CN101336116A - A bioactive substance delivery system comprising a sol-gel composition - Google Patents

Abstract

The present invention discloses an implantable medical device comprising a coating of a sol-gel composition which acts as a reservoir of biologically active substances and discloses the use of a sol-gel combination Phytocoatings are used to improve adhesion to organic and inorganic substrates.

Description

A bioactive substance delivery system comprising a sol-gel composition

Cross References to Related Applications

Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Patent Application 60/764,941, filed February 2, 2006, and is International Patent Application PCT/US2004, filed December 1, 2004 /040270, an International Patent Application claiming priority to US Provisional Patent Application 60/546,091, filed February 18, 2004, which is hereby incorporated by reference in its entirety.

technical field

The present invention relates to self-assembled sol-gel compositions containing biologically active substances. In particular, the present invention relates to the use of the above sol-gel compositions as drug depots in implantable medical devices, and also to the use of the above sol-gel compositions for improving the adhesion between organic and inorganic surfaces.

Background technique

"Sol-gel" methods are commonly used to fabricate porous materials, including self-assembled membranes. A sol is a liquid solution comprising a colloidal suspension of a substance of interest dissolved in a suitable solvent. Condensation reactions between dissolved precursor molecules lead to the formation of various structures (particles, branched chains, linear chains, etc.) in the sol. The size, growth rate and morphology of these structures depend on the kinetics of the reaction in the solvent, which in turn is determined by parameters such as solution concentration, amount of water present, temperature and pH of the solvent, agitation of the solvent, and others. Given sufficient time, the condensation reaction will cause the growing particles or chains to agglomerate until eventually a gel is formed. The gel can be viewed as a mass of cross-linked precursor molecules forming a continuous, macroscopic solid phase that encapsulates a continuous liquid phase consisting of the remaining solution. In the final step of the sol-gel process, the encapsulated solvent is removed (usually by drying) and the precursor molecules are crosslinked (a process known as aging) to yield the desired solid.

Compared with other synthetic methods, the sol-gel synthesis method of materials has the following advantages. The advantages include: mild processing conditions (low temperature, low pressure, medium pH), cheap raw materials, no need for vacuum treatment devices or other expensive devices, and high controllability of the resulting structure, especially suitable for the synthesis of porous materials. There is essentially no limitation as to the shape of the final product, as the liquid sol can be cast in any form including monoliths, films, fibers and micro- or nano-scale particles prior to gelation.

The porosity of materials produced in sol-gel processes can be controlled in a number of different ways. In the simplest sol-gel process, no specific porogen is added to the sol, and the porosity of the final solid is determined by the amount of precursor branching or agglomeration before gelation. The average pore size, volume and surface area of the porous sol-gel composition increases with the size of the precursor molecules before sol-gel processing.

Porosity can also be manipulated during the sol-gel process by the presence of additional materials in the solvent. When using the sol-gel process, the incorporation of sacrificial porogens, in particular those substances that can be easily removed by heating or other means, into the sol is generally considered an efficient way to obtain porous solids. In the past, these efforts have focused on the fabrication of low dielectric constant (low-k) insulating films for use in microelectronics processes. Sacrificial templates can also be used to create pores in inorganic materials formed using sol-gel processes. Sacrificial templates are typically amphiphilic molecules (ie, those molecules having both hydrophilic and lipophilic properties) capable of self-assembly in solution. These amphiphiles generate highly ordered structures that guide the co-assembly of precursor molecules around this structure. Once the precursor molecules have co-assembled around the structure described above, the structure can be removed, leaving a negative image cavity.

Much research has been conducted around the unique properties of sol-gel compositions for template-assisted self-assembly. For example, in 1992, the research team of Mobil Oil Corporation found that surface-active molecules (short amphiphilic molecules) self-assembled in an aqueous solution of soluble silica, and after the silica substrate was solidified, the surfactant could be removed to obtain a A material of uniform mesoporous (mesopores are pores with a pore size between about 2 nm and about 50 nm) arranged in a hexagonal honeycomb structure (also known as "MCM-41"); see US Patents 5,057,296 and 5,102,643, the aforementioned patents This text is incorporated by reference in its entirety. MCM-41 was synthesized under hydrothermal conditions using cationic surfactant alkyl trimethyl quaternary ammonium salt and various silica sources such as sodium silicate, tetraethyl orthosilicate or silica gel (Beck et al., 1992, J. Am. Chem. Soc. 114, 10834). The pore size of MCM-41 can be adjusted from about 1.6 nm to about 10 nm by using different surfactants or changing the synthesis conditions. Currently, template-assisted mesoporous materials are prepared using the following two types of self-assembled amphiphilic templates: short-molecule surfactants (see Brinker et al. (Advanced Materials 1999, 11 No.7) and Kresge et al. (Nature Vol. 22)) and triblock copolymers (see US Patent 6,592,764, which is hereby incorporated by reference in its entirety).

Porous materials made by sol-gel process can be used to deliver bioactive substances. For example, Vallet-Regi et al. (Chem. Mater. 2001, 13, 308-311) describe the loading of ibuprofen on powdered MCM-41. In this case, ibuprofen was loaded into MCM-41 by dissolving ibuprofen in hexane and adding the MCM-41 compound in powder form to said hexane. Munoz et al. (Chem. Mater. 2003, 15, 500-503) describe an experiment demonstrating that ibuprofen can be delivered at different rates from two different MCM-41 formulations, one formulation Prepared with a 16 carbon surfactant and one formulation was prepared with a 12 carbon surfactant.

Prior to International Patent Application PCT/US2004/040270 (PCT'270), which is incorporated herein by reference in its entirety, there were no references describing implantable medical devices or biologically active substance delivery devices comprising A block copolymer template based sol-gel composition forms a surface coating having substantially continuous interconnecting channels designed to function as a reservoir of biologically active species. Furthermore, there are no references describing surface coatings formed from sol-gel compositions based on triblock copolymer templates, wherein, prior to being applied to the surface of an implantable medical device, the coating itself contains The bioactive substance, and after being applied to the surface of the implantable medical device, the surface coating has substantially continuous interconnecting channels which can further function as a reservoir of the bioactive substance. Thus, the invention described in PCT '270 provides at least two additional mechanisms by which biologically active substances can be loaded onto the surface of an implantable medical device.

Although the materials and methods described in PCT '270 have a number of important benefits (described in that patent), there remains room for improvement in the preparation of bioactive material delivery materials prepared by sol-gel processes. For example, better control of bioactive material particles during sol-gel processing and after device implantation may be beneficial for more precise control of the amount of bioactive material in a particular sol-gel composition and for better control in the The rate at which biologically active substances are released from an implanted medical device into the physiological environment after the device is implanted. The present invention has the above advantages. Before describing these advantages in more detail, however, the background to other aspects of the invention is described.

One of the challenges encountered in the field of implantable medical devices is making bioactive substances and coatings containing bioactive substances adhere to the surface of the implantable device so that, once the device is implanted, biological The active substance is then released over time. One method of making bioactive substances adhere to a substrate, such as the surface of an implantable medical device, is to include the bioactive substance in a polymer coating. The polymer coating can keep the bioactive substance on the surface of the implantable medical device and release the bioactive substance through degradation of the polymer or diffusion into the fluid or tissue (in this case, the polymer is not degradable). Although polymeric coatings can be used to adhere bioactive substances to implanted medical devices, there are several problems with the application of such polymeric coatings. One problem is that it is difficult to make polymer coatings adhere to disparate substrates, such as stent metal substrates, because the various materials have different properties, such as different thermal expansion properties. Furthermore, most inorganic solids are covered by hydrophilic surface oxides characterized by the presence of surface hydroxyl groups (M-OH, where M represents an atom of an inorganic material, such as silicon or aluminium). Then, under ambient conditions, at least a monolayer of adsorbed water molecules covers the surface of the inorganic solid, thereby forming hydrogen bonds with the aforementioned hydroxyl groups. Thus, due to the aforementioned water layer, the hydrophobic organic polymer cannot spontaneously adhere to the surface of the implantable medical device. Furthermore, even when polymer/surface bonds (including covalent bonds) are formed under dry conditions, these bonds are prone to hydrolysis (ie, breakage) upon exposure to water. These effects are particularly important in applications where devices or components containing organic/inorganic interfaces must operate in aqueous, corrosive environments such as the human or other animal body. These difficulties associated with adhering the two different types of materials often result in an insufficient bond between the implantable medical device and the overlying polymer coating, resulting in possible separation of the individual materials over time. Such separation is particularly undesirable in implanted medical devices.

Traditionally, two different approaches have been employed to strengthen the organic/inorganic interface. The first approach involves introducing controlled roughness, or porosity, on inorganic surfaces that promotes mechanical bonding of the polymers. The second approach is to chemically modify the inorganic surface with amphiphilic silane coupling agents to improve the wettability, bonding, and interfacial water resistance of the polymer. Although these methods have some benefits, they are not effective in all circumstances. Thus, there is some scope for improving methods related to adhesion of inorganic and organic surfaces. Certain sol-gel embodiments according to the invention provide the improvements described above.

Contents of the invention

The present invention provides a method for producing sol-gel compositions with enhanced incorporation of bioactive substances and a method for further controlling the transition of bioactive substances from medical The rate of release from the device to the physiological environment. The method is also useful for enhancing adhesion between inorganic and organic substrates and materials. These methods provide sol-gel compositions that can be used as sustained release bioactive reservoirs and/or as bioactive coatings on implantable medical devices. The present invention enhances the incorporation of biologically active substances by modifying the chemical environment in the sol-gel processing process, modifying the chemical environment changes the hydrophobicity or hydrophilicity of the forming materials, and affects the relationship between the biologically active substance molecules and the forming materials and the sol-gel. How the chemical environment interacts during gel processing. Modifications to the chemical environment during sol-gel processing can also affect fabrication after removal from the sol-gel environment in a manner that affects the rate at which bioactive substances are released into the physiological environment once implanted in the patient. properties of the material. Specifically, the chemical environment of the sol-gel process is adjusted according to the characteristics of the specific bioactive substance, thereby controlling how the bioactive substance interacts with the environment in the sol-gel process. As a non-limiting example, adding an organomodified silane to a sol-gel mixture can increase the hydrophobicity of the forming gel (meaning the structure formed during sol-gel processing). Without being bound by any theory, increasing the hydrophobicity of the forming gel is believed to impede the movement of the bioactive substance between the forming gel and the aqueous environment during sol-gel processing, making the bioactive substance more stable. Strong retention on the forming gel, resulting in better retention of the biologically active substance in the resulting sol-gel composition. Furthermore, enhancing the hydrophobic content of the final fabricated material allows for better control of the rate at which bioactive substances are released into the biological environment once implanted in the patient. The method according to the invention can even further improve the ability to control the release of bioactive substances into the physiological environment after implantation of the device by treating the surface of the prepared sol-gel composition with an organomodified silane. The hydrophobic trimethyl group of the organomodified silane helps to prevent liquids in the physiological environment of the implanted medical device from diffusing into the composition and dissolving the bioactive substance, thereby causing premature release of the bioactive substance.

Adhesion of the sol-gel compositions of the present invention to substrates can also be enhanced by providing pores in the form of continuous interconnected channels, allowing strong interpenetration between the inorganic substrate and the organic coating.

In particular, one embodiment of the invention includes a medical device comprising a structural element and a bioactive reservoir, wherein the bioactive reservoir comprises a coating applied to the surface of the structural element, Wherein, the coating comprises one or more layers, wherein at least one of the layers comprises a matrix composition formed by a sol-gel process, and in the sol-gel process, the sol-gel The environment of the process is designed to accommodate the properties of the bioactive substance to be incorporated into the matrix composition, which design affects the content and/or the bioactive substance in the matrix composition once made The rate at which the biologically active substance is released into the physiological environment once implanted in the patient. The matrix composition may include, but is not limited to, materials selected from the group consisting of sol-gel derived inorganic oxides, sol-gel derived organomodified silanes, hybrid oxides including organomodified silanes, and Template-generated mesoporous oxides.

In certain embodiments, matrix compositions according to the present invention comprise inorganic oxides made by the sol-gel process described above. The inorganic oxide may be selected from oxides of silicon and oxides of titanium. The matrix composition may also be a mesoporous inorganic oxide. Mesoporous inorganic oxides can be obtained by sacrificial pore-forming template components and self-assembly or guided assembly preparation processes. The template component may be selected from amphiphilic block copolymers, ionic surfactants and nonionic surfactants. The template component may also be a polyoxyethylene/polyoxypropylene/polyoxyethylene triblock copolymer.

Mesoporous inorganic oxides according to the present invention may comprise substantially continuous interconnecting channels. The interior surfaces of the substantially continuous interconnecting channels may be coated with organomodified silanes to improve the following properties of the mesoporous oxide: hydrophobicity, charge, biocompatibility, mechanical properties, affinity for biologically active substances performance, storage capacity and their combination. Furthermore, one or more biologically active substances may be loaded into the interconnecting channels after the coating has been applied to the surface of the structural element.

In certain embodiments according to the present invention, the oxides in the matrix composition may be complexed with agents to modify the following properties of the oxides: hydrophobicity, charge, biocompatibility, mechanical properties, affinity for biologically active substances performance, storage capacity and their combination. In one embodiment, the modifying agent is an organomodified silane. The organomodified silane can be selected from alkylsilane, methyltrimethoxysilane, methyltriethoxysilane, dimethyldiethoxysilane, trimethylethoxysilane, vinyltrimethoxy Silane, Vinyltriethoxysilane, Ethyltriethoxysilane, Isopropyltriethoxysilane, Butyltriethoxysilane, Octyltriethoxysilane, Dodecyltriethoxysilane Aminosilane, Octadecyltriethoxysilane, Arylfunctional Silane, Phenyltriethoxysilane, Aminosilane, Aminopropyltriethoxysilane, Aminophenyltrimethoxysilane, Aminopropyltrimethylsilane Oxysilanes, Acrylate Functional Silanes, Methacrylate Functional Silanes, Acryloxypropyltrimethoxysilane, Carboxylate Functional Silanes, Phosphate Functional Silanes, Ester Functional Silanes, Sulfonate Functional Silanes, Isocyanate Functional Silanes , epoxy functional silane, chlorosilane, trimethylchlorosilane, triethylchlorosilane, trihexylchlorosilane, dimethyldichlorosilane, methyltrichlorosilane, N,O-bis(trimethylmethylsilane Silyl)-acetamide (BSA), N,O-bis(trimethylsilyl)-trifluoroacetamide (BSTFA), hexamethyldisilazane (HMDS), N-methyltrimethyl Silyl trifluoroacetamide (MSTFA), N-hexyl-N-(tert-butyldimethylsilyl) trifluoroacetamide (MTBSTFA), trimethylchlorosilane (TMCS), trimethylform Silyl imidazoles (TMSI) and combinations thereof.

One embodiment according to the invention comprises a medical device comprising a structural element and a bioactive substance eluting coating, wherein the bioactive substance eluting coating comprises a At least one layer, wherein the at least one layer is formed using a sol-gel process and comprises an organomodified silane. In certain embodiments, the at least one layer is a primer layer applied to the surface of the medical device, the medical device further comprising a topcoat layer applied to the primer layer. The bioactive material-containing spheres may be present in a location selected from within the base coat, within the top coat, between the base coat and the top coat, and combinations thereof. The spheres containing the biologically active substance can be constructed from biodegradable polymers.

In one embodiment, the undercoat and/or topcoat comprises a sol-gel inorganic oxide composition. In another embodiment, the undercoat layer comprises a mesoporous oxide having substantially continuous interconnecting channels.

Another embodiment according to the present invention comprises a medical device comprising a structural element and a bioactive substance eluting coating, wherein the bioactive substance eluting coating comprises at least two layers, wherein the at least two layers At least one comprises a matrix composition formed using a sol-gel process in which the environment of the sol-gel process is designed to accommodate the matrix composition to be incorporated into the matrix composition The properties of the bioactive substance, the design affects the content of the bioactive substance in the matrix composition once made and/or the rate of release of the bioactive substance into the physiological environment once implanted in the patient. The above two layers may include, but are not limited to, a base coat and a top coat. In these embodiments according to the present invention, each layer may respectively comprise a form selected from: a sol-gel oxide layer without biologically active substances; a sol-gel oxide layer, the sol-gel oxide layer The layer has biologically active substances incorporated into the oxide; sol-gel oxides without biologically active substances complexed with organically modified silanes; with biologically active substances complexed with organomodified silanes sol-gel oxides; organomodified silane layer without bioactive species; organomodified silane layer with bioactive species; mesoporous oxide without bioactive species; mesoporous oxide , the mesoporous oxide has a biologically active substance incorporated into the oxide; the mesoporous oxide has a biologically active substance incorporated into the oxide, and has a Porous materials are applied to the surface of the medical device to load other biologically active substances in the interconnecting channels of the oxide; mesoporous oxides, the mesoporous oxides do not have but having the bioactive material loaded in the interconnecting channels of the oxide after the oxide is applied to the surface of the medical device; and polymer spheres containing the bioactive material aggregates. body.

Another embodiment according to the invention comprises a medical device comprising a structural element and a reservoir of bioactive substances, wherein the reservoir of bioactive substances comprises a coating applied to the surface of the structural element, wherein the coating The layer comprises a matrix composition formed using a sol-gel process in which the environment of the sol-gel process is designed to accommodate the biological activity to be incorporated into the matrix composition The characteristics of the substance, the design affects the content of the bioactive substance in the matrix composition once made and/or the rate at which the bioactive substance is released into the physiological environment once implanted in the patient, and when When the coating is applied to the surface of the structural element, the coating enhances the adhesion between the inorganic surface and the organic surface selected from the group consisting of polymers, tissue, bone, and combinations thereof.

In one embodiment, the biologically active substance used in the present invention can be selected from: anti-restenotic agents, anti-inflammatory agents, HMG-CoA reductase inhibitors, antibacterial agents, anti-tumor agents, angiogenic agents, anti-angiogenic agents, Thrombolytic agents, antihypertensive agents, antiarrhythmic agents, calcium channel blockers, cholesterol-lowering agents, psychotropic drugs, antidepressant agents, anti-epileptic agents, contraceptives, analgesics, bone growth factors, bone remodeling factors, Neurotransmitters, nucleic acids, opioid antagonists, and combinations thereof. The biologically active substance can also be selected from the group consisting of paclitaxel, rapamycin, everolimus, tacrolimus, sirolimus, deaspartate angiotensin I , nitric oxide, apocynin, γ-tocopherol, recombinant human osteoblast-specific factor (pleiotrophin), estradiol, aspirin, atorvastatin, cerivastatin, fluoride fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and combinations thereof.

Medical devices of the present invention may include, but are not limited to, vascular conduits, stents, plates, screws, vertebral cages, dental implants, dental fillings, orthodontic appliances, artificial joints, embolic devices ), ventricular assist device, artificial heart, heart valve, venous filter, staples, clips, sutures, prosthetic mesh, pacemaker, pacemaker leads, defibrillation devices, neurostimulators, neurostimulator leads, implantable sensors, and external sensors.

Description of drawings

Figure 1 shows a schematic diagram of the available template structures with cubic symmetry.

Figure 2 represents a schematic diagram of a mesoporous sol-gel _SiO2 film on a substrate surface, where the pores have cubic symmetry.

3A-3D represent SEM images at four different magnifications of an implantable medical device coated with a sol-gel composition according to the teachings of the present invention.

Figure 4 shows the rate of elution of desaspartate angiotensin I (DAA-1) from implantable medical devices coated with sol-gel compositions according to the teachings of the present invention apply.

Figures 5A-5B represent the amount of DAA-I released after 72 hours from implantable medical devices coated with sol-gel compositions according to the teachings of the present invention.

Figure 6 shows the amount of cerivastatin eluted from an implantable medical device coated with a sol-gel composition according to the teachings of the present invention.

Figures 7A-7B show additional cerivastatin release profiles.

Figure 8 shows the release profile of cerivastatin from an implantable medical device treated with an organomodified silane according to the teachings of the present invention.

Definition of terms

The term "implantable medical device" refers to any entity not manufactured by an organism, which performs a function in or on an organism. Implantable medical devices include, but are not limited to: biomaterials, bioactive substance delivery devices, vessels, stents, plates, screws, vertebral cages, dental implants, dental fillings, dental aligners, artificial joints, embolic devices , ventricular assist devices, artificial hearts, heart valves, venous filters, staples, clips, sutures, artificial mesh, pacemakers, pacemaker leads, defibrillators, neurostimulators, neurostimulator leads, and implantable input sensor or external sensor. Implantable medical devices are not limited by size, including micromechanical systems and nanomechanical systems. Embodiments of the invention include the implantable medical devices described above.

The term "reservoir" or "bioactive material reservoir" refers not only to a space that can hold a biologically active material, but also to a coating comprising a sol-gel matrix composition that encapsulates one or more biologically active substances. substance, and the library or bioactive substance library can be applied to the surface of a substrate (including an implantable medical device in one example).

As used herein, the term "biologically active substance" refers to any organic, inorganic or living agent that is biologically active or biologically relevant. For example, biologically active substances can be proteins, polypeptides, polysaccharides (such as heparin), oligosaccharides, monosaccharides or disaccharides, organic compounds, organometallic compounds or inorganic compounds. The bioactive substance may include bioactive molecules such as hormones, growth factors, growth factor-producing viruses, growth factor inhibitors, growth factor receptors, anti-inflammatory agents, antimetabolites, integrin blockers or fully functional or partially Functional sense gene or antisense gene. The biologically active substance may also include artificial particles or materials bearing biologically relevant or active materials. An example is a nanoparticle comprising a drug-bearing core and a coating on the core. The nanoparticles described above can be post-loaded into individual pores or co-deposited with metal ions.

Biologically active substances may also include drugs such as chemical or biological compounds that may exert a therapeutic effect on a biological organism. Biologically active substances include those that are especially useful in long-term treatments such as hormonal therapy. Examples include drugs used in contraception and hormone replacement therapy, and drugs used to treat conditions such as osteoporosis, cancer, epilepsy, Parkinson's disease, and pain. Suitable biomaterials may include, but are not limited to, anti-restenotic agents, anti-inflammatory agents, HMG-CoA reductase inhibitors, antibacterial agents, antineoplastic agents, angiogenic agents, anti-angiogenic agents, thrombolytic agents, antihypertensive agents , antiarrhythmic agents, calcium channel blockers, cholesterol-lowering agents, psychotropic drugs, antidepressant agents, antiepileptic agents, contraceptives, analgesics, bone growth factors, bone remodeling factors, neurotransmitters, nucleic acids, opioid antagonists agents and combinations thereof. Other biologically active substances include, but are not limited to, paclitaxel, rapamycin, veveolimus, tacrolimus, sirolimus, aspartate-angiotensin I, nitric oxide, apocynin , γ-tocopherol, recombinant human osteoblast-specific factor, estradiol, aspirin, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin and combinations thereof.

Biologically active substances may also include precursor substances, which have corresponding biological activities after being metabolized, fragmented (such as dissociation of molecular components) or otherwise processed and modified in vivo. This may include precursor substances of the type which, prior to the above-mentioned modification, may be considered biologically inert or otherwise ineffective for the particular outcome associated with the medical condition to be treated.

Combinations, admixtures, or other preparations of any of the foregoing examples may be made and still be considered to be biologically active as intended herein. Various aspects of the present invention involving biologically active substances may include any or all of the foregoing embodiments.

The term "sol-gel" processing refers to a process in which a soluble precursor of a target substance is dissolved in a suitable solvent with an optional second substance (including, but not limited to, biologically active substances) in a liquid in solvent. Condensation reactions between dissolved precursor molecules lead to the formation of various structures (particles, branched chains, linear chains, etc.) in the solution (sol). The individual structures formed develop to form a "gel" in a sol-gel process, which may include an optional second substance. Once all or substantially all of the liquid solvent has been removed from the gel, a matrix composition in some embodiments of the invention is formed.

The term "mesoporous inorganic oxide" refers to a sol-gel composition prepared in the method according to the present invention, wherein the sol-gel composition has a pore size in the range of about 2 nm to about 50 nm.

The term "organically modified" means that the compound comprises at least one organic (carbon-based) ligand (in one embodiment, a direct metal-carbon bond (or semiconductor-carbon bond)).

The term "organomodified silane" refers to a compound comprising at least one non-hydrolyzable carbon-based ligand bonded to silicon. This class of compounds is also known as ORMOSIL, silane coupling agents, silane coupling agents, silane adhesion promoters or simply silanes. These compounds represent a large number of different compounds, since the non-hydrolyzable ligands can be any imaginable organic group synthesized according to the principles of organic chemistry. Non-limiting examples include alkylsilanes such as, but not limited to, methyltrimethoxysilane, methyltriethoxysilane, dimethyldiethoxysilane, trimethylethoxysilane, vinyltrimethoxysilane Oxysilane, Vinyltriethoxysilane, Ethyltriethoxysilane, Isopropyltriethoxysilane, Butyltriethoxysilane, Octyltriethoxysilane, Dodecyltriethoxysilane ethoxysilane, octadecyltriethoxysilane, etc.); aryl functional silanes (such as phenyltriethoxysilane, etc.); aminosilanes (such as aminopropyltriethoxysilane, aminophenyltrimethylsilane oxysilane, aminopropyltrimethoxysilane, etc.); acrylate- and methacrylate-functional silanes (such as acryloxypropyltrimethoxysilane, etc.); carboxylate-functional silanes; phosphate-functional silanes; ester-functional Silanes; sulfonate-functional silanes; isocyanate-functional silanes and epoxy-functional silanes.

It is important to realize that these compounds also contain hydrolyzable groups that enable them to undergo hydrolysis/condensation reactions in sol-gel processes. Thus, each of the above-mentioned compounds or any combination of two or more of the above-mentioned compounds can be used as sol-gel precursors, or they can be combined with fully hydrolyzable sol-gel precursors, such as tetraethoxysilane (TEOS) or titanium isopropoxide in combination. The sol-gel compositions thus obtained are not stoichiometric inorganic oxides. Rather, it will be a hybrid sol-gel material having bulk chemical, mechanical, physical and other properties characteristic of the particular combination of constituent components.

Exemplary organomodified silanes particularly suitable for this aspect include chlorosilane, trimethylchlorosilane, triethylchlorosilane, trihexylchlorosilane, dimethyldichlorosilane, methyltrichlorosilane , N, O-bis(trimethylsilyl)-acetamide (BSA), N,O-bis(trimethylsilyl)-trifluoroacetamide (BSTFA), hexamethyldisilazane (HMDS), N-methyltrimethylsilyl trifluoroacetamide (MSTFA), N-methyl-N-(tert-butyldimethylsilyl) trifluoroacetamide (MTBSTFA), trimethylsilyl Chlorosilane (TMCS), Trimethylsilylimidazole (TMSI) and combinations thereof. The compounds listed are particularly useful for surface treatment and are similar to the compounds included in the preceding paragraph, except that they do not contain alkoxy ligands.

Detailed ways

The present invention comprises sol-gel compositions and uses thereof. Specifically, the sol-gel compositions of the present invention have properties that allow them to be used as: (1) depots of bioactive substances, and in certain embodiments, controlled release depots of bioactive substances; and (2) as depots of bioactive substances. Coatings for enhanced adhesion between organic and inorganic surfaces. The methods used to prepare the sol-gel compositions of the present invention can enhance the incorporation of biologically active substances into the forming gel during sol-gel processing, and can provide sol-gel compositions produced as follows , the sol-gel composition has the property that once it is implanted in a patient it will help to control the rate of release of the biologically active substance into the physiological environment. Specifically, the chemical environment of the sol-gel process is adjusted according to the properties of the particular bioactive substance, thereby controlling how the bioactive substance interacts with the environment during the sol-gel process and how it is extracted from the fabric once implanted. released into the physiological environment. The elution of various bioactive substances embedded in the forming gel and from the sol-gel composition once made can be more finely controlled by varying the composition of the solution used during sol-gel processing. off rate. Furthermore, the treatment of the prepared sol-gel composition with the organomodified silane helps to inhibit the dissolution and release of the bioactive substance from the sol-gel into the physiological environment after implantation.

As stated, the sol-gel compositions encompassed by the present invention can be applied to the surface of an implantable medical device to function as a bioactive reservoir or bioactive coating. The sol-gel composition may be a mesoporous inorganic oxide prepared by a template-based sol-gel synthesis route, the mesoporous material having substantially continuously interconnected channels suitable for functioning as biological The role of the active substance depot is to be able to retain biologically active substances and to be able to release biologically active substances within a defined period of time. The sol-gel compositions of the present invention may function as a reservoir of bioactive substances by having bioactive substances in the substance of the composition material itself prior to application to the surface of an implantable medical device; and/or The bioactive substance is loaded into the interconnecting channels of the material after application to the surface of the implantable medical device. In one embodiment, the addition of organomodified silanes to the solvent during the sol-gel process can enhance or more finely control the incorporation of biologically active substances into the sol-gel compositions of the present invention. Organomodified silanes can alter the chemical environment of the sol-gel process, including altering the process and the hydrophobicity/hydrophilicity of the gel-forming material so that biologically active substances cannot be separated between the forming gel and the aqueous environment. move freely. In one embodiment, as the gel is formed, the biologically active substance is retained near the gel due to electrostatic forces and/or chemical or hydrogen bonding.

The mesoporous sol-gel compositions of the present invention have a highly ordered network of surface-accessible pores comprising three-dimensional, substantially continuous interconnected channels throughout the membrane. This ordered interconnected structure provides a mechanism by which the sol-gel compositions of the present invention can function as a reservoir of biologically active substances. Bioactive substances applied to the membrane surface will permeate the porous membrane, be loaded in the interconnecting channels, and later be released by diffusion, osmosis or electrochemical induction or other means.

The mesoporous sol-gel composition of the present invention is prepared by using a three-block copolymer template, which can be automatically Assemble into a highly ordered three-dimensional structure (Figure 1). Thermal treatment (or exposure to UV lamp/ozone source at room temperature) removes the template and causes the surrounding inorganic phase to crosslink (age) to form a mechanically robust network. Thus, the final sol-gel composition is the negative of that shown in Figure 1, in which the block copolymers have been removed, leaving a network of interconnected channels. The resulting channel has predictable uniformity. In such embodiments, the pores and channels have diameters in the mesoporous range, typically about 2 to 30 nm, more often about 5 to 30 nm. The diameter of the channels can be precisely controlled by hydrothermal treatment or addition of hydrophobic swelling reagents in the initial solution. Thus, the pores and channels of the present invention may be of any desired diameter including, but not limited to, about 2 to 100 nm, about 3 to 75 nm, about 5 to 50 nm, about 7 to 30 nm, or about 10 to 20 nm.

As stated, sustained-release, controlled-release, and prolonged-release delivery can be achieved using the sol-gel composition bioactive substance delivery library (and corresponding bioactive substance delivery device) of the present invention. By changing the properties of the sol-gel composition, various bioactive substances can be delivered with different release rates and release curves. For example, biologically active substances may be released using approximately first order or approximately second order kinetics. Delivery can be initiated at the time of implantation of the biologically active substance delivery device or at a specific time after implantation, and the delivery can rapidly increase from zero to a maximum rate within a short period of time, for example, in less than about 1 hour, at less than about 30 within minutes, within less than about 15 minutes, or within less than about 5 minutes. The above-mentioned maximum delivery rate may be maintained for a predetermined period of time until the delivery rate drops suddenly. For example, delivery can be at the highest rate for at least about 8 hours, for about 2 days, for about 4 days, for about 7 days, for about 10 days, for about 15 days, for about 30 days, for about 60 days or for At least about 90 days. On the other hand, the delivery rate of a biologically active substance may follow an approximately bell-shaped time-varying curve, initially slowly but exponentially increasing the delivery rate to a maximum rate, then the rate decreases exponentially with time, eventually falling to zero. In the field of sustained release biologically active substances, it is generally considered desirable to avoid "bursts" of large quantities of biologically active substance delivery, where most of the biologically active substance is delivered within a short period of time. The methods of the present invention can help alleviate the above-mentioned problems by enhancing the incorporation of biologically active substances into the forming sol-gel composition. Embodiments employing organomodified silanes to treat the surface and/or channels of the sol-gel composition may also be used to slow the rate of drug elution. In this approach, the hydrophobic group of the organomodified silane inhibits the diffusion of liquid into the sol-gel composition and dissolves the bioactive substance, thereby avoiding causing premature release of the bioactive substance. Thus, according to the present invention, various parameters can be adjusted to produce various changes in the desired delivery profile for a particular bioactive substance/disease/patient combination.

The bioactive substance loading and release properties (e.g., the maximum loading of the bioactive substance, the elution rate of the bioactive substance and the way the elution profile changes with time) depend on the sol-gel composition of the bioactive substance library (including Whether the bioactive substance is contained in the material itself (pre-coated to the bioactive substance delivery device), whether the bioactive substance is contained in the interconnecting channels of the material (loaded after application to the bioactive substance delivery device), or both) and the bioactive substance formulation. properties of both products. This can be achieved by changing the formulation of the bioactive substance, changing the pore size of the sol-gel material, coating the interior of the channel, treating the surface and/or through pores of the sol-gel composition with an organomodified silane, or using various Substances dope the material to alter the release kinetics.

There are several known methods for engineering the pore size of sol-gel materials. The pore size can be varied by varying the type of template material used and the amount of said template material in the sol, since the size of the hydrophobic portion of the amphiphile largely affects the pore size. For example, the pore size of MCM-41 can be adjusted in the range of about 1.6 nm to about 10 nm (US Patents 5,057,296 and 5,102,643 and Beck et al., 1992, J. Am. Chem. Soc. 114, 10834). Another method for modifying the pore size is to incorporate a hydrophobic organic co-solvent into the sol, which swells the hydrophobic regions after template self-assembly. The most commonly used swelling agent is 1,3,5-trimethylbenzene (TMB) (Schmidt-Winkel et al., Chemistry of Materials, 2000, 12, pp. 686-696), but in principle many other organic materials can also act. This effect, such as triisopropylbenzene, perfluorodecalin, alkanes, alkenes, and long-chain amines (including N,N-dimethylhexadecylamine, trioctylamine, tridodecylamine) . Other suitable methods include post-synthesis hydrothermal treatment of self-assembled gels (Khushalani et al., Advanced Materials, 1995, p. 7, 842) or temperature modification. For example, Galarneau et al. in 2003 (New J. Chem. 27:73-39) elucidated that synthesis temperature affects the structure of mesoporous materials formed in a binary fashion. When the synthesis temperature is lower than 80°C, SBA-15 has mesopores with a diameter of about 5 nm, and "ultramicropores" with a diameter of about <1 nm. When the synthesis temperature is higher than 80°C, SBA-15 has mesopores with a diameter of about >9nm and no ultramicropores.

The surface properties of the channels in the sol-gel composition can also be modified to alter the release kinetics of the biologically active substance. After completion of the sol-gel synthesis and removal of the structure-directing template, the internal surfaces of the pores can be modified to impart the desired surface functionality. The individual channels can be coated with a hydrophobic or hydrophilic coating or can be coated with a charged surface for better interaction with biologically active substances or with other substances carried within the channel. One way to achieve this is to use organomodified silanes. Organomodified silanes can be used as linkers to render the surface more hydrophobic or more hydrophilic, depending on the end segments used. For example, if a carboxyl group is used as a terminal molecule, it will confer hydrophilicity; but if a long chain fatty acid or thiol is used, it will confer a more hydrophobic character. Various hydrophilic and hydrophobic segments are well known in the art.

Alternatively, the channel walls can be modified by exposing them to a _Cl2 treatment gas activated by UV light ( _Cl2 →Cl*), resulting in the channel surface being covered with chlorosilyl groups (Si-Cl), which can then be modified according to the organic Principles of chemistry The chlorosilyl groups are further converted into any desired functional groups by various treatments. For example, other treatment gases (including, phosgene (SOCl), isocyanate (-N=C=O), malamide, and others) can also be used to initially treat the surface of the pore walls to obtain similar results. The above chemicals readily react with silanol (Si-OH) groups on the surface of the pore walls, whereby the silanol is replaced by an alternative group (e.g. Si-Cl in the case of phosgene), which is then available for selection The groups can be reacted in subsequent steps to impart any desired chemical functionality to the pore walls.

Another way to engineer the properties of the channels is by treating them with strongly acidic or basic liquid solutions, which impart a charge to the surface. Specifically, exposure to a solution with a pH below the isoelectric point of the surface (PI=2 for silica) protonates the surface silanol groups (Si-OH→Si-OH ²⁺ ), thus positively charging the surface . Similarly, treatment with a solution having a pH higher than the PI of the surface results in deprotonation of the surface silanols and a net negative charge on the surface (Si-OH→Si-O ⁻ ). It is important to note that this charge cannot be maintained when removed from an acidic or basic solution unless the solution also contains an oppositely charged solute that can attach to the charged surface by electrostatic attraction. In cases where the solution also contains a solute with an opposite charge, the surface remains charged and the solute remains attached to the surface even after removal from an acidic or basic solution. These properties can be used to stimulate the elution of polar or charged bioactive molecules from mesoporous matrices (discussed further below).

One or more of the above methods can be selected according to the particular bioactive substance or substances to be loaded into the channel, since different bioactive substances have different properties in terms of size, hydrophobicity and charge. The above properties will affect the loading and release of bioactive substances from sol-gel compositions. For example, paclitaxel is a hydrophobic (lipophilic) molecule with a size of about 1 to 2 nm. Other hydrophobic bioactive substances include, for example and without limitation, most antipsychotics, antibiotics such as amphotericin, dexamethasone, and flutamide. Paclitaxel is slightly more hydrophobic than rapamycin, and corticosteroids are generally less hydrophobic than rapamycin or paclitaxel. If a hydrophobic bioactive is used, it is desirable to coat the channels with a hydrophobic coating to maximize bioactive loading. Highly hydrophilic and water-soluble bioactives can benefit from a hydrophilic coating to maximize bioactive loading. Hydrophilic bioactive substances include, but are not limited to, most hormonal peptides, antibiotics (such as vancomycin and phenobarbital), cimetidine, atenolol, aminoglycosides, hormones (such as thyrotropin-releasing hormone), p-nitrophenyl beta-cellopentaoside, luteinizing hormone-releasing hormone, and others. Known cationic bioactive substances include, but are not limited to, vincristine, amiloride, digoxin, morphine, procainamide, quinidine ), quinine, ranitidine, triamterene, trimethoprim, vancomycin, and aminoglycosides. Anionic biologically active substances include, but are not limited to, penicillins and a number of diuretics. Therefore, the properties and desired release profile of the bioactive substance to be loaded should be considered when deciding whether channel treatment is beneficial.

Once in a matrix or channel according to the invention, biologically active substances can be eluted in several ways. Simple diffusion can be used to release bioactive substances, in which case the bioactive substance moves along a concentration gradient into the ambient solution (body fluid). Osmosis can also be used whereby dissolved biologically active substances can be carried by bulk fluid flow from regions of higher osmotic potential to regions of lower osmotic potential. Osmosis can also be used to drive biologically active substances from the matrix. For example, the matrix can be filled with increasing volumes of an aqueous solution to drive hydrophobic bioactive substances from the matrix. For example, this can be done by filling one half of the sol-gel matrix composition with a hydrophobic bioactive substance and filling the other half with a soluble salt. When implanted in a patient, water in body fluids will dissolve the salt, creating a strong osmotic force to draw water into the matrix. The introduced water displaces the hydrophobic bioactive substance, thereby forcing the hydrophobic bioactive substance out of the matrix into the surrounding physiological environment. The system described above can be designed in various ways and the osmotic pump can be separated from the sol-gel matrix composition.

The release kinetics of the bioactive substance can also be adjusted by altering the physical properties of the bioactive substance formulation itself, such as the net charge, hydrophobicity, and rheological properties of the bioactive substance formulation.

Other methods for eluting biologically active substances from sol-gel compositions include: using electrophoretic mechanisms with charged biologically active material particles; using physical gating, such as controlling the surface area of the biologically active material pool exposed to the environment; and A variety of biodegradable and semipermeable membranes are used that can be used to control the release rate of the biologically active substance from the reservoir.

An important aspect of the present invention is the delivery of anti-restenotic bioactive substances. A particularly effective anti-restenosis bioactive substance is the lipophilic bioactive substance paclitaxel (N-benzyl-β-phenylisoserine ester, M.W.853.9) and an antitumor agent isolated from the bark of the yew tree .

As stated, the sol-gel compositions of the present invention are very suitable for enhancing the adhesion between organic and inorganic surfaces because the network of highly ordered, open, surface-accessible channels is continuous and interconnected throughout the volume. Connected. For example, a polymer containing an organic bioactive material deposited on the top surface of the inorganic sol-gel composition of the present invention can enter and penetrate the porous membrane within the thickness of the membrane, thereby forming an inorganic A rigid nanocomposite phase on the surface of a substrate. This molecular interpenetration between the polymer and the sol-gel composition creates a very strong bond, corrosion resistant and resistant to mechanical removal.

Figure 2 shows a three-layer structure 10 of the present invention for enhancing adhesion between organic and inorganic surfaces. In this example, a sol-gel composition 110 is deposited on an inorganic substrate 100 . Organic polymers 120 are interspersed through the sol-gel composition 110 . In a typical sol-gel composition of the invention, pores 130 may have an average diameter of about 5-30 nm, and the areal density of pores at the top of the membrane (entry point to the channel network) may be about 10 ¹² /cm ² .

In the process of using the sol-gel composition of the present invention to enhance adhesion, the polymer to be bonded is deposited on the surface of the sol-gel composition by spin-coating a precursor formulation or any other suitable method. top. The polymeric material then penetrates into the sol-gel composition by capillary action or pressure treatment or heat treatment (but not limited thereto) into the individual pores of the sol-gel composition, in one embodiment in said sol - over substantially the entire thickness of the gel composition. After the above infiltration, the polymer is cross-linked by thermal curing, light-controlled reaction or other suitable methods. Optionally, covalent bonds or other chemical bonds are formed between the organic polymer 120 , the modified walls of the pores 130 and the surface of the inorganic substrate 100 simultaneously or after the above steps, thereby further improving the adhesion.

Whether it is to provide a library of bioactive substances or to enhance adhesion, the sol-gel composition of the present invention can be prepared and deposited on a substrate by the following non-limiting methods: (1) First, provide a substrate such as but Not limited to, surgical steel, nickel-titanium alloy (NiTi), cobalt chromium alloy (Co-Cr), carbon fiber material, plastic or other suitable biocompatible materials; (2) Then, remove any Undesirable pollutants; (3) microblasting the substrate; (4) by combining inorganic precursors with amphiphilic triblock copolymer template reagents, one or more biologically active substances, and organically modified Silanes were mixed to prepare sol-gel compositions. Non-limiting examples of typical inorganic precursors include _SiO2 and _TiO2 , such as tetraethoxysilane and titanium n-propoxide. At this stage, other solvents, such as rheology modifiers, such as ethanol, and swelling agents, such as 1,3,5-trimethylbenzene can also be added if desired; and (5) then, the template-assisted The composition is typically, but not limited to, deposited on the surface of the substrate by spin coating, dipping or spraying or by painting the item to be coated. Also, in certain embodiments, the sol-gel composition may be treated with an organomodified silane on the surface or within its channels.

Suitable organomodified silanes that can be used in the present invention include, but are not limited to, alkylsilanes (such as, but not limited to, methyltrimethoxysilane, methyltriethoxysilane, dimethyldiethylsilane Oxysilane, Trimethylethoxysilane, Vinyltrimethoxysilane, Vinyltriethoxysilane, Ethyltriethoxysilane, Isopropyltriethoxysilane, Butyltriethoxysilane silane, octyltriethoxysilane, dodecyltriethoxysilane, octadecyltriethoxysilane, etc.); aryl functional silanes (such as phenyltriethoxysilane, etc.); aminosilane (such as aminopropyltriethoxysilane, aminophenyltrimethoxysilane, aminopropyltrimethoxysilane, etc.); acrylate and methacrylate functional silanes (such as acryloxypropyltrimethoxysilane, etc. ); carboxylate-functional silanes; phosphate-functional silanes; ester-functional silanes; sulfonate-functional silanes; isocyanate-functional silanes; epoxy-functional silanes; Hexylchlorosilane, dimethyldichlorosilane, methyltrichlorosilane, etc.); N, O-bis(trimethylsilyl)-acetamide (BSA); N,O-bis(trimethylsilyl) base)-trifluoroacetamide (BSTFA); hexamethyldisilazane (HMDS); N-methyltrimethylsilyltrifluoroacetamide (MSTFA); N-methyl-N-(tert-butyl dimethylsilyl)trifluoroacetamide (MTBSTFA); trimethylchlorosilane (TMCS); trimethylsilylimidazole (TMSI) and combinations thereof.

Dip or spray coating can be easily used to coat objects with complex shapes and arbitrary curvatures, such as stents. The final thickness of the sol-gel composition can be controlled and optimized by diluting the solution, specifically by adding more solvent (usually ethanol) to the solution so that in the final working solution, the concentration of all components are reduced by the same factor, and their relative concentrations and molar ratios remain constant. As described in the examples, the thickness of the sol-gel composition can also be adjusted by varying the rate of spin coating or dip coating or both. The template material defining the channels is then removed by heat treatment or by exposure to a UV lamp/ozone source at room temperature. This step removes the template and causes the surrounding inorganic phase to cross-link to form a mechanically robust network. UV/ozone treatment is particularly beneficial if the inorganic precursor is heat sensitive.

In certain embodiments according to the invention, patterning techniques may be used to template sol-gel compositions at multiple length scales. For example, coatings of sol-gel mesoporous oxides such as silica require a hydrophilic surface with available -OH groups that can participate in condensation reactions with sol-gel precursor molecules . If conventional lithography or soft printing techniques (Whitesides et al, Angew. functional groups, then the mesoporous coating is patterned accordingly. Alternatively, sol-gel compositions can be patterned by, for example, micromolding in capillaries (Trau et al., Nature. 1997, 390, p. 674), where a flexible silicone mold can be compressed between a flexible silicone mold and the substrate surface. Limited amount of liquid sol.

Alternatively, a second sacrificial porogen may be employed, thereby patterning the deposition of the coating of the sol-gel composition. For example, well-established methods are known to produce macroporous inorganic materials (100 nm<d<10 μm) by combining commercially available or custom-synthesized latex particles such as monodisperse polystyrene spheres with radii in the range of 100 to 500 nm ( Stein et al., Science, 1998, 281, pp. 538-540)), or phase-separated emulsions such as formamide oil-in-systems (Pine et al., Nature, 1997, 389, pp. 948-951)) templated. These and other related methods can be combined with self-assembled template methods to generate the sol-gel compositions described herein. The end result is a hierarchically ordered inorganic solid with porosity on multiple scales (Whitesides et al., Science, 1998, 282, p. 2244). This approach is particularly useful in orthopedic applications where macroporous scale porous implant surfaces are required to allow cell migration and bone/implant integration, whereas mesoporous scale porosity is available For the delivery of topical bioactive substances.

Another embodiment according to the invention is the use of relatively readily available mesoporous materials such as silica as intermediate molds for patterning other inorganic solids for which no suitable sol-gel precursor exists, including Noble metals (such as, but not limited to, gold and platinum) and extending all the way to even carbon-based polymers. For example, mesoporous silica coatings can be first deposited on implantable devices, followed by "casting" of volatile precursors or liquid-based suspensions of (but not limited to) Pd or Au nanoparticles, followed by, for example, hydrofluoric Acid treatment dissolves the mesoporous silica, resulting in a silica-framed mesoporous noble metal replica (Schuth, studies in Surface Science and Catalysis, v.135, pp. 1-12).

Example

Example I

A 0.1M tetraethoxysilane (TEOS) sol-gel solution was prepared by first mixing 25 μL of concentrated HCl (12M) with 860 μL of deionized water and 3 mL of pure ethanol in a 200 mL glass scintillation vial to prepare a 0.3 M ethanolated hydrochloric acid. In a 1.5 mL microcentrifuge tube, combine 1 mL of ethanol and 112 μLTEOS. The TEOS solution was added dropwise to the acidified ethanol within 30 seconds, and the resulting TEOS solution was hydrolyzed for 45 minutes. At the end of the hydrolysis, 2 mL of the hydrolyzed TEOS solution was added to desaspartate angiotensin I (DAA-I) (2.5 mg) in a glass tube (1 dram). Sonicate briefly to ensure peptide dissolution and mixing. The resulting solution was transferred to a 5 mL gas-tight Hamilton syringe after passing through a 5 micron filter. The syringe was placed in a Harvard Scientific syringe pump and connected to an ultrasonic nebulizer.

Two clean 12mm brackets or four clean 6mm brackets were mounted on the coating mandrel using a slotted cone for suspension. The mandrel was attached to the spray device, and the scaffold was sprayed with a sufficient amount of the sol-gel solution containing DAA-I by passing the mandrel repeatedly through the spray head so that approximately 20 μg of gel was deposited on the surface after drying at 40 °C for 30 min . A top coat of 0.1M TEOS was used as an additional barrier layer to allow the desired release rate of DAA-I. A 0.1 M TEOS solution was prepared as before, but without the addition of DAA-I. The scaffolds were sprayed with sufficient TEOS to give 50 μg of topcoat after drying at 40° C. for 30 minutes.

Referring to Figures 3A-3D, scanning electron micrographs (SEM) of DAA-I coated scaffolds were taken using a Hitachi S-3000N scanning electron microscope with an Oxford Instruments INCA X-Sight Model 7021. Before the chamber was evacuated, several scaffolds pre-coated with DAA-I/TEOS were placed on the rotating stage of a scanning electron microscope using double-sided conductive adhesive discs. An identification map of the individual supports is drawn, indicating the location and then identified based on the orientation between the individual supports. Scaffolds were not surface-treated prior to imaging. Individual scaffolds were oriented in the SEM field using an internal visual camera and external controls. When the orientation was acceptable, the electron microscope system was powered on and various regions of interest were imaged at different magnifications of 60X (Figure 3A); 500X (Figure 3B); 1000X (Figure 3C) and 2000X (Figure 3D). Acquire electron microscopy images of specific regions of interest after automatically adjusting brightness and contrast.

Referring to Fig. 4, when the scaffold was cultured in the following medium at 37°C, the amount of DAA-I in 0.1% Solutol's ammonium acetate buffer (pH 5.0) was measured as a function of time to measure DAA-I from Elution on TEOS-coated stents. The DAA-I peak in the high-performance liquid chromatography (HPLC) chart obtained by Altima C-8 column (Altech, Chicago IL.) was integrated, and compared with the standard curve to determine the content of DAA-I. It can be seen from Fig. 4 that the increase of the molar ratio between TEOS and DAA-I can delay the elution rate of DAA-I.

Example II

To explore the effect of increasing TEOS dosage on the elution rate of DAA-I, incremental amounts (0.1 to 0.5 M) of TEOS were added to a constant amount of DAA-I (1.25 mg/mL) according to the method and protocol described above. As described above, each scaffold (9 mm, n=4) was sprayed with each solution, weighed, and the amount of DAA-I eluted at 24 hours was compared. Figure 5A shows the total amount of biologically active substance released at 72 hours, and Figure 5B shows the elution profile as a function of time. As can be seen from Figures 5A-5B, increasing the molar ratio of TEOS to drug significantly delayed the rate of drug release into the aqueous environment.

Example III

Sol-gels composed only of hydrolyzed TEOS or tetramethoxysilane (MEOS) are relatively hydrophilic, and even though they can trap bioactives more efficiently, they cannot be used for most hydrophobic drugs (such as paclitaxel, radium, etc.). pamycin, cyclosporine, and other compounds with limited water solubility) provide a chemically compatible environment. To increase the hydrophobic character of the resulting sol-gel, various alkylated ethoxysilanes can be added to the sol-gel forming solution. Such as methyltriethoxysilane, tert-butyltriethoxysilane, isobutyltriethoxysilane, hexyltriethoxysilane, phenyltriethoxysilane, octyltriethoxysilane, The compounds of dodecyltriethoxysilane and octadecyltriethoxysilane can be added to the mixture in different molar ratios to give distinctly different sol-gel coatings. The inclusion of the above compounds resulted in a range of compounds that differed significantly in their ability to be incorporated into the gel, and also affected the rate at which these compounds were released from the gel into the aqueous solution. Figure 6 shows an example of the above effects. Sol-gel solutions were prepared by mixing different concentrations (10 to 90%) of phenyltriethoxysilane, octyltriethoxysilane and dodecyltriethoxysilane with TEOS, where The total concentration of (TEOS+silane) was 0.1M.

Each solution contained a sufficient amount of cerivastatin to coat each stent with 10 μg of the drug. After the scaffolds were sprayed and dried, they were individually submerged in 1 mL of water in polypropylene microcentrifuge tubes. After 5 minutes, an aliquot of the solution was analyzed for the content of cerivastatin. As shown in Figure 6, less bioactive species were eluted when more hydrophobic silanes were incorporated into the gel. The most effective is dodecyltriethoxysilane, where the optimum level is greater than about 30% and less than about 90%.

Based on the above knowledge, a direct comparison of cerivastatin was made when stents were prepared coated in 0.5M 100% TEOS or in 0.2M 40% dodecyltriethoxysilane/60% TEOS elution curve. Interestingly, higher concentrations of the latter composition were structurally unstable. Significant platelet and grain formation was observed on stents coated with 0.3M and higher concentrations of 40% dodecyltriethoxysilane/60% TEOS. An important feature is that the elution profiles at 4 μg and 8 μg cerivastatin are equivalent for both sol-gels, showing that the inclusion of a hydrophobic silane reduces the sol-gel required in the gel to obtain a certain elution rate. - Total amount of gel precursor (see Figures 7A-7B).

Example IV

Another non-limiting method of modulating the release of biologically active substances from sol-gel matrix compositions is chemical treatment of the sol-gel with reactive chlorosilanes. In this example, each scaffold was spray-coated with 10 μg cerivastatin in 0.5M TEOS and then dried. Next, 0.5M TEOS without any bioactive substances was applied as a second layer. Each scaffold was then treated by immersion in a 1 M trimethylchlorosilane solution for about 10 minutes or about 30 minutes, and then dried in an oven at 40° C. overnight. To determine the effect of the aforementioned "silanization" on the sol-gel surface, the elution rate of cerivastatin from the aforementioned stents was compared to that from untreated coated stents. It can be seen from Figure 8 that the modification of the sol-gel by trimethylchlorosilane reduces the elution rate, and the longer the exposure time, the greater the impact on the elution curve.

There are a variety of applications of the invention. A non-limiting example is total hip replacement. Failure of the polymethacrylate (PMMA) adhesive/metal interface in femoral components has been recognized as a major cause of aseptic loosening of fixed hip implants. Experimental and data studies show that bond loosening at the interface can significantly increase the stress on the surrounding adhesive ring, leading to PMMA rupture and total implant failure.

The present invention is ideally used to ensure the fixation of femoral components with polymeric adhesives. The sol-gel composition can be chosen according to the implant material chosen. _SiO2 films can be deposited on Co-Cr-Mo, while _TiO2 films may be ideal on Ti6-A14-V parts. In combination with appropriate silane adhesion promoters, excellent bonds can be formed between implants and precoated PMMA materials. In addition, the surface roughness of sol-gel compositions is several orders of magnitude smaller. This property should be beneficial in preventing fragmentation and bone loss.

It has been shown that _SiO2 mesoporous films deposited on Ti6-A14-V alloy substrates and exposed to simulated body fluids promote the precipitation of hydroxyapatite crystals. However, due to the range of pore sizes, mesoporous membranes are unlikely to be used in adhesive-free joint replacement applications as suggested in the above studies. Pores in the 50 to 100 μm range in size have been reported to be the minimum pores necessary for ingrowth of skeletal tissue throughout the porous coating. In contrast, the mesopore range is ideal for accommodating polymer molecular chains, as discussed herein.

In one embodiment of the invention involving the hydrophobic drug paclitaxel, the matrix may consist of inorganic oxides obtained using sol-gel synthesis (as described above), ionic or non-ionic surfactants and block copolymers Or any combination thereof, each of the above-mentioned components has any molar ratio within a wide range. By proper selection of molar ratios and coating process parameters, this material system can be induced to self-assemble such that the matrix encapsulates the drug and controls its sustained release by diffusion. The self-assembly process can also include phase separation of the individual matrix components, where the surfactant and/or block copolymer acts as a template and can guide the assembly of the sol-gel inorganic material (as described above). Subsequent removal of the template component may provide an alternative mechanism for controlling drug release through the network of interconnected pores in the resulting inorganic matrix.

In another embodiment, the matrix consists solely of sol-gel silica and the paclitaxel/TEOS molar ratio is in the range of about 10:1 to about 1:200. For example, a solution with a paclitaxel/TEOS molar ratio of about 1:10 and a drug concentration of about 5 μg/μL is prepared by dissolving about 5 mg of paclitaxel and about 50 μL of TEOS in a solvent consisting of about 0.9 mL of ethanol and about 50 μL of deionized water. The stent can be coated with 2 μL of the solution by a capillary-assisted coating method, thereby loading a total of approximately 10 μg of drug.

In another embodiment, paclitaxel (or other bioactive substances) can be first encapsulated in polylactic acid (PLA) or block (polylactic acid)-block (polyglycolic acid) (PLGA) polymer spheres, wherein, The polymer/drug molar ratio may range from about 200:1 to about 1:1, and in another embodiment, from about 10:1 to about 3:1. The polymer/drug spheres can be suspended in deionized (DI) water to form a stable suspension. The spheres described above can then be deposited on the scaffold, for example by spraying the aqueous solution, and then topcoated with the sol-gel composition. The biodegradable polymer spheres can provide sustained drug release, while the sol-gel composition topcoat can provide mechanical strength, improve the adhesion of the spheres to the device surface, and act as a diffusion barrier to further control drug elution.

In a specific example, about 40 mg of PLA/paclitaxel spheres (at a drug concentration of about 18 wt%) can be suspended in about 2 mL of DI water. The solution was then dispensed at a rate of about 40 μL/min and the vibrating assembly operated at about 2.0 watts to obtain an aerosol beam through which the stent was sprayed 20 times. This procedure yielded a total drug loading of approximately 20 μg. Also, a sol-gel silica topcoat can be sprayed using a hydrolyzed TEOS solution. Hydrolysis may be performed in aqueous solution, optionally facilitated, for example, by acidic or basic conditions, by stirring or ultrasonic vacuum agitation, addition of organic solvents, or any combination thereof. In a specific example, the topcoat solution has a pH ≈ 3 and can be prepared by mixing about 210 μL of TEOS, about 9.25 mL of DI water, about 0.5 mL of ethanol, and about 100 μL of dilute (0.1 M) hydrochloric acid ( HCl) was mixed and stirred vigorously at about 1500 rpm for about 1 hour using a magnetic stir bar. Top coating involved passing about 20 stents through the spray beam while the solution was dispensed at a rate of about 40 μL/min and aerosolized at about 2.0 W.

In another example, a middle layer of PLA/cerivastatin spheres can be sandwiched between a drug-containing base coat and a sol-gel composition top coat. This intermediate layer can be obtained by dissolving, for example, about 20 mg of PLA/cerivastatin spheres in about 1 mL of DI water and spraying about 20 times at a dispensing rate of about 40 μL/min and an aerosolization power of about 1 W. The purpose of the above intermediate layer is to further prolong the drug release through the interaction between the diffusing molecules and the spheres.

The primer layer in these embodiments of the invention may, but need not, include other biologically active substances. The bioactive substance contained in the base coat may be the same or different from the other bioactive substance in the spheres or optionally in the top coat of the inorganic sol-gel composition. For example, the primer layer may be a bioactive material-free metal layer as described in co-pending US Patent Publication No. 2006-0051397, wherein the disclosure of the aforementioned patent regarding the deposition of drug-free metal layers is incorporated by reference. All content is contained here. Alternatively, as described in co-pending US Patent Publication Nos. 2006-0062820, 2006-0051397, and 2006-0115512, the primer layer may be a metal layer, wherein the bioactive material is directly electrochemically deposited on the metal layer or The resulting pores are loaded electrochemically, and the disclosures of the aforementioned patents for these techniques are hereby incorporated by reference in their entirety. Alternatively, the primer layer may be an inorganic sol-gel composition that is free of biologically active substances and that contains biologically active substances within the composition before it is applied to the surface of the medical device; or until it is applied to the device surface. or the sol-gel composition of this type may contain bioactive substances through the above two mechanisms. The primer coats of the present invention may also be applied according to the method described in Ragheb et al., US Patent No. 6,730,064, issued May 4, 2004, which teaches by reference both non-biologically active and biologically-containing The entirety of the application of the active substance coating is included here.

The scope of the foregoing description clearly shows that the invention encompasses a wide variety of advantageous embodiments. These embodiments may include multiple coatings or layers, the thickness of each layer being limited only by the physical function of the device. In certain embodiments, the aforementioned thickness does not exceed about 5 microns. Furthermore, different layers may comprise different biologically active substances, different concentrations of the same or different biologically active substances and/or mixtures of biologically active substances in a particular layer or layers. As a non-limiting example, one layer may contain two different bioactive substances, two different layers may contain two different bioactive substances, or multiple layers may contain different concentrations of the same bioactive substance. As a specific, non-limiting example, a device may include three layers: a bottom layer may contain paclitaxel; a middle layer may contain no bioactive substance, and an outer topcoat layer may include an anti-inflammatory bioactive substance, such as a statin. In this embodiment, the statin is released rapidly after implantation of the device, while the release of paclitaxel will be delayed. Alternatively, the outer topcoat can be rendered hydrophobic with, but not limited to, dodecylsilane to provide a water barrier. As a non-limiting example within the scope of the present invention, it should be understood that the sol-gel composition of any layer may be a sol-gel derived inorganic oxide; a sol-gel derived organomodified silane; comprising Hybrid oxides of organomodified silanes and oxides with mesopores generated using templates.

Various adaptations and modifications may be made to the above-described embodiments without departing from the scope and spirit of the invention, which may be practiced otherwise than as specifically described herein. The above description is intended to be illustrative, not limiting. The scope of the present invention is limited only by the claims.

The terms and expressions used herein are used as terms of description rather than limitation. In the use of said terms and expressions, equivalents or parts thereof to the features shown and described are not excluded, and it will be recognized that various modifications may be made within the scope of the invention claimed. Furthermore, any one or more features of any embodiment of the invention may be combined with any one or more other features of other embodiments of the invention without departing from the scope of the invention.

Unless otherwise indicated, all numbers expressing quantities of ingredients used in the specification and claims, as well as properties such as molecular weights, reaction conditions, etc., should be understood as being modified by the term "about" in all cases. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Unless otherwise indicated herein, or otherwise clearly contradicted by context, the terms "a," "an," and "the" and similar references used in the context of describing the present invention should be read to include both the singular and the plural. Recitation of ranges of values herein are merely intended to serve as a shorthand method for each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limiting. Each group member may be employed and claimed individually or in any combination with other members of the group or other elements found herein. It is contemplated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is hereby deemed to contain the group as modified, thus satisfying support for all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, modifications to those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors of the present invention foresee skilled artisans employing such modifications as appropriate, and the inventors contemplate that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, in all possible variations, any combination of the above-mentioned elements is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

In addition, numerous references, including patents and printed publications, are cited throughout this specification. Each of the aforementioned references and printed publications is hereby incorporated by reference in its entirety, respectively.

In conclusion, it should be understood that the embodiments of the invention disclosed herein are for the purpose of illustrating the principles of the invention. Other modifications may be made within the scope of the invention. Thus, by way of example and not limitation, alternative configurations of the invention may be employed in accordance with the teachings herein. Accordingly, the invention is not limited to only that described and illustrated herein.

Claims (27)

1. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance storehouse, wherein, described bioactive substance storehouse comprises the lip-deep coating that is applied to described structural detail, wherein, described coating comprises one or more layers, and comprise one of at least the base composition that utilizes sol-gel technology to form in described each layer, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, and described design influence is in case the content of the described bioactive substance in the described base composition after making and/or be discharged into speed in the physiological environment in case implant described bioactive substance behind the patient.

2. medical apparatus and instruments as claimed in claim 1, wherein, described base composition comprises and is selected from following material: sol-gel derived inorganic oxide, sol-gel derived through organically-modified silane, comprise through the hydridization oxide of organically-modified silane and have the mesoporous oxide that the template utilized produces.

3. medical apparatus and instruments as claimed in claim 1, wherein, the inorganic oxide of described base composition for making by described sol-gel technology.

4. medical apparatus and instruments as claimed in claim 3, wherein, described inorganic oxide is selected from the oxide and the titanyl compound of silicon.

5. medical apparatus and instruments as claimed in claim 3, wherein, described base composition is the mesoporous inorganic oxide.

6. medical apparatus and instruments as claimed in claim 5 wherein, utilizes and sacrifices pore-forming template component and self assembly or guide assembling preparation technology to obtain described mesoporous inorganic oxide.

7. medical apparatus and instruments as claimed in claim 6, wherein, described template group branch is selected from amphiphilic block copolymer, ionic surfactant and nonionic surfactant.

8. medical apparatus and instruments as claimed in claim 7, wherein, described template group is divided into polyethylene oxide/polypropylene oxide/polyethylene oxide block copolymer.

9. medical apparatus and instruments as claimed in claim 5, wherein, described mesoporous inorganic oxide comprises successive basically interconnecting channel.

10. medical apparatus and instruments as claimed in claim 9, wherein, the inner surface of described successive interconnecting channel basically is by through organically-modified silane coating, describedly through organically-modified silane the following characteristic of described mesopore oxide carried out modification: hydrophobicity, electric charge, biocompatibility, engineering properties, bioactive substance affinity, storage capacity and combination thereof.

11. medical apparatus and instruments as claimed in claim 10, wherein, be applied on the described surface of described structural detail in described coating after, one or more bioactive substances are loaded in the described interconnecting channel.

12. medical apparatus and instruments as claimed in claim 3, wherein, described oxide participant reagent that the following characteristic of described oxide is carried out modification is compound: hydrophobicity, electric charge, biocompatibility, engineering properties, bioactive substance affinity, storage capacity and combination thereof.

13. medical apparatus and instruments as claimed in claim 12, wherein, described modifying agent is through organically-modified silane.

14. medical apparatus and instruments as claimed in claim 13 wherein, describedly is selected from through organically-modified silane: alkyl silane; MTMS; MTES; Dimethyldiethoxysilane; Trimethylethoxysilane; Vinyltrimethoxy silane; VTES; Ethyl triethoxysilane; The isopropyl triethoxysilane; The butyl triethoxysilane; Octyltri-ethoxysilane; The dodecyl triethoxysilane; Octadecyltriethoxy silane etc.; The aryl functional silane; Phenyl triethoxysilane etc.; Amino silane; Aminopropyl triethoxysilane; The aminophenyl trimethoxy silane; Aminopropyl trimethoxysilane etc.; Acrylate-functional silane; The methacrylate functional silane; Acryloyl-oxy propyl trimethoxy silicane etc.; The carboxylate functional silane; Phosphate functional silane; The ester functional silane; Sulfonate functional silane; Isocyanate-functional silane; Epoxy functional silane; Chlorosilane; Trim,ethylchlorosilane; Chlorotriethyl silane; Three hexyl chloride silane; Dimethyldichlorosilane; Methyl trichlorosilane; N, O-two (trimethyl silyl)-acetamide (BSA); N, O-two (trimethyl silyl)-trifluoroacetamide (BSTFA); Hexamethyldisiloxane (HMDS); N-methyl-trimethyl-silyl-trifluoroacetamide (MSTFA); N-methyl-N-(t-butyldimethylsilyl) trifluoroacetamide (MTBSTFA); Trimethyl chlorosilane (TMCS); Trimethyl-silyl-imidazole (TMSI) and combination thereof.

15. medical apparatus and instruments as claimed in claim 1, wherein, described bioactive substance is selected from anti-restenosis reagent, anti-inflammatory agents, HMG-CoA reductase inhibitor, antibacterial agent, anti-tumor agent comprising salmosin, angiogenic reagent, anti-angiogenic reagent, thrombus reagent, resisting hypertension reagent, arrhythmia reagent, calcium channel blocker, cholesterol reducing reagent, psychotropic drugs, anti-depressed reagent, anti-epilepsy reagent, contraceptive, analgesic, SGF, skeleton is reinvented the factor, neurotransmitters, nucleic acid, opiate antagonist and combination thereof.

16. medical apparatus and instruments as claimed in claim 1, wherein, described bioactive substance is selected from paclitaxel, rapamycin, clothing Wei Mosi, tacrolimus, sirolimus, goes aspartic acid angiotensin I, nitric oxide, 4-hydroxy-3-methoxyacetophenone, Gamma-Tocopherol, recombined human osteoblast specific factor, estradiol, aspirin, atorvastatin, western power to cut down his spit of fland, fluvastatin, lovastatin, pravastatin, Rosuvastatin, simvastatin and combination thereof.

17. medical apparatus and instruments as claimed in claim 1, wherein, described medical apparatus and instruments is to be selected from following apparatus: vascular, support, plate, screw, vertebra cage, dental implant, dentistry implant, dental aligners, artificial joint, embolus device, ventricular assist device, artificial heart, cardiac valve, vein filter device, nail, clip, stitching thread, artificial net, pacemaker, pacemaker lead, defibrillator, nerve stimulator, nerve stimulator lead, implantable sensor and external pick off.

18. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance eluting coatings, wherein, described bioactive substance eluting coatings comprises the lip-deep one deck at least that is applied to described medical apparatus and instruments, wherein, described one deck at least utilizes sol-gel technology to form, and described one deck at least comprises through organically-modified silane.

19. as medical apparatus and instruments as described in the claim 18, wherein, described one deck at least is a priming coat, and described medical apparatus and instruments also comprises the top coat that is applied on the described priming coat.

20. medical apparatus and instruments as claimed in claim 19, wherein, in being selected from described priming coat, in the described top coat, between described priming coat and the described top coat and have the spheroid of matters of containing biological activities in the place of combination.

21. medical apparatus and instruments as claimed in claim 20, wherein, the spheroid of described matters of containing biological activities is made of biodegradable polymers.

22. medical apparatus and instruments as claimed in claim 19, wherein, described priming coat and/or described top coat comprise sol-gel inorganic oxide compositions.

23. medical apparatus and instruments as claimed in claim 18, wherein, described priming coat comprises mesopore oxide, and described mesopore oxide has successive basically interconnecting channel.

24. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance eluting coatings, wherein, described bioactive substance eluting coatings comprises two-layer at least, one of at least comprise the base composition that utilizes sol-gel technology to form in described each layer, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, and described design influence is in case the content of the described bioactive substance in the described base composition after making and/or be discharged into speed in the physiological environment in case implant described bioactive substance behind the patient.

25. medical apparatus and instruments as claimed in claim 24, wherein, described two-layer at least priming coat and the top coat of comprising, described priming coat is applied to the described surface of described medical apparatus and instruments, and described top coat is applied on the described priming coat.

26. medical apparatus and instruments as claimed in claim 24 wherein, describedly comprises one of at least the following form that is selected from two-layer at least: the sol-gel oxide skin(coating) of biologically active material not; The sol-gel oxide skin(coating), described sol-gel oxide skin(coating) has the bioactive substance that mixes in the described oxide; Not the biologically active material with through the compound sol-gel oxide of organically-modified silane; The biologically active material with through the compound sol-gel oxide of organically-modified silane; The biologically active material not through organically-modified silylation layer; The biologically active material through organically-modified silylation layer; The mesopore oxide of biologically active material not; Mesopore oxide, described mesopore oxide has the bioactive substance that mixes in the described oxide; Mesopore oxide, described mesopore oxide has the bioactive substance that mixes in the described oxide, and has other bioactive substance that is carried in later on the described surface that described mesoporous material is applied to described medical apparatus and instruments in the interconnecting channel of described oxide; Mesopore oxide, described mesopore oxide does not have the bioactive substance that mixes in the described oxide, but has the bioactive substance that is carried in later on the described surface that described oxide is applied to described medical apparatus and instruments in the interconnecting channel of described oxide; Aggregation with the polymer spheres that contains bioactive substance.

27. medical apparatus and instruments, described medical apparatus and instruments comprises structural detail and bioactive substance storehouse, wherein, described bioactive substance storehouse comprise be applied to described structural detail lip-deep one or more layers, wherein, described each layer in one or more layers comprises the base composition that utilizes sol-gel technology to form respectively, in described sol-gel technology, the environment of described sol-gel technology is designed to adapt to the characteristic of waiting to be incorporated into the bioactive substance in the described base composition, described design influence is in case the content of the described bioactive substance in the described base composition after making and/or be discharged into speed in the physiological environment in case implant described bioactive substance behind the patient, and when described layer is applied on the described surface of described structural detail, described layer has strengthened the cohesive between inorganic surfaces and the organic surface, and described organic surface is selected from polymer, tissue, skeleton and combination thereof.

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