EP2150493A1 - Particules poreuses et leurs procédés de fabrication - Google Patents

Particules poreuses et leurs procédés de fabrication

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Publication number
EP2150493A1
EP2150493A1 EP08780571A EP08780571A EP2150493A1 EP 2150493 A1 EP2150493 A1 EP 2150493A1 EP 08780571 A EP08780571 A EP 08780571A EP 08780571 A EP08780571 A EP 08780571A EP 2150493 A1 EP2150493 A1 EP 2150493A1
Authority
EP
European Patent Office
Prior art keywords
porous
particles
particle
substrate
region
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Withdrawn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
EP08780571A
Other languages
German (de)
English (en)
Inventor
Mauro Ferrari
Xuewu Liu
Ming-Cheng Cheng
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.)
Ohio State University Research Foundation
University of Texas System
Original Assignee
Ohio State University Research Foundation
University of Texas System
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US11/836,004 external-priority patent/US20080311182A1/en
Application filed by Ohio State University Research Foundation, University of Texas System filed Critical Ohio State University Research Foundation
Publication of EP2150493A1 publication Critical patent/EP2150493A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/113—Silicon oxides; Hydrates thereof
    • C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C99/00—Subject matter not provided for in other groups of this subclass
    • B81C99/0075—Manufacture of substrate-free structures
    • B81C99/008—Manufacture of substrate-free structures separating the processed structure from a mother substrate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • 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
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/28—Compounds of silicon
    • C09C1/30—Silicic acid
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/28—Compounds of silicon
    • C09C1/30—Silicic acid
    • C09C1/3081—Treatment with organo-silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C2201/00—Manufacture or treatment of microstructural devices or systems
    • B81C2201/01—Manufacture or treatment of microstructural devices or systems in or on a substrate
    • B81C2201/0101—Shaping material; Structuring the bulk substrate or layers on the substrate; Film patterning
    • B81C2201/0111—Bulk micromachining
    • B81C2201/0115—Porous silicon
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/03—Particle morphology depicted by an image obtained by SEM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/61—Micrometer sized, i.e. from 1-100 micrometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/14—Pore volume

Definitions

  • the present application relates generally to the field of nanotechnology and, in particular, to porous particles and methods of making thereof.
  • Porous particles such as porous silicon particles and porous silica particles
  • porous silicon particles and methods of their making are disclosed in the following documents: US patents no. 6,355,270 and 6,107,102; US patent publication no. 2006/0251562; Cohen et al, Biomedical Microdevices 5:3, 253-259, 2003; Meade et al., Advanced Materials, 2004, 16(20), 1811-1814; Thomas et al. Lab Chip, 2006, 6, 782-787; Meade et al., phys. stat. sol. (RRL) 1(2), R71-R-73 (2007); Salonen et al. Journal of Pharmaceutical Sciences 97(2), 2008, 632-653; Salonen et al. Journal of Controlled Release 2005, 108, 362-374.
  • One embodiment is a particle comprising a body defined by an outer surface, wherein the body comprises a first porous region and a second porous region, that differs from the first region in at least one property selected from the group consisting of a pore density, a pore size, a pore shape, a pore charge, a pore surface chemistry, and a pore orientation.
  • compositions comprising a plurality of particles, wherein each particle of the plurality comprises a body defined by an outer surface, wherein the body comprises a first porous region and a second porous region, that differs from the first region in at least one property selected from the group consisting of a pore density, a pore size, a pore shape, a pore charge, a pore surface chemistry, and a pore orientation.
  • a particle comprising a body defined by an outer surface, wherein the body comprises a wet etched porous region and wherein the particle does not include a nucleation layer associated with wet etching.
  • composition comprising a plurality of particles that each have a body defined by an outer surface, wherein the body comprises a wet etched porous region and wherein the particle does not include a nucleation layer associated with wet etching.
  • yet another embodiment is a method of making porous particles comprising providing a substrate having a surface; forming a first porous layer in the substrate; patterning one or more particles on the substrate; forming in the substrate a second porous layer having a porosity larger that that of the first porous; and releasing the patterned one or more particles from the substrate, wherein the releasing comprises breaking the second porous layer and wherein the released one or more particles contain at least a portion of the first porous layer.
  • Yet another embodiment is a method of making porous particles comprising providing a substrate having a surface; forming a first porous layer in the substrate via wet etching; removing a nucleation layer associated with the wet etching; patterning one or more particles on the surface of the substrate; and releasing the patterned one or more particles from the substrate, wherein the released one or more particles contain at least a portion of the first porous layer.
  • FIG. 1(A)-(B) schematically illustrate a method of fabricating porous particles that involves releasing particles from a substrate via electropolishing.
  • Fig. 2(A)-(B) schematically illustrate a method of fabricating porous particles that involves releasing particles from a substrate via formation of a release porous layer.
  • Fig. 3 schematically illustrates of a method of fabricating porous particles, in which a formation of a porous layer on a substrate precedes patterning of particles.
  • Fig. 4 schematically illustrates a method of fabricating porous particles, in which formation of multiple porous layers on a substrate precedes patterning of particles.
  • Fig. 5 schematically illustrates a method of fabricating porous particles, in which patterning of particles on a substrate precedes formation of multiple porous layers.
  • Fig. 6 is a Scanning Electron Microscope (SEM) image of a bottom view of a 1.2 ⁇ m of porous silicon particle. The inset shows a close view of ⁇ 30 nm pores in the central region of the particle.
  • SEM Scanning Electron Microscope
  • Fig. 7 is an SEM image of a top view of a 3 ⁇ m silicon particle having an oval cross section.
  • Fig. 8 is an SEM image of 3.1 ⁇ m particles that have a semispherical shape. The inset shows a detailed view of a surface of one of the particles with ⁇ 10 nm pores.
  • Fig. 9A-C present SEM images of a porous silicon film with a nucleation layer
  • Fig. 10 presents an SEM image of 3.2 micron silicon particles with a 500 nm trench formed by silicon RIE etching.
  • Fig. 11 presents an SEM image of silicon particles with a 1.5 ⁇ m trench formed by silicon etching.
  • Fig. 12 presents two SEM images of silicon particles: the left image shows a particle with a nucleation layer, while the right image shows a particle, on which a nucleation layer has been removed by RIE.
  • Fig. 13 is an SEM cross-section image of a silicon particle with two different porous regions along a longitudinal direction.
  • Nanoporous or “nanopores” refers to pores with an average size of less than 1 micron.
  • Biodegradable refers to a material that can dissolve or degrade in a physiological medium or a biocompatible polymeric material that can be degraded under physiological conditions by physiological enzymes and/or chemical conditions.
  • Biocompatible refers to a material that, when exposed to living cells, will support an appropriate cellular activity of the cells without causing an undesirable effect in the cells such as a change in a living cycle of the cells; a change in a proliferation rate of the cells and a cytotoxic effect.
  • Microroparticle refers to a particle having a maximum dimension from 1 micrometer to 1000 micrometers, or, in some embodiments from 1 micron to 100 microns as specified.
  • a particle refers to a particle having a maximum dimension of less than 1 micron.
  • the present inventors developed new porous particles and new methods of making porous particles.
  • a particle may comprise a body defined by an outer surface, such that the body includes a first porous region and a second porous region, that differs from the first region in at least one property, such as a pore density, a pore size, a pore shape, a pore charge, a pore surface modification or a pore orientation.
  • the particle having two different porous regions may be used, for example, for loading two different populations of smaller particles, which may comprise at least one active agent such as a therapeutic agent or an imaging agent, as disclosed in a co-pending U.S.
  • first and a second porous region may be composed of a porous oxide material or a porous etched material.
  • both the first and second porous regions may be composed of a porous oxide material or a porous etched material.
  • porous oxide materials include, but not limited, porous silicon oxide, porous aluminum oxide, porous titanium oxide and porous iron oxide.
  • porous etched materials refers to a material, in which pores are introduced via a wet etching technique, such as electrochemical etching.
  • porous etched materials include porous semiconductors materials, such as porous silicon, porous germanium, porous
  • GaAs porous InP, porous SiC, porous Si x Gei_ x , porous GaP, porous GaN.
  • the first and the second porous regions comprise porous silicon. In many embodiments, at least a portion of or the whole body of the particles is composed of porous silicon.
  • the body of the particle may have a regular, i.e. non-random shape, in at least one cross section or as viewed from at least one direction using, for example, a microscopic technique, such as SEM.
  • regular shapes include a semispherical, a bowl, a frustum, a pyramid, a disc.
  • the dimensions of the particle are not particularly limited and depend on an application for the particle.
  • a maximum characteristic size of the particle can be smaller than a radius of the smallest capillary, which is about 4 to 5 microns in humans.
  • the maximum characteristic size of the particle may be less than about 100 microns or less than about 50 microns or less than about 20 microns or less than about 10 microns or less than about 5 microns or less than about 4 microns or less than about 3 microns or less than about 2 microns or less than about 1 micron. Yet in some embodiments, the maximum characteristic size of the particle may be from 500 nm to 3 microns or from 700 nm to 2 microns. Yet in some embodiments, the maximum characteristic size of the particle may be greater than about 2 microns or greater than about 5 microns or greater than about 10 microns.
  • the first porous region may differ from the second porous region in a pore size, i.e. a pore size of pores in the first porous region may be larger than a pore size in the second region or vice versa.
  • a pore size in one of the first and the second porous region may be at least 2 times, or at least 5 times, or at least 10 times, or at least 20 times or at least 50 times, or from 2 to 50 times or from 5 to 50 times or from 2 to 20 times or from 5 to 20 times larger than a pore size in the other of the first and the second porous region.
  • At least one of the first and the second porous regions can be a nanoporous region. In certain embodiments, both the first and the second porous regions can be nanoporous regions.
  • a pore size in at least one of the first and the second porous regions may be from about 1 nm to about 1 micron or from about 1 nm to about 800 nm or from about 1 nm to about 500 nm or from about 1 nm to about 300 nm or from about 1 nm to about 200 nm or from about 2 nm to about 100 nm.
  • At least one of the first and the second porous regions can have an average pore size of no more than 1 micron or no more than 800 nm or more than 500 nm or more than 300 nm or no more than 200 nm or no more than 100 nm or no more than 80 nm or no more than 50 nm.
  • both the first and the second porous regions can have their respective average pore size of no more than 1 micron or no more than 800 nm or more than 500 nm or more than 300 nm or no more than 200 nm or no more than 100 nm or no more than 80 nm or no more than 50 nm.
  • at least one of the first and the second porous regions can have an average pore size from about 10 to about 60 nm or from about 20 to about 40 nm.
  • At least one of the first and the second porous regions can have an average pore size from about 1 nm to about 10 nm or from about 3 nm to about 10 nm or from about 3 nm to about 7 nm.
  • one of the first and the second porous regions can have an average pore size from about 10 to about 60 nm or from about 20 to about 40 nm, while the other of the first and the second porous regions can have an average pore size from about 1 nm to about 10 nm or from about 3 nm to about 10 nm or from about 3 nm to about 7 nm.
  • pores of the first porous region and the second porous regions may have the same or substantially the same orientation but have different average sizes.
  • pores sizes may be determined using a number of techniques including N 2 adsorption/desorption and microscopy, such as scanning electron microscopy.
  • the first porous region and the second porous region may have different pore orientations.
  • the outer surface of the particle may include a planar subsurface and pores of the first porous region may be perpendicular or substantially to the subsurface, while pores of the second porous region may be oriented in a direction, that is substantially different from the perpendicular direction, such as a direction parallel to the subsurface. Pore orientation may be determined using a microscopic technique such as SEM.
  • pores of at least one of the first and second porous regions may be linear pores.
  • pores of both the first and second porous regions may be linear pores.
  • pores of at least one of the first and second porous regions may be sponge like pores. In some embodiments, pores of both the first and second porous regions may be sponge like pores.
  • pores of one of the first and second porous regions may be linear pores, while pores of the other of the first and second porous regions may be sponge like pores.
  • pores of the first and second porous regions may have different pore surface charges.
  • a pore surface of the first porous region may be positively charged, while a pore surface of the second porous region may neutral or negatively charged.
  • pores of the first and second porous regions may have different shapes.
  • pores of one of the first and second porous regions may cylindrical pores, while pores of the other of the first and second porous regions may be non-cylindrical pores. Pores shape may be determined using a microscopic technique, such as SEM.
  • pores of the first and second porous regions may have different surface chemistry. A pore surface of the first porous region may be chemically modified with a first surface group, while a pore surface of the second porous region may be unmodified or chemically modified with a second surface group, which is different from the first surface group.
  • the pore surface of the first porous region may be silanized with an aminosilane, such as 3-aminopropyltriethoxysilane, while the pore surface of the second porous region may be silanized with a mercaptosilane, such as 3- mercaptopropyltrimethoxysilane.
  • an aminosilane such as 3-aminopropyltriethoxysilane
  • a mercaptosilane such as 3- mercaptopropyltrimethoxysilane.
  • pores of the first and second porous regions may have different porous density.
  • the first porous region may have a higher porous density and vice versa.
  • At least one of the first and second porous regions may be a biodegradable region. In some embodiments, both of the first and second porous regions may be biodegradable. In some embodiments, the whole body of the particle may be biodegradable.
  • porous silicon may be bioinert, bioactive or biodegradable depending on its porosity and pore size. Also, a rate or speed of biodegradation of porous silicon may depend on its porosity and pore size, see e.g. Canham, Biomedical Applications of Silicon, in
  • the biodegradation rate may also depend on surface modification.
  • the particle may be such that the first porous region has a first rate of biodegradation, while the second porous region has a second rate of biodegradation, which is different from the first biodegradation rate.
  • each the first porous and second regions may have a thickness, or the smallest characteristic dimension of more than 200 nm or more than 250 nm or more than 300 nm.
  • the particle may be free or substantially free of a nucleation layer, which is an irregular porous layer, which is usually formed at the initial stage of electrochemical wet etching , when the etching solution starts to penetrate into a substrate.
  • a thickness of the nucleation layer may depend on parameters of an etched substrate and electrochemical etching process. For the substrate's and etching parameters, that can be used to produce nanosized pores, a thickness of the nucleation layer can be from 1 nm to about 200 nm.
  • the outer surface of the particle may have a surface chemistry different from a surface chemistry of at least one of the first and the second porous regions.
  • the outer surface of the particle may have a surface chemistry different from a surface chemistry of both the first and the second porous regions.
  • the particle may be a top-down fabricated particle, i.e. a particle produced utilizing top-down microfabrication or nanofabrication technique, such as photolithography, electron beam lithography, X-ray lithography, deep UV lithography, nanoimprint lithography or dip pen nanolithography.
  • top-down microfabrication or nanofabrication technique such as photolithography, electron beam lithography, X-ray lithography, deep UV lithography, nanoimprint lithography or dip pen nanolithography.
  • Such fabrication methods may allow for a scaled up production of particles that are uniform or substantially identical in dimensions.
  • the present inventions also provide a composition comprising a plurality of particles, wherein each particle of the plurality comprises a body defined by an outer surface, wherein the body comprises a first porous region and a second porous region, that differs from the first region in at least one property selected from the group consisting of a pore density, a pore size, a pore shape, a pore charge, a pore surface chemistry, and a pore orientation.
  • a particle may comprise a body defined by an outer surface, wherein the body comprises a wet etched porous region, i.e. a porous region produced by a wet etching technique, such as an electrochemical wet etching, and wherein the particle does not include a nucleation layer associated with wet etching.
  • the particle of the second embodiment may have the same dimensions and shape as discussed above for the particle of the first embodiment.
  • the wet etched porous region may have the same properties as properties of the first or the second porous regions of the particle of the first embodiment.
  • the outer surface of the particle of the second embodiment may have the same properties as the outer surface of the particle of the second embodiment.
  • the particle of the second embodiment may be a top- down fabricated particle.
  • the particle of the second embodiment may be a part of a composition that includes a plurality of particles, that are uniform in dimension and are substantially identical to the particle.
  • the particles of the first and second embodiments may prepared according to methods of making porous particles that are detailed below. Particles of the present inventions may be used for a variety of applications including drug delivery.
  • an active agent such as a therapeutic agent or an imaging agent, may be loaded directly in pores of the particles.
  • smaller size particles, which in turn comprise an active agent may be loaded in the pores as disclosed, for example, in US application no. 11/836,004.
  • a method of making porous particles may involve providing a substrate, forming a porous layer on a surface of the substrate, patterning one or more particles on a substrate and releasing the particles from the substrate, so that an individual released particle includes a portion of the porous layer.
  • the porous layer formation and the patterning may be performed in a direct or reverse order. In other words, in some cases, the porous layer formation may precede the patterning, while, in some other embodiments, the porous layer formation may follow the patterning.
  • micro/nanofabrication techniques which have the following advantages 1) capability to make particles having a variety of predetermined shapes including but not limited to spherical, square, rectangular and ellipse; 2) very precise dimensional control; 3) control over porosity and pore profile; 4) complex surface modification is possible.
  • the substrate may be composed of any of a number of materials.
  • the substrate has at least one planar surface, on which one or more particles can be patterned.
  • the substrate comprises a wet etchable material, i.e. the material that can be porosified by a wet etching technique, such as electrochemical etching.
  • the substrate may be a crystalline substrate, such a wafer.
  • the substrate may be a semiconducting substrate, i.e. a substrate comprising one or more semiconducting materials.
  • Non-limiting examples of semiconducting materials include Ge, GaAs, InP, SiC, Si x Gei_ x , GaP, and GaN. In many embodiments, it may be preferred to utilize silicon as the substrate's material. Properties of the substrate, such as doping level, resistivity and a crystalline orientation of the surface, may be selected to obtain desired properties of pores.
  • the porous layer may be formed on the substrate using a number of techniques.
  • the porous layer is formed using a wet etching technique, i.e. by exposing the substrate to an etching solution that includes at least one etchant, such as a strong acid.
  • etchant may depend on the material of the substrate.
  • germanium substrates such an etchant may be a hydrochloric acid (HCl)
  • silicon substrates the etchant may be a hydrofluoric etchant.
  • the formation of the porous layer is performed using an electrochemical etching process, during which an etching electric current is run through the substrate.
  • Electrochemical etching of silicon substrates to form porous silicon layers is detailed, for example, in Salonen et al., Journal of Pharmaceutical Sciences, 2008, 97(2), 632.
  • the etching solution may include, in addition to HF, water and/or ethanol.
  • the substrate may act as one of the electrodes.
  • the silicon substrate may act as an anode, while a cathode may be an inert metal, such as Pt.
  • a porous layer is formed on a side of the substrate facing away from the inert metal cathode.
  • the substrate may be placed between two electrodes, which each may comprise an inert metal.
  • the electrochemical etching process may be performed in a reactor or a cell resistant to the etchant.
  • the electrochemical etching process may be performed in a reactor or a cell comprising an HF-resistant material.
  • HF- resistant materials include fluoropolymers, such as polytetrapfruoroethylene.
  • the electrochemical etching may be performed by monitoring a current at one of the electrodes, e.g. by monitoring anodic current, (galvanostatically) or voltage (potentiostatically). In some embodiments, it may be preferable to perform electrochemical etching at a constant current density, which may allow for a better control of the formed porous layer properties and /or for a better reproducibility from sample to sample.
  • two different constant currents may be applied. For example, a first current density may applied to form a first stable porous layer and then a second current density may be applied to form a second stable porous layer, which may differ from the first stable porous layer in a pore size and/or porosity.
  • parameters of the formed porous layer such as pore size, porosity, thickness, pore profile and/ or pore shape, and thus the respective parameters of the fabricated particles may be tuned by selecting parameters of the electrochemical etching process, such as a concentration and a composition of the etching solution, applied electrical current (and potential), etching time, temperature, stirring conditions, presence and absence of illumination (and parameters of illumination, such as intensity and wavelength) as well as parameters the etched substrate, such as the substrate's composition, the substrate's resistivity, the substrate's crystallographic orientation and the substrate's level and type of doping.
  • parameters of the electrochemical etching process such as a concentration and a composition of the etching solution, applied electrical current (and potential), etching time, temperature, stirring conditions, presence and absence of illumination (and parameters of illumination, such as intensity and wavelength) as well as parameters the etched substrate, such as the substrate's composition, the substrate's resistivity, the substrate's crystallographic orientation and the substrate's level and type of doping.
  • the pores in the formed porous layer may have a predetermined longitudinal profile, which is a profile perpendicular or substantially perpendicular to the surface of the substrate.
  • Such longitudinal profile may be generated by varying the electrical current density during the electrochemical etching.
  • both porosity and pore size may be varied.
  • a profiled pore in the porous layer and in the fabricated porous particles may have a smaller size at top, i.e. at the surface of the substrate, and a larger pore at bottom, i.e. deeper in the substrate.
  • a profiled pore in the porous layer and in the fabricated porous particles may have a larger size at the top, and a small size at the bottom.
  • profiled pores in the porous layer and in the fabricated particles may also have different porosity at the top and at the bottom.
  • the electrochemical etching may start with a pulse of a larger electrical current for a short time to prevent or reduce the formation of a nucleation layer.
  • the nucleation layer may be also removed by etching the nucleation layer after the formation of the porous layer.
  • Such etching may be performed by dry etching technique, such as RIE.
  • An appropriate measure may be taken to protect the areas underneath. For example, a photoresist may be placed on the surface, and planation may be performed by baking, and then plasma etch-back may be applied to expose a portion of the surface of the substrate that has to be etched.
  • a backside of the substrate i.e. the side of the substrate opposite to the one of which the porous layer is formed, may be coated with a conductive layer, such as a metal layer, to ensure electrical contact.
  • a conductive layer may be coated using a number of techniques, including thermal evaporation and sputtering.
  • the etching solution can start its pore formation through a formation of a nucleation layer, which is a surface layer of the substrate and in which pores have properties different from the desired properties of the porous layer.
  • the nucleation layer may be characterized by irregularities of its pore properties and associated surfaces roughness, which may on a scale larger than a pore size.
  • the nucleation layer on the surface of porous particles is undesirable.
  • the silicon porous particles are used for loading smaller size particles inside them, the nucleation layer on the surface of the larger may reduce loading efficiency.
  • a nucleation layer is removed or prevented from forming.
  • a larger current may be applied to prevent the formation of the nucleation layer.
  • the nucleation layer may be removed by dry etching, such as RIE.
  • Patterning the one or more particles on a surface of the substrate may be performed using any of a number of techniques.
  • the patterning may be performed using a lithographic technique, such as photolithography, X-ray lithography, deep UV lithography, nanoimprint lithography or dip-pen lithography.
  • the photolithographic technique can be, for example, contact aligner lithography, scanner lithography, or immersion lens lithography.
  • a different mask in case of photolithography, or mold, it may be possible to design particles having a number of predetermined regular, i.e. non-random shapes, such as spherical shape, square, rectangular, ellipse, disk and semi-spherical shapes.
  • Patterning may be used to define lateral shape and dimensions of the particle, i.e. shape and dimensions of the particle in the cross section parallel to the surface of the substrate.
  • the lateral dimensions of the fabricated particles are substantially the same as the lateral dimensions of the patterned features.
  • the lateral dimensions of the fabricated particles may be larger than the lateral dimensions of the patterned features. Patterning allows one to produce particles having a predetermined regular, i.e. non-random, lateral shape.
  • predetermined non-random lateral shapes for the particles are not particularly limited.
  • the particles may have circular, square, polygonal and elliptical shapes.
  • the particles may be released from the wafer after the patterning and porous layer formation steps via electropolishing, which may involve applying a sufficiently large electrical current density to the wafer.
  • the releasing of the particles from the wafer may involve a formation of an additional porous layer, which has a larger porosity than the already formed porous layer. This higher porosity layer will be referred to as a release layer.
  • the release layer can have a porosity large enough so that it can be easily broken when desired using, for example, mechanical techniques, such as exposing the substrate to ultrasonic energy. At the same time, the release layer can be strong enough to hold the earlier formed porous layer intact with the substrate.
  • any of a number of techniques may be used to modify surface properties of the particles, i.e. surface properties of particle's outside surface, and/or surface properties of particle's pores.
  • surface modification of fabricated particles may be done while the particles are still intact with the substrate, before the particles are released.
  • the types of surface modification for the particles may include, but are not limited to, chemical modification including polymer modification and oxidation; plasma treatment; metal or metal ion coating; chemical vapor deposition (CVD) coating, atomic layer deposition; evaporation and sputtered films, and ion implantation.
  • the surface treatment is biological for biomedical targeting and controlled degradation.
  • the surface modification of the particles may be performed before the particles are released from the substrates, asymmetrical surface modification is also possible.
  • the asymmetric surface modification means a surface modification on one side of the particle is different than that on the other side of the particle.
  • one side of the surface of the particle may be modified, while the other side of the surface of the particle may remain unmodified.
  • pores of the particles may be fully or partially filled with a sacrificial material, such as a sacrificial photoresist.
  • a sacrificial material such as a sacrificial photoresist.
  • the outer surface may be patterned by, for example, photolithography, so that one part of the outer surface may have one modification, while another part of the outer surface may have another modification.
  • Exemplary surface modification protocols are presented further in the text. Embodiments described herein are further illustrated by, though in no way limited to, the following working examples.
  • Example 1 Fabrication of porous silicon particles. Electropolishing release.
  • particles patterning precedes the porous layer formation and release of the particles is performed via electropolishing.
  • the fabrication may start with obtaining a silicon wafer 101.
  • the surface of the wafer 101 may be optionally roughened by a treatment, such as KOH dipping or reactive-ion etching (RIE).
  • RIE reactive-ion etching
  • the roughening of the surface may help in removing or preventing the formation of the nucleation layer on the surface.
  • a protective layer 102 may be then deposited on at least one surface of the wafer 101 to protect the wafer from electrochemical etching in HF based solution.
  • the protective layer 102 can be a material resistant to electrochemical etching in HF solution. Examples of such materials include silicon nitride or photoresist.
  • Figures IA and IB illustrate patterning of the protective layer by a lithographic technique.
  • a layer of a resistant material 103 is deposited over the protective layer 102.
  • the resistant material may be a material that does not get removed under the conditions, for which the protective layer gets removed.
  • One example of such a material is a photoresist.
  • the undesired area of the protective layer 102 on the front surface of the wafer may be removed as well as the protective layer on the back side on the wafer, see Figures IAc and IBc.
  • the resistant material 103 may be removed as well, see Figure IAd.
  • the protective layer may be patterned is such a way so that the spaces between the patterned areas 110 of the protective layer define the shape and dimensions of the fabricated particles.
  • trenches may be formed in the spaces 104 between the patterned areas 110 of the protective layer.
  • the trenches may be formed by, for example, by a dry etching technique, such as RIE.
  • the depth and shape of trenches may be used to define the cross section of the particles perpendicular to the surface of the substrate and thus the shape of the particles.
  • the depth and shape of the trenches may be also to control mechanical and/or porous properties of the fabricated particle.
  • a porous layer 106 may be formed in and around the spaces unprotected by the patterned areas 110 of the protective layer, see Figure IAf and IBf.
  • the wafer may be exposed to a solution that may include HF and optionally a surfactant, such as an ethanol, under a DC electrical current, a value of which may be selected to generate pores of a desired size. If a nucleation layer 105 is undesirable, a larger DC current may be applied prior to applying the DC current corresponding to the desired pore size, see Figure IAe.
  • the formed porous layer 106 may have two different pore orientations in the region unprotected by the patterned areas 110 and in the region of the substrate under the protective layer areas 110.
  • the former may have pores oriented perpendicular or substantially perpendicular to the surface of the substrate, while the latter may have pores oriented parallel to the surface of the substrate or angled to the surface with an angle substantially different from 90°.
  • the particles 108 or 109 may be released via electropolishing, which may form a gap 107 underneath the porous layer 106, see Figures lAg,h and lBg,h.
  • the remaining protective layer may be then removed.
  • the particles may be collected in the solution by a number of techniques, including filtration.
  • the particles 109 have a trench formed in them that may define their shape and their mechanical and porous properties. For example, a part of the particle 109 under the trench may have a pore size and porosity that are different from a pore size and porosity at the sides of the particle 109, i.e. non-trench part of the particle 109.
  • FIG. 2A and 2B particles patterning precedes a porous layer formation and release of the particles is performed via a formation of a second porous layer.
  • the fabrication process may start with obtaining of a silicon wafer 201.
  • a surface the wafer 201 may roughened by, for example, KOH dipping or RIE.
  • a protective layer 202 may be then deposited on the wafer to protect the wafer from electrochemical etching in HF based solution, see Figure 2Aa.
  • the protective film 202 may be then patterned using, for example, a lithographic technique, see Figures 2Ab,c and 2Bb,c.
  • the patterning may involve deposition of a resistant film 203, see Figures 2Bb and 2Ab.
  • the undesired area of the protective film on the front side of the wafer may be removed, as well as the protective film on the back side of the wafer 201, see Figure 2Bc and 2Ac.
  • the protective layer 202 may be patterned is such a way so that the spaces between the patterned areas 210 define the shape and dimensions of the fabricated particles.
  • trenches 204 may be formed in the spaces between the patterned areas 210 of the protective layer.
  • the trenches may be formed by dry etching, such as RIE.
  • the depth and shape of trenches may be used to define the cross section of the particles perpendicular to the surface of the substrate and thus the shape of the particles.
  • the depth and shape of the trenches may be also used to control mechanical and porous properties of the formed particles.
  • a porous layer 206 may be formed in and around the spaces unprotected by the patterned areas 210 of the protective layer, see Figures 2Ae,f and 2Bf.
  • the wafer may be exposed to a solution that may include HF and optionally a surfactant under a DC electrical current, a value of which may be selected to generate pores of a desired size. If a nucleation layer is undesirable, a larger DC current may be applied prior to applying the DC current corresponding to the desired pore size.
  • the formed porous layer 206 may have two different pore orientations in the region unprotected by the patterned areas 210 and in the region of the substrate under the protective layer areas 210.
  • the former may have pores oriented perpendicular or substantially perpendicular to the surface of the substrate, while the latter may have pores oriented parallel to the surface of the substrate or angled to the surface of the substrate with an angle substantially different from 90°.
  • a larger electrical current may be applied to form a second porous layer 207 that has a larger porosity than the first layer, see Figures 2Bf and 2Af.
  • This larger electrical current can be selected to be such that that the second porous layer 207 is fragile enough for mechanical break-down, but still can hold the particles in place.
  • the nucleation layer may be removed at this stage by using a dry etching technique, such as RIE.
  • RIE reactive ion etching
  • the patterned areas 210 of the protective film may be then removed, see Figures 2Ag and 2Bg.
  • the particles kept in the wafer 201 by the second porous layer 207 can be then chemically modified, if desired.
  • the particles 208 or 209 may be released from the wafer 201 in a solution by breaking the second porous layer 207, which can be done for example by mechanical means such as exposing the wafer to ultrasonic vibrations, see Figures 2Ah and 2Bh.
  • the particles 209 have a trench formed in them that may define their shape and their mechanical and porous properties.
  • a part of the particle 209 under the trench may have a pore size and porosity that are different from a pore size and porosity at the sides of the particle 209, i.e. non-trench part of the particle 209.
  • the shapes of particles fabricated in Examples 1 and 2 may be semispherical, bowl, frustum, etc., depending on the etching condition.
  • a depth of the bowl can depend on a depth of the trench formed into the particle patterns prior to electrochemical wet etching.
  • porous layer formation precedes particles patterning.
  • the process may start with obtaining a silicon wafer 301.
  • the wafer may then exposed to a solution that may include HF and optionally surfactant, under a DC electrical current, a value of which may be selected to obtain a desired size of pores in the layer 302, see Figure 3a.
  • a larger electrical current may be subsequently applied to form a second porous layer 303 in the substrate 301 underneath the first porous layer.
  • This larger electrical current may be selected so that the second porous layer 303 has a larger porosity than the first porous layer 302, see Figure 3b.
  • this larger electrical current is selected to be such that the porous layer 303 is fragile enough for mechanical break-down if necessary, but, at the same time, can hold formed particles in place within the wafer.
  • particles may be patterned.
  • a photoresist layer onto the porous silicon film 301.
  • the photoresist layer may then patterned to define particles.
  • patterned areas 304 of the photoresist layer ( Figure 3c) define the particles.
  • the undesired area of the porous silicon layer 302, i.e. the areas of the porous layer 302 not covered by the patterned areas 304 of the photoresist layer, may be removed by, for example, dry etching, such as RIE, see Figure 3d.
  • the patterned areas 304 of the photoresist layer may be then removed.
  • the particles kept in the wafer 301 by the second porous layer 303, see Figure 3e, can be then chemically modified, if desired.
  • the particles 306 may be released from the wafer 301 in a solution by breaking the second porous layer 302, which can be done for example by mechanical means, such as exposing the wafer to ultrasonic vibrations, see Figure 3f.
  • Example 3 may be transformed to a multilayer method, which may allow for producing a high yield of fabricated particles.
  • the method may start with obtaining a silicon wafer 401.
  • the wafer 401 may be then exposed to HF/surfactant solution, and DC electrical current may applied for certain time to form a first porous silicon layer 402, see Figure 4a.
  • a larger electrical current may be applied to form a second porous layer 403 with larger porosity as a release layer.
  • This larger current may be selected to be such that the second porous layer 403 is fragile enough for mechanical break-down, but, at the same time, can hold the particles in the wafer 401.
  • a stable porous layer such as the first porous layer 402
  • a breakable release porous layer such as the second porous layer 403
  • Figure 4b shows such a periodic structure, in which stable porous layers 402 are separated by breakable release layers 403. Patterning of particles may then be performed.
  • a masking layer such as a metal film
  • a photoresist layer may be placed on top of the masking film.
  • the photoresist may be placed directly of the top first porous layer 402.
  • a lithographic technique may be applied to pattern the photoresist layer.
  • the patterned photoresist layer may include patterned photoresist areas, which may define shape and dimensions of fabricated particles. An undesired area of the periodical porous structure, i.e.
  • the photoresist film and/or the masking film may be removed from the top of the stacks 406, see Figure 4e, by using, for example, piranha solution (1 volume H 2 O 2 and 2 volumes of H 2 SO 4 ).
  • particles 405, which are formed from portions of stable porous layers and which are kept in the stacks 406 by releasable porous layers may then chemically modified.
  • a release of the particles 405 from the stacks 406 into a solution may be performed by mechanical means, such as exposing the wafer 401 with the stacks 406 to ultrasonic vibrations, see Figure 4f.
  • the present example presents an alternative method for a high yield fabrication of porous silicon particles.
  • a protective layer may be deposited on the wafer to protect the wafer from anisotropic etching, such as Deep RIE.
  • the protective layer may be, for example, as a silicon dioxide film or a photoresist film.
  • the protective film may be patterned to form patterned areas 502 of the protective layer that define a cross section shape and dimensions of particles to be fabricated, see Figure 5a. This initial patterning of the protective layer may performed similarly to the patterning of the protective layer illustrated in Figure IA (a)-(d).
  • An anisotropic etching technique may be then applied to unprotected areas of the wafer to form pillars 503 underneath the patterned areas 502 of the protective film, see Figure 5b.
  • the protective film 502 on the top of the pillars 503 may be then removed.
  • a second protective layer 504 may be deposited over the pillars 503 and in the etched areas 508 between the pillars 503, see Figure 5c.
  • the second protective layer 504 can be such so that it can protect the wafer from electrochemical etching in HF based solution.
  • the second protective layer 504 can be a silicon nitride film or a photoresist film.
  • the tops of the pillars 503 may be then exposed by removing portions of the second protective layer 504 by, for example, etching or planation. Preferably, after such removal, the second protective layer 504 remains intact on the sides and at the bottom of the etched areas 508, see Figures 5d.
  • the wafer with the patterned pillars may be exposed to HF-based solution under applied DC electrical current to form a first porous layer 505, which is a stable porous layer from which the particles may be formed.
  • the applied DC current may be selected to form pores with a size desired in the particle.
  • a larger electrical current may be applied to form a second porous layer 506, which is a release porous layer with a larger porosity than the first porous layer 505.
  • This larger electrical current may be selected to be such so that the release porous layer is, on one hand, fragile enough for mechanical breakdown, and, on the other, it is strong enough to hold the particles in place before the release.
  • the steps of formation a stable porous layer, such as the layer 505 and formation of a release layer, such as a layer 506 may be repeated a desired number of times to form a periodical layered structure in the pillars 503.
  • Figure 5(e) shows a periodical structure 509 formed by interchanging stable porous layers 505 and release porous layers 506.
  • the remaining second protective layer 504 may be removed, see Figure 5f.
  • particles 507 which are formed from portions of stable porous layers 505 and which are kept in the periodic stack structures 509 by releasable porous layers 506, may then chemically modified.
  • a release of the particles 507 from the stacks 509 into a solution may be performed by mechanical means, such as exposing the wafer 501 with the stacks 509 to ultrasonic vibrations, see Figure 5g.
  • the step of forming large porosity release layers may be replaced by electropolishing.
  • the formed periodic structures may include interchanging stable porous layers and gaps formed by electropolishing, instead of the release porous layer.
  • the stable porous layers may be hold intact with the wafer by the remaining second protective layer 504.
  • the release of the particles formed from the stable porous layers may be performed by removing the remaining second protective layer. Prior to the release, the particles may be chemically modified while still intact with the wafer.
  • Silicon microparticles in IPA can be dried in a glass beaker kept on a hot plate (80-
  • Silicon particles can be oxidized in piranha (1 volume H2O2 and 2 volumes of H 2 SO 4 ). The particles can be sonicated after H 2 O 2 addition and then acid can be added. The suspension can be heated to 100-110 0 C for 2 hours with intermittent sonication to disperse the particles. The suspension can be then washed in DI water till the pH of the suspension is about 5.5 - 6. Particles can be then transferred to appropriate buffer, IPA (isopropyl alcohol) or stored in water and refrigerated till further use.
  • IPA isopropyl alcohol
  • the oxidized particles Prior to the silanization process, the oxidized particles can be hydroxylated in 1.5 M HNO3 acid for approximately 1.5 hours (room temperature). Particles can be washed 3-5 times in DI water (washing can include suspending in water and centrifuging, followed by the removal of supernatant and the repeating of the procedure).
  • APTES Treatment The particles can be suspended in IPA (isopropyl alcohol) by washing them in IPA twice. Then the particles can be suspended in IPA solution containing 0.5% (v/v) of APTES (3-aminopropyltriethoxysilane) for 45 minutes at room temperature. The particles can be then washed with IPA 4-6 times by centrifugation and stored in IPA refrigerated. Alternatively, the particles can be aliquoted, dried and stored under vacuum and desiccant till further use.
  • the particles can be hydroxylated in HN03 using the same procedure as above. After the washes with water and IPA, the particles can be silanized with MPTMS (3-mercaptopropyltrimethoxysilane) 0.5% v/v and 0.5% v/v in IPA for 4 hours. The particles can be then washed with IPA 4-6 times, and then stored in IPA refrigerated or aliquoted, dried, and stored under vacuum and desiccant.
  • MPTMS 3-mercaptopropyltrimethoxysilane
  • Microparticles can be modified with APTES and/or MPTMS as described above.
  • Sulfo-SMCC a water soluble analog of succinimidyl 4-N- maleimidomethyl cyclohexane-1-carboxylate (SMCC) crosslinker, can be used to crosslink the particles with the anti-VEGFR2 antibody.
  • the total number of particles used for conjugating both APTES and MPTMS particles with the anti-VEGFR2 can be about 7.03 X 10 6 .
  • the particles can be washed and centrifuged in phosphate buffer containing 0.5% Triton X-100 6 times followed by 4 washes in plain phosphate buffer and then read on the plate reader.
  • porous silicon particles can be hydroxylated in
  • Amine groups are introduced on the surface by silanization with a solution comprising 0.5% v/v 3-aminopropyltriethoxysilane (APTES) in isopropanol (IPA) for 30 min at room temperature.
  • APTES 0.5% v/v 3-aminopropyltriethoxysilane
  • IPA isopropanol
  • Thiol groups can be coated on the surface using 0.5% v/v 3- mercaptopropyltrimethoxysilane (MPTMS) and 0.5%v/v H 2 O in IPA.
  • APTES-coated and MPTMS-coated particles can be suspended in phosphate-buffered ssline (PBS) and reacted with the crosslinker ImM N-succinimidyl-S-acetylthioacetate (SATA), 1 mM sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-l-carboxylate (Sulfo-SMCC), ImM N-Succinimidyl[4-iodoacetyl]aminobenzoate (Sulfo-SIAB), or ImM succinimidyl 6-(3-[2- pyridyldithio]-propionamido)hexanoate (SPDP) for Ih at room temperature. Then the antibodies can be bioconjugated on the particles.
  • SATA phosphate-buffered ssline
  • SPDP pyridyldithio]-propionamido)
  • Figure 6 shows a scanning electron image of a 1.2 ⁇ m silicon porous particle fabricated as follows. Heavily doped p++ type (100) wafer with resistivity of 0.005 ohm-cm (Silicon Quest Inc) was used as the substrate. A 200 nm layer of silicon nitride was deposited by Low Pressure Chemical Vapor Deposition (LPCVD) System. Standard photolithography was used to pattern the 1 ⁇ m circular particle patterns using EVG 620 aligner (vacuum contact). The silicon nitride was then selectively removed by reactive ion etching (RIE). The silicon nitride on the back side of the wafer was removed by RIE.
  • RIE reactive ion etching
  • the morphology of the silicon particles was determined using LEO 1530 scanning electron microscopy. Particles in IPA were directly placed on aluminum SEM sample stage and dried. The SEM stages with particles are loaded into LEO 1530 sample chamber. The acceleration voltage of electron beam is 10 kV, and working distance is about 5 mm.
  • the SEM image in Figure 6 shows a bottom view, i.e. a view of a side, which was away from a front surface of the wafer during the fabrication, of a particle having a circular (1.2 ⁇ m in diameter) shape parallel to the surface of the wafer.
  • the overall 3 dimensional shape of the particle in Figure 6 is semispherical.
  • the image in Figure 6 shows regions 601 and 602, which correspond to pores parallel or angled to the surface and pores perpendicular to the surface, respectively.
  • the pore size in the center of particle is about 30 nm.
  • the resulting particles are bigger than the original patterns because the porous layer may penetrate beneath and into the protected area of the substrate during electrochemical etching.
  • Figure 7 shows an SEM image of a silicon particle having an oval cross section.
  • the particle was fabricated as follows. Heavily doped p++ type (100) wafer with resistivity of 0.005 ohm-cm (Silicon Quest Inc) was used as the substrate. A 200 nm layer of silicon nitride was deposited by Low Pressure Chemical Vapor Deposition (LPCVD) System. Standard photolithography was used to pattern the 2 ⁇ m oval shaped particles using EVG 620 aligner. The nitride was then selectively removed by reactive ion etching (RIE). The silicon nitride on the back side of the wafer was removed by RIE. 600nm silicon trenches are etched into silicon in exposed particle patterns.
  • RIE reactive ion etching
  • the wafer was then placed in a home-made Teflon® cell for electrochemical etching.
  • the etching solution was a mixture of hydrofluoric acid (HF) and ethanol (3:7 v/v).
  • a high density electrical current of 400 mA/cm2 was applied for 1 second to remove a nucleation layer.
  • the nanopores were formed with applied current density of 80 mA/cm 2 for 25 second.
  • a high porosity release layer was formed by applying a current density of 400 mA/cm 2 for 6 second.
  • the IPA solution containing porous silicon particles was collected and stored.
  • a drop of the IPA solution containing the fabricated particles was directly placed on aluminum SEM sample stage and dried.
  • the SEM image was measured using a LEO 1530 scanning electron microscope. The acceleration voltage of electron beam is 10 kV, and working distance is about 5 mm.
  • the SEM image in Fig. 7 shows the top view of the resulting particle.
  • the particle has a region 701, in which pores are parallel or angled to the surface, and a region 702, in which pores are perpendicular to the surface.
  • Figure 8 is an SEM image showing 3.1 ⁇ m particles that have a semispherical shape.
  • RIE reactive ion etching
  • the wafer was then placed in a home-made Teflon® cell for electrochemical etching.
  • the nanopores were formed in a mixture of hydrofluoric acid (HF) and Ethanol (1 : 1 v/v) with a current density of 6 mA/cm 2 applied for 1 min 45 second.
  • a high porosity release layer was formed by applying a higher current density of 320 mA/cm 2 for 6 second in the mixture of hydrofluoric acid (HF) and Ethanol (2:5 v/v).
  • HF hydrofluoric acid
  • Ethanol 2:5 v/v
  • the SEM image was measured using a LEO 1530 scanning electron microscope.
  • the acceleration voltage of electron beam is 10 kV, and working distance is about 5mm.
  • the SEM image in Figure 8 shows the fabricated particles.
  • the inset demonstrates that the fabricated particle have a pore size of less than 10 nm.
  • Figure 10 shows an SEM image of 3.2 ⁇ m silicon particles with 500 nm trench.
  • the particles were fabricated as follows. Heavily doped p++ type (100) wafer with resistivity of 0.005 ohm-cm (Silicon Quest Inc) was used as a substrate. A 100 nm layer of low stress silicon nitride was deposited on the substrate by Low Pressure Chemical Vapor Deposition (LPCVD) System. Standard photolithography was used to pattern the 2 ⁇ m circular particle patterns using EVG 620 aligner. The nitride was then selectively removed by reactive ion etching (RIE). The silicon nitride on the back side of the wafer was removed by RIE.
  • RIE reactive ion etching
  • the particles were released in IPA by exposing the wafer to ultrasonic vibration for 1 minute.
  • the IPA solution containing porous silicon particles was collected and stored.
  • a drop containing the particles in IPA was directly placed on an aluminum SEM sample stage and dried.
  • the SEM image was measured using a LEO 1530 scanning electron microscope.
  • the acceleration voltage of electron beam was 10 kV, and working distance is about 5 mm.
  • the SEM image in Fig. 10 shows the resulting bowl shaped particles.
  • the particles have about 30 nm pores on the bottom of the bowl and smaller pores on the sides.
  • FIG. 11 shows an SEM image of fabricated silicon particles with ⁇ 1.5 ⁇ m deep trench formed by silicon etching.
  • the particles were fabricated as follows. [0121] Heavily doped p++ type (100) wafer with resistivity of 0.005 ohm-cm (Silicon Quest Inc) was used as a substrate. A 100 nm layer of low stress silicon nitride was deposited on the substrate by Low Pressure Chemical Vapor Deposition (LPCVD) System. Standard photolithography was used to pattern the 2 ⁇ m circular particle patterns using EVG 620 aligner.
  • LPCVD Low Pressure Chemical Vapor Deposition
  • the nitride was then selectively removed by reactive ion etching (RIE).
  • RIE reactive ion etching
  • the silicon nitride on the back side of the wafer was removed by RIE.
  • the silicon trenches of 1500 nm were etched into silicon on the exposed particle patterns.
  • the wafer was then placed in a home-made Teflon® cell for electrochemical etching.
  • the nanopores were formed in a mixture of hydrofluoric acid (HF) and Ethanol (1 :3 v/v) by applying a current density of 16 mA/cm 2 for 105 second.
  • HF hydrofluoric acid
  • Ethanol (1 :3 v/v
  • a high porosity release layer was formed by applying a current density of 220 mA/cm for 6 second. After removing the nitride layer by HF, the particles were released in IPA by exposing the wafer to ultrasonic vibrations for 1 minute. The IPA solution containing porous silicon particles was collected and stored.
  • a drop containing the particles in IPA was directly placed on an aluminum SEM sample stage and dried.
  • the SEM image was measured using a LEO 1530 scanning electron microscope.
  • the acceleration voltage of electron beam is 10 kV, and working distance is about 5 mm.
  • the SEM image in Fig. 11 shows the resulting bullet shaped particles.
  • the tip 1101 of the bullet has pores of about 30 nm, while the body 1102 of the bullet has smaller pores.
  • Example 11 Fabrication of "Large Pore” Silicon Particles with a nucleation layer removed by RIE
  • Figure 12 shows SEM cross-section images of fabricated 3.2 ⁇ m silicon particles with
  • the particles were not released from the wafer. Instead, after removing the nitride layer by HF, the wafer was cleaved, and mounded on a 45 degree aluminum SEM sample stage. The SEM image was measured using a LEO 1530 scanning electron microscope. The acceleration voltage of electron beam is 10 kV, and working distance is about 5 mm. The SEM image in Fig. 12 compares the cross-section of resulting particles with nucleation layer and particles after removed nucleation layer.
  • the particles with nucleation layer have less than 10 nm pores in the top area 1201, and about 30 nm pores underneath the nucleation layer 1202, while the particles without nucleation layer have about 30 nm pores in both the top area 1203 and the area 1204 beneath the top.
  • Example 12 Fabrication of "Large Pore” Silicon Particles with two different porosity along pore direction
  • Figure 13 shows an SEM image a porous particle having two different porous regions along pore direction.
  • the particle was fabricated as follows: heavily doped p++ type (100) wafer with resistivity of 0.005 ohm-cm (Silicon Quest Inc) was used as a substrate. A 100 nm layer of low stress silicon nitride was deposited on the substrate by Low Pressure Chemical Vapor Deposition (LPCVD) System. Standard photolithography was used to pattern the 2 ⁇ m circular particle patterns using EVG 620 aligner. The nitride was then selectively removed by reactive ion etching (RIE). The silicon nitride on the back side of the wafer was also removed by RIE.
  • RIE reactive ion etching
  • the wafer was cleaved, and mounded on a 45 degree aluminum SEM sample stage.
  • the SEM image was measured using a LEO 1530 scanning electron microscope.
  • the acceleration voltage of electron beam is 10 kV, and working distance is about 5mm.
  • the SEM image in Fig. 13 shows the resulting particles with two different porosity regions 1301 and 1302 along a longitudinal direction besides a nucleation layer 1303. Pores in both regions 1301 and 1302 are perpendicular to the surface.
  • the region 1301 has larger porosity than the region 1302.
  • Figure 9 shows images of two porous silicon films one with a nucleation layer
  • the etching solution is a mixture of hydrofluoric acid (HF) and
  • a method of fabricating nanoporous silicon particles comprising: providing a silicon substrate comprising a surface; forming a porous layer on said surface; lithographically patterning a plurality of particles on said substrate, said particles comprising said porous layer; and releasing said particles from the resulting substrate containing patterned porous particles.
  • lithographic patterning is performed before forming said porous area on said surface.
  • releasing said particles comprises mechanically releasing said particles from the lithographically patterned porous particles.
  • forming said porous layer comprises forming a first porous layer and forming a second porous layer, wherein the porosity of said second layer is greater than that of the first layer.
  • a protective layer is applied on said substrate.
  • the protective layer comprises silicon nitride or a photoresist film.
  • releasing said particles from said substrate comprises removing the undesired area of said protective layer.
  • patterning comprises defining a predetermined shape for the resulting particles.
  • said predetermined shape is selected from the group consisting of spherical, square, rectangular, ellipse, disk and semi-spherical.
  • forming of said porous layer comprises tuning the properties of the resulting silicon particles.
  • said properties comprise the porosity, pore size and pore profile of said resulting silicon particles.
  • said forming of said porous layer comprises electrochemically treating said substrate.
  • electrochemically treating said substrate comprises treatment with a solution containing hydrofluoric acid and a surfactant.
  • tuning the properties of said silicon particles comprises selecting a concentration of said solution, selecting an electrical current, selecting an etching time, and selecting a doped silicon substrate to provide silicon particles having predetermined properties.
  • said silicon particles comprise an outer surface and a porous interior
  • said method further comprises functionalizing at least a portion of said particles.
  • said functionalizing comprises modifying at least said outer surface of said particles by application of at least one treatment selected from the group consisting of chemicals, biochemicals, polymers, oxidation, plasma treatment, metal or metal ion coating, CVD film coating, atomic layer deposition, evaporated films, sputtered films and ion implants.
  • said functionalizing is performed prior to said releasing of said silicon particles.
  • the product of the method of any of the above-described methods comprises about 1-3 micron silicon-based nanoporous particles.

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  • Chemical & Material Sciences (AREA)
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  • Nanotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Manufacturing & Machinery (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Microelectronics & Electronic Packaging (AREA)
  • Physics & Mathematics (AREA)
  • Composite Materials (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Materials Engineering (AREA)
  • Micromachines (AREA)
  • Weting (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Silicon Compounds (AREA)

Abstract

La présente invention concerne une particule qui comprend une première région poreuse et une seconde région poreuse qui est différente de la première région poreuse. L'invention concerne également une particule poreuse qui présente une région poreuse gravée par voie humide et qui présente une couche de germination associée à la gravure humide. L'invention concerne également des procédés de fabrication de particules poreuses.
EP08780571A 2007-04-27 2008-04-28 Particules poreuses et leurs procédés de fabrication Withdrawn EP2150493A1 (fr)

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US91435807P 2007-04-27 2007-04-27
US91434807P 2007-04-27 2007-04-27
US11/836,004 US20080311182A1 (en) 2006-08-08 2007-08-08 Multistage delivery of active agents
PCT/US2008/061775 WO2008134637A1 (fr) 2007-04-27 2008-04-28 Particules poreuses et leurs procédés de fabrication

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JP (2) JP2010526652A (fr)
KR (1) KR20100051591A (fr)
CN (1) CN101778796B (fr)
AU (1) AU2008245496A1 (fr)
CA (1) CA2685544C (fr)
WO (1) WO2008134637A1 (fr)

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WO2012065825A2 (fr) 2010-10-29 2012-05-24 Em-Silicon Nano-Technologies, S.L. Matériaux semi-conducteurs nanostructurés, procédé de fabrication de ceux-ci et générateur d'impulsions de courant permettant de mettre en oeuvre ledit procédé
TWI625885B (zh) * 2013-01-07 2018-06-01 威廉馬許萊斯大學 用於多孔性矽顆粒生產之經結合之電化學及化學蝕刻方法
CN103482566B (zh) * 2013-09-30 2016-01-20 杭州士兰集成电路有限公司 用于mems工艺中的深槽制造方法
GB202012302D0 (en) 2020-08-07 2020-09-23 Kings College Lithiated silicon
CN113638035A (zh) * 2021-07-09 2021-11-12 江苏大学 一种多孔硅-银纳米枝晶颗粒及其制备和sers检测方法

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AU2008245496A1 (en) 2008-11-06
CA2685544A1 (fr) 2008-11-06
CN101778796A (zh) 2010-07-14
WO2008134637A1 (fr) 2008-11-06
CA2685544C (fr) 2016-08-09
KR20100051591A (ko) 2010-05-17
JP2010526652A (ja) 2010-08-05
JP2013034991A (ja) 2013-02-21
AU2008245496A8 (en) 2010-01-07
CN101778796B (zh) 2012-11-14

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