KR20100051591A - Porous particles and methods of making thereof - Google Patents

Abstract

The present invention provides particles comprising a first porous region and a second porous region different from the first porous region. Also provided are particles having a wet etched porous region and having a nucleation layer associated with the wet etch. Also provided are methods of making porous particles.

Description

POROUS PARTICLES AND METHODS OF MAKING THEREOF}

Reference to federally assisted research or development

The U.S. Government has the full patent rights of the present invention and, in limited circumstances, grants patent rights to others on reasonable terms as provided in connection with grant number W81XWH-04-2-0035 granted by the Department of Defense and contract NNJ06HE06A granted by NASA. You have the right to ask this patent owner to grant you permission. The government has certain rights in this invention.

Background technology

The present application generally relates to nanotechnology, in particular porous particles, and methods of making the same.

Description of the related technology

Porous particles such as porous silicon particles and porous silica particles have many uses, including those used as drug delivery carriers. For example, porous silicon particles and methods for their preparation are disclosed in the following documents: US Pat. Nos. 6,355,270 and 6,107,102; US Patent Publication 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), R 71-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.

There is a need for new types of porous particles and new methods of preparation thereof.

Summary of the Invention

One embodiment is a particle comprising a body defined by an outer surface, wherein the body comprises a first porous region and a second porous region (which is pore density, pore size, pore morphology, pore charge, pore surface chemistry and porosity). Different from the first region in at least one property selected from the group consisting of orientations).

Another embodiment is 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 (which is a pore density). Different from the first region in at least one property selected from the group consisting of pore size, pore shape, pore charge, pore surface chemistry and pore orientation.

Another embodiment is a particle comprising a body defined by an outer surface, wherein the body comprises a wet etched porous region, wherein the particle does not comprise a nucleation layer associated with wet etching.

Another embodiment 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, wherein the particles comprise a nucleation layer associated with wet etching. I never do that.

Another embodiment includes providing a substrate having a surface; Forming a first porous layer on the substrate; Patterning one or more particles on the substrate; Forming a second porous layer on the substrate, the second porous layer having a larger porosity than the first porous layer; And releasing the patterned one or more particles from the substrate, disrupting the second porous layer, wherein the released one or more particles contain at least a portion of the first porous layer. It is a way. Another embodiment includes providing a substrate having a surface; Forming a first porous layer on the substrate through wet etching; Removing the nucleation layer associated with the wet etch; Patterning one or more particles on the surface of the substrate; Releasing the patterned one or more particles from the substrate, wherein the released one or more particles contain at least a portion of the first porous layer.

Brief description of the drawings

1 (A)-(B) schematically illustrate a method for producing porous particles comprising releasing particles from the substrate via electropolishing.

2 (A)-(B) schematically illustrate a method of making porous particles comprising releasing the particles from the substrate through the formation of the release porous layer.

3 schematically illustrates a method for producing porous particles in which formation of a porous layer on a substrate precedes pattern processing of the particles.

4 schematically illustrates a method for producing porous particles in which formation of multiple porous layers on a substrate precedes pattern processing of the particles.

5 schematically illustrates a method of producing porous particles in which the patterning of the particles on the substrate precedes the formation of the multiple porous layer.

FIG. 6 is a scanning electron microscope (SEM) image of a bottom view of porous silicon particles 1.2 μm. FIG. The inset photograph shows an enlarged view of ˜30 nm pores in the central region of the particles.

7 is an SEM image of a top view of 3 μm silicon particles having an elliptical cross section.

8 is an SEM image of 3.1 μm particles having a hemispherical shape. The inset shows details of the surface of one of the particles with <10 nm pores.

9A-C show SEM images of the porous silicon film with the nucleation layer (FIGS. 9A-B) and the porous silicon film without the nucleation layer (FIG. 9C).

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 with a 1.5 μm trench formed by silicon etching.

12 shows two SEM images of silicon particles, the left image showing the image with the nucleation layer, while the right image shows the particles from which the nucleation layer was removed by RIE.

13 is an SEM cross-sectional image of silicon particles having two different porous regions along the length direction.

Detailed description of the invention

The following documents, which are incorporated by reference in their entirety herein, may be useful for understanding the present text:

(1) PCT Publication WO 2007/120248 published October 25, 2007;

2) US Patent Application Publication 2003/0114366;

3) US patent application Ser. No. 11 / 641,970, filed December 20, 2006;

4) US patent application Ser. No. 11 / 870,777, filed Oct. 10, 2007;

5) US Patent Application 12 / 034,259, filed February 20, 2008;

6) Tasciotti et al., Nature Nanotechnology, vol. 3, 151-158, 2008].

Justice

Unless otherwise specified, a singular expression means one or more.

'Nano voids' or 'nano voids' means pores whose average size is less than 1 micron.

By "biodegradable" is meant a material that can be dissolved or degraded in a physiological medium, or a biocompatible polymer material that can be degraded under physiological and / or chemical conditions by physiological enzymes.

'Biocompatibility' refers to undesirable effects on cells when exposed to living cells, such as cell survival cycle changes; By a substance that will support the proper cellular action of the cell without causing a change in cell proliferation rate, and cytotoxic effects.

By "microparticle" is meant a particle having a maximum dimension of 1 to 1000 micrometers, or in some embodiments 1 to 100 microns, as specified. 'Nanoparticles' means particles having a maximum dimension of less than 1 micron.

The inventors have developed a new pore particle and a new method for producing the pore particle. According to a first embodiment, the particles are characterized in that the body has a first porous region and a second porous region (which is characterized by one or more properties in one or more properties such as pore density, pore size, pore morphology, pore charge, pore surface modification or pore orientation). And a body defined by the outer surface.

Particles having two different porous regions are for example co-pending U.S. As disclosed in Application 11 / 836,004, it may be used to load two different groups of smaller particles which may include one or more active agents such as therapeutic agents or imaging agents.

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 can be composed of 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' means a material into which voids are introduced through 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, porous GaN.

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.

The body of particles may have a regular, ie non-random, shape when viewed in one or more cross-sections or in one or more directions, for example using microscopy techniques such as SEM. Non-limiting examples of such regular forms include hemispheres, bowls, truncations, pyramids, and discs.

The dimension of the particles is not particularly limited and depends on the application to the particles. For example, for intravascular administration, the maximum characteristic size of the particles can be less than the minimum capillary radius, which is about 4-5 microns in humans.

In some embodiments, the maximum characteristic size of the particles 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 less than about 4 microns or less than about 3 microns or about 2 microns Less than or less than about 1 micron. In some embodiments, the maximum characteristic size of the particles may be 500 nm to 3 microns, or 700 nm to 2 microns. In some embodiments, the maximum characteristic size of the particles may be greater than about 2 microns or greater than about 5 microns or greater than about 10 microns.

In some embodiments, the first porous region can be different from the second porous region in pore size, that is, the pore size of the pores in the first porous region can be greater than the pore size in the second region or vice versa. have. For example, the pore size in one of the first and second porous regions is at least two times, or at least five times, or at least ten times, or 20 than the pore size in the other of the first and second porous regions. It may be twice or more, or 50 times or more, or 2 to 50 times, or 5 to 50 times, or 2 to 20 times, or 5 to 20 times larger.

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.

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

In some embodiments, at least one of the first and second porous regions has an average pore size of 1 micron or less or 800 nm or less or more than 500 nm or more than 300 nm, or 200 nm or less or 100 nm or less or 80 nm or less or 50 or less than nm. In certain embodiments, both the first and second porous regions have respective average pore sizes of 1 micron or less or 800 nm or less or 500 nm or less or 300 nm or less or 200 nm or less or 100 nm or less or 80 nm or less It may be 50 nm or less. In some embodiments, at least one of the first and second porous regions may have an average pore size of about 10 to about 60 nm or about 20 to about 40 nm.

In some embodiments, at least one of the first and second porous regions may 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.

In some embodiments, one of the first and second porous regions has an average pore size of about 10 to about 60 nm or about 20 to about 40 nm, while the other of the first and second porous regions has an average pore. The size may be about 1 nm to about 10 nm or about 3 nm to about 10 nm or about 3 nm to about 7 nm.

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 may have different average sizes.

In general, the pore size can be measured using a number of techniques including N ₂ adsorption / desorption and microscopy, such as scanning electron microscopy.

In some embodiments, the first porous region and the second porous region can have different pore orientations. For example, the outer surface of the particle may comprise a planar subsurface, and the voids of the first porous region may be perpendicular to or substantially present with respect to the subsurface, while the voids of the second porous region are It may be oriented in a direction substantially different from the vertical direction, for example in a direction parallel to the subsurface. Pore orientation can be measured using microscopic techniques such as SEM.

In some embodiments, one or more of the pores of the first and second porous regions can be linear pores. In some embodiments, both the first and second porous regions can be linear voids.

In some embodiments, one or more of the pores of the first and second porous regions can be sponge-like pores. In some embodiments, the pores of both the first and second porous regions can be sponge-like pores.

In some embodiments, the pores of one of the first and second porous regions may be linear pores, while the other pores of the first and second porous regions may be sponge-like pores.

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

In some embodiments, the pores of the first and second porous regions can have different forms. For example, the pores of one of the first and second porous regions may be cylindrical pores, while the pores of the other of the first and second porous regions may be non-cylindrical pores. Pore morphology can be measured using microscopy techniques such as SEM.

In some embodiments, the pores of the first and second porous regions can have different surface chemical properties. The pore surface of the first porous region can be chemically modified by the first surface group, whereas the pore surface of the second porous region can be chemically modified by a second surface group that is not modified or is different from the first surface group. have. For example, the pore surface of the first porous region can be silanized by an aminosilane, such as 3-aminopropyltriethoxysilane, while the pore surface of the second porous region is a mercaptosilane, such as 3-mer. Silanized by captopropyltrimethoxysilane.

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

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

In general, the porous silicon may be bioinert, bioactive or biodegradable depending on its porosity and pore size. In addition, the rate or rate of biodegradation of the porous silicon may vary depending on its porosity and pore size, see, eg, Canham, Biomedical Applications of Silicon, in Canham LT, editor. Properties of porous silicon. EMIS data review series No. 18. London: INSPEC. p. 371-376. Biodegradation rates may also vary with surface denaturation. Thus, the particles may be present such that the first porous region has a first biodegradation rate, while the second porous region has a second biodegradable rate that is different from the first biodegradable rate.

In some embodiments, each of the first porous and second porous regions may have a thickness, or minimum characteristic value, greater than 200 nm or greater than 250 nm or greater than 300 nm.

In some embodiments, the particles may be free or substantially free of nucleation layers, which may be irregular porous layers, which are typically formed at an early stage of electrochemical wet etching where the etchant begins to penetrate into the substrate. The thickness of the nucleation layer can vary depending on the parameters of the etched substrate and the electrochemical etching process. For substrates and etching parameters that can be used to form nanosized pores, the thickness of the nucleation layer can be from 1 nm to about 200 nm.

In some embodiments, the outer surface of the particles can have a surface chemical property that is different from the surface chemical property of at least one of the first and second porous regions. However, in some embodiments, the outer surface of the particles may have a surface chemistry that is different from the surface chemistry of both the first and second porous regions.

The particles may be prepared particles comprehensively, i.e. comprehensive microfabrication or nanofabrication techniques such as photolithography, electron beam lithography, X-ray lithography, deep UV lithography, nanoimprint lithography or dip pen lithography. It may be particles generated using. Such a manufacturing method may enable scaled up production of particles having uniform or substantially identical dimensions.

Accordingly, 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, Different from the first region in at least one property selected from the group consisting of pore density, pore size, pore shape, pore charge, pore surface chemistry and pore orientation.

According to a second embodiment, the particles may comprise a body defined by external particles, wherein the body is formed of a wet etched porous region, ie a porous region produced by a wet etching technique, such as an electrochemical wet etching. Wherein the particles do not comprise a nucleation layer associated with wet etching.

The particles of the second embodiment may have the same dimensions and shapes as discussed above for the particles of the first embodiment. The wet etched porous region may have the same properties as that of the first or second porous region of the particles of the first embodiment. The outer surface of the particles of the second embodiment may have the same properties as the outer surface of the particles of the second embodiment. Like the particles of the first embodiment, the particles of the second embodiment may be particles prepared comprehensively.

The particles of the second embodiment may be part of a composition comprising a plurality of particles having uniform dimensions or substantially the same as said particles. The particles of the first and second embodiments can be prepared according to the method for producing the porous particles described below. The particles of the invention can be used in a variety of applications, including drug delivery. In certain cases, active agents such as therapeutics or imaging agents may be loaded directly into the pores of the particles. In some cases, however, consequently smaller sized particles comprising the active agent may be charged into the voids, for example as disclosed in US application Ser. No. 11 / 836,004.

Method of producing porous particles

The method of making porous particles includes providing a substrate, forming a porous layer on the surface of the substrate, patterning one or more particles on the substrate, and releasing the particles from the substrate. Each released particle comprises a portion of the porous layer. Porous layer formation and a pattern process can be performed in an order or reverse order. That is, in some cases, porous layer formation may precede pattern processing, while in some other embodiments, porous layer formation may be after pattern formation. The method of the present invention utilizes micro / nanofabrication techniques, which can allow the particles to have a variety of predetermined shapes including, but not limited to, spheres, squares, rectangles, and ellipses; (2) very sophisticated dimensional control; (3) control over porosity and pore profile; (4) holds the possibility of complex surface denaturation.

materials

The substrate may be comprised of any of a variety of materials. Preferably, the substrate has one or more planes, on which one or more particles can be patterned. Preferably, the substrate comprises a wet etchable material, ie, a material that can be porous by wet etching techniques such as electrochemical etching.

In certain embodiments, the substrate can be a crystalline substrate, such as a wafer. In certain embodiments, the substrate may be a semiconductive substrate, ie, a substrate comprising one or more semiconducting materials. Non-limiting examples of semiconducting materials include Ge, GaAs, InP, SiC, Si _x Ge _1-x , GaP, and GaN. In many embodiments, it may be desirable to use silicon as the base material. Substrate properties such as doping level, resistivity and crystal orientation of the surface can be selected to obtain desired properties of the voids.

Formation of porous layer

The porous layer can be formed on a substrate using a number of techniques. Preferably, the porous layer can be formed using a wet etching technique, ie, exposing the substrate to an etchant comprising at least one etchant, such as a strong acid. Specific etchant may vary depending on the materials of the above description. For example, for a germanium based, the etchant may be hydrochloric acid (HCl), while for silicon based, the etchant may be a hydrofluoric acid etchant. Preferably, the formation of the porous layer is carried out using an electrochemical etching process, during which the etching current flows through the substrate. Silicon-based electrochemical etching to form a porous silicon layer is described, for example, in Salonen et al., Journal of Pharmaceutical Sciences, 2008, 97 (2), 632. For silicon based electrochemical etching, the etchant may comprise water and / or ethanol in addition to HF.

In some embodiments, during the electrochemical etching process, the substrate can act as one of the electrodes. For example, during the electrochemical etching of silicon, the silicon substrate can act as an anode, while the cathode can be an inert metal such as Pt. In this case, a porous layer is formed on the substrate surface facing away from the inert metal cathode. However, in some other embodiments, during the electrochemical etching, the substrate may be positioned between two electrodes, each of which may comprise an inert metal.

The electrochemical etching method can be carried out in a reactor or cell resistant to the etchant. For example, when the etchant is HF, the electrochemical etching process may be performed in a reactor or cell containing an HF resistant material. Examples of HF resistant materials include fluoropolymers such as polytetrafluoroethylene. The electrochemical etching can be carried out by monitoring the current at one of the electrodes, for example by monitoring the anode current (constantly) or the voltage (potentially). In some embodiments, it may be desirable to perform an electrochemical etch at a constant current density, which may allow for good control of the formed porous layer properties and / or good reproducibility of each of the samples.

In some embodiments, if it is desired to form two different porous regions stably, two different constant currents may be applied. For example, a first stable density may be applied to form a first stable porous layer, and then a second stable current layer may be applied, which may be different from the first stable porous layer in pore size and / or porosity. The porous layer can be formed.

In some embodiments, the parameters of the formed porous layer, such as pore size, porosity, thickness, pore profile and / or pore morphology, and therefore individual parameters of the prepared particles, are parameters of the electrochemical etching process, such as concentration and composition of the etchant. , Applied current (and potential), etching time, temperature, stirring conditions, presence and absence of illumination (and illumination parameters such as intensity and wavelength), as well as parameters of the etched substrate, such as the composition of the substrate, resistivity of the substrate, It can be controlled by selecting the crystallographic orientation and doping level and type of substrate.

In some embodiments, there may be a predetermined longitudinal profile along the voids in the formed porous layer, which is perpendicular or substantially perpendicular to the surface of the substrate. This longitudinal profile can be created by varying the current density during the electrochemical etching. For the longitudinal pores in the porous layer, both porosity and pore size can be varied. Thus, in some embodiments, the profiled pores in the porous layer and the prepared porous particles may be smaller in size at the top, i.e., the surface of the substrate, and may be larger at the bottom, i. have. However, in some embodiments, the profiled pores in the porous layer and the prepared porous particles can be larger in size at the top and smaller in the bottom. In some embodiments, the profiled pores in the porous layer and the particles produced may also differ in porosity at the top and bottom.

In many embodiments, the electrochemical etching can start with the impact of larger currents for a short time to prevent or reduce the formation of nucleation layers. The nucleation layer can also be removed by etching the nucleation layer after formation of the porous layer. Such etching can be performed by dry etching techniques such as RIE. Appropriate measures can be taken to protect the lower part. For example, the photoresist may be placed on a substrate, planarized by firing, and then a plasma etch-back may be applied to expose the surface portion of the substrate to be etched. .

For electrochemical etching, the electrical contacts can be secured by coating the back side of the substrate, ie the surface of the substrate opposite to the surface on which the porous layer is formed, with a conductive layer, for example a metal layer. Such conductive layers may be coated using various techniques, such as thermal deposition and sputtering.

Nucleation layer

During the electrochemical etching, the etchant can begin to form its pores through the formation of a nucleation layer, which is the surface layer of the substrate, where the pores have properties that differ from those of the porous layer. The nucleation layer may be characterized by its porosity characteristics and irregularities in the associated surface roughness, which may be larger than the pore size.

In many applications, nucleation layers on the porous particle surface are undesirable. For example, when silicon porous particles are used to load smaller sized particles therein, the nucleation layer on the surface of the layer can reduce the charging efficiency.

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

Pattern processing

Patterning one or more particles on the substrate surface can be carried out using any of a number of techniques. In many embodiments, pattern processing can be carried out using lithography techniques such as photolithography, X-ray lithography, far-ultraviolet lithography, nanoimprint lithography or deep pen lithography. Photolithography techniques can be, for example, contact alignment lithography, scanner lithography or impregnated lens lithography. In the case of photolithography it may be possible to devise particles with a number of predetermined regular, ie non-random, spherical, square, rectangular, elliptical, disc-shaped, hemispherical shapes. Patterning can be used to define the lateral shape and dimensions of the particles, ie the shape and dimensions of the particles on the cross section parallel to the surface of the substrate. If the formation of the porous layer precedes the patterning process, the lateral dimensions of the particles produced are substantially the same as the lateral dimensions of the patterned features. If the patterning precedes the formation of the porous layer, the lateral dimensions of the particles produced can be greater than the lateral dimensions of the patterned features. The patterning process can produce particles with some regular, i.e., non-random, side shape. For example, in photolithographic pattern processing, various predetermined masks can be used to produce certain desired shapes, while nanoimprint lithography can use various types of molds or stamps for the same purpose. The predetermined nonrandom side shape for the particles is not specifically limited. For example, the particles can be circular, square, polygonal and elliptical in shape.

Release

In some embodiments, the particles may be released by electropolishing the particles from the wafer after the patterning and porous layer forming steps, which may include applying a sufficiently large current density to the wafer. However, in some embodiments, the release of the particles from the wafer may include forming an additional porous layer, which has a higher porosity than the already formed porous layer. This higher porosity layer is called the emissive layer. The emissive layer may have a porosity large enough to be easily destroyed in some cases, for example using mechanical techniques such as exposing the substrate to ultrasonic energy. At the same time, the emissive layer may be strong enough for the previously formed porous layer to be held and fixed to the substrate.

Surface denaturation

Any of a number of techniques can be used to modify the surface properties of the particles, ie the properties of the outer surface of the particles and / or the surface properties of the particle voids. In many embodiments, surface modification of the particles produced can be carried out while the particles are still retained on the substrate before the particles are released. Types of surface modification of the particles include, but are not limited to, chemical modification such as polymer modification and oxidation; Plasma treatment; Metal or metal ion coatings; Chemical vapor deposition (CVD) coating, atomic layer deposition; Evaporation and sputtering films and ion implantation. In some embodiments, the surface treatment is biological for biomedical targets and controlled degradation.

Since surface modification of the particles can be carried out before the particles are released from the substrate, 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 denatured, while the other side of the particle surface may remain unmodified. For example, the pores of the particles may be filled in whole or in part by a sacrificial material, such as a sacrificial photoresist. Thus, only the outer surface of the particles can be treated during surface modification. After selective removal of the sacrificial material, only the outer surface of the particles may be denatured, ie the void surface of the particles remains undenatured. In some embodiments, the outer surface is patterned such that one portion of the outer surface can retain one denaturation, for example by photolithography, while another portion of the outer surface retains another denaturation. Can be. Exemplary surface denaturation protocols are further presented herein. The embodiments described herein are further illustrated in any manner by way of the following working examples, without being limited thereto.

Example 1: Preparation of Porous Silicon Particles. Electropolishing Emission

In the process schematically illustrated in FIGS. 1A and 1B, the particle pattern treatment precedes the formation of the porous layer and the release of particles is carried out via electropolishing. The manufacture can begin with the acquisition of silicon wafer 101. The surface of the wafer 101 may be optionally roughened by a process such as KOH dipping or reactive ion etching (RIE). Surface roughness treatment may help to remove or prevent the formation of nucleation layers on the surface. A protective layer 102 may then be deposited on at least one surface of the wafer 101 to prevent the wafer from being electrochemically etched in a solution based primarily on HF. The protective layer 102 may be a material resistant to electrochemical etching in an HF solution. Examples of such materials include silicon nitride or photoresist.

The protective layer 102 may be patterned. 1A and 1B illustrate patterning of a protective layer by lithographic technique. As in FIGS. 1Ac and 1Bc, a layer of resistive material 103 is deposited on protective layer 102. The resistive material may be a material that is not removed under the condition that the protective layer is removed. One example of such a material is photoresist. In addition to the unwanted portions of the protective layer 102 on the front surface of the wafer, the protective layer on the backside of the wafer may be removed, see FIGS. 1Ac and 1Bc. The resistive material 103 may also be removed, see FIG. 1 Ad. The protective layer may be patterned in such a way that the space between the patterned portions 110 of the protective layer defines the shape and dimensions of the manufactured particles.

In some cases, trenches may be formed in the space 104 between the patterned portions 110 of the protective layer, as illustrated in FIG. 1BD. The trench may be formed, for example, by a dry etching technique such as RIE. The depth and shape of the trench can be used to define the particle cross section perpendicular to the substrate surface, and thus the shape of the particle. The depth and shape of the trench may also be for controlling the mechanical and / or porous properties of the particles produced.

The porous layer 106 may be formed in and around the unprotected space by the patterned portion 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 include HF and optionally a surfactant such as ethanol under a DC current, at a value that may be selected to produce a void of desired size. If nucleation layer 105 is undesirable, a larger DC current may be applied before applying a DC current corresponding to a predetermined pore size, see FIG. 1AE.

The formed porous layer 106 may have two different pore orientations in the region not protected by the patterned portion 110 and in the substrate region under the protective layer portion 110. The former can have pores oriented perpendicular or substantially perpendicular to the substrate surface, while the latter can create pores oriented at an angle parallel to the substrate surface or tilted relative to the surface at an angle substantially different from 90 °. I can hold it.

Particles 108 or 109 may be released by electropolishing, which may form a gap 107 under porous layer 106, see FIGS. 1Ag, h and 1Bg, h. The remaining protective layer can then be removed. The particles can be collected in solution by a number of techniques including filtration. A trench is formed in the particle 109, which may define particle morphology and mechanical and porous properties. For example, a portion of the particles 109 under the trench may have a pore size and porosity that is different from the pore size and porosity at the side of the particle 109, ie, the bit trench portion of the particle 109.

Example 2. Preparation of Porous Silicon Particles. Emission through Formation of Second Porous Layer

In the process schematically illustrated in FIGS. 2A and 2B, the particle pattern treatment is preceded by the formation of the porous layer, and the release of the particles is carried out through the formation of the second porous layer. The manufacturing process can begin with obtaining the silicon wafer 201. As in the previous protocol, the surface of the wafer 201 may be roughened, for example by KOH dipping or RIE. As in Example 1, a protective layer 202 may then be deposited on the wafer to prevent the wafer from being electrochemically etched in a solution based primarily on HF, see FIG. 2A. As in Example 1, the protective layer 202 may then be patterned using, for example, lithographic techniques, see FIGS. 2Ab, c and 2Bb, c. As in Example 1, the pattern treatment may include the deposition of the resistive film 203, see FIGS. 2Bb and 2Ab. Undesired portions of the protective film on the front side of the wafer, as well as the protective film on the back side of the wafer 201, can be removed, see FIGS. 2BC and 2Ac. As in Example 1, the protective layer 202 may be patterned such that the space between the patterned portions 201 defines the shape and dimensions of the manufactured particles.

In some cases, as illustrated in FIG. 2BD, trench 204 may be formed in the space between the patterned portions 210 of the protective layer. The trench may be formed by dry etching, such as RIE. The depth and shape of the trench can be used to define the cross section of the particle perpendicular to the substrate surface, and thus the shape of the particle. The depth and shape of the trenches can be used to control the mechanical and porous properties of the formed particles.

The porous layer 206 may be formed in and around the unprotected space by the patterned portion 210 of the protective layer, see FIGS. 2Ae, f and 2Bf. To form the porous layer 106, the wafer may be exposed to a solution that may include HF and optionally a surfactant under a DC current, at a value that may be selected to produce voids of a desired size. If a nucleation layer is not desired, a larger DC current can be applied before applying a DC current corresponding to a predetermined pore size.

The formed porous layer 206 may have two different pore orientations in the region not protected by the patterned portion 210 and in the substrate region under the protective layer portion 210. The former can have pores oriented perpendicularly or substantially perpendicular to the substrate surface, while the latter can create pores oriented at an angle parallel to the substrate surface or inclined to the substrate surface at an angle substantially different from 90 °. I can hold it.

After formation of the porous layer 206, a larger current may be applied to form a second porous layer 207 having a larger porosity than the first layer, see FIGS. 2BF and 2Af. This large current may be chosen so that the second porous layer 207 is weak enough to mechanically collapse but still hold the particles in place.

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

Particles 208 or 209 can be released from the wafer 201 in solution by breaking the second porous layer 207, which is for example exposed to mechanical means such as exposing the aper to ultrasonic vibrations. By way of example, see Figs. 2Ah and 2Bh. Particles 209 may retain a trench therein that may define its shape and its mechanical and porous properties. For example, a portion of the particles 209 under the trench may have a pore size and porosity that is different from the pore size and porosity at the side of the particle 209, ie, the bit trench portion of the particle 209.

The shape of the particles prepared in Examples 1 and 2 may be hemispherical, bowl-shaped, truncated, etc., depending on the etching conditions. For example, in the bowl shape, the depth of the bowl shape may depend on the depth of the trench formed in the particle pattern prior to the electrochemical wet etching.

Example 3 Preparation of Porous Silicon Particles

In the process schematically illustrated in FIG. 3, the porous layer formation precedes the particle pattern processing. The process 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 include HF and optionally a surfactant under DC current, a number that may be selected to obtain a desired size of voids in the layer 302. See FIG. 3A. Thereafter, a larger current may be applied to form the second porous layer 303 on the substrate 301 under the first porous layer. This larger current may be selected such that the second porous layer 303 has a larger porosity than the first porous layer 302, see FIG. 3B. Preferably, this larger current is chosen such that the porous layer 303 is weak enough to mechanically collapse when needed, but at the same time maintain the formed particles in position in the wafer.

After formation of the second porous layer, the particles can be patterned. For example, a photoresist layer may be deposited on the porous silicon film 301. The photoresist layer may then be patterned to define the particles. For example, the patterned portion 304 (FIG. 3C) of the photoresist layer in FIG. 3 defines particles. Unwanted areas of the porous silicon layer 302, ie portions of the porous layer 302 that are not covered by the patterned portions 304 of the photoresist layer, may be removed, for example, by dry etching, such as RIE. 3D may be referred to. The patterned portion 304 of the photoresist layer may then be removed.

Subsequently, the particles retained on the wafer 301 by the second porous layer 303 may be chemically modified if desired, see FIG. 3E. The particles 306 can be released from the wafer 301 in solution by breaking the second porous layer 302, which can be done, for example, by exposing the wafer to ultrasonic vibration, for example by mechanical means. See FIG. 3F.

Example 4 High Yield Preparation of Porous Silicon Particles I

The process of Example 3 can be modified in a multi-layered manner that allows the produced particles to be produced in high yield. The method may begin with obtaining a silicon wafer 401. Subsequently, the wafer 401 may be exposed to an HF / surfactant solution, and a DC current may be applied for a period of time to form the first porous silicon layer 402, see FIG. 4A. Subsequently, a larger current can be applied to form the second porous layer 403 having a larger porosity as the emission layer. This greater current is weak enough to cause the second porous layer 403 to mechanically collapse, but at the same time can be selected to retain the particles within the wafer 401.

Forming a stable porous layer, such as the first porous layer 402, and forming a collapsible release porous layer, such as the second porous layer 403, may be repeated to form a periodic layered structure. For example, FIG. 4B shows this periodic structure, where the stable porous layer 402 is separated by the collapsible release layer 403. Subsequently, patterning of the particles may be performed.

For example, a masking layer, such as a metal film, may be deposited on top first porous layer 402. The photoresist layer may be placed on top of the masking film. If no metal masking film is deposited, the photoresist may be placed directly on top first porous layer 402. Lithographic techniques can then be applied to pattern the photoresist layer. As shown in FIG. 4C, the patterned photoresist layer may include a patterned portion of the photoresist, which may define the shape and dimensions of the particles to be produced. Subsequently, an undesired portion of the periodic porous structure, i.e., a portion of the periodic structure not covered by the patterned photoresist portion 404, is removed and covered with the patterned photoresist portion 404. May be formed and reference may be made to FIG. 4D. The photoresist film and / or masking film can then be removed from the top of the stack 406 using, for example, a piranha solution (1 volume of H ₂ O ₂ and 2 volumes of H ₂ SO ₄ ). Reference may be made to FIG. 4E. If desired, the particles 405 formed from a portion of the stable porous layer and retained in the stack 406 by the releaseable porous layer may then be chemically modified. Release of the particles 405 from the stack 406 into the solution may be effected by exposing the mechanical means, such as the wafer 401 with the stack 406 to ultrasonic vibrations, see FIG. 4F.

Example 5 High Yield Preparation of Porous Silicon Particles II

This example shows an alternative method for high yield production of porous silicon particles. Starting from the silicon wafer 501, a protective layer can be deposited on the wafer to protect the wafer from anisotropic etching, such as a deep RIE. The protective layer may be, for example, a silicon dioxide film or a photoresist film. The protective layer may be patterned to form a patterned portion 502 of the protective layer that defines the cross-sectional shape and dimensions of the particles to be manufactured, see FIG. 5A. This initial pattern processing of the protective layer can be performed similarly to the protective layer pattern processing illustrated in Figs. 1A (a)-(d).

An anisotropic etching technique may then be applied to the deprotected portion of the wafer to form a pillar 503 under the patterned portion 502 of the protective film, see FIG. 5B. The protective film 502 on the top of the filler 503 can then be removed. A second protective layer 504 may then be deposited on the pillar 503 and in the etched portion 508 between the pillars 503, see FIG. 5C. The second protective layer 504 may be present to prevent the wafer from being electrochemically etched in a solution based primarily on HF. For example, the second protective layer 504 may be a silicon nitride film or a photoresist film. The top of the filler 503 may then be exposed by removing a portion of the second protective layer 504 by, for example, etching or planarization. Preferably, after such removal, the second protective layer 504 remains intact on the side and bottom of the etched portion 508, see FIG. 5D.

Thereafter, the wafer with the patterned filler may be exposed to a solution containing HF as a main component under an applied DC current to form the first porous layer 505, which is a stable porous layer in which particles may be formed. The applied DC current can be selected to form voids with the desired size in the particles. Thereafter, a larger current may be applied to form the second porous layer 506, which is an emission porous layer having a larger porosity than the first porous layer 505. This greater current may be chosen such that the emitting porous layer is weak enough to mechanically collapse on the one hand and strong enough to hold the particles in position before the release on the other hand. The formation of a stable porous layer, such as layer 505 and the formation of a release layer, such as layer 506, may be repeated a predetermined number of times to form a periodic layered structure in filler 503. For example, FIG. 5E shows a periodic structure 509 formed by an alternating stable porous layer 505 and an emitting porous layer 506. In forming the periodic stack structure 509, the remaining second protective layer 504 may be removed, see FIG. 5F.

If desired, the particles 507 formed from a portion of the stable porous layer 505 and held in the periodic stack structure 509 by the releaseable porous layer 506 may be chemically modified. Release of the particles 507 from the stack 509 into the solution may be effected by exposing the mechanical means, such as the wafer 501 holding the stack 509 to ultrasonic vibrations, see FIG. 5G.

In this method, the step of forming a large porosity emitting layer can be replaced by electropolishing. In this case, the formed periodic structure may include an alternating stable porous layer and a cap formed by electropolishing instead of the emitting porous layer. The stable porous layer may be maintained on the wafer by the remaining second protective layer 504. In this case, the release of the particles formed from the stable porous layer can be carried out by removing the remaining second protective layer. Prior to the release, the particles can be chemically modified while the wafer is still intact.

Surface denaturation protocol

The following experimental protocols are provided, which can be used for surface denaturation of silicon particles by oxidation, silanization and binding of target moieties such as antibodies.

Oxidation of Silicon Microparticles

Silicon microparticles in IPA can be dried in a glass beaker held on a hotplate (80-90 ° C.). Silicon particles can be oxidized in piranhas (one volume of H ₂ O ₂ and two volumes of H ₂ SO ₄ ). The particles can be sonicated after the addition of H ₂ O ₂ and then 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 with DI water until the pH of the suspension is about 5.5-6. The particles can then be transferred to an appropriate buffer, IPA (isopropyl alcohol) or stored in water and refrigerated until further use.

Silanized

Oxidation. Prior to the silanization process, the oxidized particles may be hydroxide in 1.5 M HNO ₃ acid for approximately 1.5 hours (room temperature). The particles may be washed 3-5 times with DI water (washing may include suspending in water, centrifuging, removing the supernatant and repeating the above procedure).

APTES processing. The particles can be suspended in IPA by washing it twice with IPA (isopropyl alcohol). The particles can then be suspended in an IPA solution containing 0.5% (volume / volume) of APTES (3-aminopropyltriethoxysilane) for 45 minutes at room temperature. The particles can then be washed 4-6 times with IPA by centrifugation and stored in refrigerated IPA. Alternatively, the particles can be aliquoted, dried, stored under vacuum and dried until further use.

MPTMS treatment. The particles can be hydroxide in HNO ₃ using the same procedure as above. After washing with water and IPA, the particles can be silanized for 4 hours by 0.5 volume / vol% MPTMS (3-mercaptopropyltrimethoxysilane) and 0.5 volume / vol% IPA. The particles can then be washed 4-6 times with IPA and then stored or aliquoted in refrigerated IPA, dried, stored in vacuo and dried.

Conjugation of Antibodies. Microparticles can be denatured by APTES and / or MPTMS as described above. Water-soluble homologues of sulfo-SMCC, succinimidyl 4-N-maleimidomethyl cyclohexane-1-carboxylate (SMCC) crosslinker may be used to crosslink the anti-VEGFR2 antibody with the particles. The total number of particles used to conjugate the particles of both APTES and MPTMS with anti-VEGFR2 may be about 7.03 × 10 ⁶ . The particles can be washed and centrifuged six times with phosphate buffer containing 0.5% Triton X-100, then washed four times in pure phosphate buffer and then read in a plate reader.

After immobilization of antibodies such as IgG, EGFR, VEGFR to nanoporous silicon particles via chemical backbone by surface silanization, subsequent coupling methods comprising readily available protein crosslinkers capable of covalently binding to these antibodies are experimental. Proved to be.

Surface denaturation by APTES

In an exemplary surface modification, the porous silicon particles may be hydroxide for 1 hour in 1.5M HNO ₃ . The amine groups are introduced into the surface by silanization at room temperature for 30 minutes with a solution comprising 0.5 vol / vol% of 3-aminopropyltriethoxysilane (APTES) in isopropanol (IPA). Thiol groups can be coated onto the surface using 0.5 vol / vol% H ₂ O and 0.5 vol / vol% 3- mercaptopropyltrimethoxysilane (MPTMS) in IPA. APTES coated and MPTMS coated particles are suspended in phosphate buffered saline (PBS) and the crosslinker 1 mM N-succinimidyl-S-acetylthioacetate (SATA), 1 mM sulfosuccinimidyl 4- (N-maleic). Midomethyl) cyclohexane-1-carboxylate (sulfo-SMCC), 1 mM N-succinimidyl [4-iodoacetyl] aminobenzoate (sulfo-SIAB) or 1 mM succinimidyl 6- (3- [2-pyridyldithio] -propionamido) hexanoate (SPDP) can be reacted at room temperature for 1 hour. The antibodies can then be bioconjugated onto the particles.

Example 6: Preparation of 'large void' silicon particles

6 shows a scanning electron image of 1.2 μm silicon porous particles prepared as follows. A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A 200 nm silicon nitride layer was deposited by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 1 μm circular particle patterns using an EVG 620 array (vacuum contact). Silicon nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was removed by RIE. A 300 nm silicon trench was etched into the silicon in the exposed particle pattern. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 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 vol / vol) with a current density of 80 mA / cm ² for 25 seconds. A current density of 400 mA / cm ² was applied for 6 seconds to form a high porosity emitting layer. After removing the nitride layer by HF, the particles were exposed to ultrasound for 1 minute to release at IPA. IPA containing porous silicon particles was collected and stored.

The shape of the silicon particles was measured using a LEO 1530 scanning electron microscope. Particles in IPA were placed directly on an aluminum SEM sample stage and dried. The SEM stage with particles was placed in a LEO 1530 sample chamber. The acceleration voltage of the electron beam was 10 kV and the working distance was about 5 mm.

The SEM image in FIG. 6 shows a bottom view, ie, a view of a particle in the form of a circle (1.2 μm in diameter) parallel to the surface of the wafer, away from the front of the wafer during manufacture. In Figure 6 the overall three-dimensional shape of the particles is hemispherical. The image in FIG. 6 shows regions 601 and 602, which correspond to pores parallel or inclined to the surface, and pores perpendicular to the surface, respectively. The pore size at the particle center is about 30 nm. The resulting particles are larger than the original pattern because the porous layer can penetrate into and into the protected portion of the substrate during the electrochemical etching.

Example 7. Preparation of 'large pore' silicon particles in elliptical form

7 shows an SEM image of silicon particles having an elliptical cross section. Particles were prepared as follows. A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A 200 nm silicon nitride layer was deposited by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 2 μm oval shaped particles using an EVG 620 array. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was removed by RIE. A 600 nm silicon trench was etched into the silicon in the exposed particle pattern. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. The etchant was a mixture of hydrofluoric acid (HF) and ethanol (3: 7 vol / vol). A high density current of 400 mA / cm ² was applied for 1 second to remove the nucleation layer. Then, a current density of 80 mA / cm ² was applied for 25 seconds to form nanopores. A high porosity emitting layer was formed by applying a current density of 400 mA / cm ² for 6 seconds. After the nitride layer was removed by HF, the particles were sonicated for 1 minute to release at IPA. IPA solutions containing porous silicon particles were collected and stored. Droplets of IPA solution containing the prepared particles were placed directly on an aluminum SEM sample stage and dried. SEM images were measured using a LEO 1530 scanning electron microscope. The electron beam acceleration voltage was 10 kV and the working distance was about 5 mm. The SEM image in FIG. 7 shows a plan view of the generated particles. The particles have regions 701 in which the pores are parallel or inclined to the surface and regions 702 in which the pores are perpendicular to the surface.

Example 8: Preparation of 'small pore' silicon particles

8 is an SEM image showing 3.1 μm particles having a hemispherical shape. Particles were prepared as follows. A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A silicon nitride layer of 200-350 nm was deposited on the substrate by a low pressure chemical vapor deposition (LPCVD) system. Photolithography was used to pattern the 2 μm circular particle pattern. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was removed by RIE. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. A current density of 6 mA / cm ² was applied for 1 minute 45 seconds to form nanopores in the mixture of hydrofluoric acid (HF) and ethanol (1: 1 volume / volume). A high porosity emitting layer was formed by applying a high current density of 320 mA / cm ² in a mixture of hydrofluoric acid (HF) and ethanol (2: 5 volume / volume). After the nitride layer was removed by HF, the substrate was exposed to ultrasonic vibrations for 1 minute to release particles. Droplets containing particles in IPA were 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 was 10 kV and the working distance was about 5 mm. The SEM image of Figure 8 shows the particles produced. The inserted image demonstrates that the pore size of the prepared particles is less than 10 nm.

Example 9: Preparation of 'large void' silicon particles

10 shows an SEM image of 3.2 μm silicon particles with a trench of 500 nm. Particles were prepared as follows. A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A 100 nm low stress silicon nitride layer was deposited on the substrate by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 2 μm circular particle patterns using an EVG 620 array. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was removed by RIE. A 500 nm silicon trench was etched by RIE into the silicon in the exposed particle pattern. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. A current density of 16 mA / cm ² was applied for 105 seconds to form nanopores in a mixture of hydrofluoric acid (HF) and ethanol (1: 3 volume / volume). A higher porosity emitting layer was formed by applying a current density of 220 mA / cm ² for 6 seconds. After removal of the nitride layer by HF, the wafer was exposed to ultrasonic vibrations for 1 minute to release particles from the IPA. IPA solutions containing porous silicon particles were collected and stored.

Droplets containing particles in IPA were 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 was 10 kV and the working distance was about 5 mm. The SEM image in FIG. 10 shows the resulting bowl shaped particles. The particles have pores of about 30 nm at the bottom of the bowl-shaped particles and smaller pores at the sides.

Example 10 Preparation of 'Large Pore' Silicon Particles by Deep Trench Etching

FIG. 11 shows an SEM image of fabricated silicon particles having a depth trench of ˜1.5 μm formed by silicon etching. The particles were prepared as follows.

A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A 100 nm low stress silicon nitride layer was deposited on the substrate by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 2 μm circular particle patterns using an EVG 620 array. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was removed by RIE. A silicon trench of 1500 nm was etched into the silicon in the exposed particle pattern. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. A current density of 16 mA / cm ² was applied for 105 seconds to form nanopores in a mixture of hydrofluoric acid (HF) and ethanol (1: 3 volume / volume). A high porosity emitting layer was formed by applying a current density of 220 mA / cm ² for 6 seconds. After removal of the nitride layer by HF, the wafer was exposed to ultrasonic vibrations for 1 minute to release particles from the IPA. An IPA solution containing porous silicon particles was collected and stored.

Droplets containing particles in IPA were 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 was 10 kV and the working distance was about 5 mm. The SEM image in FIG. 11 shows the resulting bullet shaped particles. The distal end 1101 of the bullet retains pores of about 30 nm, while the body 1102 of the bullet retains smaller pores.

Example 11: Preparation of 'large pore' silicon particles with nucleation layer removed by RIE

12 is an SEM cross-sectional image of 3.2 μm silicon particles prepared by etching a 500 nm silicon trench, in which a nucleation layer is present on the left side and a nucleation layer is removed by the RIE on the right side. The particles were prepared as follows. A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A 100 nm low stress silicon nitride layer was deposited on the substrate by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 2 μm circular particle patterns using an EVG 620 array. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was also removed by RIE. A 500 nm silicon trench was etched into the silicon in the exposed particle pattern. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. A current density of 16 mA / cm ² was applied for 105 seconds to form nanopores in a mixture of hydrofluoric acid (HF) and ethanol (1: 3 volume / volume). A high porosity emitting 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.

For cross sectional studies, particles were not released from the wafer. Instead, after removing the nitride layer by 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 was 10 kV and the working distance was about 5 mm. The SEM image in FIG. 12 compares the resulting particles with nucleation layer and the particles after removal of the nucleation layer. Particles with a nucleation layer retain less than 10 nm of pores in top portion 1201 and about 30 nm of pores below nucleation layer 1202, whereas particles without nucleation layer have top portion 1203. And pores of about 30 nm in both the portion 1204 below its top.

Example 12 Preparation of 'Large Pore' Silicon Particles with Two Different Porosities Depending on Pore Direction

FIG. 13 shows SEM images of porous particles having two different porosities depending on the pore directions. The particles were prepared as follows: A strongly doped p ++ type (100) wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. A 100 nm low stress silicon nitride layer was deposited on the substrate by a low pressure chemical vapor deposition (LPCVD) system. Standard photolithography was used to pattern 2 μm circular particle patterns using an EVG 620 array. The nitride was then selectively removed by reactive ion etching (RIE). Silicon nitride on the wafer backside was also removed by RIE. A 500 nm silicon trench was etched into the silicon in the exposed particle pattern. Photoresist was removed by piranha (by H ₂ SO ₄ : H ₂ O ₂ = 3: 1 volume). The wafer was then placed in a homemade Teflon® cell for electrochemical etching. Applying a current density of 16 mA / cm ² for 50 seconds and a current density of 37 mA / cm ² for 22 seconds to form nanopores in a mixture of hydrofluoric acid (HF) and ethanol (1: 3 volume / volume) It was.

For cross sectional studies, particles were not released from the wafer. Instead, after removing the nitride layer by 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 was 10 kV and the working distance was about 5 mm. The SEM image in FIG. 13 shows the resulting particles having two different porosity regions 1301 and 1302 along the length direction in addition to the nucleation layer 1303. The voids in both regions 1301 and 1302 are perpendicular to the surface. Region 1301 has a larger porosity than region 1302.

Example 13: Preparation of Porous Silicon Film

9 shows an image of two porous silicon films, a film with a nucleation layer (FIGS. 9A-B) and a film without a nucleation layer (FIG. 9C). The film was prepared as follows:

A strongly doped p ++ type 100 wafer (Silicon Quest Inc) with a resistivity of 0.005 ohm-cm was used as the substrate. The wafer was then placed in a homemade Teflon® cell for electrochemical etching. The etchant is a mixture of hydrofluoric acid (HF) and ethanol (2: 5 vol / vol). 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 the foregoing refers to specific preferred embodiments, it is to be understood that the invention is not so limited. Various modifications may be made to the disclosed embodiments and such modifications will come to mind to one skilled in the art to be within the scope of the present invention.

Some specific embodiments include the following. Providing a silicon substrate comprising a surface; Forming a porous layer on the surface; Lithographically patterning a plurality of particles comprising the porous layer on the substrate; And releasing said particles from the resulting substrate containing patterned porous particles. In some embodiments, lithographic patterning is performed prior to forming the porous portion on the surface.

In some embodiments, releasing the particles comprises mechanically releasing the particles from the lithographic patterned porous particles. In some embodiments, the formation of the porous layer includes the formation of a first porous layer and a second porous layer, wherein the porosity of the second layer is greater than the porosity of the first layer. In some embodiments, a protective layer is applied to the substrate. In certain embodiments, the protective layer comprises a silicon nitride or photoresist film. In some embodiments, the release of the particles from the substrate includes removing unwanted portions of the protective layer.

According to some embodiments of the method described above, the patterning process includes defining a predetermined form for the resulting particles. In some embodiments, the predetermined form is selected from the group consisting of spherical, square, rectangular, oval, disc-shaped, and hemispherical.

According to some embodiments, the formation of the porous layer comprises adjusting the properties of the resulting silicon particles. In certain embodiments, the properties include porosity, pore size, and pore profile of the resulting silicon particles. In certain embodiments, said forming of said porous layer comprises electrochemically treating said substrate. In certain embodiments, electrochemically treating the substrate comprises treating with a solution containing hydrofluoric acid and a surfactant. In certain embodiments, adjusting the properties of the silicon particles comprises providing silicon particles retaining certain properties by selecting a concentration of the solution, selecting a current, selecting an etching time, and selecting a doped silicon substrate. .

According to some embodiments of the aforementioned method, the silicon particles comprise an outer surface and a porous interior, the method comprising functionalizing at least a portion of the particles. In certain embodiments, the functionalization is a chemical, biochemical, polymer, oxidation, plasma treatment, metal or metal ion coating, CVD film coating, atomic layer deposition, evaporated film, sputtered film and ion implantation. Applying at least one treatment selected from the group consisting of denaturing at least the outer surface of the particles. In certain embodiments, applying the sacrificial polymer to the porous interior of the particles prior to the functionalization. In certain embodiments, said functionalization takes place prior to said release of said silicon particles.

According to embodiments of the present invention there is also provided the product of any of the above methods. In certain embodiments, the product comprises nanoporous particles of about 1 to 3 microns of silicon main component.

Without further effort, it is contemplated that one skilled in the art, using the present description, can apply the present invention to its fullest extent. The embodiments described herein are illustrative and should not be considered as limiting the remainder of the disclosure in any way. While preferred embodiments of the invention have been shown and described, many modifications and variations thereof can be made by those skilled in the art without departing from the spirit and teachings of the invention. Accordingly, the scope of protection is not limited by the above mentioned description, but only by the claims, including all equivalents of the claims entity. The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference to the extent that the disclosure provides procedural or other details consistent with, or ancillary to, the references herein.

Claims (61)

A particle comprising a body defined by an outer surface, wherein the body is at least one selected from the group consisting of a first porous region and pore density, pore size, pore morphology, pore charge, chemical properties of the pore surface, and pore orientation A particle comprising a second porous region that is different in properties from the first region. The particle of claim 1, wherein the pore size of the first region is greater than the pore size of the second region. The particle of claim 1, wherein at least one of the first and second regions is a biodegradable region. The particle of claim 1, wherein at least one of the first porous region and the second porous region is a nanoporous region. The particle of claim 4, wherein both the first porous region and the second porous region are nanoporous regions. The particle of claim 4, wherein the thickness of the porous region is greater than 200 nm. The particle of 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 comprise a nucleation layer. The particle of claim 1, wherein the first porous region and the second porous region comprise porous silicon. The particle of claim 1, wherein the first porous region is an outer region of the body and the second porous region is an inner region of the body. The particle of claim 1, which is a microfabricated particle. The particle of claim 1, wherein the body has a shape selected from the group consisting of hemispherical shape, bowl shape, truncated shape, and pyramidal shape. The particle of claim 1, wherein the outer surface of the particle comprises a first surface and a second surface, and at least one of the first surface and the second surface is planar. The particle of claim 13, wherein the outer surface further comprises a third surface defining a trench in the body along with the first surface. 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. . 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 each of the first and second porous regions has an average pore size of 100 nm or less. A composition comprising a plurality of particles, each of the plurality of particles comprising a body defined by an outer surface, the body having a first porous region and pore density, pore size, pore shape, pore charge, pore surface chemistry And a second porous region that is different from the first region in at least one property selected from the group consisting of pore orientations. The composition of claim 18, wherein the plurality of particles is a plurality of substantially identical particles. 20. A particle comprising a body defined by an outer surface, the body comprising a wet etched porous region and no nucleation layer associated with the wet etch. 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 do not comprise a nucleation layer associated with wet etching. The composition of claim 21, wherein the plurality of particles are a plurality of substantially identical particles. Providing a substrate having a surface; Forming a first porous layer on the substrate; Patterning one or more particles on the substrate; Forming a second porous layer on the substrate, the second porous layer having a larger porosity than the first porous layer; And Releasing at least one patterned particle from the substrate, wherein the releasing comprises disrupting the second porous layer, wherein the released one or more particles contain at least a portion of the first porous layer. Method for producing a porous particle comprising a. The method of claim 23, wherein the substrate is a semiconductor substrate. The method of claim 23, wherein the substrate is a silicon substrate. The method of claim 23, wherein the first porous layer is formed before pattern processing. The manufacturing method of Claim 23 with which the said 1st porous layer is formed after a pattern process. 24. The method of claim 23, wherein forming the first porous layer comprises wet etching the substrate. The method of claim 28, wherein the wet etching is electrochemically performed. The method of claim 29, wherein forming the second porous layer comprises electrochemically wet etching the substrate. The method of claim 29, wherein the substrate is a silicon substrate and the wet etch comprises exposing the substrate to a solution comprising HF. 32. The method of claim 31, wherein said solution further comprises at least one of water or ethanol. The method of claim 29, further comprising preventing nucleation layer formation associated with the wet etch. 34. The method of claim 33, wherein said prevention comprises applying a high density current. The method of claim 29, further comprising removing the nucleation layer associated with the wet etch. The production method according to claim 23, wherein the formation of the first porous layer and the formation of the second porous layer are performed one or more times. The method of claim 23, wherein said pattern processing step is performed by lithography. The method of claim 23, wherein the largest dimension of each of the one or more particles parallel to the substrate surface is 5 microns or less. The method of claim 23, wherein the largest dimension of each of the one or more particles perpendicular to the substrate surface is 5 microns or less. 24. The method of claim 23, wherein the cross section of each of the one or more particles parallel to the substrate surface is of a predetermined regular shape. 41. The method of claim 40, wherein the predetermined regular shape is elliptical. The method of claim 23, wherein the cross-section of each of the one or more particles perpendicular to the substrate surface is of a predetermined regular shape. 43. The method of claim 42, wherein the predetermined regular form is semi-circular or semi-elliptic. The method of claim 23, further comprising forming a trench in each of the one or more particles. 45. The method of claim 44, wherein the individual particles released comprise a first porous region that is a trenched particle portion and a second porous region that is a trenched particle portion, wherein the second porous region is void density, pore size. Wherein the first region differs in at least one property selected from the group consisting of pore morphology, pore charge, pore surface chemistry and pore orientation. The method of claim 23, further comprising chemically modifying the surface of the one or more particles. 47. The method of claim 46, wherein said chemical denaturation takes place prior to said release step. 48. The method of claim 47, wherein said chemical modification modifies asymmetrically the surface of each of said at least one particle. 49. The method of claim 48, wherein said chemical modification comprises filling at least a portion of the pores of said first porous layer with a sacrificial material. 49. The method of claim 48, wherein said chemical denaturation comprises at least one of silanization, oxidation and antibody conjugation. The method of claim 23, wherein the first porous layer is a nanoporous layer. The method of claim 23, wherein the pore size of the first porous layer is 100 nm or less. The method of claim 23, wherein each of the one or more emitted particles has one or more properties selected from the group consisting of a first porous region and pore density, pore size, pore shape, pore charge, pore surface chemistry, and pore orientation. And a second porous region different from said first region. 24. The method of claim 23, wherein forming the first porous layer comprises adjusting at least one parameter of the first porous layer selected from thickness, pore size, porosity, pore orientation, and pore shape. 55. The method of claim 54, wherein the adjusting comprises at least one of material composition selection of the substrate, resistivity selection of the substrate, crystal orientation selection of the substrate, etching current selection, chemical composition selection of the etching solution, etching concentration selection, and etching time selection. Phosphorus manufacturing method. 24. The method of claim 23, wherein forming the first porous layer comprises forming voids of a predetermined profile in the first porous layer. The method of claim 23, wherein said emitting comprises exposing said substrate to ultrasonic waves. The method of claim 23, further comprising depositing a protective layer on the substrate surface. Providing a substrate having a surface; Forming a first porous layer on the substrate via an electrochemical wet etch; Removing the nucleation layer associated with the electrochemical wet etch; Patterning one or more particles on the substrate surface; And Releasing the patterned one or more particles from the substrate, wherein the released one or more particles contain at least a portion of the first porous layer Method for producing a porous particle comprising a. 60. The method of claim 59, wherein said removing comprises applying a large current density effective to prevent the formation of a nucleation layer prior to formation of the first porous layer. 60. The method of claim 59, wherein the removing comprises dry etching the nucleation layer after formation of the first porous layer.

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