CN101778796B - Porous particles and methods of making thereof - Google Patents

Porous particles and methods of making thereof Download PDF

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CN101778796B
CN101778796B CN2008800220199A CN200880022019A CN101778796B CN 101778796 B CN101778796 B CN 101778796B CN 2008800220199 A CN2008800220199 A CN 2008800220199A CN 200880022019 A CN200880022019 A CN 200880022019A CN 101778796 B CN101778796 B CN 101778796B
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porous
substrate
porous layer
particle
layer
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CN101778796A (en
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M·费拉里
刘学武
郑明正
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Ohio State University Research Foundation
University of Texas System
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Ohio State University Research Foundation
University of Texas System
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00Silicon; Compounds thereof
    • C01B33/113Silicon oxides; Hydrates thereof
    • C01B33/12Silica; Hydrates thereof, e.g. lepidoic silicic acid
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81CPROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C99/00Subject matter not provided for in other groups of this subclass
    • B81C99/0075Manufacture of substrate-free structures
    • B81C99/008Manufacture of substrate-free structures separating the processed structure from a mother substrate
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82BNANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B1/00Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00Nanotechnology for materials or surface science, e.g. nanocomposites
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09CTREATMENT 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
    • C09C1/00Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/28Compounds of silicon
    • C09C1/30Silicic acid
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09CTREATMENT 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
    • C09C1/00Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/28Compounds of silicon
    • C09C1/30Silicic acid
    • C09C1/3081Treatment with organo-silicon compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1611Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81CPROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C2201/00Manufacture or treatment of microstructural devices or systems
    • B81C2201/01Manufacture or treatment of microstructural devices or systems in or on a substrate
    • B81C2201/0101Shaping material; Structuring the bulk substrate or layers on the substrate; Film patterning
    • B81C2201/0111Bulk micromachining
    • B81C2201/0115Porous silicon
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00Manufacture or treatment of nanostructures
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01PINDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00Particle morphology
    • C01P2004/01Particle morphology depicted by an image
    • C01P2004/03Particle morphology depicted by an image obtained by SEM
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01PINDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00Particle morphology
    • C01P2004/60Particles characterised by their size
    • C01P2004/61Micrometer sized, i.e. from 1-100 micrometer
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01PINDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00Particle morphology
    • C01P2004/60Particles characterised by their size
    • C01P2004/62Submicrometer sized, i.e. from 0.1-1 micrometer
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01PINDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00Physical properties of inorganic compounds
    • C01P2006/14Pore volume

Abstract

Provided is a particle that includes a first porous region and a second porous region that differs from the first porous region. Also provided is a particle that has a wet etched porous region and that does have a nucleation layer associated with wet etching. Methods of making porous particles are also provided.

Description

Porous particle and preparation method thereof
Statement about federal funding research or exploitation
The clause defined of the contract NNJ06HE06A that Grant No.W81XWH-04-2-0035 that authorizes like Department of Defense and NASA authorize, United States Government has the permission of all reimbursemens in the present invention and under limited situation, requires the patentee on reasonable terms to permit other people right.Government enjoys some rights in this invention.
Background of invention
Description of Related Art
Porous particle for example porous silicon particle and porous silica particle has the many application that comprise as drug conveying carrier.For example, porous silicon particle and their preparation method have been disclosed below in the document: USP no.6,355,270 and 6,107,102; The open no.2006/0251562 of USP; Cohen etc., Biomedical Microdevices 5:3,253-259,2003; Meade etc., Advanced Materials, 2004,16 (20), 1811-1814; Thoma s etc., Lab Chip, 2006,6,782-787; Meade etc., phys.stat.sol. (RRL) 1 (2), R71-R-73 (2007); Salonen etc., Journalof Pharmaceutical Sciences 97 (2), 2008,632-653; Salonen etc., Journal of Controlled Release 2005,108,362-374.
Existence is to novel porous particle and prepare the needs of their novel method.
General introduction
An embodiment is the particle that comprises the body (body) that is limited outside surface; Wherein said body comprises first porous zone and second porous zone, and at least a aspect of performance of this second porous zone in being selected from void density, pore dimension, pore shape, hole electric charge, pore surface chemical property (chemistry) and hole orientation is different with the first area.
Another embodiment is to comprise a plurality of grains of composition; Each particle in wherein said a plurality of particle comprises the body that is limited outside surface; Wherein said body comprises first porous zone and second porous zone, and at least a aspect of performance of this second porous zone in being selected from void density, pore dimension, pore shape, hole electric charge, pore surface chemical property and hole orientation is different with the first area.
Be the particle that comprises the body that is limited outside surface in another embodiment, porous zone and wherein said particle that wherein said body comprises wet etching do not comprise the nucleating layer relevant with wet etching.
Another embodiment is to comprise a plurality of grains of composition, and said a plurality of particles have the body that is limited outside surface separately, and porous zone and wherein said particle that wherein said body comprises wet etching do not comprise the nucleating layer relevant with wet etching.
And another embodiment is the method for preparing porous particle, and this method comprises: the substrate with surface is provided; In this substrate, form first porous layer; Pattern dissolves one or more particles on this substrate; In substrate, form and have more second porous layer of open grain than first porous layer; Discharge from substrate with one or more particles that pattern is dissolved, wherein said release comprises that the one or more particles with second porous layer broken (break) and wherein said release comprise part first porous layer at least.And another embodiment is the method for preparing porous particle, and this method comprises: the substrate with surface is provided; In this substrate, form first porous layer through wet etching; Remove the nucleating layer relevant with wet etching; Pattern dissolves one or more particles on the surface of substrate; Discharge from substrate with one or more particles that pattern is dissolved, one or more particles of wherein said release comprise part first porous layer at least.
Accompanying drawing
Fig. 1 (A)-(B) schematically illustrates and comprises through the porous particle preparation method of electropolishing from the substrate release particles.
Fig. 2 (A)-(B) schematically illustrates the formation that comprises through the discharging porous layer porous particle preparation method from the substrate release particles.
Fig. 3 schematically illustrates the porous particle preparation method, wherein before the particulate patterning, on substrate, forms porous layer.
Fig. 4 schematically illustrates the porous particle preparation method, wherein before the particulate patterning, on substrate, forms a plurality of porous layers.
Fig. 5 schematically illustrates the porous particle preparation method, wherein before forming a plurality of porous layers on substrate pattern dissolve particle.
Fig. 6 is sem (SEM) image of the porous silicon particulate fish-eye view of 1.2 μ m.Illustration shown in the particle central zone~close-up view of 30nm hole.
Fig. 7 is the SEM image of top view with 3 μ m silicon grains of oval cross section.
Fig. 8 is 3.1 μ m particulate SEM images with hemispherical shape.Illustration has shown to have<the detailed view on the surface of one of the particle of 10nm hole.
Fig. 9 A-C has represented the SEM image of porous silicon film (Fig. 9 A-B) with nucleating layer and the porous silicon film (Fig. 9 C) that does not have nucleating layer.
Figure 10 has represented the SEM image of 3.2 microns silicon grains with the 500nm groove that forms through silicon RIE etching.
Figure 11 has represented the SEM image of the silicon grain with the 1.5 μ m grooves that form through the silicon etching.
Figure 12 has represented the SEM image of two silicon grains: the pictorial display on the left side have the particle of nucleating layer, and the pictorial display on the right removed the particle of nucleating layer on it through RIE.
Figure 13 is the SEM cross sectional image that longitudinally has the silicon grain in two different porous zones.
Detail
Can be useful with its following document of incorporating this paper in full into for understanding the present invention by reference all: 1) the open no.WO 2007/120248 of disclosed PCT October 25 in 2007; 2) the open no.2003/0114366 of U.S. Patent application; 3) the U.S. Patent application no.11/641 that submitted on December 20th, 2006,970; 4) the U.S. Patent application no.11/870 that submitted on October 10th, 2007,777; 5) the U.S. Patent application no.12/034 that submitted on February 20th, 2008,259; 6) Tasciotti etc., Nature Nanotechnology, vol.3,151-158,2008.
Definition
Only if stipulate in addition, " a " or " an " expression is one or more.
" nanoporous " or " nanoaperture " is meant the hole that has less than 1 micron mean sizes.
" biodegradable " is meant the material that in Physiological Medium, can decompose or degrade, perhaps can be under physiological condition by the physiology enzyme liberating and/or by the electrochemical conditions degraded can biocompatible polymer materials.
" can be biocompatible " be meant material when being exposed to viable cell, with the suitable cytoactive that promotes cell, and in cell, do not cause undesirable effect for example change, the change and the cytotoxic effect of cell proliferation speed in cytoactive cycle.
" micron particle " is meant to have 1 micron-1000 microns 1 micron-100 microns the maximum sized particles of perhaps stipulating in some embodiments." nano particle " is meant the maximum sized particle that has less than 1 micron.
The inventor has developed the novel method of new porous particle and preparation porous particle.According to first embodiment; Particle can comprise the body that is limited outside surface; Make this body comprise first porous zone and second porous zone, at least a performance in this second porous zone for example void density, pore dimension, pore shape, hole electric charge, pore surface modification or hole orientation is different with the first area.
Like common unsettled U. S. application No.11/836; Disclosed in 004; For example for two kinds of different distributions of load (population) than small-particle (said can comprise at least a promoting agent for example therapeutical agent or preparation) than small-particle, can use particles with two different porous zones.
In some embodiments, regional at least one of first and second porous can be made up of porous oxide material or porous etching material.In certain embodiments, the first and second porous zones all can be made up of porous oxide material or porous etching material.The porous oxide examples of material includes but not limited to porous silica, porous alumina, porous titanium oxide and porous red stone.Term " porous etching material " is meant and wherein passes through the for example material of chemical etching introducing hole of wet etch technique.The example of porous etching material comprises porous semi-conductor material for example porous silicon, porous germanium, porous GaAs, porous InP, porous SiC, porous Si xGe 1-x, porous GaP, porous GaN.
In a plurality of embodiments, first and second porous regions comprise porous silicon.In a plurality of embodiments, particulate at least the part or whole body constitute by porous silicon.
The particulate body is at least one xsect or for example using microtechnique such as SEM when at least one direction is observed, can have rule shape nonvoluntary.The non-limitative example of such regular shape comprises semisphere, bowl-type, taper type, pyramid, dish type.
The particulate size does not receive specific limited and depends on that particulate uses.For example, for intravascular administration, the maximum characteristic dimension of particulate can be less than the radius of minimum capillary vessel, and this radius is about 4-5 micron in the human body.
In some embodiments, the maximum characteristic dimension of particulate can 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.And in some embodiments, the maximum characteristic dimension of particulate can be 500nm-3 micron or 700nm-2 micron.And in some embodiments, the maximum characteristic dimension of particulate can be greater than about 2 microns or greater than about 5 microns or greater than about 10 microns.
In some embodiments, the first porous zone can be different with the pore dimension in second porous zone, and promptly the pore dimension of the hole in first porous zone can be greater than the pore dimension in the second area, and vice versa.For example, the pore dimension in one of first and second porous zone can at least 2 times of the pore dimension in another of the first and second porous zones or at least 5 times or at least 10 times or at least 20 times or at least 50 times or 2-50 doubly or 5-50 doubly or 2-20 doubly or 5-20 times.
In a plurality of embodiments, at least one of first and second porous zone can be the nanoporous zone.In certain embodiments, the first and second porous zones all can be the nanoporous zone.
In some embodiments, the pore dimension at least one of first and second porous zones can be about 1nm-about 1 micron or the about 800nm of about 1nm-or the about 500nm of about 1nm-or the about 300nm of about 1nm-or about 200nm of about 1nm-or the about 100nm of about 2nm-.
In some embodiments, at least one average pore size that has in first and second porous zones can be not more than 1 micron or be not more than 800nm or be not more than 500nm or be not more than 300nm or be not more than 200nm or be not more than 100nm or be not more than 80nm or be not more than 50nm.In certain embodiments, their average pore size of having separately of first and second porous zones all can be not more than 1 micron or be not more than 800nm or be not more than 500nm or be not more than 300nm or be not more than 200nm or be not more than 100nm or be not more than 80nm or be not more than 50nm.In some embodiments, at least one average pore size that has in first and second porous zone can be about 60nm of about 10-or the about 40nm of about 20-.
In some embodiments, at least one average pore size that has in first and second porous zone can be the about 10nm of about 1nm-or about 10nm of about 3nm-or the about 7nm of about 3nm-.
In some embodiments; The average pore size that one of first and second porous regions have can be about 60nm of about 10-or the about 40nm of about 20-, and another average pore size that has in the first and second porous zones can be the about 10nm of about 1nm-or about 10nm of about 3nm-or the about 7nm of about 3nm-.
In some embodiments, first porous zone can have identical or essentially identical orientation with the hole in second porous zone, yet has different mean sizess.
Generally speaking, can use and comprise N 2Absorption/desorption and microscopy be many technical measurement pore dimensions of scanning electron microscopy for example.
In some embodiments, first porous zone can have different hole orientations with the second porous zone.For example; The particulate outside surface can comprise smooth subsurface (subsurface) and first porous zone hole can perpendicular to or be basically perpendicular to this subsurface, and the hole in second porous zone can be orientated along the direction that the direction that is different from said vertical direction basically for example is parallel to this subsurface.Can use for example SEM mensuration hole orientation of microtechnique.
In some embodiments, at least one the hole in first and second porous zones can be linear hole.In some embodiments, the hole in first and second porous zone all can be linear hole.
In some embodiments, at least one the hole in first and second porous zones can be the sponge-type porosity.In some embodiments, the hole in first and second porous zone all can be the sponge-type porosity.
In some embodiments, the hole of at least one of first and second porous zones can be linear hole, and another the hole in the first and second porous zones can be the sponge-type porosity.
In some embodiments, the hole in first and second porous zone can have different pore surface electric charges.For example, the pore surface in first porous zone can be positively charged, and the pore surface in second porous zone can be a neutral or electronegative.
In some embodiments, the hole in first and second porous zone can have different shapes.For example, the hole in one of first and second porous zone can be the cylindrical pore, and another the hole in the first and second porous zones can the right and wrong cylindrical pore.Can use for example SEM mensuration pore shape of microtechnique.
In some embodiments, the hole in first and second porous zone can have the different surface chemical property.The pore surface in first porous zone can carry out chemical modification with the first surface group, and the pore surface in second porous zone can not modification perhaps carry out chemical modification with the second surface group that is different from the first surface group.For example, the pore surface in first porous zone can with aminosilane for example the 3-aminopropyl triethoxysilane carry out silylanization, and the pore surface in second porous zone can with hydrosulphonyl silane for example 3-sulfydryl propyl trimethoxy silicane carry out silylanization.
In some embodiments, the hole in first and second porous zone can have different void densities.For example, the first porous zone can have higher void density, and vice versa.
In some embodiments, regional at least one of first and second porous can be biodegradable region.In some embodiments, the first and second porous zones all can be biodegradable.In some embodiments, the whole particle body can be biodegradable.
Generally speaking, porous silicon depends on that its porosity and pore dimension can be biologically inert, biological activity or biodegradable.The biodegradation rate of porous silicon or speed also can depend on its porosity and pore dimension, see for example Canham, BiomedicalApplications of Silicon, and Canham LT edits.Properties of poroussilicon.EMIS datareview series No.18.London:INSPEC.371-376 page or leaf.Biodegradation rate can also depend on surface-treated.Therefore, can be so that this particulate first porous zone have first biodegradation rate, and the second porous zone has second biodegradation rate different with first biodegradation rate.
In some embodiments, each in first porous and the second area can have greater than 200nm or greater than 250nm or greater than thickness or the minimum feature size of 300nm.
In some embodiments, particle can not have or do not have basically nucleating layer, and this nucleating layer is irregular porous layer, and it promptly forms when etching solution begins to infiltrate in the substrate in the starting stage of electrochemistry wet etching usually.The thickness of nucleating layer can depend on the parameter of etched substrate and electrochemical etching process.For the substrate and the etched parameter that can be used for preparing the nanoscale hole, the thickness of nucleating layer can be the about 200nm of 1nm-.
In some embodiments, the particulate outside surface can have at least one the surface chemical property different surface chemical property with first and second porous zones.Yet in some embodiments, the particulate outside surface can have the equal different surface chemical property of surface chemical property with first and second porous zone.
Particle can be the particle of top-down preparation, promptly utilizes top-down micron processing or nanofabrication technique for example optical lithographic methods (photolithography), beamwriter lithography method, X-ray lithography method, deep-UV lithography method, nano-imprint lithography method (nanoimprintlithography) or dip in the particle that a nanometer etching method (dip-pen lithography) makes.These preparing methods can allow to amplify in proportion the even or essentially identical particle of preparation size.
Therefore; The present invention also provides and has comprised a plurality of grains of composition; Each particle in wherein said a plurality of particle comprises the body that is limited outside surface; Wherein said body comprises first porous zone and second porous zone, and at least a aspect of performance of this second porous zone in being selected from void density, pore dimension, pore shape, hole electric charge, pore surface chemical property and hole orientation is different with the first area.
According to second embodiment; Particle can comprise the body that is limited outside surface; Wherein said body comprises the porous zone of wet etching and promptly passes through the for example porous zone of electrochemistry wet etching generation of wet etch technique, and wherein said particle does not comprise the nucleating layer relevant with wet etching.
The particle of second embodiment can have and top same size and the shape of discussing with regard to the particle of first embodiment.The performance that the porous zone of wet etching has can be identical with the performance in the particulate first of first embodiment or second porous zone.The particulate outside surface of second embodiment can have identical performance with the particulate outside surface of second embodiment.Like the particle of first embodiment, the particle of second embodiment can be the particle of top-down preparation.
The particle of second embodiment can be a part that comprises a plurality of grains of composition, and said a plurality of particulate sizes are even and basic identical with the particle of second embodiment.The particle of first and second embodiments can make according to the porous particle preparation method of following detailed description.Particle of the present invention can be used for comprising the various application of delivery of drug.In some cases, can for example therapeutical agent or preparation directly load in the particle hole with promoting agent.And in some situations, can and then load in the above-mentioned hole the smaller sized particles that comprises promoting agent, U. S. application no.11/836 for example, 004 discloses.The method for preparing porous particle
The method for preparing porous particle can comprise provides substrate, on substrate surface, forms porous layer, and pattern dissolves one or more particles and discharges said particle from this substrate on substrate, makes individual d/d particle comprise partially porous layer.Can carry out porous layer by direct or reverse order forms and patterning.In other words, in some situations, porous layer forms can be before patterning, and in some of the other embodiments, porous layer forms and can be connected on after the patterning.Method of the present invention is utilized the micro-/ nano technology of preparing, and these technology have advantage 1) preparation has the particulate ability of the sphere of including but not limited to, square, rectangle and oval-shaped various predetermined shapes; 2) point-device size control; 3) to the control of porosity and void distribution; 4) the complex surface modification is possible.Substrate
Substrate can be made up of any or some in many materials.Preferably, substrate has at least one flat surfaces, and patternable goes out one or more particles on this surface.Preferably, but substrate comprises the etched material of wet method, can through wet etch technique for example chemical etching produce porous material.
In certain embodiments, substrate can be a for example wafer of crystalline state substrate.In certain embodiments, substrate can be a semiconducter substrate, promptly comprises the substrate of one or more semiconductor materials.The non-limitative example of semiconductor material comprises Ge, GaAs, InP, SiC, Si xGe 1-x, GaP and GaN.In a plurality of embodiments, can preferably utilize the material of silicon as substrate.Can to the performance of substrate for example the crystalline orientation on doped level, resistivity and surface select to obtain required hole performance.Form porous layer
Can use many technology on substrate, to form porous layer.Preferably, use wet etch technique promptly through substrate is exposed to comprise at least a etching reagent for example the etching solution of strong acid form porous layer.Specific etching reagent can be depending on the material of substrate.For example, for the germanium substrate, such etching reagent can be hydrochloric acid (HCl), and for silicon substrate, etching reagent can be the hydrogen fluoride etch agent.Preferably, use electrochemical etching process to carry out the formation of porous layer, its chien shih etching electric current passes substrate.For example at Salonen etc., Journal ofPharmaceutical Sciences, the chemical etching that silicon substrate has been detailed in 2008,97 (2), 632 is to form porous silicon layer.For the chemical etching of silicon substrate, etching solution removes HF can also comprise water and/or ethanol.
In some embodiments, during electrochemical etch process, substrate can serve as one of electrode.For example, during the chemical etching of silicon, silicon substrate can serve as anode, and negative electrode can be for example Pt of inert metal.In such situation, with the inert metal negative electrode dorsad the substrate side of (facing away) form porous layer.And in some of the other embodiments, during chemical etching, can substrate be placed between two electrodes that can comprise inert metal separately.
Can in the reactor drum of etch resistant agent or groove, carry out electrochemical etch process.For example, when etching reagent is HF, can in the reactor drum of the material that comprises anti-HF or groove, carry out electrochemical etch process.The examples of material of anti-HF comprises for example tetrafluoroethylene (polytetrapfruoroethylene) of fluoropolymer.Can for example carry out chemical etching at the electric current of one of electrode through monitoring through monitor anode electric current (continuous current) or voltage (permanent electromotive force).In some embodiments, can preferably carry out chemical etching with constant current density, this better control and/or sample room that can allow formed porous layer performance is circulation ratio preferably.
In some embodiments, form two different stable porous zones if desired, can apply two kinds of different constant currents.For example, can apply first current density and stablize porous layer to form first, can apply then second current density with form pore dimension and/or porosity can with first stablize porous layer different second stablize porous layer.
In some embodiments; Parameter that can be through selecting electrochemical etching process for example etching solution concentration and composition, the electric current (and voltage) that applies, etching period, temperature, agitation condition, have or not illumination (with illumination parameter such as intensity and wavelength); And the parameter of etched substrate for example composition, the resistivity of substrate, the crystalline orientation of substrate and the doped level and the type of substrate of substrate; The parameter of regulating formed porous layer is pore dimension, porosity, thickness, void distribution and/or pore shape for example, and therefore regulates each autoregressive parameter of particulate of preparation.
In some embodiments, can have predetermined vertical distribution along the hole of formed porous layer, it is vertical or is basically perpendicular to the distribution of substrate surface.Can produce so vertical distribution through the current density during the change chemical etching.Vertical hole in the porous layer can change porosity and pore dimension.Therefore, in some embodiments, in the porous layer with the porous particle of preparation in the hole that distributes can promptly have reduced size at the top on the surface of substrate, and promptly have than macrovoid than the depths in the bottom of substrate.And in some embodiments, in the porous layer with the porous particle of preparation in the hole that distributes can have large-size at the top, and have small size in the bottom.In some embodiments, in the porous layer with the porous particle of preparation in the hole that distributes can also the top with have different porositys in the bottom.
In a plurality of embodiments, chemical etching can beginning to prevent or to be reduced to the formation of stratum nucleare than heavy current pulse with the short period of time.Can also be through removing nucleating layer at formation porous layer after etching nucleating layer.Can through dry etch technique for example RI E carry out such etching.Can take appropriate measure to protect following zone.For example, can photo-resist be placed on the surface, and can carry out planarization, can apply plasma body then and lose (etch-back) deeply and treat etched surface portion to expose substrate through roasting.
For chemical etching, can with conductive layer for example the dorsal part of metal level coated substrate (backside) promptly with the relative substrate side of a side that forms porous layer, electrically contact guaranteeing.Can use the many technology that comprise thermal evaporation and sputter to apply such conductive layer.Nucleating layer
During chemical etching, etching solution can begin its hole through the formation of nucleating layer and form, and said nucleating layer is that the upper layer of substrate and hole wherein have the performance different with the desired properties of porous layer.The characteristic of this nucleating layer can be that its hole performance and relevant surfaceness are than pore dimension irregularity greatly.
In many application, the lip-deep nucleating layer of porous particle is undesirable.For example, be used for smaller sized particles is carried on it when inner at the silicon porous particle, the nucleating layer on the larger particle surfaces can reduce load efficiency.
In some embodiments, remove or prevent to be formed into stratum nucleare.In some embodiments, during the chemical etching,, can apply bigger electric current to prevent the formation of nucleating layer applying electric current with before in porous layer, producing required hole.And in some embodiments, after forming porous layer, can through dry etching for example RIE remove nucleating layer.Patterning
Can use in many technology any or arbitrary on substrate surface pattern dissolve one or more particles.In a plurality of embodiments, use photoetching technique for example optical lithographic methods, X-ray lithography method, deep-UV lithography method, nano-imprint lithography method or dip in a nanometer etching method and carry out patterning.Optical lithography techniques can for example be contact float device photolithography (contactaligner lithography), scanning device photoetching method (scanner lithography) or immersion lens photolithography (immersion lens lithography).Use different masks (in the optical lithographic methods situation) or mould, might design the particle that to have many pre-defined rule shapes be non-random shape, said shape is for example spherical, square, rectangle, ellipse, dish type and semisphere.Can use patterning to limit particulate side view and size, promptly particle is in the shape and size of the xsect that is parallel to substrate surface.When before patterning, forming porous layer, the lateral dimension of the profile (feature) of the particulate lateral dimension of preparation and patterning is basic identical.When before forming porous layer, carrying out patterning, the particulate lateral dimension of preparation can be greater than the lateral dimension of patterned profiles.Patterning allows preparation to have the particle that pre-defined rule is a side view nonvoluntary.For example, in the optical lithography patterning, can use the mask of different shape to produce required predetermined shape, and in the nano-imprint lithography method, can use difform mould or die from identical purpose.The predetermined non-random side view of particle does not receive specific limited.For example, particle can have circle, square, Polygons and oval in shape.Discharge
In some embodiments, can be from the wafer release particles after patterning and porous layer form step through electropolishing, said electropolishing can comprise to wafer and applies enough high current densities.And in some embodiments, particle discharges the porous layer that can comprise that formation is other from wafer, and this porous layer has bigger porosity than established porous layer.The layer of this higher porosity can be called a releasing layer.This a releasing layer can have enough big porosity, thereby makes it for example can be easy to use mechanical skill to carry out fragmentation as substrate is exposed to ultrasonic energy when needed.Simultaneously, a releasing layer can have sufficient intensity to keep the previous porous layer that is not touched by substrate that forms.Surface-treated
Can use any or some in many technology is that the surface property of particle outside surface and/or the surface property of particle hole carry out modification to the particulate surface property.In many embodiments, before release particles, carry out prepared particulate surface-treated and make particle still not touch substrate simultaneously.The type of particulate surface-treated can include but not limited to chemical modification (comprising polymer modification and oxidation); Plasma treatment; Metal or metals ion apply; Chemical vapor deposition (CVD) applies, ald; Evaporation and sputtered film, and ion implantation.In some embodiments, for biomedical target and control degradation, surface treatment is biological.
Because can be in that particle was carried out the particulate surface-treated before substrate discharges, so asymmetric surface-treated also is possible.Asymmetric surface-treated representes that the surface-treated on particle one side is different from the surface-treated on the particle opposite side.For example, a side of particle surface can be modification, and that the opposite side of particle surface can keep is unmodified.For example, the particulate hole can be used expendable material such as all or part of filling of sacrificial photo-resist.Therefore, during surface-treated, only the particle outside surface is handled.After optionally removing expendable material, only the particle outside surface is modification, and promptly the particulate pore surface keeps unmodified.In some embodiments, can make the part of outside surface can have a kind of modification, and another part of outside surface can have another kind of modification the outside surface patterning through for example optical lithographic methods.To further provide exemplary surface-treated operating process (protocol) in the text.Further describe embodiment described here through following embodiment (though being limited to this absolutely not).Embodiment 1: the preparation of porous silicon particulate.Electropolishing discharges.
In the method that Figure 1A and 1B schematically explain, particle patternization is before porous layer forms and carries out particulate through electropolishing and discharge.This preparation can begin under the situation that obtains silicon wafer 101.Can be randomly through handling for example KOH submergence or reactive ion etching (RIE) surface roughening with wafer 101.Surface roughening can help to remove or prevent the upward formation of nucleating layer of surface.Can at least one surface of wafer 101, deposit resist 102 then and in the HF based sols, not receive chemical etching with the protection wafer.Resist 102 can be the material of opposing chemical etching in HF solution.Such examples of material comprises silicon nitride or photo-resist.
Then can be with resist 102 patternings.Figure 1A and 1B have explained that this resist carries out patterning through photoetching technique.Like Figure 1A c and Figure 1B c, resistant material layer 103 is deposited on resist 102 tops.This resistant material can be the material that under the condition that resist is removed, is not removed.An example of such material is a photo-resist.See Figure 1A c and Figure 1B c, can remove the unwanted zone of the resist 102 on the wafer front and the resist on the wafer backside.See Figure 1A d, can also remove resistant material 103.Can be with the resist patterning so that prepared coating of particles and the size of the space boundary between the pattered region of resist 110.
In some situations,, can in the space 104 between the pattered region 110 of resist, form groove as illustrated among Figure 1B d.Can form groove through for example dry etch technique such as RIE.Can utilize the degree of depth and the shape of groove to limit particle perpendicular to the xsect of substrate surface and therefore limit coating of particles.The degree of depth of groove and shape can also be controlled prepared particulate machinery and/or porous performance.
See Figure 1A f and 1Bf, around porous layer 106 can be formed on and reach in the space of pattered region 110 protections of not protected layer.Be to form porous layer 106, can galvanic current under, wafer is exposed to can comprises HF and randomly comprise for example alcoholic acid solution of tensio-active agent, can select hole to the value of said electric current with the generation desired size.See Figure 1A e,, can before the galvanic current that applies corresponding to required pore dimension, apply bigger galvanic current if nucleating layer 105 is undesirable.
Formed porous layer 106 can have two kinds of different holes in the area regional and under resist zone 110 that does not receive pattered region 110 protections and be orientated.The former can have perpendicular to or be basically perpendicular to the hole of substrate surface orientation, and the latter can have the hole that is parallel to substrate surface orientation or become the hole of the angle that is different from 90 ° basically with this surface.
See Figure 1A g, h and 1Bg, h can be through electropolishing release particles 108 or 109, and it can form gap 107 below porous layer 106.Can remove remaining resist then.Can particle be collected in the solution through comprising filtering many technology.Particle 109 has the shape that limits them and their machinery and the groove of porous performance that is formed among them.For example, the pore dimension that has of the part of the particle under the groove 109 and porosity can be that the pore dimension and the porosity of no trench portions of particle 109 is different with the sidepiece of particle 109.The preparation of embodiment 2. porous silicon particulate.Formation through second porous layer discharges.
In the method that Fig. 2 A and 2B schematically explain, particle patternization is carried out particulate and is discharged before porous layer forms and through forming second porous layer.This preparation method can begin under the situation that obtains silicon wafer 201.As in the operating process formerly, can pass through for example KOH submergence or R I E surface roughening with wafer 201.As in embodiment 1, can in the HF based sols, not receive chemical etching with the protection wafer at deposition resist 202 on the wafer then, see Fig. 2 Aa.As in embodiment 1, for example can use photoetching technique protective membrane 202 patternings to be seen Fig. 2 Ab, c and 2Bb, c then.As in embodiment 1, patterning can comprise deposition resistance film 203, sees Fig. 2 Bb and 2Ab.That can remove the wafer front side upper protective film does not need the zone, and the protective membrane on the dorsal part of wafer 201, sees Fig. 2 Bc and 2Ac.As in embodiment 1, can be with resist 202 patternings so that prepared coating of particles and the size of the space boundary between the pattered region 210.
In some situations,, can in the space between the pattered region 210 of resist, form groove 204 as illustrated among Fig. 2 Bd.Can form groove through dry etch technique such as RIE.Can utilize the degree of depth and the shape of groove to limit particle perpendicular to the xsect of substrate surface and therefore limit coating of particles.The degree of depth of groove and shape also can be used for controlling formed particulate machinery and porous performance.
F and 2Bf, porous layer 206 see Fig. 2 Ae, around can be formed on and reach in the space that the pattered region 210 of not protected layer protected.For forming porous layer 206, can under galvanic current, wafer be exposed to the solution that can comprise HF and randomly comprise tensio-active agent, can select to produce the hole of desired size the value of said electric current.If nucleating layer is undesirable, can before the galvanic current that applies corresponding to required pore dimension, apply bigger galvanic current.
Formed porous layer 206 can have two kinds of different holes in the area regional and under resist zone 210 that does not receive pattered region 210 protections and be orientated.The former can have perpendicular to or be basically perpendicular to the hole of substrate surface orientation, and the latter can have the hole that is parallel to substrate surface orientation or become the hole of the angle that is different from 90 ° basically with substrate surface.
After porous layer 206 forms, can apply bigger electric current and have more second porous layer 207 of open grain than the first layer to form, see Fig. 2 Bf and 2Af.Can select to make that second porous layer 207 is enough crisp for physical disturbance to this big electric current, but still can particle be remained on the original place.
If early do not remove nucleating layer, can this stage use dry etch technique for example RIE be removed.Remove the pattered region 210 of protective membrane then, see Fig. 2 Ag and 2Bg.If desired, then can be with being remained on the particle chemical modification in the wafer 201 by second porous layer 207.
Can fall second porous layer 207 and in solution, particle 208 or 209 is discharged from wafer 201 through fragmentation, this can for example be exposed to ultrasonic vibration with wafer through mechanical means and carries out, and sees Fig. 2 Ah and 2Bh.Particle 209 has and is formed on the shape among them, that can limit them and the groove of their machinery and porous performance.For example, the pore dimension that has of the part of the particle under the groove 209 and porosity can be that the pore dimension and the porosity of no trench portions of particle 209 is different with the sidepiece of particle 209.
Technical field
Present invention relates in general to field of nanometer technology, and be particularly related to porous particle and preparation method thereof.
The coating of particles of preparation can be semisphere, bowl-type, taper type etc. according to etching condition among the embodiment 1 and 2.For example, for bowl-like shape, the degree of depth of bowl-shaped body can be depending on the degree of depth that before the wet chemical etching, is formed into the groove in the particle pattern.The preparation of embodiment 3. porous silicon particulate
In the method that Fig. 3 schematically explains, porous layer is formed on before the particle patternization.This method can begin under the situation that obtains silicon wafer 301.For forming porous layer 302, can under galvanic current, wafer be exposed to the solution that can comprise HF and randomly comprise tensio-active agent then, can select to see Fig. 3 a to the value of said electric current in layer 302, to obtain required pore dimension.Can be with after-applied bigger electric current to form second porous layer 303 in the substrate below first porous layer 301.Can select to make second porous layer, 303 to the first porous layers 302 to have bigger porosity to this big electric current, see Fig. 3 b.Preferably, can select to make that porous layer 303 is enough crisp in case of necessity physical disturbance to this big electric current, but still can the particle original place of formation be remained in the wafer simultaneously.
After forming second porous layer, can be with particle patternization.For example, can photo-resist be deposited on the porous silicon film 301.Then can be with this photo-resist patterned to limit particle.For example, in Fig. 3, the pattered region 304 of photo-resist layer (Fig. 3 c) limits particle.Can through for example dry etching such as RIE remove porous silicon layer 302 do not need the zone be porous layer 302 not by pattered region 304 region covered of photo-resist layer, see Fig. 3 d.Can remove the pattered region 304 of photo-resist layer then.
If desired, can the particle (seeing Fig. 3 e) that remained on by second porous layer 303 in the wafer 301 be carried out chemical modification.Can in solution, fall second porous layer 302 through fragmentation particle 306 is discharged from wafer 301, this for example can carry out as wafer being exposed to ultrasonic vibration through mechanical means, sees Fig. 3 f.The produced in high yields of embodiment 4. porous silicon particle I
Can change the method for embodiment 3 into multilevel method, this method can allow to produce the particle of produced in high yields.This method can begin under the situation that obtains silicon wafer 401.Can wafer 401 be exposed to the HF/ surfactant soln then, and can apply the galvanic current certain hour, see Fig. 4 a to form first porous silicon layer 402.Can apply second porous layer 403 that big electric current has open grain more with formation then as a releasing layer.Can select to make that second porous layer 403 is enough crisp for physical disturbance to this big electric current, but can particle be remained in the wafer 401 simultaneously.
Can repeat to form and stablize porous layer for example first porous layer 402 and the easy broken for example step of second porous layer 403 of porous layer that discharges of formation, to form the periodicity layered structure.For example, Fig. 4 b has shown such periodic structure, and it is spaced apart by breakable a releasing layer 403 wherein to stablize porous layer 402.Can carry out the particulate patterning then.
For example, can be on first porous layer 402 of top with mask layer such as metal film deposition.Can photo-resist be placed on the top of this mask.In the situation of metal refining mask not, can photo-resist directly be placed on first porous layer 402 of top.Then, can use photoetching technique with the photo-resist patterned.Shown in Fig. 4 c, the photo-resist layer of patterning can comprise the photo-resist zone of patterning, and this zone can limit prepared coating of particles and size.Can remove the periodically unwanted zone of vesicular structure then, promptly photo-resist zone 404 region covered that are not patterned of this periodic structure to form the lamination 406 that the top is patterning photo-resist zone 404, are seen Fig. 4 d.Then, see Fig. 4 e, through using for example piranha solution (1 volume H 2O 2With 2 volume H 2SO 4), can remove photoresist film and/or mask from the top of lamination 406.If desired, form by partially stabilized porous layer and can be discharged the particle 405 that porous layer remains in the lamination 406 and can carry out chemical modification then.For example wafer 401 is exposed to ultrasonic vibration with lamination 406 through mechanical means and carries out the release of particle 405, see Fig. 4 f from lamination 406 to solution.The produced in high yields of embodiment 5. porous silicon particle II
Present embodiment has provided and has been used for produced in high yields porous silicon particulate alternative approach.From silicon wafer 501 beginnings, can on wafer, deposit resist and not suffer the for example dark RIE of anisotropic etching with the protection wafer.This resist can for example be silicon dioxide film or photoresist film.Can be with this protective membrane patterning to form the pattered region 502 of resist, this area limiting goes out particulate shape of cross section and size to be prepared, sees Fig. 5 a.Can carry out this initial patternization of this resist by the patterning that is similar to resist illustrated among Figure 1A (a)-(d).
Fig. 5 b is seen with formation pillars 503 below the pattered region 502 of protective membrane in the not protection zone that can anisotropic etch techniques be applied to wafer then.Can remove the protective membrane 502 on pillars 503 tops then.Then, can in the etching area above the pillars 503 and between pillars 503 508, deposit second resist 504, see Fig. 5 c.Second resist 504 can make it can protect wafer in the HF based sols, not receive chemical etching.For example, second resist 504 can be silicon nitride film or photoresist film.Then through remove part second resist 504 with for example etching or planarization, with the top exposure of pillars 503.Preferably, after such removal, second resist 504 keeps not touched on the side and in the bottom of etching area 508, sees Fig. 5 d.
Afterwards, the wafer that can under the galvanic current that applies, will have the pillars of patterning is exposed to the HF based sols to form first porous layer 505, and this porous layer is can form particulate by it to stablize porous layer.Can select in particle, to form hole the galvanic current that is applied with desired size.Afterwards, can apply big electric current to form second porous layer 506, this porous layer is to have the more release porous layer of open grain than first porous layer 505.Can select this big electric current, make that this release porous layer is enough crisp for physical disturbance and is enough strong for particle was remained on the original place before discharging on the other hand on the one hand.Can repeat to form stablize porous layer for example layer 505 with form a releasing layer for example the step desired times of layer 506 in pillars 503, to form periodically layered structure.For example, Fig. 5 (e) demonstration is stablized porous layer 505 and is discharged the periodic structure 509 that porous layer 506 forms by alternative.When forming periodic stack structure 509, can remove remaining second resist 504, see Fig. 5 f.
If desired, can carry out chemical modification with forming by partially stabilized porous layer 505 and can being discharged the particle 507 that porous layer 506 remains in the periodic stack structure 509.Can for example wafer 501 be exposed to ultrasonic vibration with lamination 509 through mechanical means and carry out the release of particle 507, see Fig. 5 g from lamination 509 to solution.
In aforesaid method, available electropolishing substitutes the step that forms the open grain a releasing layer.In this situation, the periodic structure of formation can comprise gap rather than the release porous layer that alternative is stablized porous layer and formed through electropolishing.Should stablize porous layer can be kept not touched by wafer by remaining second resist 504.In such situation, can carry out formed particle from stablizing the release of porous layer through removing remaining second resist.Before discharging, particle can carry out chemical modification and still do not touched by wafer simultaneously.The surface-treated operating process
Example operational flow is provided below, this operating process can be used for through oxidation, silylanization and linking objective part for example antibody silicon grain is carried out surface-treated.The oxidation of silicon particle
Can be in the glass beaker on remaining in hot-plate (80-90 ℃) that the silicon particle among the IPA is dry.Can be at piranha solution (1 volume H 2O 2With 2 volume H 2SO 4) in the silicon grain oxidation.Adding H 2O 2After can particle be carried out supersound process and can add acid then.Can suspensoid be heated to 100-110 ℃ kept 2 hours and carried out simultaneously the intermittence supersound process with discrete particles.Can in deionized water, wash suspensoid then is about 5.5-6 up to the pH of suspensoid.Then can be in suitable damping fluid, the IPA (Virahol) or be stored in the water and refrigerate up to next step use with transfer of granules.Silylanization
Oxidation.Before silylanization is handled, can be at 1.5M HNO 3In the acid with about 1.5 hours of the particle hydroxylation of oxidation (room temperature).Can be in deionized water particle be washed 3-5 time (washing can comprise be suspended in the water and spinning, then be the removal of supernatant and the repetition of this operation).
APTES handles.Can through twice of IPA washing granule and with this particle suspension in IPA (Virahol).Then can be at room temperature with particle suspension in the IPA solution that contains 0.5% (v/v) APTES (3-aminopropyltriethoxywerene werene) 45 minutes.Can be stored among the IPA of refrigeration with IPA washing granule 4-6 time and with it through spinning then.As replacement scheme, can with particle carry out five equilibrium (aliquot), dry and under vacuum and siccative storage up to next step use.
MPTMS handles.Can use operation same as described above at HNO 3In with the particle hydroxylation.After water and IPA washing, can be in IPA with MPTMS (3-sulfydryl propyl trimethoxy silicane) 0.5%v/v and 0.5%v/v with grain silicon alkanisation 4 hours.IP available A washs particle 4-6 time then, and is stored in it among IPA of refrigeration then or carries out five equilibrium, drying and storage under vacuum and siccative.
Puting together of antibody.Can by above-mentioned with APTES and/or MPTMS with the microparticle modification.Can use the water-soluble analogues of sulfo group SMCC, 4-N-dimaleoyl imino methylcyclohexane-1-carboxylic acid succinimide ester (SMCC) linking agent that particle and anti-VEGFR2 is antibody linked.Be used for the total number of particles that APTES and MPTMS particle the two and anti-VEGFR2 put together can be about 7.03 * 10 6Can wash these particles and with the phosphate buffered saline buffer spinning that contains 0.5%Triton X-100 6 times, then wash 4 times, on ELIASA (plate reader), read then with common (plain) phosphate buffered saline buffer.
Proved that experimentally for example IgG, EGFR, VEGFR fix to the nano-structure porous silicon particulate antibody; It is through surface silicon alkanisation (sialinization), then follow and fix via chemical support by cross-linking method, and said cross-linking method relates to the protein cross agent that is easy to obtain that can covalency connects these antibody.Carry out surface-treated with APTES
In exemplary surface-treated, can be at 1.5M HNO 3In with porous silicon particle hydroxylation 1 hour.Carry out silylanization and introduced amido in 30 minutes from the teeth outwards through at room temperature being used in the solution that comprises 0.5%v/v 3-aminopropyltriethoxywerene werene (APTES) in the Virahol (IPA).Can in IPA, use 0.5%v/v 3-sulfydryl propyl trimethoxy silicane (MPTMS) and 0.5%v/v H 2O with the thiol group coating from the teeth outwards.Can with the particle suspension of APTES coating and MPTMS coating phosphate buffered saline (PBS) (ssline) (PBS) in and at room temperature itself and following linking agent were reacted 1 hour: 1mM N-succinimido-S-acetyl thio acetic ester (SATA); 1mM 4-(N-maleimide ylmethyl) hexanaphthene-1-carboxylic acid sulfosuccinimide ester (sulfo group SMCC); 1mM [4-iodoacetyl] benzaminic acid N-succinimide ester (sulfo group SIAB) or 1mM 6-(3-[2-pyridine disulfide group]-propionamido) caproic acid succinimide ester (SPDP).Can the antibody biology be conjugated on the said particle then.Embodiment 6: the preparation of " macropore " silicon grain
Fig. 6 has shown the scanning electron image by the 1.2 μ m silicon porous particles that are prepared as follows.Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm (ohm-cm) resistivity as substrate.Silicon nitride layer through the deposition 200nm of low-pressure chemical vapor deposition (LPCVD) system.With EVG 620 aligners (vacuum contact), use normalized optical photolithography pattern to dissolve the circular granular pattern of 1 μ m.Optionally remove silicon nitride through reactive ion etching (RIE) then.Remove the silicon nitride on the wafer backside through RIE.The silicon trench of 300nm is etched in the silicon in the particle pattern of exposure.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.The aluminium film is coated in the dorsal part of wafer.Place homemade
Figure G2008800220199D00221
groove in order to chemical etching this wafer then.Along with applying 80mA/cm 225 seconds of current density, at hydrofluoric acid (HF) and ethanol (3: form nanoaperture in mixture 7v/v).Through applying 400mA/cm 26 seconds of current density form and discharge the high porosity layer.After removing nitride layer with HF, through be exposed to UW 1 minute with particle release in IPA.Collect and store and comprise porous silicon particulate IPA.
Use LEO 1530 sem to measure the pattern of silicon grain.Particle among the IPA is directly placed on the aluminium SEM sample table and carries out drying.To have this particulate SEM platform packs in LEO 1530 sample chambers.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.
SEM pictorial display among Fig. 6 have the particulate fish-eye view of circle (diameter the is 1.2 μ m) shape that is parallel to wafer surface, i.e. a view of the sidepiece of the front surface of remote wafer during the preparation.Whole 3 dimensions of particulate are shaped as semisphere among Fig. 6.Pictorial display among Fig. 6 zone 601 and 602, these zones correspond respectively to and are parallel to the surface or with the angled hole in surface and perpendicular to the hole on surface.The pore dimension at particle center is about 30nm.The gained particle is bigger than initial pattern, this be because during chemical etching porous layer penetrable to below and get into the protected field of substrate.The preparation of embodiment 7. ellipses " macropore " silicon grain
Fig. 7 has shown the SEM image of the silicon grain with oval cross section.This particle is by being prepared as follows.Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm resistivity as substrate.Silicon nitride layer through the deposition 200nm of low-pressure chemical vapor deposition (LPCVD) system.Use EVG 620 aligners, utilize normalized optical photolithography pattern to dissolve the oval particle of 2 μ m.Optionally remove this nitride through reactive ion etching (RIE) then.Remove the silicon nitride on the wafer backside through RIE.The silicon trench of 600nm is etched in the silicon in the particle pattern of exposure.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.Place homemade
Figure G2008800220199D00222
groove in order to chemical etching wafer then.Etching solution is hydrofluoric acid (HF) and alcoholic acid mixture (3: 7v/v).Apply 400mA/cm 21 second of high-density current to remove nucleating layer.Then along with applying 80mA/cm 2Current density form nanoaperture 25 seconds.Through applying 400mA/cm 2Current density form the high porosity a releasing layer 6 seconds.After removing nitride layer with HF, through supersound process 1 minute with particle release in IPA.Collect and store and comprise porous silicon particulate IPA solution.The particulate IPA drips of solution that will contain preparation directly places on the aluminium SEM sample table and carries out drying.Use LEO 1530 sem to measure the SEM image.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.SEM pictorial display among Fig. 7 gained particulate top view.This particle has zone 701, is parallel to surface or angled and regional 702 with the surface in this mesoporosity, zone, in this mesoporosity, zone perpendicular to the surface.Embodiment 8: the preparation of " aperture " silicon grain
Fig. 8 shows 3.1 μ m particulate SEM images with hemispherical shape.By being prepared as follows this particle.Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm resistivity as substrate.On substrate, deposit the silicon nitride layer of 200-350nm through low-pressure chemical vapor deposition (LPCVD) system.Use optical lithographic methods to come pattern to dissolve the circular granular pattern of 2 μ m.Optionally remove this nitride through reactive ion etching (RIE) then.Remove the silicon nitride of wafer backside through RIE.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.Place homemade
Figure G2008800220199D00231
groove in order to chemical etching wafer then.Along with applying 6mA/cm 21 minute 45 second of current density at hydrofluoric acid (HF) and ethanol (1: form nanoaperture in mixture 1v/v).Through at hydrofluoric acid (HF) and ethanol (2: apply 320mA/cm in mixture 5v/v) 2Higher current density form the high porosity a releasing layer 6 seconds.After removing nitride layer, through substrate being exposed to ultrasonic vibration 1 minute with particle release with HF.To in IPA, contain the particulate drop directly places on the aluminium SEM sample table and carries out drying.Use LEO 1530 sem to measure the SEM image.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.SEM pictorial display among Fig. 8 the preparation particle.Illustration confirms that prepared particle has the pore dimension less than 10nm.Embodiment 9: the preparation of " macropore " silicon grain
Figure 10 has shown the SEM image of 3.2 μ m silicon grains with 500nm groove.By being prepared as follows this particle.Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm resistivity as substrate.Low stress nitride silicon layer through the deposition 100nm of low-pressure chemical vapor deposition (LPCVD) system.With EVG 620 aligners, use normalized optical photolithography pattern to dissolve the circular granular pattern of 2 μ m.Optionally remove this nitride through reactive ion etching (RIE) then.Remove the silicon nitride of wafer backside through RIE.Through RIE the silicon trench of 500nm is etched in the silicon on the particle pattern of exposure.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.Place homemade
Figure G2008800220199D00241
groove in order to chemical etching wafer then.Along with applying 16mA/cm 2105 seconds of current density at hydrofluoric acid (HF) and ethanol (1: form nanoaperture in mixture 3v/v).Through applying 220mA/cm 2Current density form the higher porosity a releasing layer 6 seconds.After removing nitride layer with HF, through wafer is exposed to ultrasonic vibration 1 minute with particle release in IPA.Collect and store and contain porous silicon particulate I PA solution.
To in I PA, contain the particulate drop directly places on the aluminium SEM sample table and carries out drying.Use LEO 1530 sem to measure the SEM image.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.SEM pictorial display among Figure 10 the bowl-type particle of gained.This particle has the hole of about 30nm in the bottom of bowl-type, and has less hole at sidepiece.Embodiment 10: with deep trench etching preparation " macropore " silicon grain
Figure 11 has shown the SEM image of the silicon grain with the 1.5 μ m deep trench that form through the silicon etching of preparation.This particle is by being prepared as follows.
Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm resistivity as substrate.Low stress nitride silicon layer through the deposition 100nm of low-pressure chemical vapor deposition (LPCVD) system.Use EVG 620 aligners, utilize normalized optical photolithography pattern to dissolve the circular granular pattern of 2 μ m.Optionally remove this nitride through reactive ion etching (RIE) then.Remove the silicon nitride on the wafer backside through RIE.The silicon trench of 1500nm is etched in the silicon on the particle pattern of exposure.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.Place homemade
Figure G2008800220199D00242
groove in order to chemical etching wafer then.Through applying 16mA/cm 2105 seconds of current density at hydrofluoric acid (HF) and ethanol (1: form nanoaperture in mixture 3v/v).Through applying 220mA/cm 2Current density form the high porosity a releasing layer 6 seconds.After removing nitride layer with HF, through wafer is exposed to ultrasonic vibration 1 minute with particle release in IPA.Collect and store and contain porous silicon particulate IPA solution.
To in IPA, contain the particulate drop directly places on the aluminium SEM sample table and carries out drying.Use LEO 1530 sem to measure the SEM image.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.SEM pictorial display among Figure 11 the bullet-shaped particle that makes.The tip 1101 of bullet-shaped thing has the hole of about 30nm, and the main body 1102 of this bullet-shaped thing has less hole.Embodiment 11: remove the layer that is shaped through RIE and prepare " macropore " silicon grain
Figure 12 has shown the SEM cross sectional image with the etched prepared 3.2m silicon grain of 500nm silicon trench, and the left side is for having nucleating layer, the right for to remove nucleating layer through RIE.This particle is by being prepared as follows.Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm resistivity as substrate.On substrate, deposit the low stress nitride silicon layer of 100nm through low-pressure chemical vapor deposition (LPCVD) system.Use the EVG620 aligner, use normalized optical photolithography pattern to dissolve the circular granular pattern of 2 μ m.Optionally remove this nitride through reactive ion etching (RIE) then.Also remove the silicon nitride on the wafer backside through RIE.The silicon trench of 500nm is etched in the silicon on the particle pattern of exposure.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.Place homemade
Figure G2008800220199D00251
groove in order to chemical etching wafer then.Through applying 16mA/cm 2105 seconds of current density at hydrofluoric acid (HF) and ethanol (1: form nanoaperture in mixture 3v/v).Through applying 220mA/cm 2Current density form the high porosity a releasing layer 6 seconds.Apply short period of time CF4 RIE then to remove nucleating layer.
For xsect research, particle is not discharged from wafer.But after removing nitride layer, wafer is split (cleave) and be stacked in 45 and spend on the aluminium SEM sample table with HF.Use LEO 1530 sem to record the SEM image.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.The particle with nucleating layer of SEM image among Figure 12 and gained and the particulate xsect of removing behind the nucleating layer are compared.Particle with nucleating layer has the hole less than 10nm in top area 1201; Below nucleating layer 1202, have the hole of about 30nm, and the particle that does not have a nucleating layer all has the hole of about 30nm in the zone 1204 below top area 1203 and the top.Embodiment 12: the preparation that has " macropore " silicon grain of two kinds of different porosities along the hole direction
Figure 13 has shown the SEM image that has the porous particle in two kinds of different porous zones along the hole direction.This particle is by being prepared as follows: use heavy doping p++ type (100) wafer (Silicon Quest Inc) with 0.005 Ω-cm resistivity as substrate.On substrate, deposit the low stress nitride silicon layer of 100nm through low-pressure chemical vapor deposition (LPCVD) system.Use the EVG620 aligner, use normalized optical photolithography pattern to dissolve the circular granular pattern of 2 μ m.Optionally remove this nitride through reactive ion etching (RIE) then.Also remove the silicon nitride on the wafer backside through RIE.The silicon trench of 500nm is etched in the silicon on the particle pattern of exposure.With piranha solution (H 2SO 4: H 2O 2=3: 1, volume) removes photic etching reagent.Place homemade
Figure G2008800220199D00261
groove in order to chemical etching wafer then.Through applying 16mA/cm 250 seconds of current density and 37mA/cm 222 seconds of current density at hydrofluoric acid (HF) and ethanol (1: form nanoaperture in mixture 3v/v).
For xsect research, particle is not discharged from wafer.But after removing nitride layer, wafer is split and is stacked on the 45 degree aluminium SEM sample table with HF.Use the LEO1530 sem to record the SEM image.The acceleration voltage of electron beam is 10kV, and operating distance is about 5mm.SEM image among Figure 13 removes the particle that longitudinally has two different porosities zones 1301 and 1302 that nucleating layer 1303 has also shown gained.Hole in 1301 and 1,302 two zones is all perpendicular to the surface.Zone 1301 has bigger porosity than zone 1302.Embodiment 13: the preparation of porous silicon film
Fig. 9 has shown the image of two porous silicon films, one have nucleating layer (Fig. 9 A-B) and one do not have nucleating layer (Fig. 9 C).Said film is by being prepared as follows:
Use has heavy doping p++ type (100) wafer (Silicon Quest Inc) of 0.005 Ω-cm resistivity as substrate.Place homemade
Figure G2008800220199D00262
groove in order to chemical etching this wafer then.Etching solution is hydrofluoric acid (HF) and ethanol (2: mixture 5v/v).Apply 320mA/cm 21 second of high-density current to remove nucleating layer.Along with applying 80mA/cm 2Current density form nanoaperture 25 seconds.Though preamble refers to specific preferred embodiment, it is not limited to understand the present invention.Can make various modifications and such modification is defined as within the scope of the invention to disclosed embodiment for those of ordinary skills.
Some particular comprise as follows.Preparation nano-structure porous silicon particulate method comprises: the silicon substrate that comprises the surface is provided; On said surface, form porous layer; With a plurality of particles of photolithographicallpatterned patterning, said particle comprises said porous layer on said substrate; Discharge said particle with the substrate that comprises the patterning porous particle from gained.In some embodiments, on said surface, form said porous zone and carry out lithographic patterning before.
In some embodiments, discharge said particle and comprise the said particle of porous particle machinery release from lithographic patterning.In some embodiments, wherein form said porous layer and comprise formation first porous layer and form second porous layer that the porosity of the wherein said second layer is greater than the porosity of the first layer.In some embodiments, on said substrate, apply resist.In certain embodiments, resist comprises silicon nitride or photoresist film.In some embodiments, discharge said particle from said substrate and comprise the non-zone that needs of removing said resist.
According to some embodiments of aforesaid method, patterning comprises with regard to the gained particle and limits predetermined shape.In some embodiments, said predetermined shape is selected from sphere, square, rectangle, ellipse, dish type and semisphere.
According to some embodiments, form said porous layer and comprise the performance of regulating the gained silicon grain.In certain embodiments, said performance comprises porosity, pore dimension and the void distribution of said gained silicon grain.In certain embodiments, the said porous layer of said formation comprises the said substrate of electrochemical treatment.In certain embodiments, wherein the said substrate of electrochemical treatment comprises with the solution-treated that contains hydrofluoric acid and tensio-active agent.The performance of in certain embodiments, regulating said silicon grain comprises the concentration of selecting said solution, selects electric current, is selected from etching period and selects adulterated silicon substrate so that the silicon grain with pre-determined characteristics to be provided.
According to some embodiments of aforesaid method, said silicon grain comprises outside surface and porous is inner, and said method also comprises the said particle of part is functionalized at least.In certain embodiments, saidly functionalizedly comprise that being selected from following at least a processing through application carries out modification with the said at least outside surface of said particulate: chemical, biochemicals, polymkeric substance, oxidation, plasma treatment, metal or metals ion coating, cvd film coating, ald, evaporating film, sputtered film and ion implantation.In certain embodiments, the sacrificial polymkeric substance to be applied to said particulate porous before functionalized inner said.In certain embodiments, carry out said functionalized before in the said release of said silicon grain.
According to embodiment of the present invention the product of any method in the aforesaid method is provided also.In certain embodiments, this product comprises the silicon-based nano porous particle of about 1-3 micron.
Think that those skilled in the art do not need other detailed description farthest to utilize the present invention through the description of this paper.Embodiment described herein is interpreted as illustrative and is interpreted as absolutely not and limits rest part of the present invention by any way.Though show and described the preferred embodiments of the invention, those skilled in the art can make multiple change and modification and not deviate from spirit of the present invention and instruction it.Therefore, the description that protection scope of the present invention is not provided by preceding text limits, and (all equivalents that comprise the claim theme) limit and only receive claim.The disclosure of all patents, patented claim and publication that this paper quotes is incorporated this paper by reference into, its degree of incorporating into make they provide meet and those programs of the content that additional this paper provides on or other details.

Claims (39)

1. the method for preparing porous particle, this method comprises:
Substrate with surface is provided;
In this substrate, form first porous layer;
Pattern dissolves one or more particles on this substrate;
In substrate, form and have more second porous layer of open grain than first porous layer; With
One or more particles that pattern is dissolved discharge from substrate, and wherein said release comprises that one or more particles of second porous layer is broken and wherein said release comprise part first porous layer at least.
2. the process of claim 1 wherein that substrate is a semiconducter substrate.
3. the process of claim 1 wherein that substrate is a silicon substrate.
4. the process of claim 1 wherein and before patterning, form first porous layer.
5. the process of claim 1 wherein and after patterning, form first porous layer.
6. the process of claim 1 wherein that forming first porous layer comprises substrate is carried out wet etching.
7. the method for claim 6, wherein said wet etching carries out with electrochemical means.
8. the method for claim 7 wherein forms second porous layer and comprises substrate is carried out wet etching with electrochemical means.
9. the method for claim 7, wherein substrate is that silicon substrate and wet etching comprise substrate is exposed to the solution that comprises HF.
10. the method for claim 9, wherein solution also comprises at least a in water or the ethanol.
11. the method for claim 7 also comprises preventing to form the nucleating layer relevant with said wet etching.
12. the method for claim 11, wherein said prevent to comprise apply high-density current.
13. the method for claim 7 also comprises and removes the nucleating layer relevant with said wet etching.
14. the process of claim 1 wherein said formation first porous layer and said formation second porous layer are carried out more than once.
15. the process of claim 1 wherein that said patterning carries out with photolithographicallpatterned.
16. the process of claim 1 wherein that the overall dimension that is parallel to substrate surface of the individual particles in one or more particles is not more than 5 microns.
17. the process of claim 1 wherein that the overall dimension perpendicular to substrate surface of the individual particles in one or more particles is not more than 5 microns.
18. the process of claim 1 wherein that the xsect that is parallel to substrate surface of the individual particles in one or more particles has the pre-defined rule shape.
19. the method for claim 18, wherein said pre-defined rule shape are oval.
20. the process of claim 1 wherein that the xsect perpendicular to substrate surface of the individual particles in one or more particles has the pre-defined rule shape.
21. the method for claim 20, wherein said pre-defined rule shape is semicircle or half elliptic.
22. the method for claim 1 also is included in the individual particles in one or more particles and forms groove.
23. the method for claim 22; The individual particles that wherein discharges comprises this particulate and forms first porous zone in the fluted part; Do not form second porous zone in the fluted part with this particulate, wherein at least a aspect of performance of this second porous zone in being selected from void density, pore dimension, pore shape, hole electric charge, pore surface chemical property and hole orientation is different with the first area.
24. the method for claim 1 is also with one or more particulate surface chemical modifications.
25. the method for claim 24, wherein said chemical modification was carried out before said release.
26. the method for claim 25, wherein said chemical modification is with the surperficial asymmetric ground modification of the individual particles in one or more particles.
27. the method for claim 26, wherein said chemical modification comprise the hole of part at least of filling first porous layer with expendable material.
28. the method for claim 26, wherein said chemical modification comprise at least a in puting together of silylanization, oxidation and antibody.
29. the process of claim 1 wherein that first porous layer is a nano porous layer.
30. the process of claim 1 wherein that the pore dimension in first porous layer is not more than 100nm.
31. the method for claim 1; Individual particles in the particle of wherein one or more releases comprises first porous zone and second porous zone, and at least a aspect of performance of this second porous zone in being selected from void density, pore dimension, pore shape, hole electric charge, pore surface chemical property and hole orientation is different with the first area.
32. the process of claim 1 wherein that said formation first porous layer comprises at least one parameter in thickness, pore dimension, porosity, hole orientation and the pore shape that is selected from of regulating first porous layer.
33. the method for claim 32, wherein said adjusting comprise the material of selecting substrate form, select the resistivity of substrate, select substrate crystalline orientation, select the etching electric current, select etching solution chemical constitution, select etching concentration and select at least a in the etching period.
34. the process of claim 1 wherein that said formation first porous layer is included in the hole that forms predetermined distribution in said first porous layer.
35. the process of claim 1 wherein that said release comprises is exposed to UW with substrate.
36. the method for claim 1 also is included in and deposits resist on the substrate surface.
37. prepare the method for porous particle, this method comprises:
Substrate with surface is provided;
In this substrate, form first porous layer through the electrochemistry wet etching;
Remove the nucleating layer relevant with this electrochemistry wet etching;
Pattern dissolves one or more particles on the surface of substrate; With
One or more particles that pattern is dissolved discharge from substrate, and one or more particles of wherein said release comprise part first porous layer at least.
38. the method for claim 37, wherein said removal apply the high current density that prevents to be formed into stratum nucleare effectively before being included in and forming first porous layer.
39. the method for claim 37, wherein said removal are carried out dry etching to nucleating layer after being included in and forming first porous layer.
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