equence ⁇ each located near a terminu ⁇ of said molecule, i.e. near the locus to which a ⁇ ample fragment i ⁇ ligated.
  • each tag sequence corre ⁇ pond ⁇ to a terminus of a sample fragment in the library constructed with said vector.
  • Molecules of said first fragment type having exactly one of said two different, unique tag sequences are produced by known art methods which will be related in consideration to the design of said vector (e.g. restriction digestion, transcription from an artificial promoter, etc., according to corresponding vector feature ⁇ in relation to said two different, unique tags and the in ⁇ erted ⁇ aid sample fragment.) Said molecules of said first fragment type having exactly one of said two different, unique tag sequences are analyzed according to the above library analysi ⁇ method ⁇ , probing in each ca ⁇ e with the member ⁇ of only one tag probe ⁇ et. Becau ⁇ e each terminus is as ⁇ ociated with a different tag in each clone, the tag from one terminu ⁇ mu ⁇ t be correlated with the tag of the other terminu ⁇ .
  • Thi ⁇ ⁇ econd correlation ⁇ tep is accomplished by the ⁇ ame method, binding chimera or fragment ⁇ compri ⁇ ing the vector termini with a one dimen ⁇ ional tag probing oligo array complementary to the first tag ⁇ et, where line ⁇ of different cla ⁇ ifying oligo ⁇ in the array are replaced with line ⁇ of different tag probing oligo ⁇ , corre ⁇ ponding to tho ⁇ e which bind tag ⁇ equence ⁇ of the second tag set.

Abstract

On décrit des procédés de formation et de reproduction de motifs, lesquels s'adressent notamment à une microfabrication et à une nanofabrication économiques, conçues à la fois pour une petite production et pour une production de masse. On forme des motifs sur une surface mère à l'aide de diverses techniques, motifs que l'on reproduit ensuite sur des surfaces filles. On décrit également des procédés de réduction ou d'élimination de défauts. On peut mettre diverses compositions sous forme de motifs, afin de couvrir une large gamme d'applications. A l'aide des procédés de l'invention, on peut effectuer une régulation spatiale sur la synthèse des copolymères, sur la synthèse de couches monomoléculaires ou de multicouches, sur la fabrication de dispositifs microélectroniques, microélectromécaniques et microfluides. On décrit encore plusieurs articles de fabrication et leurs usages, de même que des procédés améliorés et des moyens d'analyse de génomes.
PCT/IB1996/000912 1995-07-28 1996-07-26 Formation, reproduction, fabrication d'un motif et dispositifs ainsi obtenus WO1997006468A2 (fr)

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WO1998036827A1 (fr) * 1997-02-19 1998-08-27 Clondiag Chip Technologies Gmbh Procede de production de monocouches moleculaires structurees auto-organisees d'especes moleculaires individuelles, en particulier de bibliotheques de substances
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WO2000032809A2 (fr) * 1998-11-27 2000-06-08 Noxxon Pharma Ag Clonage et copie sur des surfaces
WO2000032809A3 (fr) * 1998-11-27 2000-10-19 Noxxon Pharma Ag Clonage et copie sur des surfaces
US6534271B2 (en) 1998-11-27 2003-03-18 Noxxon Pharma Ag Cloning and copying on surfaces
WO2000044939A1 (fr) * 1999-01-29 2000-08-03 Surmodics, Inc. Reseau de sondes replicables
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WO2001020402A1 (fr) * 1999-09-14 2001-03-22 Massachusetts Institute Of Technology Fabrication de dispositif a motifs fins par etampage par liquides
US6517995B1 (en) 1999-09-14 2003-02-11 Massachusetts Institute Of Technology Fabrication of finely featured devices by liquid embossing
US7470540B2 (en) 2000-10-17 2008-12-30 Febit Ag Method and device for the integrated synthesis and analysis of analytes on a support
US6936181B2 (en) 2001-10-11 2005-08-30 Kovio, Inc. Methods for patterning using liquid embossing
US6848462B2 (en) 2001-12-06 2005-02-01 Nanostream, Inc. Adhesiveless microfluidic device fabrication
WO2003064026A1 (fr) 2002-01-31 2003-08-07 Nimblegen Systems Llc Substrat predessine, dispositif et procede pour la synthese optique de sondes d'adn
JP2006501807A (ja) * 2002-01-31 2006-01-19 ニンブルゲン システムズ リミテッド ライアビリティ カンパニー Ｄｎａプローブの光学的合成のためのあらかじめパターン形成された基板、装置、及び方法
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US7153421B2 (en) 2002-02-13 2006-12-26 Nanostream, Inc. Frit material and bonding method for microfluidic separation devices
WO2003068401A1 (fr) * 2002-02-13 2003-08-21 Nanostream, Inc. Materiau fritte pour dispositifs de separation microfluidique multicouche
US6957608B1 (en) 2002-08-02 2005-10-25 Kovio, Inc. Contact print methods
WO2005038525A1 (fr) * 2003-09-26 2005-04-28 Infineon Technologies Ag Dispositif tampon pour lithographie douce et procede de fabrication associe
DE102004008241A1 (de) * 2004-02-19 2005-11-24 Universität Bremen Enzymgestützte Nanolithografie
DE102004008241B4 (de) * 2004-02-19 2006-09-07 Universität Bremen Enzymgestützte Nanolithografie
WO2006061600A1 (fr) * 2004-12-07 2006-06-15 University Of Southampton Particules destinees a servir de supports solides, et leur procede de preparation
EP1731961A1 (fr) 2005-06-10 2006-12-13 Obducat AB Méthode pour la reproduction d'un modèle
US7854873B2 (en) 2005-06-10 2010-12-21 Obducat Ab Imprint stamp comprising cyclic olefin copolymer
US8426025B2 (en) 2008-12-19 2013-04-23 Obducat Ab Process and method for modifying polymer film surface interaction
US9063408B2 (en) 2008-12-19 2015-06-23 Obducat Ab Methods and processes for modifying polymer material surface interactions
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