JP2013034991A - Porous particles and method of making the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide particles having two porous surface regions of different properties and to provide a method of making particles.SOLUTION: The method of making porous particles including a part of a first porous layer and a second porous layer on the surface includes steps of: 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 than that of the first porous layer; and releasing the patterned one or more particles from the substrate, wherein the releasing comprises breaking the second porous layer.

Description

Detailed Description of the Invention

Description of research and development funded by the federal government
[0001] The US government granted a paid-up license in this invention and, in limited circumstances, to patent holders with grant number W81XWH-04-2-0035 and NASA awarded by the Department of Defense Have the right to request permission to others in the right conditions provided by the conditions of grant number SA23-06-017.

  [0002] The present application relates generally to the field of nanotechnology, and in particular to porous particles and methods for their production.

[0003] Porous particles, such as porous silicon particles and porous silica particles, have many uses, including being used as a carrier for drug delivery. For example, porous silicon particles and methods for their production are disclosed in the following documents: US Pat. Nos. 6,355,270 and 6,107,102; US Patent Publication No. 2006/0251562; Cohen et al. 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.

  [0004] There is a need for new types of porous particles and new methods of making them.

US Pat. No. 6,355,270 US Pat. No. 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

  [0005] One embodiment is a particle comprising a body defined by an outer surface, wherein the body comprises a first porous region as well as a second porous region, which comprises a pore density, a pore size, a pore size. And at least one characteristic selected from the group consisting of the shape of the hole, the charge of the small hole, the chemical nature of the surface of the small hole, and the directionality of the small hole.

  [0006] Another aspect is a composition comprising a plurality of particles, wherein each particle in the plurality includes a body defined by an outer surface, wherein the body comprises a first porous region as well as a second porosity. A region comprising at least one selected from the group consisting of pore density, pore size, pore shape, pore charge, pore surface chemistry, and pore orientation It differs from the first region in the characteristics of the type.

  [0007] Yet another aspect is a particle comprising a body defined by an outer surface, wherein the body comprises a porous region that has been wet etched and the particle does not comprise a nucleation layer associated with wet etching.

  [0008] Yet another aspect is a composition comprising a plurality of particles each having a body defined by an outer surface, wherein the body comprises a wet etched porous region, and the particles are associated with wet etching. Does not include nucleation layer.

  [0009] Yet another aspect is a method of making porous particles, the method comprising: providing a support having a surface; forming a first porous layer on the support; Patterning one or more particles on the body; forming a second porous layer on the support having a porosity greater than the porosity of the first porosity; and one or more patterned The particles are released from the support, wherein the release includes breaking of the second porous layer, and the released one or more particles include at least a portion of the first porous layer. Yet another aspect is a method of making porous particles, comprising: providing a support having a surface; forming a first porous layer on the support by wet etching; wet Removing the nucleation layer associated with the etching; patterning one or more particles on the surface of the support; and releasing the patterned one or more particles from the support; The one or more particles include at least a portion of the first porous layer.

[0010] FIG. 1 (A) schematically illustrates a method of making porous particles that includes releasing particles from a support by electropolishing. FIG. 1 (B) schematically illustrates a method of making porous particles that includes releasing particles from a support by electropolishing. [0011] FIG. 2 (A) schematically illustrates a method of making porous particles that includes releasing particles from a support by forming a release porous layer. FIG. 2 (B) schematically illustrates a method of making porous particles that includes releasing particles from a support by forming a release porous layer. [0012] FIG. 3 schematically illustrates a method of making porous particles, where formation of a porous layer on a support precedes particle patterning. [0013] FIG. 4 schematically illustrates a method of making porous particles, where the formation of multiple porous layers on a support precedes particle patterning. [0014] FIG. 5 schematically illustrates a method of making porous particles, where the patterning of the particles on the support precedes the formation of multiple porous layers. FIG. 6 is a scanning electron microscope (SEM) image of 1.2 μm porous silicon particles as seen from the back side. The inset shows a small hole of about 30 nm in the central region of the particle viewed closely. FIG. 7 is an SEM image of 3 μm silicon particles having an oval cross section viewed from above. FIG. 8 is an SEM image of 3.1 μm particles having a hemispherical shape. The inset shows one surface of a particle with small pores of less than 10 nm looking at the details. [0018] FIG. 9A shows SEM images of a porous silicon film with a nucleation layer (FIGS. 9A-B) and a porous silicon film without a nucleation layer (FIG. 9C). FIG. 9B shows SEM images of a porous silicon film with a nucleation layer (FIGS. 9A-B) and a porous silicon film without a nucleation layer (FIG. 9C). FIG. 9C shows SEM images of a porous silicon film with a nucleation layer (FIGS. 9A-B) and a porous silicon film without a nucleation layer (FIG. 9C). [0019] FIG. 10 shows an SEM image of 3.2 micron silicon particles with a 500 nm trench formed by silicon RIE etching. FIG. 11 shows an SEM image of silicon particles having 1.5 μm grooves formed by silicon etching. [0021] FIG. 12 shows 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 the nucleation layer has been removed by RIE. Show. FIG. 13 is an SEM cross-sectional image of silicon particles having two different porous regions along the vertical direction.

[0023] The following documents may be helpful in understanding the present invention, all of which are incorporated herein by reference in their entirety:
1) PCT Publication No. WO2007 / 120248 published on October 25, 2007;
2) US Patent Application Publication No. 2003/0114366;
3) US patent application Ser. No. 11 / 641,970 filed on Dec. 20, 2006;
4) US patent application Ser. No. 11 / 870,777 filed Oct. 10, 2007;
5) US patent application Ser. No. 12 / 034,259, filed on Feb. 20, 2008;
6) Tasciotti et al., Nature Nanotechnology, vol. 3, 151-158, 2008.

Definition
[0024] Unless otherwise specified, "a" or "an" means one or more.
[0025] "Nanoporous" or "nanopores" refers to pores having an average size of less than 1 micron.

  [0026] "Biodegradable" refers to a material that is soluble or degradable in a physiological medium, or that is degraded by physiological enzymes under physiological conditions and / or under chemical conditions. A biocompatible polymeric material that can be made.

  [0027] "Biocompatibility" refers to an undesirable effect in a cell when it is exposed to a living cell, such as a change in the life cycle of the cell; a change in the growth rate of the cell and a cytotoxic effect It refers to material that will maintain the proper cellular function of the cell.

  [0028] "Particle" 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. “Nanoparticle” refers to a particle having a maximum dimension of less than 1 micron.

  [0029] The present inventors have developed a novel porous particle and a method for producing a novel porous particle. According to the first aspect, the particle comprises a body comprising a first porous region and a second porous region, wherein it has at least one characteristic such as pore density, pore size, pore shape, A body defined by the outer surface may be included that differs from the first region in stoma charge, stoma surface modification or stoma orientation.

  [0030] As disclosed in copending US application Ser. No. 11 / 836,004, particles having two different porous regions are loaded, for example, two different populations of smaller particles. Which may contain at least one active agent, such as a therapeutic agent or an imaging agent.

[0031] In some embodiments, at least one of the first and second porous regions may be comprised of a porous oxide material or a porous etched material. In certain embodiments, both the first and second porous regions may comprise a porous oxide material or a porous etched material. Examples of porous oxide materials include, but are not limited to, porous silicon oxide, porous aluminum oxide, porous titanium oxide, and porous iron oxide. The term “porous etched material” refers to a material in which the pores are introduced by wet etching techniques, such as electrochemical etching. Examples of porous etched materials include porous semiconductor materials such as porous silicon, porous germanium, porous GaAs, porous InP, porous SiC, porous Si _x Ge _1-x , porous GaP, and porous GaN are included.

[0032] In many embodiments, the first and second porous regions comprise porous silicon. In many embodiments, at least some or all of the particles consist of porous silicon.
[0033] The body of the particles may have a regular, i.e. non-random, shape in at least one cross-section or when viewed from at least one direction, for example using a microscopic technique such as SEM. . Non-limiting examples of regular shapes include hemisphere, bowl, frustum, cone, and disk.

  [0034] The size of the particle is not particularly limited, and depends on the use of the particle. For example, for intravascular administration, the largest characteristic size of the particles can be smaller than the radius of the smallest capillary, which is about 4-5 microns in humans.

  [0035] In some embodiments, the maximum characteristic size of the particle is 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 about 4 It may be less than micron, or less than about 3 microns, or less than about 2 microns, or less than about 1 micron. Further, in some embodiments, the maximum feature size of the particles may be from 500 nm to 3 microns, or from 700 nm to 2 microns. Further, in some embodiments, the maximum characteristic size of the particles can be greater than about 2 microns, can be greater than about 5 microns, or can be greater than about 10 microns.

  [0036] In some embodiments, the first porous region may differ from the second porous region in the pore size, that is, the pore size of the pores in the first porous region is the first pore size. It may be larger than the size of the small holes in the two regions, and vice versa. For example, the pore size in one of the first and second porous regions is 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 2 to 50 times, Alternatively, it may be 5 to 50 times, or 2 to 20 times, or 5 to 20 times larger than the pore size in the other of the first and second porous regions.

  [0037] In many embodiments, at least one of the first and second porous regions can be a nanoporous region. In certain embodiments, both the first and second porous regions can be nanoporous regions.

  [0038] In some embodiments, the pore size in at least one of the first and second porous regions is about 1 nm to about 1 micron, or about 1 nm to about 800 nm, or about 1 nm to about 500 nm. Or about 1 nm to about 300 nm, or about 1 nm to about 200 nm, or about 2 nm to about 100 nm.

[0039] In some embodiments, at least one of the first and second porous regions is not greater than 1 micron, or not greater than 800 nm, or not greater than 500 nm, or not greater than 300 nm. Or it may have an average pore size not greater than 200 nm, or not greater than 100 nm, or not greater than 80 nm, or not greater than 50 nm. In certain embodiments, both the first and second porous regions are not greater than 1 micron, or not greater than 800 nm, or not greater than 500 nm, or not greater than 300 nm, or greater than 200 nm. They may have their respective average pore size not greater than 100 nm, not greater than 80 nm, or not greater than 50 nm. In some embodiments, at least one of the first and second porous regions can have an average pore size of from about 10 to about 60 nm, or from about 20 to about 40 nm.

  [0040] In some embodiments, at least one of the first and second porous regions has an average pore size of about 1 nm to about 10 nm, or about 3 nm to about 10 nm, or about 3 nm to about 7 nm. Can have a size.

  [0041] In some embodiments, one of the first and second porous regions can have an average pore size of about 10 nm to about 60 nm, or about 20 nm to about 40 nm, while And the other of the first and second porous regions can have an average pore size of about 1 nm to about 10 nm, or about 3 nm to about 10 nm, or about 3 nm to about 7 nm.

[0042] In some embodiments, the pores of the first porous region and the second porous region may have the same or substantially the same orientation, but have different average sizes. Good.
[0043] In general, the pore size may be measured using a number of techniques including N ₂ adsorption / desorption and microscopy, eg, scanning electron microscopy.

  [0044] In some embodiments, the first porous region and the second porous region may have different pore orientations. For example, the outer surface of the particle may include a flat inner surface, and the pores in the first porous region may be substantially perpendicular to the inner surface, while the second porous region. The small holes may face a direction substantially different from the vertical direction, for example, a direction parallel to the inner layer surface. The orientation of the stoma can be determined using microscopic techniques such as SEM.

  [0045] In some embodiments, at least one small hole in the first and second porous regions may be a linear small hole. In some embodiments, the small holes in both the first and second porous regions may be linear small holes.

  [0046] In some embodiments, at least one of the pores of the first and second porous regions may be a sponge-like pore. In some embodiments, the pores in both the first and second porous regions may be sponge-like pores.

  [0047] In some embodiments, one of the pores of the first and second porous regions may be a linear pore, while the other of the first and second porous regions is a sponge. It may be a small hole.

  [0048] In some embodiments, the pores of the first and second porous regions may have different pore surface charges. For example, the stoma surface of the first porous region may be positively charged, while the stoma surface of the second porous region may be neutral or negatively charged.

  [0049] In some embodiments, the pores of the first and second porous regions may have different shapes. For example, one small hole in the first and second porous regions may be a cylindrical small hole, while the other small hole in the first and second porous regions is a non-cylindrical small hole. It's okay. The pore shape may be determined using microscopic techniques, such as SEM.

  [0050] In some embodiments, the pores of the first and second porous regions may have different surface chemistries. The microporous surface of the first porous region may be chemically modified with a first surface group, while the microporous surface of the second porous region is unmodified or the first surface group And may be chemically modified with a different second surface group. For example, 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 is mercaptosilane, such as 3-mercaptopropyl. Silane treatment may be performed with trimethoxysilane.

  [0051] In some embodiments, the pores of the first and second porous regions may have different pore densities. For example, the first porous region may have a higher pore density and vice versa.

  [0052] In some embodiments, at least one of the first and second porous regions may be a biodegradable region. In some embodiments, both the first and second porous regions can be biodegradable. In some embodiments, the entire body of particles can be biodegradable.

[0053] Generally, porous silicon may be bioinert, bioactive, or biodegradable depending on its porosity and pore size. Also, the rate of speed or rate of porous silicon biodegradation may depend on its porosity and pore size, for example Canham, Biomedical Applications of Silicon, in Canham LT, editor. Properties of porous silicon. See EMIS datareview series No. 18. London: INSPEC. p. 371-376. The biodegradation rate may also depend on the surface modification. Thus, the particles are such that the first porous region has a first biodegradation rate, while the second porous region has a second biodegradation rate different from the first biodegradation rate. It may be.

  [0054] In some embodiments, each of the first porosity and the second region has a thickness or smallest feature dimension that is greater than 200 nm, or greater than 250 nm, or greater than 300 nm. It's okay.

  [0055] In some embodiments, the particles may be free or substantially free of a nucleation layer, which is an irregular porous layer, which is usually an etching solution at an early stage of electrochemical wet etching. Is formed when it begins to penetrate into the support. The thickness of the nucleation layer may depend on the substrate being etched and the parameters of the electrochemical wet etching method. With respect to the parameters that can be used to generate nano-sized pores of the support and etch, the thickness of the nucleation layer can be from 1 nm to about 200 nm.

  [0056] In some embodiments, the outer surface of the particle may have a surface chemistry that is different from the chemistry of the surface of at least one of the first and second porous regions. Further, in some embodiments, the outer surface of the particle may have a surface chemistry that is different from the surface chemistry of both the first and second porous regions.

[0057] Particles are top-down fabricated particles, ie top-down microfabrication or nanofabrication techniques such as photolithography, electron beam lithography, X-ray lithography, deep ultraviolet lithography, nanoimprint lithography or immersion pen The particles may be manufactured using nanolithography. The fabrication method can allow for scale-up production of particles that are uniform or substantially identical in size.

  [0058] Thus, the present invention also provides a composition comprising a plurality of particles, wherein each of the plurality of particles comprises a body defined by an outer surface, wherein the body comprises a first porous region and A second porous region comprising a pore density, pore size, pore shape, pore charge, pore surface chemistry, and pore orientation; The at least one characteristic is different from the first region.

  [0059] According to a second aspect, the particles may comprise a body defined by an outer surface, wherein the body is produced by a wet etched porous region, ie a wet etching technique, eg electrochemical wet etching. And the particles are free of nucleation layers associated with wet etching.

  [0060] The particles of the second aspect may have the same dimensions and shapes as discussed above for the particles of the first aspect. The wet-etched porous region may have the same characteristics as the first or second porous region of the particles of the first aspect. The outer surface of the particles of the second aspect may have the same properties as the outer surface of the particles of the second aspect. Like the particles of the first aspect, the particles of the second aspect may be top-down fabricated particles.

  [0061] The particles of the second aspect may be part of a composition comprising a plurality of particles that are uniform in size and substantially identical to the particles. The particles of the first and second embodiments may be produced according to the method of making porous particles detailed below. The particles of the present invention may be used in a variety of applications including drug delivery. In certain cases, an active agent, such as a therapeutic agent or imaging agent, may be placed directly into the pores of the particle. Further, in some cases, smaller sized particles containing the active agent may now be placed in the stoma as disclosed, for example, in US application Ser. No. 11 / 836,004.

How to make porous particles
[0062] Methods for making porous particles include providing a support, forming a porous layer on the surface of the support, patterning one or more particles on the support, and individual It may include releasing the particles from the support such that the released particles comprise a portion of the porous layer. The formation and patterning of the porous layer may be performed in the direct or reverse order. In other words, in some cases, formation of the porous layer may precede pattern formation, while in some other embodiments, formation of the porous layer may be after pattern formation. The method of the present invention utilizes micro / nano fabrication techniques, which have the following advantages: 1) Various predetermined, including but not limited to spherical, square, rectangular and elliptical The ability to make particles with shape; 2) very precise dimensional control; 3) control over porosity and small pore profile; 4) complex surface modifications are possible.

Support
[0063] The support can consist of any of a number of materials. Preferably, the support has at least one flat surface on which one or more particles can be patterned. Preferably, the support comprises a material that can be wet etched, i.e. a material that can be porous by wet etching techniques, e.g. electrochemical etching.

[0064] In certain embodiments, the support may be a crystalline support, such as a wafer. In certain embodiments, the support may be a semiconducting support, i.e. a support comprising one or more semiconducting materials. Non-limiting examples of semiconducting materials include Ge, GaA, InP, SiC, Si _x Ge _1-x , GaP, and GaN. In many embodiments, it may be preferred to utilize silicon as the support material. The properties of the support, such as the level of doping, the resistivity and the orientation of the surface crystals, may be selected to obtain the desired pore characteristics.

Formation of porous layer
[0065] The porous layer may be formed on the support using a number of techniques. Preferably, the porous layer is formed using wet etching techniques, i.e. by exposing the support to an etching solution comprising at least one etchant, such as a strong acid. The particular etchant may depend on the support material. For example, for a germanium support, the etchant may be hydrochloric acid (HCl), while for a silicon support, the etchant may be a hydrofluoric acid etchant. Preferably, the formation of the porous layer is performed using an electrochemical etching method, during which an etching current is passed through the support. Electrochemical etching of a silicon support to form a porous silicon layer is described in detail, for example, in Salonen et al., Journal of Pharmaceutical Sciences, 2008, 97 (2), 632. For electrochemical etching of a silicon support, the etching solution may contain water and / or ethanol in addition to HF.

  [0066] In some embodiments, the support may serve as one of the electrodes during the electrochemical etching process. For example, during the electrochemical etching of silicon, the silicon support may serve as the anode, while the cathode may be an inert metal, such as Pt. In that case, the porous layer is formed on the side of the support facing away from the inert metal cathode. Furthermore, in some other embodiments, during electrochemical etching, the support may be placed between two electrodes, each of which may contain an inert metal.

  [0067] The electrochemical etching process may be performed in a reactor or cell that is resistant to the etchant. For example, if the etchant is HF, the electrochemical etching process may be performed in a reactor or cell that contains a material that is resistant to HF. Examples of materials resistant to HF include fluoropolymers such as polytetrafluoroethylene. Electrochemical etching may be performed by monitoring the current at one of the electrodes, for example by monitoring the anode current (at constant current) or voltage (at low voltage). In some embodiments, it may be preferable to perform the electrochemical etching at a constant current density, which may provide better control of the properties of the porous layer that is formed and / or better reproducibility between samples. Can be made possible.

  [0068] In some embodiments, two different constant currents may be applied if it is desired to form two different stable porous regions. For example, a first current density may be 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 is a small pore. May be different from the first stable porous layer in size and / or porosity.

[0069] In some embodiments, the parameters of the porous layer that is formed, eg, pore size, porosity, thickness, pore cross-sectional shape and / or pore shape, and thus the particles produced Each of the parameters of the electrochemical etch process parameters such as the concentration and composition of the etching solution, applied current (and voltage), etching time, temperature, agitation conditions, presence or absence of illumination (and illumination parameters such as intensity and Wavelength), and further parameters of the substrate to be etched, such as the composition of the substrate, the resistivity of the substrate, the crystallographic orientation of the substrate, and the level and type of doping of the substrate.

  [0070] In some embodiments, it may have a predetermined longitudinal cross-sectional shape along the pores in the formed porous layer, which is perpendicular or substantially to the surface of the support. The cross-sectional shape is perpendicular to. The longitudinal cross-sectional shape may be generated by varying the current density during electrochemical etching. With respect to the longitudinal pores in the porous layer, both porosity and pore size may be varied. Thus, in some embodiments, the cross-sectional shape of the pores in the porous layer and in the fabricated porous particles has a smaller size at the top, ie, the surface of the support, and at the bottom, ie, the support. It may have larger pores in the deeper part. Further, in some embodiments, the cross-sectional shape of the pores in the porous layer and in the fabricated porous particles may have a larger size at the top and a smaller size at the bottom. In some embodiments, the cross-sectional shape of the pores in the porous layer and in the fabricated particles may have different porosity at the top and at the bottom.

  [0071] In many embodiments, electrochemical etching may be initiated with short pulses of higher current to prevent or reduce nucleation layer formation. The nucleation layer may be removed by etching the nucleation layer after formation of the porous layer. The etching may be performed by dry etching techniques such as RIE. Appropriate measurements may be made to protect the area below. For example, photoresist may be placed on the surface, planarization may be performed by baking, and plasma etchback may then be applied to expose a portion of the surface of the support that must be etched. .

  [0072] With respect to electrochemical etching, the back side of the support, i.e., the side opposite the side where the porous layer of the support is formed, is a conductive layer, for example a layer of metal, to ensure electrical contact. It may be coated with. The conductive layer may be coated using a number of techniques including thermal evaporation and sputtering.

Nucleation layer
[0073] During electrochemical etching, the etching solution can begin to form its pores through the formation of a nucleation layer, which is a layer on the surface of the support, where the pores are porous layers. Have different properties than desired. The nucleation layer may be characterized by irregularities in the characteristics of its pores and the associated surface roughness, which may be on a scale larger than the pore size.

  [0074] In many applications, a nucleation layer on the surface of the porous particles is undesirable. For example, if silicon porous particles are used to enclose smaller sized particles inside them, the nucleation layer on the larger surface may reduce the efficiency of insertion.

  [0075] In some embodiments, the nucleation layer is removed or prevented from forming. In some embodiments, during electrochemical etching, a larger current may be applied to prevent formation of the nucleation layer before the current is applied to create the desired pores in the porous layer. Further, in some embodiments, after the formation of the porous layer, the nucleation layer may be removed by dry etching, such as RIE.

Pattern formation
[0076] Patterning of one or more particles on the surface of a support may be performed using any of a number of techniques. In many embodiments, patterning is a lithographic technique,
For example, it may be performed using photolithography, X-ray lithography, deep ultraviolet lithography, nanoimprint lithography or immersion pen nanolithography. The photolithography technique can be, for example, contact aligner lithography, scanner lithography, or immersion lens lithography. By using different masks (in the case of photolithography) or molds, it has many predetermined regular or non-random shapes such as spherical, square, rectangular, elliptical, disc and hemispherical shapes There is a possibility that the particles can be designed. Patterning may be used to define the lateral shape and dimensions of the particles, ie the shape and dimensions of the particles in a cross section parallel to the surface of the support. If the formation of the porous layer precedes patterning, the lateral dimensions of the fabricated particles are substantially the same as the lateral dimensions of the features to be patterned. If the patterning precedes the formation of the porous layer, the lateral dimensions of the fabricated particles may be larger than the lateral dimensions of the features to be patterned. Patterning makes it possible to produce particles having a predetermined regular, ie non-random lateral shape. For example, patterning in photolithography can produce the desired predetermined shape using various shapes of masks, while in nanoimprint lithography the same for various shapes or stamps. Can be used for purposes. The predetermined non-random lateral shape for the particles is not particularly limited. For example, the particles may have a circular, square, polygonal or elliptical shape.

release
[0077] In some embodiments, the particles may be released from the wafer by electropolishing after the patterning and porous layer formation steps, which may include applying a sufficiently high current density to the wafer. Further, in some embodiments, releasing the particles from the wafer may include forming an additional porous layer having a greater porosity than the previously formed porous layer. This higher porosity layer will be referred to as the release layer. The release layer can have a porosity large enough to be able to break it easily when desired, for example using mechanical techniques, e.g. exposing the support to ultrasonic energy. . At the same time, the release layer can be strong enough to keep the previously formed porous layer intact with the support.

Surface modification
[0078] Any of a number of techniques may be used to modify the surface properties of the particles, ie, the surface properties of the outer surface of the particles and / or the surface properties of the pores of the particles. In many embodiments, modification of the surface of the fabricated particle may be made before the particle is released while the particle is still intact with the support. Types of surface modification for particles include chemical modification including polymer modification and oxidation; plasma treatment; metal or metal ion coating; chemical vapor deposition (CVD) coating, atomic layer deposition; vapor deposition and sputtered film, and ion implantation However, it is not limited to them. In some embodiments, the surface treatment is biological for biomedical targeting and controlled degradation.

[0079] Since modification of the surface of the particles may be performed before the particles are released from the support, asymmetric surface modification is also possible. Asymmetric surface modification means that the surface modification on one side of the particle is different from that on the other side of the particle. For example, one side of the particle surface may be modified while the other side of the particle surface may be left unmodified. For example, the pores of the particles may be completely or partially filled with a sacrificial material, such as a sacrificial photoresist. Thus, only the outer surface of the particles is treated during surface modification. After selective removal of the sacrificial material, only the outer surface of the particle is modified, i.e. the pore surface of the particle remains unmodified. In some embodiments, the outer surface may be patterned, for example, by photolithography, so that some portion of the outer surface may have one modification while another portion of the outer surface has another modification. You can do it. A typical surface modification protocol is further indicated in the text. The embodiments described herein are further illustrated by, but not limited to, the following working examples.

Example 1: Fabrication of porous silicon particles. Release by electropolishing.
[0080] In the method schematically illustrated in FIGS. 1A and 1B, the patterning of the particles precedes the formation of the porous layer, and the release of the particles is performed by electropolishing. Fabrication may begin with obtaining a silicon wafer 101. The surface of the wafer 101 may optionally be roughened by treatment, such as immersion in KOH or reactive ion etching (RIE). Roughening the surface can help remove the nucleation layer on the surface or prevent its formation. A protective layer 102 may then be deposited on at least one surface of the wafer 101 to protect the wafer from electrochemical etching in a HF-based solution. The protective layer 102 may be a material resistant to electrochemical etching in HF solution. Examples of the material include silicon nitride or photoresist.

  Next, the protective layer 102 may be patterned. 1A and 1B illustrate patterning of a protective layer by lithographic techniques. As shown in FIGS. 1Ac and 1Bc, a layer of resistant material 103 is deposited on the protective layer 102. The resistant material may be a material that does not come off under conditions where the protective layer comes off. One example of the material is a photoresist. Undesired regions 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 of the wafer; see FIGS. 1Ac and 1Bc. Resistant material 103 may be removed as well; see FIG. 1Ad. The protective layer may be patterned in such a way that the space between the patterned areas 110 of the protective layer defines the shape and dimensions of the particles to be fabricated.

  [0082] In some cases, grooves may be formed in the spaces 104 between the patterned regions 110 of the protective layer, as illustrated in FIG. 1Bd. The trench may be formed by, for example, a dry etching technique, such as RIE. The depth and shape of the grooves may be used to define the cross section of the particles perpendicular to the surface of the support and hence the shape of the particles. The depth and shape of the grooves may be for controlling the mechanical and / or pore characteristics of the fabricated particles.

  [0083] The porous layer 106 may be formed in and around a space that is not protected by the patterned region 110 of the protective layer; see FIGS. 1Af and 1Bf. To form the porous layer 106, the wafer may be exposed to a solution that may contain HF and optionally a surfactant, such as ethanol, under DC current, which results in pores of the desired size. May be selected. If the nucleation layer 105 is not desired, a larger DC current may be applied before applying a DC current corresponding to the desired pore size; see FIG. 1Ae.

  [0084] The formed porous layer 106 has two different pore orientations in the region not protected by the patterned region 110 and in the region of the support under the protective layer region 110. You may have. The former may have a stoma oriented in a direction perpendicular or substantially perpendicular to the surface of the support, while the latter is oriented parallel to the surface of the support or on the surface. It may have a small hole angled at an angle substantially different from 90 °.

  [0085] The particles 108 or 109 may be released by electropolishing, which may form a gap 107 under the porous layer 106; see FIGS. 1Ag, h and 1Bg, h. The remaining protective layer may then be removed. The particles may be collected in solution by a number of techniques including filtration. The particles 109 have grooves formed in them that may define their shape and their mechanical and pore characteristics. For example, the portion below the groove of the particle 109 may have a pore size and porosity that is different from the pore size and porosity on the side of the particle 109, ie, the non-groove portion of the particle 109.

Example 2 Production of porous silicon particles. Release by forming a second porous layer
[0086] In the method schematically illustrated in FIGS. 2A and 2B, the patterning of the particles precedes the formation of the porous layer, and the release of the particles is performed by the formation of the second porous layer. The fabrication method may begin with obtaining a silicon wafer 201. As in the above protocol, the surface of the wafer 201 may be roughened, for example, by immersion in KOH or RIE. As in Example 1, a protective layer 202 may then be deposited on the wafer to protect the wafer from electrochemical etching in an HF-based solution; see FIG. 2Aa. As in Example 1, the protective film 202 may then be patterned using, for example, lithographic techniques; see FIGS. 2Ab, c and 2Bb, c. As in Example 1, patterning may include deposition of a resistant film 203; see FIGS. 2Bb and 2Ab. Undesired areas 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 FIGS. 2Ac and 2Bc. As in Example 1, the protective layer 202 may be patterned in such a way that the space between the patterned areas 210 defines the shape and dimensions of the particles to be fabricated.

  [0087] In some cases, grooves 204 may be formed in the spaces between the patterned regions 210 of the protective layer, as illustrated in FIG. 2Bd. The groove may be formed by dry etching, for example, RIE. The depth and shape of the grooves may be used to define the cross section of the particles perpendicular to the surface of the support and hence the shape of the particles. The depth and shape of the grooves may be used to control the mechanical and pore properties of the formed particles.

  [0088] The porous layer 206 may be formed in and around the space not protected by the patterned region 210 of the protective layer; see FIGS. 2Ae, f, and 2Bf. To form the porous layer 206, the wafer may be exposed to a solution that may contain HF and optionally a surfactant under DC current, the value selected to produce pores of the desired size. May be. If a nucleation layer is not desired, a larger DC current may be applied before applying a DC current corresponding to the desired pore size.

  [0089] The formed porous layer 206 has two different pore orientations in the region not protected by the patterned region 210 and in the region of the support below the protective layer region 210. You may have. The former may have small holes oriented in a direction perpendicular or substantially perpendicular to the surface of the support, while the latter is oriented parallel to the surface of the support, or the support There may be a small hole angled at an angle substantially different from 90 ° with respect to the surface.

  [0090] After formation of the porous layer 206, a larger current may be applied to form a second porous layer 207 having a greater porosity than the first layer; see FIGS. 2Bf and 2Af. This larger current can be selected so that the second porous layer 207 is brittle enough for mechanical disruption but still holds the particles in place.

[0091] If the nucleation layer has not been removed earlier, it may be removed at this stage by using dry etching techniques such as RIE. The patterned area 210 of the protective film may then be removed; see FIGS. 2Ag and 2Bg. The particles retained by the second porous layer 207 in the wafer 201 can then be chemically modified if desired.

  [0092] The particles 208 or 209 may be released from the wafer 201 by breaking the second porous layer 207 in solution, which can be done, for example, by exposing the wafer to ultrasonic vibrations, for example. See FIGS. 2Ah and 2Bh. The particles 209 have grooves formed in them, which may define their shape and their mechanical and pore characteristics. For example, the portion of the particle 209 below the groove may have a pore size and porosity that is different from the size and porosity of the side of the particle 209, ie, the non-groove portion of the particle 209.

  [0093] The shape of the particles produced in Examples 1 and 2 may be hemispherical, bowl-shaped, frustum or the like depending on the etching conditions. For example, for saddle-shaped shapes, the depth of the wrinkles can depend on the depth of the grooves formed in the particle pattern prior to electrochemical wet etching.

Example 3 Fabrication of porous silicon particles
[0094] In the method schematically illustrated in FIG. 3, the formation of the porous layer precedes the patterning of the particles. The method may begin with obtaining a silicon wafer 301. To form the porous layer 302, the wafer may then be exposed to a solution that may contain HF and optionally a surfactant under DC current, the value of which obtains pores of the desired size in the layer 302. May be selected; see FIG. 3a. Subsequently, a larger current may be applied to form the second porous layer 303 in the support 301 below the first porous layer. This larger current may be selected such that the second porous layer 303 has a greater porosity than the first porous layer 302; see FIG. 3b. Preferably, this larger current is selected so that the porous layer 303 is brittle enough to dynamically collapse if necessary, while at the same time holding the particles in place in the wafer.

  [0095] After formation of the second porous layer, the particles may be patterned. For example, a photoresist layer can be deposited on the porous silicon film 301. The photoresist layer may then be patterned to define the particles. For example, in FIG. 3, the patterned region 304 (FIG. 3c) of the photoresist layer defines the particles. Undesired regions of the porous silicon layer 302, i.e. regions of the porous layer 302 not covered by the patterned region 304 of the photoresist layer, may be removed, for example, by dry etching, eg, RIE; FIG. reference. The patterned region 304 of photoresist may then be removed.

  [0096] The particles retained by the second porous layer 303 in the wafer 301 (see FIG. 3e) may then be chemically modified if desired. The particles 306 may be released from the wafer 301 by breaking the second porous layer 302 in solution, which can be done, for example, by mechanical means, for example by exposing the wafer to ultrasonic vibrations; FIG. reference.

Example 4 High yield production of porous silicon particles I
[0097] The method of Example 3 may be transformed into a multi-layer method, which may allow for high yields of fabricated particles. The method may begin with obtaining a silicon wafer 401. The wafer 401 may then be exposed to the HF / surfactant solution and a DC current may be applied for a specified time to form the first porous silicon layer 402; see FIG. 4a. Then, a larger current may be applied to form a second porous layer 403 having a greater porosity as a release layer. This larger current may be selected so that the second porous layer 403 is brittle enough for mechanical disruption, while at the same time retaining the particles in the wafer 401.

  [0098] A periodic layer structure is formed by repeating the steps of forming a stable porous layer, for example, the first porous layer 402, and a breakable release porous layer, for example, the second porous layer 403. It's okay. For example, FIG. 4 b shows its periodic structure, where the stable porous layer 402 is separated by a breakable release layer 403. Particle patterning may then be performed.

[0099] For example, a masking layer, such as a metal film, may be deposited over the top first porous layer 402. The photoresist layer may be placed on top of the masking film. If no metal masking film is to be deposited, the photoresist may be placed directly on the top first porous layer 402. Lithographic techniques may then be applied to pattern the photoresist layer. As shown in FIG. 4c, the patterned photoresist layer may include a patterned photoresist region, which may define the shape and dimensions of the fabricated particles. The unwanted region of the periodic porous structure is then removed, i.e. the region not covered by the patterned photoresist region 404 of the periodic structure, and the top is covered by the patterned photoresist region 404. A covered stack 406 may be formed; see FIG. 4d. The photoresist film and / or masking film may then be removed from the top of the stack 406, for example by using a piranha solution (1 volume H ₂ O ₂ and 2 volumes H ₂ SO ₄ ); FIG. See If desired, the particles 405 formed from a portion of the stable porous layer and retained in the stack 406 by a releasable porous layer may then be chemically modified. Release of the particles 405 from the stack 406 into the solution may be performed by subjecting the wafer 401 having the stack 406 to ultrasonic vibrations, such as mechanical means; see FIG. 4f.

Example 5 FIG. High yield fabrication of porous silicon particles II
[0100] This example shows another method for high yield fabrication of porous silicon particles. Starting from the silicon wafer 501, 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, a silicon dioxide film or a photoresist film. The protective film may be patterned to form a patterned area 502 of the protective layer, which defines the cross-sectional shape and dimensions of the fabricated particles; see FIG. 5a. The pattern formation of the first protective layer may be performed in the same manner as the pattern formation of the protective layer illustrated in FIGS.

  [0101] An anisotropic etching technique may then be applied to the unprotected area of the wafer to form pillars 503 below the patterned area 502 of the protective film; see FIG. 5b . Then, the uppermost protective film 502 of the pillar 503 may be removed. A second protective layer 504 may then be deposited over the pillars 503 and in the etched regions 508 between the pillars 503; see FIG. 5c. The second protective layer 504 can be such that it can protect the wafer from electrochemical etching in a HF-based solution. For example, the second protective layer 504 can be a silicon nitride film or a photoresist film. Next, a part of the second protective layer 504 may be removed by, for example, etching or planarization to expose the uppermost portion of the pillar 503. Preferably, after its removal, the second protective layer 504 remains intact on the sides of the etched region 508 and at the bottom; see FIG. 5d.

[0102] A wafer having patterned pillars may then be exposed to an HF-based solution under an applied DC current to form a first porous layer 505 from which particles are formed. A stable porous layer. The applied DC current may be selected to form pores having the desired size in the particles. Thereafter, a larger current may be applied to form the second porous layer 506, which is an open porous layer having a greater porosity than the first porous layer 505. This larger current makes the open porous layer brittle enough for fragmentation and mechanical disruption, while it is strong enough to hold the particles in place before release. May be selected. The steps of forming a stable porous layer, such as layer 505, and a release layer, such as layer 506, may be repeated as many times as desired to form a periodic layer structure in pillar 503. For example, FIG. 5 (e) shows a periodic structure 509 formed by alternating stable porous layers 505 and open porous layers 506. Once the periodic layer structure 509 is formed, the remaining second protective layer 504 may be removed; see FIG. 5f.

  [0103] If desired, the particles 507 formed from a portion of the stable porous layer 505 and retained in the periodic stack 509 by the releasable porous layer 506 are then chemically modified. You can do it. Release of the particles 507 from the stack 509 into the solution may be accomplished by exposing the wafer 501 with mechanical means, eg, the stack 509, to ultrasonic vibration; see FIG. 5g.

  [0104] In the above method, the step of forming a release layer having a large porosity may be replaced by electropolishing. In this case, the periodic structure formed may include gaps formed by electropolishing instead of alternating stable and open porous layers. The stable porous layer may be held intact on the wafer by the remaining second protective layer 504. In that case, release of the formed particles from the stable porous layer may be carried out by removing the remaining second protective layer. Prior to release, it may be chemically modified while the particles are still intact and with the wafer.

Surface modification protocol
[0105] Provided below is a typical protocol that may be used for surface modification of silicon particles by oxidation, silanization and targeting moieties such as antibody binding.

Oxidation of silicon fine particles
[0106] Silicon microparticles in IPA can be dried in a glass beaker placed on a hot plate (80-90 ° C). Silicon particles can be oxidized in piranha (1 volume H ₂ O ₂ and 2 volumes H ₂ SO ₄ ). After the H ₂ O ₂ addition, the particles can be sonicated and then the acid can be added. The suspension can be heated to 100-110 ° C. for 2 hours with intermittent sonication to disperse the particles. The suspension can then be washed in DI water until the pH of the suspension is about 5.5-6. The particles can then be transferred to a suitable buffer, IPA (isopropyl alcohol), or stored in water and refrigerated until further use.

Silane treatment
[0107] Oxidation. Prior to the silane treatment process, the oxidized particles can be hydroxylated in 1.5M HNO ₃ acid for approximately 1.5 hours (at room temperature). The particles can be washed 3-5 times in DI water (washing can include suspension and centrifugation in water followed by removal of the supernatant and repetition of the procedure).

[0108] APTES processing. The particles can be suspended in IPA (isopropyl alcohol) by washing them twice in IPA. The particles can then be suspended in an IPA solution containing 0.5% (v / v) APTES (3-aminopropyltriethoxysilane) for 45 minutes at room temperature. The particles can then be washed 4-6 times with IPA and stored refrigerated in IPA. Alternatively, the particles can be aliquoted to dry and stored under vacuum and desiccant until further use.

  [0109] MPTMS processing. The particles can be hydroxylated in HNO3 using the same procedure as described above. After washing with water and IPA, the particles can be silanized with 0.5% v / v and 0.5% v / v MPTMS (3-mercaptopropyltrimethoxysilane) in IPA for 4 hours. The particles can then be washed 4-6 times with IPA and then refrigerated in IPA, or aliquoted and dried and stored under vacuum and desiccant.

[0110] Conjugation of antibodies. Microparticles can be modified with APTES and / or MPTMS as described above. Sulfoimidsyl 4-N-maleimidomethyl cyclohexane-1-carboxylate (SMCC), a water-soluble analog of the crosslinker, can be used to crosslink particles and anti-VEGFR2 antibodies. The total number of particles used to complex both APTES and MPTMS particles with anti-VEGFR2 can be about 7.03 × 10 ⁶ . Wash and centrifuge the particles 6 times in phosphate buffer containing 0.5% Triton X-100, followed by 4 washes in phosphate buffer with nothing added, then read on a plate reader Can do.

  [0111] Cups comprising antibodies, eg, IgG, EGFR, VEGFR, surface silanized to nanoporous silicon particles, followed by readily available protein crosslinkers that can covalently bind these antibodies. Immobilization via a chemical scaffold by the ring method has been shown experimentally.

Surface modification using APTES
[0112] In a typical surface modification, porous silicon particles can be hydroxylated in 1.5M HNO ₃ for 1 hour. Amine groups are introduced on the surface by silanization for 30 minutes at room temperature with a solution containing 0.5% v / v 3-aminopropyltriethoxysilane (APTES) in isopropanol (IPA). It can be coated with a thiol group of 0.5% in IPA on the surface of the v / v 3- mercaptopropyltrimethoxysilane (MPTMS) and _{0.5% v / v H 2 O} . APTES coated and MPTMS coated particles are suspended in phosphate-buffered saline (PBS) and the cross-linking agent 1 mM N-succinimidyl-S-acetylthioacetate (SATA), 1 mM sulfosuccinimidyl 4- (N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC), 1 mM N-succinimidyl [4-iodoacetyl] aminobenzoate (sulfo-SIAB), or 1 mM succinimidyl 6- ( It can be reacted with 3- [2-pyridyldithio] -propionamido) hexanoate (SPDP) for 1 hour at room temperature. The antibody can then be bioconjugated onto the particle.

Example 6: Fabrication of "large pore" silicon particles
FIG. 6 shows a scanning electron microscope image of 1.2 μm porous silicon particles produced as follows. A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as the support. A 200 nm layer of silicon nitride was deposited by a low pressure chemical vapor deposition (LPCVD) system. Using standard photolithography, a 1 μm circular particle pattern was patterned using an EVG620 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. A 300 nm silicon trench was etched into the silicon in the exposed particle pattern. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). An aluminum film was coated on the back side of the wafer. The wafer was then placed in a homemade Teflon® cell for electrochemical etching. Nanopores were formed in a mixture of hydrofluoric acid (HF) and ethanol (3: 7 v / v) by applying a current density of 80 mA / cm ² for 25 seconds. An open high porosity layer was formed by applying a current density of 400 mA / cm ² for 6 seconds. After removal of the nitride layer by HF, the particles were released by exposure to ultrasound in IPA for 1 minute. IPA containing porous silicon particles was collected and stored.

  [0114] The morphology of the silicon particles was measured using a LEO 1530 scanning electron microscope. The particles in IPA were placed directly on an aluminum SEM sample stage and dried. Place the SEM platform with the particles into the LEO 1530 sample chamber. The acceleration voltage of the electron beam is 10 kV, and the working distance is about 5 mm.

  [0115] The SEM image of FIG. 6 has a circular (1.2 μm diameter) shape parallel to the wafer surface as seen from the back side, ie, the side away from the front surface of the wafer during fabrication. Particles. The overall three-dimensional shape of the particles in FIG. 6 is hemispherical. The image in FIG. 6 shows regions 601 and 602, which correspond to small holes parallel or angled to the surface and small holes perpendicular to the surface, respectively. The size of the small hole in the center of the particle is about 30 nm. The resulting particles are larger than the original pattern, because the porous layer can enter under and within the protected area of the support during electrochemical etching.

Example 7 Fabrication of oval-shaped “large pore” silicon particles
FIG. 7 shows an SEM image of silicon particles having an oval cross section. The particles were made as follows. A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as the support. A 200 nm layer of silicon nitride was deposited by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 2 μm oval shaped particles using an EVG620 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. A 600 nm silicon trench was etched into the silicon in the exposed particle pattern. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. The etching solution was a mixture of hydrofluoric acid (HF) and ethanol (3: 7 v / v). The nucleation layer was removed by applying a high density current of 400 mA / cm 2 for 1 second. Next, a current density of 80 mA / cm ² was applied for 25 seconds to form nanopores. A high porosity release layer was formed by applying a current density of 400 mA / cm ² for 6 seconds. After removing the nitride layer by HF, the particles were released in IPA by sonication for 1 minute. An IPA solution containing porous silicon particles was collected and stored. One drop of the IPA solution containing the prepared particles was placed directly on an aluminum SEM sample stage and dried. SEM images were measured using a LEO 1530 scanning electron microscope. The acceleration voltage of the electron beam is 10 kV, and the working distance is about 5 mm. The SEM image in FIG. 7 shows the resulting particles viewed from above. The particles have a region 701 where the pores are parallel or angled with respect to the surface and a region 702 where the pores are perpendicular to the surface.

Example 8: Production of "small pore" silicon particles
FIG. 8 is an SEM image showing 3.1 μm particles having a hemispherical shape. The particles were made as follows. A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as the support. A 200-350 nm layer of silicon nitride was deposited on the support by a low pressure chemical vapor deposition (LPCVD) system. A 2 μm circular particle pattern was formed using photolithography. 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. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. In a mixture of hydrofluoric acid (HF) and ethanol (1: 1 v / v), a current density of 6 mA / cm ² was applied for 1 minute 45 seconds to form nanopores. A high porosity release layer was formed by applying a higher current density of 320 mA / cm ² in a mixture of hydrofluoric acid (HF) and ethanol (2: 5 v / v) for 6 seconds. After removing the nitride layer by HF, the particles were released by exposing the support to ultrasonic vibration for 1 minute. A drop containing particles in IPA was placed directly on an aluminum SEM sample stage and allowed to dry. SEM images were measured using a LEO 1530 scanning electron microscope. The acceleration voltage of the electron beam is 10 kV, and the working distance is about 5 mm. The SEM image in FIG. 8 shows the fabricated particles. The inset shows the fabricated particles having a pore size of less than 10 nm.

Example 9: Fabrication of "large pore" silicon particles
FIG. 10 shows an SEM image of 3.2 μm silicon particles having a 500 nm groove. The particles were made as follows. A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as the support. A 100 nm layer of low stress silicon nitride was deposited on the support by a low pressure chemical vapor deposition (LPCVD) system. Using standard photolithography, a 2 μm circular particle pattern was patterned using an EVG620 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. A 500 nm silicon trench was etched by RIE into the silicon on the exposed particle pattern. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. 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 seconds. A higher porosity release layer was formed by applying a current density of 220 mA / cm ² for 6 seconds. After removing the nitride layer by HF, the particles were released by exposing the wafer to ultrasonic vibration for 1 minute in IPA. An IPA solution containing porous silicon particles was collected and stored.

  [0119] A drop containing particles in IPA was placed directly on an aluminum SEM sample stage and allowed to dry. SEM images were measured using a LEO 1530 scanning electron microscope. The acceleration voltage of the electron beam was 10 kV; the working distance is about 5 mm. The SEM image of FIG. 10 shows the obtained bowl-shaped particles. The particles have about 30 nm pores on the bottom of the wrinkles and smaller pores on the sides.

Example 10: Fabrication of "large pore" silicon particles by deep groove etching
[0120] FIG. 11 shows an SEM image of fabricated silicon particles having about 1.5 μm deep grooves formed by silicon etching. The particles were made as follows.

[0121] A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as a support. A 100 nm layer of low stress silicon nitride was deposited on the support by a low pressure chemical vapor deposition (LPCVD) system. Using standard photolithography, a 2 μm circular particle pattern was patterned using an EVG620 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. A 1500 nm silicon trench was etched into the silicon on the exposed particle pattern. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. 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 seconds. A high porosity release layer was formed by applying a current density of 220 mA / cm ² for 6 seconds. After removing the nitride layer by HF, the particles were released by exposing the wafer to ultrasonic vibration for 1 minute in IPA. An IPA solution containing porous silicon particles was collected and stored.

  [0122] A drop containing particles in IPA was placed directly on an aluminum SEM sample stage and allowed to dry. SEM images were measured using a LEO 1530 scanning electron microscope. The acceleration voltage of the electron beam is 10 kV, and the working distance is about 5 mm. The SEM image in FIG. 11 shows the resulting bullet-shaped particles. The bullet tip 1101 has a small hole of about 30 nm, while the bullet body 1102 has a smaller hole.

Example 11: Fabrication of "large pore" silicon particles with nucleation layers removed by RIE
[0123] FIG. 12 shows SEM cross-sectional images of fabricated 3.2 μm silicon particles with 500 nm silicon trench etching: left: with nucleation layer; right: nucleation layer removed by RIE. The particles were made as follows. A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as the support. A 100 nm layer of low stress silicon nitride was deposited on the support by a low pressure chemical vapor deposition (LPCVD) system. Using standard photolithography, a 2 μm circular particle pattern was patterned using an EVG620 aligner. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the back side of the wafer was also removed by RIE. A 500 nm silicon trench was etched into the silicon on the exposed particle pattern. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. 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 seconds. A high porosity release layer was formed by applying a current density of 220 mA / cm ² for 6 seconds. A short time CF4 RIE was then applied to remove the nucleation layer.

  [0124] The particles were not released from the wafer for cross-sectional studies. Instead, after removing the nitride layer with HF, the wafer was split and mounted on a 45 degree aluminum SEM sample stage. SEM images were measured using a LEO 1530 scanning electron microscope. The acceleration voltage of the electron beam is 10 kV, and the working distance is about 5 mm. The SEM image of FIG. 12 compares the resulting particles with a nucleation layer and the cross section of the particles after removal of the nucleation layer. Particles with a nucleation layer have pores of less than 10 nm in the top region 1201 and have pores of about 30 nm below the nucleation layer 1202, while particles without a nucleation layer have top region. There is a small hole of about 30 nm in both 1203 and the region 1204 below the top.

Example 12: Production of "large pore" silicon particles with two different porosities along the direction of the pores
FIG. 13 shows an SEM image of porous particles having two different porous regions along the direction of the small holes. The particles were made as follows. A highly doped p ++ type (100) wafer (Silicon Quest Inc) having a resistivity of 0.005 ohm-cm was used as the support. A 100 nm layer of low stress silicon nitride was deposited on the support by a low pressure chemical vapor deposition (LPCVD) system. Using standard photolithography, a 2 μm circular particle pattern was patterned using an EVG620 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. A 500 nm silicon trench was etched into the silicon on the exposed particle pattern. The photoresist was removed using piranha (H ₂ SO ₄ : H ₂ O ₂ = 3: 1 by volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. A mixture of hydrofluoric acid (HF) and ethanol: in (1 3 v / v) in 50 seconds a current density of 16 mA / cm ^2, and to form a nanopore current density of 37 mA / cm ² was added 22 seconds .

  [0126] The particles were not released from the wafer for cross-sectional studies. Instead, after removing the nitride layer with HF, the wafer was split and mounted on a 45 degree aluminum SEM sample stage. SEM images were measured using a LEO 1530 scanning electron microscope. The acceleration voltage of the electron beam is 10 kV, and the working distance is about 5 mm. The SEM image of FIG. 13 shows the resulting particles having two different porosity regions 1301 and 1302 along the longitudinal direction in addition to the nucleation layer 1303. The stoma in both regions 1301 and 1302 is perpendicular to the surface. Region 1301 has a greater porosity than region 1302.

Example 13: Fabrication of porous silicon film
[0127] Figure 9 shows images of two types of porous silicon films, one with a nucleation layer (Figures 9A-B) and the other without a nucleation layer (Figure 9C). The film was made as follows:
[0128] Highly doped p ++ type (100) wafer (Silicon Quest
Inc) was used as the support. The wafer was placed in a homemade Teflon® cell for electrochemical etching. The etching solution is a mixture of hydrofluoric acid (HF) and ethanol (2: 5 v / v). A high density current of 320 mA / cm ² was applied for 1 second to remove the nucleation layer. A nanopore was formed by applying a current density of 80 mA / cm ² for 25 seconds. While reference has been made to certain preferred embodiments above, it will be understood that the invention is not so limited. Those skilled in the art will recognize that various modifications may be made to the disclosed aspects and that the modifications are intended to be within the scope of the present invention.

  [0129] Some specific embodiments include the following. A method of fabricating nanoporous silicon particles comprising: providing a silicon support including a surface; forming a porous layer on the surface; patterning a plurality of particles on the support by lithography Forming, the particles comprising the porous layer; and releasing the particles from the resulting support comprising the patterned porous particles. In some embodiments, lithographic patterning is performed prior to the formation of the porous region on the surface.

  [0130] In some embodiments, releasing the particles comprises dynamically releasing the particles from lithographically patterned porous particles. In some embodiments, forming the porous layer includes forming a first porous layer and forming a second porous layer, wherein the porosity of the second layer is that of the first layer. Bigger than. In some embodiments, a protective layer is applied over the support. In certain embodiments, the protective layer comprises a silicon nitride or photoresist film. In some embodiments, releasing the particles from the support includes removing unwanted regions of the protective layer.

  [0131] According to some embodiments of the above method, patterning comprises defining a predetermined shape for the resulting particles. In some embodiments, the predetermined shape is selected from the group consisting of a sphere, a square, a rectangle, an ellipse, a disk, and a hemisphere.

  [0132] According to some embodiments, forming the porous layer includes adjusting the properties of the resulting silicon particles. In certain embodiments, the characteristics include the porosity, pore size and pore cross-sectional shape of the resulting silicon particles. In certain embodiments, the formation of the porous layer includes electrochemically treating the support. In certain embodiments, electrochemically treating the support includes treatment with a solution comprising hydrofluoric acid and a surfactant. In certain embodiments, adjusting the properties of the silicon particles can include selecting a concentration of the solution, selecting a current, and selecting an etching time to provide silicon particles having predetermined properties. And selecting a doped silicon support.

  [0133] According to some embodiments of the above method, the silicon particle includes an outer surface and a porous interior, and the method further includes imparting a function to at least a portion of the particle. In certain embodiments, the functionalization includes modifying at least the outer surface of the particle by applying 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, vapor deposition film, sputtered film and ion implantation. In certain embodiments, application of the sacrificial polymer to the porous interior of the particle prior to its functionalization. In certain embodiments, the functionalization is performed prior to the release of the silicon particles.

  [0134] In accordance with an embodiment of the present invention, a product of any of the above methods is also provided. In certain embodiments, the product comprises about 1-3 micron silicon based nanoporous particles.

  [0135] Without further elaboration, those skilled in the art will believe that the description herein can be used to the full extent of the invention. The aspects described herein are to be construed as illustrative and in no way restrictive of the remainder of the disclosure. While the preferred embodiment of the invention has been illustrated and described, those skilled in the art can make many changes and modifications thereto without departing from the spirit and teachings of the invention. Accordingly, the scope of protection is not limited by the above description, but only by the claims, including all equivalents of the claimed subject matter. The disclosure of all patents, patent applications and publications cited herein to the extent that they are consistent with and provide supplemental procedural or other details to those set forth herein. This is incorporated herein.

DESCRIPTION OF SYMBOLS 101 Silicon wafer 102 Protective layer 103 Resistant substance 104 Space 105 Nucleation layer 106 Porous layer 107 Crevice 108 Particle 109 Particle 110 Patterned region 201 Silicon wafer 202 Protective layer 203 Resistive film 204 Groove 206 Porous layer 207 Second porous 208 layer 209 particle 210 patterned region 301 silicon wafer 302 porous layer 303 second porous layer 304 patterned region 306 particle 401 silicon wafer 402 first porous silicon layer 403 second porous layer 404 Patterned photoresist region 405 particles 406 stacking 501 silicon wafer 502 patterned region 503 pillar 504 second protective layer 505 first porous layer 506 second porous Layer 507 particle 508 etched region 509 periodic structure 601 region 602 region 701 region 702 region 1101 tip 1102 body 1201 top region 1202 nucleation layer 1203 top region 1204 region under top 1301 region 1302 region 1303 Nucleation layer

Claims (61)

A particle comprising a body defined by an outer surface, the body comprising a first porous region as well as a second porous region, which comprises a pore density, a pore size, a pore shape, a pore shape, Particles that differ from the first region in at least one characteristic selected from the group consisting of charge, pore surface chemistry, and pore orientation. 2. Particles according to claim 1, wherein the size of the small holes in the first region is larger than the size of the small holes in the second region. The particle according to claim 1, wherein at least one of the first region and the second region is a biodegradable region. The particle according to claim 1, wherein at least one of the first porous region and the second region is a nanoporous region. 5. The particle of claim 4, wherein both the first porous region and the second porous region are nanoporous regions. 5. The particle of claim 4, wherein the nanoporous region has a thickness greater than 200 nm. The particle according to claim 1, wherein at least one of the first porous region and the second porous region is an etched porous region. 8. The particle of claim 7, wherein the etched porous region does not include a nucleation layer. The particle according to claim 1, wherein the first porous region and the second porous region contain porous silicon. The particle of claim 1, wherein the first porous region is a region outside the main body and the second porous region is a region inside the main body. 2. The particle of claim 1 which is a microfabricated particle. The particle according to claim 1, wherein the main body has a shape selected from the group consisting of a hemispherical shape, a bowl-shaped shape, a frustum, and a cone. 2. The particle of claim 1, wherein the outer surface of the particle includes a first surface and a second surface, and at least one of the first surface and the second surface is a flat surface. 14. The particle of claim 13, wherein the outer surface further comprises a third surface defining a groove in the body with the first surface. 15. The particle of claim 14, wherein at least a portion of the first surface defines a first porous region in the body of the particle and at least a portion of the third surface defines a second porous region in the body of the particle. particle. The particle of claim 1, wherein the surface chemistry of the outer surface is different from the surface chemistry of the pores of the first and second porous regions. The particle of claim 1, wherein the first and second porous regions each have an average pore size that is not greater than 100 nm. A composition comprising a plurality of particles, each particle of the plurality comprising a body defined by an outer surface, the body comprising a first porous region as well as a second porous region, wherein the density of the pores , Different from the first region in at least one characteristic selected from the group consisting of pore size, pore shape, pore charge, pore surface chemistry, and pore orientation Composition. 19. The composition of claim 18, wherein the plurality of particles are a plurality of substantially identical particles. Particles comprising a body defined by an outer surface, wherein the body comprises a porous region wet etched and the particles do not comprise a nucleation layer associated with wet etching. A composition comprising a plurality of particles, each comprising a body defined by an outer surface, the body comprising a porous region that has been wet etched, and wherein the particles do not comprise a nucleation layer associated with wet etching. object. 23. The composition of claim 21, wherein the plurality of particles are a plurality of substantially identical particles. A method of making porous particles comprising the following:
Providing a support having a surface;
Forming a first porous layer on a support;
Pattern one or more particles on a support;
Forming a second porous layer in the support having a porosity greater than that of the first porous layer; and releasing the one or more patterned particles from the support, wherein the release is the second The released one or more particles, including the destruction of the porous layer, comprise at least a portion of the first porous layer. 24. The method of claim 23, wherein the support is a semiconducting support. 24. The method of claim 23, wherein the support is a silicon support. 24. The method of claim 23, wherein the first porous layer is formed prior to pattern formation. 24. The method of claim 23, wherein the first porous layer is formed after pattern formation.
24. The method of claim 23, wherein forming the first porous layer comprises wet etching the support. 30. The method of claim 28, wherein the wet etching is performed electrochemically. 30. The method of claim 29, wherein forming the second porous layer comprises electrochemically wet etching the support. 30. The method of claim 29, wherein the support is a silicon support and the wet etching comprises exposing the support to a solution comprising HF. 32. The method of claim 31, wherein the solution further comprises at least one of water or ethanol. 30. The method of claim 29, further comprising preventing formation of a nucleation layer associated with the wet etching. 34. The method of claim 33, wherein blocking comprises applying a high density current. 30. The method of claim 29, further comprising removing a nucleation layer associated with the wet etch. 24. The method of claim 23, wherein the formation of the first porous layer and the formation of the second porous layer are performed more than once. 24. The method of claim 23, wherein the patterning is performed by lithography. 24. The method of claim 23, wherein the largest dimension of individual particles of the one or more particles parallel to the surface of the support is not greater than 5 microns. 24. The method of claim 23, wherein the largest individual particle dimension of the one or more particles that is perpendicular to the surface of the support is not greater than 5 microns. 24. The method of claim 23, wherein the cross-section of individual particles of one or more particles that are parallel to the surface of the support have a predetermined regular shape. 41. The method of claim 40, wherein the predetermined regular shape is oval. 24. The method of claim 23, wherein the cross-section of individual particles of one or more particles that are perpendicular to the surface of the support has a predetermined regular shape. 43. The method of claim 42, wherein the predetermined regular shape is a semi-circle or semi-oval. 24. The method of claim 23, further comprising forming grooves in individual particles of the one or more particles. 45. The method of claim 44, wherein the released individual particles comprise a first porous region in a portion of the particle, where a groove is formed, and a second porous region is a portion of the particle. No grooves are formed, where the second porous region has a pore density, pore size, pore shape, pore charge, pore surface chemistry, and pore direction. A method different from the first region in at least one characteristic selected from the group consisting of sex. 24. The method of claim 23, further comprising chemically modifying the surface of one or more particles. 48. The method of claim 46, wherein the chemical modification is performed prior to the release. 48. The method of claim 47, wherein the chemical modification asymmetrically modifies the surface of individual particles of one or more particles. 49. The method of claim 48, wherein the chemically modifying comprises filling at least a portion of the pores of the first porous layer with a sacrificial material. 49. The method of claim 48, wherein the chemically modifying comprises at least one of silane treatment, oxidation, and antibody conjugation. 24. The method of claim 23, wherein the first porous layer is a nanoporous layer. 24. The method of claim 23, wherein the pore size in the first porous layer is not greater than 100 nm. 24. The method of claim 23, wherein each individual particle of the one or more released particles comprises a first porous region as well as a second porous region, which comprises a pore density, a pore size, a small pore size. A method different from the first region in at least one characteristic selected from the group consisting of pore shape, pore charge, pore surface chemistry, and pore orientation. 24. The method of claim 23, wherein forming the first porous layer is selected from thickness, pore size, porosity, pore orientation, and pore shape. Adjusting at least one parameter of the sex layer. 55. The method of claim 54, wherein the adjustment comprises selecting a material composition of the support, selecting a resistivity of the support, selecting a crystal orientation of the support, selecting an etching current, etching A method comprising at least one of selecting a chemical composition of the solution, selecting an etching concentration, and selecting an etching time. 24. The method of claim 23, wherein forming the first porous layer comprises forming small holes of a predetermined cross-sectional shape in the first porous layer. 24. The method of claim 23, wherein releasing comprises exposing the support to ultrasound. 24. The method of claim 23, further comprising depositing a protective layer on the surface of the support. A method of making porous particles comprising the following:
Providing a support having a surface;
Forming a first porous layer on the support by electrochemical wet etching;
Removing the nucleation layer associated with electrochemical wet etching;
Patterning one or more particles on the surface of the support; and releasing the patterned one or more particles from the support, wherein the one or more particles released are in the first porous layer Including at least a portion. 60. The method of claim 59, wherein removing comprises applying a large current density effective to prevent nucleation layer formation prior to formation of the first porous layer. 60. The method of claim 59, wherein removing comprises dry etching the nucleation layer after formation of the first porous layer.