EP2315822A1 - Création d'ensembles adressables multidimensionnels haute densité - Google Patents

Création d'ensembles adressables multidimensionnels haute densité

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Publication number
EP2315822A1
EP2315822A1 EP09805582A EP09805582A EP2315822A1 EP 2315822 A1 EP2315822 A1 EP 2315822A1 EP 09805582 A EP09805582 A EP 09805582A EP 09805582 A EP09805582 A EP 09805582A EP 2315822 A1 EP2315822 A1 EP 2315822A1
Authority
EP
European Patent Office
Prior art keywords
polynucleobase
complementary
producing
pattern
assemblies
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09805582A
Other languages
German (de)
English (en)
Other versions
EP2315822A4 (fr
Inventor
Vincent Suzara
Paul Bentley
Troy Lapsys
Viswanath Krishnamoorthy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Incitor Inc
Original Assignee
Incitor Inc
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Filing date
Publication date
Application filed by Incitor Inc filed Critical Incitor Inc
Publication of EP2315822A1 publication Critical patent/EP2315822A1/fr
Publication of EP2315822A4 publication Critical patent/EP2315822A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C40B50/18—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support using a particular method of attachment to the solid support
    • 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
    • B01J2219/00427—Means for dispensing and evacuation of reagents using masks
    • 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
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00527—Sheets
    • B01J2219/00529—DNA chips
    • 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
    • B01J2219/00608—DNA chips
    • 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
    • B01J2219/00621—Delimitation of the attachment areas by physical means, e.g. trenches, raised areas
    • 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
    • B01J2219/00659—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
    • 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
    • B01J2219/00729—Peptide nucleic acids [PNA]

Definitions

  • This invention relates to methods and apparatuses for molecular scale assembly of structures, including the creation of high density, geometrically patterned, two and three dimensional addressable assemblies of nucleobase containing polymers, and the construction of shapes compatible therewith.
  • SSDC Single Strand Dimensional Construction-based catalysts
  • ssDNA single strand DNA
  • PNA peptide nucleic acid
  • RNA ribonulceic acid
  • Such addresses localize complementary polynucleobase probes via Watson-Crick hybridization for the purpose of locating in three dimensional (3D) space the physico- chemical groups that facilitate: (i) enzyme-like and transbiotic catalysis, (ii) 2D and 3D construction of useful nanoscale components and devices, (iii) supramolecular assembly, (iv) other assemblies dependent on hybridization-based localization and assembly, and (v) the combinatorial discovery and development of any and all such devices.
  • SSDC can be dependent on technologies which - when conceived, applied, and executed in this manner - can produce high density, 3D addressable arrays of polynucleobases at large scales and reproducibly accurate to the nanometer.
  • Such related technologies can include: (1) photo-electron-beam lithography, (2) soft lithography, in which 3D patterns are replicated via phase changes from the liquid or colloid to the solid, (3) polynucleobase probes having physico-chemical groups attached via linkers, (4) complementary and "mirror-image" polynucleobase pattern replication, and, for the purposes of this document, (5) self and/or directed assemblies of polynucleobases that initially and ultimately define the parameters of the 3D high density addresses at each stage of fabrication.
  • SSDC can begin with the construction of a Template, components of which include a 3D foundation of positively and/or negatively structured solid material and polynucleobases lithographed therein that conform to the contours of the foundation.
  • This construction can serve as the basis for the fabrication of multiple numbers of production Platforms which can be created by mirror-image pattern replication of the foundational shape and polynucleobase sequence of the Template, utilizing materials that facilitate scaled quantities of replication.
  • the manner of Template fabrication might or might not be based on polynucleobase pattern replication from an earlier stage Master, in so much as a goal of Template creation is the backbone-based lithography of sequence addresses complementary to both a previous Master and subsequent Platforms.
  • Fig. 1 is a 2D representation of polynucleobase sequence- and geometrical shape-based pattern replication.
  • Master foundation (pastel) is contoured with depressions coated with material (cardinal) that supports the lithography and/or assembly of polynucleobase strands.
  • Left Side A permanent Template (yellow-on-blue; polynucleobases mounted in red) is constructed by hybridization of complementary bases and replication of the lithographed Master pattern.
  • Right Side Platforms are produced in an analogous manner to that of Templates from Masters, in that polynucleobase sequence & pattern geometry, and 3D contours and shapes are reproduced in a "miror-image" format. Templates are hybridized with Addresses desired on Platforms and the latter are fabricated via impression molding, thin filming (as shown, an overlay of purple, ash, green, hatched layers), and other techniques.
  • SSDC based Platform catalysts can be dependent on the precise localization in 3D space of physico- chemical groups that facilitate catalysis within an enclosure which is typically the production Platform. Such groups are typically on the termini of linkers that are attached to the backbone of polynucleobase probes that hybridize to complementary polynucleobase Addresses within the Platform. The geometrical pattern of the Addresses (as a function of their successful reproduction from Templates based on the manner of production described) determines the 3D orientation and spatial location of catalytic groups.
  • Fig. 1 is a 2D representation of polynucleobase sequence- and geometrical shape-based pattern replication.
  • Fig. 2 is a schematic of assembly: square hatch pattern and dashed addresses.
  • Fig. 3 is a schematic of assembly: hexagonal pattern and indented addresses.
  • Fig. 4 is a schematic of finished template: dashed addresses from square hatch pattern.
  • Fig. 5 is a schematic of design: square hatch pattern and dashed addresses.
  • Fig. 6 illustrates a Level 1 photomask.
  • Fig. 7 illustrates a Level 2 photomask.
  • Fig. 8 illustrates a coated substrate after exposure with the Level 1 photomask.
  • Fig. 10 illustrates the same substrate after removal of the remaining photosensitive material.
  • Fig. 11 illustrates the same substrate after processing using the Level 2 photomask.
  • Fig. 12 illustrates the same substrate after application of another coating, for example deposition of a coating comprising 5nm Ti and 15nm Au.
  • Fig. 13 illustrates the same substrate after removal of the photosensitive material.
  • Fig. 14 illustrates a plan view of the substrate after the above processing.
  • Fig. 15 illustrates a 3d view of the substrate after the above processing.
  • Fig. 16 is an example of SSDC strategy for heterogeneous catalysis, two dimensional.
  • Fig. 17 depicts a geometric approximation of the catalytic site of a simple catabolic enzyme.
  • Fig. 18 depicts conversion of the geometric approximation into a universal cleft for catalysis.
  • Fig. 19 depicts a design of a stamp for soft lithography of the universal cleft foundation.
  • Fig. 20 depicts stamp (template array) fabrication and preparation for soft lithography.
  • Fig. 21 depicts platform fabrication via soft lithography.
  • Fig. 22 depicts DNA weaving-based self-assembly of 2D addressable array.
  • Fig. 23 depicts DNA geometry based directed-assembly of 3D addressable array.
  • Fig. 24 depicts stacking conformation of catalytic functions from a hybridized polynucleobase library.
  • Fig. 25 depicts exemplary methodologies for mounting of polynucleobases to foundational materials.
  • Fig. 26 depicts boundary layer flow as a function of assembly fabrication schemes.
  • Fig. 27 depicts devices designed to enhance boundary layer flow at the assembly level.
  • Assemblies" - can be fabricated with a high degree of uniformity, reproduciblity and usability for the lithography of Masters and Templates:
  • the invention is compatible with various current technologies adequately described as: (i) atomic force or dip pen nanolithography (DPN), (ii) receding mensicus or other phase differential-based extension, elongation or stretching of polynucleobases, (iii) the use of electric, magnetic, optical, intertial and other fields and energies for the accomplishment of iii, whether such fields are acting on the polynucleobase strands or on a solid object - typically a bead anchored to the terminus of the strand, and which has optical or magnetic susceptibility, (iv) the extension of polynucleobase strands within or atop lithographed patterns that facilitate a desired conformation, or (v) any combination or variation on the above non-dependent technologies.
  • Fig. 2 is a schematic of assembly: square hatch pattern and dashed addresses. On the left is depicted diametrically opposed polynucleobases (grey and blue; colors refer to orientation, not sequence) with regular complementarity to neighboring strands. Regions of close overlap represent sites of hybridization. On the right is depicted locations of oligobases complementary to hybridization-free sites (green for gray polynucleobases; red for blue). All complementary oligobases are in the same orientation.
  • Fig. 3 is a schematic of assembly: hexagonal pattern and indented addresses. On the left is depicted diametrically opposed polynucleobases with different neighboring strand complementarity to those in Fig. 2.
  • the design of probes that hybridize to only one address - e.g., for polymerase chain reaction (PCR) or other primer based techniques such as site directed mutagenesis, site- specific targeting, microarrays, etc. - requires a sequence of approximately 21-27 bases in oligobase length. If a 25-mer address is adequate, then hybridization resulting in the above exemplary assemblies will reveal geometrically precise groupings of 25 base pair long unhybridized sites that are approximately 12.5 nm in length and separated by a similar or lesser distance based on the sequence design and intended address pattern.
  • PCR polymerase chain reaction
  • other primer based techniques such as site directed mutagenesis, site- specific targeting, microarrays, etc.
  • a Template suitable for scaled production of Platforms via polynucleobase sequence and pattern, and 3D shape replication is created.
  • the Template will be an array of many (e.g., billions) identical convex extensions each having the generalized shape of a cylinder resected along its long axis, with dimensions approximately 150 nm long, 30 nm wide and 15 nm tall.
  • each unit shape will be covered with a "webbing" of Addressable Assemblies in a manner that: (1) maximizes the usable surface area of the template unit, i.e., address sites along most of the surface area of the half cylinder, (2) lithographs the assemblies onto the template unit - via surface functionalization, polynucleobase backbone modification and solvation management, and (3) preserves the ability to undertake complementary pattern replication, i.e., with the assemblies lithographed "backbone side down" and "bases pointing upwards.”
  • the material can be Si(IOO), vapor deposited with 10 nm titanium and 5 nm gold - which will represent the majority of the height aspect.
  • the template array should be lithographed with the 150x30x15 nm cylinder shape every 50 nm on both axes to maximize productivity.
  • a 100 cm 2 template array should then represent approximately a micromole of productive capacity per batch of Platform stamping.
  • Fig. 4 is a schematic of finished template: dashed addresses from square hatch pattern.
  • polynucleobases complementary to the phosphorothioate backbone ssDNAs lithographed on the Template are transferred to soft-cast polymer and and imprinted by impression, brief casting to form a negative shape, heating to delink the Platform Addresses from the Template DNA, removal of the Template array and hard casting of the Platform.
  • Fig. 5 is a schematic of design: square hatch pattern and dashed addresses.
  • an exemplary, simplified Assembly (truncated) placed atop a Template unit - convex half cylinder.
  • the pre-made Assembly a combination of hybridized and unhybridized regions , is designed to conform in 3D to the fabricated shape of the template unit. Edges of the assembly (not shown) are sealed with oligomers to prevent loss of shape integrity and add resilience to the structure.
  • the 5' termini of one central strand (dark blue), and 3' termini of its compliment are biotinylated in order to attach a 10 nm Streptavidin bead (mustard).
  • a top view of a finished Platform with lithographed Address sites (red and green).
  • the previous location of a lithographed or deposited biotin anchor point is placed for reference relative to the contour of the platform unit.
  • the location of each 25-mer addressable site is complementary to the unhybridized sites on the Assembly about the Template.
  • FIG. 6 through Fig. 15 illustrate one method to generate shapes at the nanometer & micron scales that can be activated with ssDNA lines or dsDNA weaves to make various molecular structures.
  • the process shown demonstrates gold as the binding substrate, but other substrates such as polymers or other materials are also possible. This example is not intended to be limited by structure shape nor materials, but is used solely as an example. Those skilled in the art will appreciate variations of the illustrated process.
  • Fig. 6 illustrates a Level 1 photomask.
  • the photomask can comprise, as an example, lines of approximately 120nm width, separated by approximately 300nm. Such lines can extend to cover one dimension of the mask, and the line/separation pattern repeated to cover another dimension of the mask.
  • Fig. 7 illustrates a Level 2 photomask.
  • the photomask can comprise, as an example, a grid of elements approximately 140nm wide by 200nm long, with 280nm separation along the dimension of width and 200nm separation along the dimension of length. The pattern can be repeated to fill the mask.
  • the Level 2 photomask can be designed such that the elements in the Level 2 photomask are substantially aligned with the lines in the Level 1 photomask.
  • Fig. 8 illustrates a coated substrate after exposure with the Level 1 photomask.
  • a substrate for example a silicon substrate, can be coated with a photosensitive material, and then the coated substrate exposed to light through the Level 1 photomask. After removal of the exposed areas, the substrate is left with a coating substantially corresponding to the Level 1 photomask.
  • Fig. 9 illustrates the same substrate after etching, such as by isotropic etching. The regions masked by the Level 1 photomask are protected by the photosensitive material; the other regions have been etched below the original surface of the substrate.
  • Fig. 10 illustrates the same substrate after removal of the remaining photosensitive material.
  • the substrate has regions substantially corresponding to the lines on the Level 1 photomask that are substantially the same as the original substrate surface.
  • the substrate also has regions substantially corresponding to the separation spaces in the Level 1 photomask that have been etched below the original substrate surface.
  • Fig. 11 illustrates the same substrate after processing using the Level 2 photomask.
  • the substrate can be coated with a photosensitive material, and then the coated substrate exposed to light through the Level 2 photomask. After removal of the exposed areas, the substrate is left with a coating substantially corresponding to the Level 2 photomask.
  • Fig. 12 illustrates the same substrate after application of another coating, for example deposition of a coating comprising 5nm Ti and 15nm Au.
  • the coating adheres to the exposed surfaces, which correspond to the remaining photosensitive material, the regions etched below the original substrate surface, and the portions of the original substrate surface left exposed by the Level 2 photomask.
  • Fig. 13 illustrates the same substrate after removal of the photosensitive material.
  • the regions that were covered by the photosensitive material have no metal coating, while those that were not so covered have a metal coating.
  • Fig. 14 illustrates a plan view, and Fig. 15 a 3d view, of the substrate after the above processing.
  • the substrate is free of metal coating except for those regions left coated after the processing discussed in connection with Fig. 12 and Fig. 13.
  • the metalized regions accordingly form a grid of controllable sized elements (in this example, consistently sized elements), with controllable separations between the elements (in this example, consistently sized separations).
  • Photomasks such as those described can be realized using techniques known in the art. For example, this technique is commonly used in fabrication of semiconductor devices. Photosensitive materials are known in the art, for example photoresists are routinely used for patterning in semiconductor device fabrication. Substrate processing using photomasks and photosensitive materials, and coating processes, are commonly used in semiconductor device fabrication. Other processing techniques such as e-beam patterning, focused ion beam lithography, x-ray lithography and molecular imprinting can also be used instead of photolithography to generate the desired shapes.
  • the present invention also comprises methods for the fabrication of Three Dimensional Assemblies of Nucleobase Containing Polymers (referred-to as 3D Addressable Assemblies or 3DAA), and their incorporation into Solid or Colloidal phase foundations for the purpose of constructing catalysts and other useful nanoscale products.
  • 3DAA Three Dimensional Assemblies of Nucleobase Containing Polymers
  • Particular emphasis is placed on simplification of the design, fabrication and manufacture of 3DAAs in so much that the number of steps in the construction of heterogeneous catalysts based on Single Strand Dimensional Construction (SSDC), as described in some of the applications referenced above, is both greatly decreased and technically simplified.
  • SSDC Single Strand Dimensional Construction
  • a particular improvement emphasized herein is a defined method of stabilizing the geometry and structure of 3DAA, wherein the contribution of solid or stably-cast phases that serve as a foundation or structural scaffold is significantly contributive to the geometric integrity and catalytic activity of the resultant product.
  • ssDNA single stranded DNA
  • PNA peptide nucleic acid
  • 3D three dimensional
  • concave depressions or clefts in a solid phase are manufactured at scale where the number of locations receptive for 3DAA is congruent to that of the structures intended for mounting.
  • Example manufacturing techniques include industry standard soft lithography processes, industry standard semiconductor etching procedures, and other techniques, from a hard cast stamp on which a negative shape of the cleft, typically convex, is used as a template.
  • the self-assembled ssDNA and PNA are allowed to encounter, develop location-specific interactions with, conform to, and form stable electrostatic or covalent bonds with the array of depressions on the previously soft-cast polymer that now serves as a foundation.
  • the intention, design, fabrication and lithography of 3DAA can be dependent on the application of several technologies.
  • the present inventions allow the number and degrees of dependences to be lessened - though still include: hard (beam) and soft (polymer) lithography, bulk solution conditions, physical (electromagnetic, inertial and liquid-gas interfacial) and tribological (IES: solid-liquid interfacial, electrostatic and solvation) management.
  • Other technologies such as computer-based programs and algorithms that aid in the design and optimization of Addressable Assemblies, and the benefit from atomic force, scanning or transmission electron microscopy (AFM, SEM and TEM) for quality determination remain implicit as described previously.
  • the present inventions allow the application of hybridization-based self-assembly of ssDNA-PNA oligomers that produce geometrically-precise patterns, three dimensionally-stable in physiological conditions and that address backbone-functionalized PNA segments orthogonal to the Assembly perimeter and generally in a radial direction inwards toward a foci or center.
  • Such 3DAA can be predictably and accurately designed with the help of current-in-the-art computer software, with additional discoveries described herein being: (i) improved accuracy of physico-chemical function orientation in three dimensions, (ii) the incorporation of copolymerized PNA in a non-helical ("ladder") conformation, oriented as described above, and (iii) the incorporation of IES factors that encourage 3DAA structure placement into a destination cleft or depression. [0042]
  • the manufacture of SSDC Catalysts can be achieved in a cost-effective, rapid and accurate fashion by concurrent and iterative application of the following methodologies. These technologies are discussed in a generally temporal, though not necessarily completion-dependent, order.
  • Figure 16 is an example of SSDC strategy for heterogeneous catalysis, two dimensional. Orthogonal chemical functions necessary for mimetization of the alpha-Chymotrypsin enzyme. SER (above left) and HIS (bottom left) are attached via sterol-based linkers to the amide backbone of a PNA segment address. Residues free of catalytic groups also have sterol linkers - resulting in a stacked conformation via Van der Walls interactions, improving the directional alignment of catalytic groups.
  • a typically concave shape is then defined as a foundation for localizing a high density addressable polynucleobase array that will successfully localize and orient the catalytic functions.
  • the encosure approximates the size and shape of the DNA Assembly congruent with surface modification, functionalization, linker molecules and other factors which facilitate anchoring, positioning and mounting of the 3DAA within the cleft of the enclosure.
  • Fig. 17 depicts a geometric approximation of the catalytic site of a simple catabolic enzyme.
  • Half cylinder depression of approximate dimensions of the binding, transitional, stabilizing and release site of A. cellulolyticus Endoglucanse 1.
  • Radial design is meant to incorporate lithography of ssDNA and PNA and directional orientation of catalytic groups generally towards a central axis, mimicking active site positioning.
  • an actual SSDC cleft can be designed such that the end product Platform geometry is optimized to act as a catalyst with minimal complexity of addressing physico-chemical functional groups.
  • a geometrically repetitive pattern can be utilized for both: (i) 3DAA design and fabrication, which disambiguates computer modeling of dynamic catalysis via application of predictable address location, and (ii) increased structural tenacity of the 3DAA, which conserves address location and orientation, and encourages mounting of the assembly to the solid or colloidal phase foundation.
  • sub-assemblies of polynucleobases that are designed for folding, stiffening and other 2D and 3D conformational determination of the Assembly can be synthesized and integrated via covalent or non- covalent linkages.
  • Such sub-assemblies can include terminal and intervening units which bend, fold, brace and otherwise conform the normally flat Addressable Assembly into a geometry that is congruent to the intended Catalyst Model and Fabricated Enclosure.
  • Fig. 18 depicts conversion of the geometric approximation into a universal cleft for catalysis.
  • Linker- and PNA-based physico-chemical functions determine an approximately cylindrical cleft.
  • Sloped ends enhance mass transport of soluble substrates (e.g., small peptides and polysaccharides) into, and end products out-of, the cleft site.
  • Hemispherical end walls (sloped) and a centrally-located, removable integral hemispherical brace (normal to plane, not shown) are in blue.
  • Honeycomb pattern (yellow) not to scale.
  • the foundation for a hard-cast and metallized shape, convex and negative to that of the catalytic cleft, can be fabricated by (as examples) focused ion beam (FIB), photo-/electron-beam lithography, hard cast lithography processes or laser ablation.
  • FIB focused ion beam
  • photo-/electron-beam lithography photo-/electron-beam lithography
  • hard cast lithography processes or laser ablation.
  • This can be used as a template, mold or stamp for the repetitive generation of concave shapes onto receptive soft-cast polymer or other substance that, upon final hard casting, will form the foundation or enclosure.
  • the template can be grooved, textured or otherwise surface-modified in order to enhance IES factors, e.g., lubricity or tribology, which optimize soft lithography-based generation of enclosures. Efficient and cost-effective manufacturing of enclosures necessitates rapid and uniform production in a manner that generates the intended shape over scaled iterations without damage or loss of shape integrity of the mold or product.
  • Fig. 19 depicts a design of a stamp for soft lithography of the universal cleft foundation. On the left is depicted negative and reverse orientation image of the catalytic cleft described in Fig. 18.
  • the starting material is generally a silicon derivative (e.g., Si(IOO)) and an array of "angled end quonset hut" shapes approximately 150 nm apart on both (x, y) axes is fabricated by FIB, photolithography or more advanced methods. Lines indicate contours and may indicate lubricant "grooves" for enhancement of tribological management and ease of iterative generation of product.
  • stamping metal e.g., titanium
  • desired lubrication options e.g., titanium
  • a supportive metal backing that will produce a galvanic effect e.g., aluminum
  • an electro-conductive adhesive e.g., graphite carbon- doped polyacrylate
  • Fig. 20 depicts stamp (template array) fabrication and preparation for soft lithography.
  • stamp template array
  • On the left is depicted an extended negative shape of catalytic cleft defined for lithography on silicon (fuscia).
  • Layer of conductive adhesive (olive) is applied to the bottom of the template.
  • On the right is depicted an [Al] plate (light blue) is mounted to the template via the adhesive, and the assembly subjected to PVD of [Ti] approx. 10 nm on the stamping surface.
  • a "metallization lip" residual material from PVD is expected and defined the limit of impression molding and pressure application (defined further in Fig. 21).
  • a thin layer of low volatility, high surface tension solvent can be applied to the soft cast polymer or template and a shape formed by stamping.
  • the solvent can act as a (1) lubricant, to manage the dynamic tribology of metal-to-polymer interaction, and as an (2) incompressible thin film layer, that: (i) accepts and transmits the force of stamping, (ii) insulates the polymer from direct contact with the template, and (iii) equilibrates the induced force over the entire template surface that submerges into polymer.
  • Fig. 21 depicts platform fabrication via soft lithography. On the left is depicted components of the template and platform as previously described. I. L, impression limit; A.D., application distance. In the middle is depicted geometry of compression limits of lubrication layer and dynamic polymer at point of maximal compression (template removed for ease of viewing, though presence is implied). A hydrostatic-thermal compression limit is shown (cherry). On the right is depicted contractive changes in polymer geometry due to post-casting relaxation (curve within green) beyond a compression limit defined by the template. [0057] Hybridization-based Assembly of Addressable Polynucleobase Structures.
  • polynucleobase sites for the addressing of probes contributive to catalysis can be fabricated in a geometrical fashion.
  • Current-in-the-art methods such as DNA Weaving, Origami and self-assembled Scaffolds can be used to construct the 3DAA; knowledge of one skilled in the art combined with the above-referenced applications describe those technologies.
  • a novel and preferential evolution of this technology is the design and fabrication of typically rectangular "sheets" of hybridized polynucleobases that incorporate PNA and other modified sections integral to the structure of the assembled DNA. Sequences of individual oligonucleotide strands are designed such that PNA and other portions are addressed at desired - and preferentially regularly repeating - parts of the resultant assembly.
  • Fig. 22 depicts DNA weaving-based self-assembly of 2D addressable array.
  • exemplary 3DAA constructed from hybridization of oligonucleotides to generate a regular hexagonal array: 100 address blocks each are woven into a 2D rectangular sheet.
  • exemplary pattern of geometrically repetitive PNA sites woven into address blocks via hybridization (off colors).
  • an address showing an exemplary PNA sequence in ladder (non-helical conformation) with the orthogonal functions of SER and HIS addressed via sterol-based linkers radially towards a 3D axial center (see Fig. 16).
  • Exemplary strategies for conforming the 2D sheet into a shape amenable to both (1) radial addressing of orthogonal physico-chemical functions, and (2) mounting on enclosures include: (i) identical or similar geometric patterns that form terminal end or intervening middle segment "walls/' (ii) one or polynucleobase "braces" integral to the addressable structure, and (iii) site-specific "stiffening" of portions of the 3DAA via, e.g., psoralen-mediated creation of cyclobutane-pyrimidine dimers between specific adenosyl and thymidine bases.
  • Fig. 23 depicts DNA geometry based directed-assembly of 3D addressable array.
  • Fig. 24 depicts stacking conformation of catalytic functions from a hybridized polynucleobase library.
  • exemplary ladder non-helical
  • Sterol/alkaloid/polycyclic-based linker elements bridge SER (hydroxyl) and HIS (indolic/imidazolic) functions at certain residues and contribute to directional integrity via hydrophobic interactions that limit range of motion of functions.
  • SER hydroxyl
  • HIS indolic/imidazolic
  • USPTO 61/086,633 specifies the ability of 3DAA which are biotin-functionalized on an extremity, optionally via a linker, to be anchored directly to lithographed streptavidin (SA), e.g., atop fabricated enclosures, or indirectly, via lithographed biotin and SA beads in the 10 nanometer scale.
  • SA lithographed streptavidin
  • This methodology can be reasonably extended to other recepto ⁇ ligand systems, including Digoxigenin and its antibody (anti- DIG), other antibody-based systems, as well as less specific electrostatic systems such as poly-L-Lysine and anionic ligands.
  • Metastable epoxide groups on polymeric material can be condensed (surface terminally cured) to alkyl diamines. Remaining free amine termini are attached to a bi-functional crosslinker (e.g., SSMCC, as described in 60/918,144) comprising a succinimide group - for covalent binding to amines, and a maleimide group - for covalent binding to sulfhydryls. The latter can be covalently bonded to phosphorothioate moieties of dsDNA.
  • SSMCC succinimide group
  • maleimide group - for covalent binding to sulfhydryls.
  • the latter can be covalently bonded to phosphorothioate moieties of dsDNA.
  • [0070] Indirect mounting of Phosphorothioate-Modified DNA Assemblies to Gold.
  • Pure (> 99.99997%) gold surfaces can be functionalized with bifunctional alkanes (e.g., MUAM, as described in 60/918,144) comprising a sulfhydryl group - for covalent binding to gold, maleimide groups, or other free reduced thiol groups, and an amine group.
  • the free amine can be covalently bonded to SSMCC, presenting a free maleimide group.
  • Covalent binding of the latter to, e.g., phosphorothioate moieties of dsDNA can accomplish mounting.
  • Fig. 25 depicts exemplary methodologies for mounting of polynucleobases to foundational materials.
  • Chain motifs denote multiple (indirect/horizontal) and singlet (direct/vertical) covalent bonds between backbone-modified residues of DNA-PNA Assemblies and polymeric material are generated by soft lithography.
  • Options 4 and 5 imply a thin gold film is PVD onto the enclosures.
  • Design of Flow Regimes on Material for Enhancement of Catalysis A number of fabrication options are suitable for the shaping of foundational enclosures, the ultimate shapes of which determine not only the locations and orientation of orthogonal physico-chemical functions, but also catalytic rates via solute (substrate, intermediary and product) mass transport into and out-of the enclosures.
  • sub-assemblies can be dispensed with entirely (optionally, as cleavable end or middle sections after proper anchoring and mounting of the 3DAA into their receptacles), resulting in a continuous groove with flow proximal to the vicinal boundary layer constantly in the laminar realm - where the Reynolds Number (Re) is very small (generally under 10).
  • Foundational enclosure options also include confining regions, where laminar flow is intentionally disrupted in order to enhance mixing. The latter generally increases intrinsic catalytic flow rates, but risks lowering overall rates of substrate conversion because of the possibility of retarding flow into subsequent assemblies. As implied in Figure BIl. Right, turbulent flow has successfully increased catalysis in the confined region, yet complicated the flow downstream to the next enclosure, where, like the indicated trough, laminar flow is initially required.
  • VFR volumetric flow rate
  • Fig. 26 depicts boundary layer flow as a function of assembly fabrication schemes. On the left is predicted and generalized behavior of supra-vicinal volumetric flow in continuously grooved (light blue), sloped and segmented (purple), and partially braced (red) foundations supporting respective 3D Assemblies. All close-in flow regimes remain laminar (Re ⁇ 10) due to Assembly design. As indicated in the text, continuous grooves preserve nearly constant Re, whereas segmented or braced grooves retard flow to different extents.
  • 3DAA (with orthogonal functions denoted in dark colors) is preferentially mounted on confining region at termini of trough, where turbulent flow (Re > 25) is encouraged to enhance mixing and catalytic activity.
  • turbulent flow Re > 25
  • 3DAA-based SSDC Catalysts A number of micro-to-meter scale fabrication options are suitable for the inclusion of finished 3DAA-based SSDC Catalysts into manufacturing processes that enhance catalysis and catalytic rates of turnover via optimization of the flow regimes in the nanoscale described in the previous section.
  • Kd and Tr are optimized in a processing system under biotic conditions, parameters that transcend the biotic, including increased temperatures, extremes of pH and pi, higher flow rates and more confined geometries, and the presence of abiotic cofactors that are potentially damaging to protein-based enzymes (e.g., heavy metals, ionic liquids, and processing in multi-phasic systems and emulsifications of aqueous liquid-organic solvent) - yet are known to maximize catalysis in other systems - can be performed, predictably without undue damage to the enclosure-supported catalytic assemblies.
  • protein-based enzymes e.g., heavy metals, ionic liquids, and processing in multi-phasic systems and emulsifications of aqueous liquid-organic solvent
  • the present invention can provide the specific application of existing techniques and protocols that elaborate and enable the design, evolution, activation, qualification, optimization and manufacturing to scale of SSDC Catalysts via the flow geometries and devices described herein and henceforth.
  • Exemplary engineering methodologies include any device or bulk scale fabrication that maximizes catalytic rate of the 3DAA array via flow rates, Re and flow profiles that approach the theoretical maximum Kd under the conditions in which processing occurs.
  • turnover rate can also be increased by inclusion of arrays of enclosed assemblies into beads, packed columns of such, mixing fins and walls of processing devices.
  • These options can enhance catalysis by maximizing the surface area available for substrate to encounter catalyst, and for mass transfer to occur.
  • These options can be incorporated into confined flow systems (i) separately in-line as a parallel or series portion of the overall manufacturing process, (ii) iteratively or (iii) sequentially as separate units that perform a certain aspect or part of the catalytic process, or variations thereof.
  • Fig. 27 depicts devices designed to enhance boundary layer flow at the assembly level.
  • On the left is depicted symmetric undulating coil, bulk grooved to force fluid flow in the downwards direction and to sequentially facilitate confined flow geometries at points of decreased distance between the coil and the walls (both dark grey).
  • In the middle is depicted assymetric screw, bulk grooved in a helical fashion to force downwards fluid flow.
  • the radial assymetry enhances mixing by facilitating torsional as well as longitudinal movement of the boundary layer and bulk liquids.
  • On the right is depicted standard in-line, sequential turbine- type mixing device.

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Abstract

L'invention concerne des procédés et appareils pour un assemblage de structures à échelle moléculaire, comprenant la création d'ensembles adressables bidimensionnels et tridimensionnels à motif géographique haute densité de polymères contenant une nucléobase, et la construction de formes compatibles avec ceux-ci. L'invention fournit des procédés de production d'un article fini comprenant des biopolymères fixés de manière covalente configurés selon une forme définie, générés depuis une forme principale complémentaire qui affiche une polynucléobase à brin unique complémentaire. L'invention fournit un procédé de production d'un article fini, comprenant la production d'une formation de forme concave uniforme en une matrice de substrat solide photosensibilisée, puis un dépôt de métal en phase vapeur pour permettre la fixation de motifs de biopolymères auto-assemblés.
EP09805582.5A 2008-08-06 2009-08-06 Création d'ensembles adressables multidimensionnels haute densité Withdrawn EP2315822A4 (fr)

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US20050089890A1 (en) * 1998-05-20 2005-04-28 Cubicciotti Roger S. Multimolecular devices and drug delivery systems
WO2008112980A2 (fr) * 2007-03-15 2008-09-18 Incitor, Llc Procédé et système pour l'assemblage de macromolécules et de nanostructures
WO2009152109A1 (fr) * 2008-06-13 2009-12-17 Incitor, Llc Construction dimensionnelle monocaténaire d'adn dans un espace 3d

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US5946594A (en) * 1996-01-02 1999-08-31 Micron Technology, Inc. Chemical vapor deposition of titanium from titanium tetrachloride and hydrocarbon reactants
US9040090B2 (en) * 2003-12-19 2015-05-26 The University Of North Carolina At Chapel Hill Isolated and fixed micro and nano structures and methods thereof

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US20050089890A1 (en) * 1998-05-20 2005-04-28 Cubicciotti Roger S. Multimolecular devices and drug delivery systems
WO2008112980A2 (fr) * 2007-03-15 2008-09-18 Incitor, Llc Procédé et système pour l'assemblage de macromolécules et de nanostructures
WO2009152109A1 (fr) * 2008-06-13 2009-12-17 Incitor, Llc Construction dimensionnelle monocaténaire d'adn dans un espace 3d

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