Implantable medical devices employing a sol-gel composition coatings that functions as a bioactive material reservoir, and the use of sol-gel composition coatings for improved adhesion of organic and inorganic substrates are disclosed.

Description of the Invention

FIELD OF THE INVENTION

This invention is related to bioactive material-containing self-assembled sol-gel compositions. Specifically the invention relates to the use of such sol-gel compositions as drug reservoirs on implantable medical devices, and also the use of such sol-gel compositions to improve adhesion between organic and inorganic surfaces.

BACKGROUND OF THE INVENTION

"Sol-gel" processes are generally used to fabricate porous materials including self-assembled films. A sol is a liquid solution containing a colloid suspension of a material of interest dissolved in an appropriate solvent. Condensation reactions between the dissolved precursor molecules result in structures (particles, branched chains, linear chains, etc.) forming within the sol. The size, growth rate and morphology of these structures depend on the kinetics of the reactions within the solvent, which in turn are determined by parameters such as solution concentration, amount of water present, the temperature and pH of the solvent, agitation of the solvent and other parameters. Given enough time, condensation reactions will lead to the aggregation of growing particles or chains until eventually, a gel is formed. The gel can be visualized as a very large number of cross-linked precursor molecules forming a continuous, macroscopic-scale, solid phase, which encloses a continuous liquid phase consisting of the remaining solution. In the final steps of the sol-gel process, the enclosed solvent is removed (generally by drying) and the precursor molecules cross-link (a process called aging) resulting in the desired solid.

Sol-gel synthesis of materials offers several advantages over other synthetic routes. These advantages can include mild processing conditions (low temperature, low pressure, mild pH), inexpensive raw materials, no need for vacuum processing or other expensive equipment, and a high level of control over the resulting structure, particularly as it pertains to porosity. Regarding shape of the final product, there is essentially no limitation, because the liquid sol can be cast in any conceivable form before allowed to gel, including monoliths, thin films, fibers and micro- or nano-scale particles.

Porosity of materials produced in sol-gel processes can be controlled in a number of different ways. In the simplest sol-gel process, no special porogen is added to the sol and the porosity of the final solid is determined by the amount of precursor branching or aggregation before gelling. Average pore size, volume and surface area of porous sol-gel compositions increase with the size of the precursor molecules prior to the sol-gel processing.

Porosity can also be manipulated by the presence of additional materials within the solvent during the sol-gel process. The incorporation of sacrificial porogens in the sol (particularly those that can be easily removed via heating or other methods), is generally viewed as an efficient method to obtain porous solids when using sol-gel processes. Historically, these efforts were focused upon the fabrication of low dielectric constant (low-k) insulating films for the microelectronics industry. Sacrificial templates can also be used to create pores in inorganic materials formed using sol-gel processes. Sacrificial templates are usually amphiphilic molecules (i.e. those having hydrophilic and hydrophobic properties) capable of self-assembling in solution. These amphiphilic molecules create a highly-ordered structure that guides the precursor molecules to co-assemble around the structure. Once the precursor molecules co-assemble around the structure, it can be removed, leaving a negative image void.

The unique properties of self-assembling template-assisted, sol-gel compositions have generated a great deal of research. For example, in 1992, a group of researchers at Mobil Oil Corporation discovered that surfactant molecules (short amphiphilic molecules) will self-assemble in an aqueous solution of soluble silica, and upon solidification of the silica substrate, the surfactant can be removed leaving a material (called "MCM-41") having a hexagonal honeycombed array of uniform mesopores (mesopores are those with a pore size of between about 2 and about 50 nm; see U.S. Pat. Nos. 5,057,296 and 5,102,643, which are fully incorporated by reference herein). MCM-41 is synthesized using a cationic surfactant, quaternary alkyltrimethylammonium salts and various silica sources, such as sodium silicates, tetraethyl orthosilicate, or silica gel, under hydrothermal conditions (Beck et al., 1992, J. Am. Chem. Soc. 114, 10834). The pore size of MCM-41 can be adjusted from about 1.6 nm up to about 10 nm by using different surfactants or altering synthesis conditions. Presently, template-assisted mesoporous materials are fabricated using two broad classes of self-assembling amphiphilic templates: short molecule surfactants (see Brinker et al. (Advanced materials 1999, 11 No. 7) and Kresge et al. (Nature Vol. 359 22 October 1992)) and triblock copolymers (see U.S. Pat. No. 6,592,764 which is incorporated by reference herein).

Porous materials made using sol-gel processes can be used to deliver bioactive materials. For example, Vallet-Regi et al. (Chem. Mater. 2001, 13, 308-311) described charging powdered MCM-41 with ibuprofen. In this case, the ibuprofen was loaded into MCM-41 by dissolving the ibuprofen in hexane and adding the MCM-41 compound to the hexane in a powdered form. Munoz et al. (Chem. Mater. 2003, 15 500-503) described an experiment which demonstrated that ibuprofen could be delivered at a different rate from two different formulations of MCM-41, one made using a 16 carbon surfactant and one made using a 12 carbon surfactant.

Prior to International Patent Application Number PCT/US2004/040270 (PCT '270), which is fully incorporated by reference herein, no reference described an implantable medical device or bioactive material delivery device comprising a triblock copolymer template-based sol-gel composition formed surface coating with substantially continuously interconnected channels designed to function as a bioactive material reservoir. Moreover, no reference described a triblock copolymer template-based sol-gel composition surface coating with bioactive material found within the coating itself before being applied to the surface of an implantable medical device as well as having substantially continuously interconnected channels that could further function as a bioactive material reservoir after being applied to the surface of an implantable medical device. Thus, the invention described in PCT '270 provided at least two additional mechanisms through which bioactive materials could be loaded onto the surface of an implantable medical device.

While the materials and methods described in PCT '270 provided a number of important benefits (described therein), there is still room for improvement in the creation of bioactive material carrying materials made with sol-gel processes. For instance, better control of bioactive material particles during sol-gel processing and after device implantation could provide a benefit in allowing more accurate control over the amount of bioactive materials within a particular sol-gel composition as well as more control over the release rate of bioactive materials from an implanted medical device into the physiological environment after device implantation. The present invention provides such benefits. Before describing these benefits in more detail, however, background relating to a further aspect of the present invention is described.

One challenge in the field of implantable medical devices has been adhering bioactive materials and bioactive material-containing coatings to the surfaces of implantable devices so that the bioactive materials will be released over time once the device is implanted. One approach to adhering bioactive materials to substrates, such as the surface of implantable medical devices has been to include the bioactive materials in polymeric coatings. Polymeric coatings can hold bioactive materials onto the surface of implantable medical devices, and release the bioactive materials via degradation of the polymer or diffusion into liquid or tissue (in which case the polymer is non-degradable). While polymeric coatings can be used to adhere bioactive materials to implanted medical devices, there are problems associated with their use. One problem is that adherence of a polymeric coating to a substantially different substrate, such as a stent's metallic substrate, is difficult due to differing characteristics of the materials (such as differing thermal expansion properties). Further, most inorganic solids are covered with a hydrophilic native surface oxide that is characterized by the presence of surface hydroxyl groups (M-OH, where M represents an atom of the inorganic material, such as silicon or aluminum). At ambient conditions then, at least a monolayer of adsorbed water molecules covers the surface, forming hydrogen bonds with these hydroxyl groups. Therefore, due to this water layer, hydrophobic organic polymers cannot spontaneously adhere to the surface of the implantable medical device. Furthermore, even if polymer/surface bonds (including covalent bonds) are formed under dry conditions, those bonds are susceptible to hydrolysis (i.e. breakage) upon exposure to water. This effect is particularly important in applications where devices or components containing organic/inorganic interfaces must operate in aqueous, corrosive environments such as a human or other animal's body. These difficulties associated with adhering two different material types often leads to inadequate bonding between the implantable medical device and the overlying polymeric coating which can result in the separation of the materials over time. Such separation is an exceptionally undesirable property in an implanted medical device.

Two different approaches have traditionally been followed to reinforce organic/inorganic interfaces. The first is the introduction of controlled roughness or porosity on an inorganic surface that induces polymer mechanical interlocking. The second is chemical modification of the inorganic surface via amphiphilic silane coupling agents that improve polymer wetting, bonding and interface resistance to water. While these methods provide some benefits, they are not effective in all circumstances. Thus, there is room for improvement in methods associated with adhering inorganic and organic surfaces. Certain sol-gel composition embodiments according to the present invention provide such improvements.

SUMMARY OF THE INVENTION

The present invention provides methods of creating sol-gel compositions with enhanced bioactive material incorporation and methods to further control the rate of bioactive material release into the physiological environment from medical devices during clinical use. The methods also provide for enhanced adhesion between inorganic and organic substrates and materials. These methods provide sol-gel compositions that can be used as sustained-release bioactive material reservoirs and/or as bioactive material coatings on implantable medical devices. The present invention allows for enhanced bioactive material incorporation by modifying the chemical environment during sol-gel processing which alters the hydrophobicity or hydrophilicity of the forming material (among other characteristics), which affects how bioactive material molecules interact with the forming material and its chemical environment during sol-gel processing. Modification of the chemical environment during sol-gel processing can also affect the characteristics of the formed material after removal from the sol-gel environment in such a way to affect the release rate of bioactive materials into the physiological environment once implanted in a patient. Specifically, depending on the characteristics of a particular bioactive material, the chemical environment of the sol-gel process is adjusted to control how the bioactive materials will interact with the environment during the sol-gel process. As a non-limiting example, the addition of an organically modified silane to the sol-gel mixture can increase the hydrophobicity of the forming gel (meaning the structure forming during sol-gel processing). Without being bound by theory, it is believed that an increase in the hydrophobicity of the forming gel will impede the bioactive material's ability to move between the forming gel and the aqueous environment during sol-gel processing, holding the bioactive material more tightly to the forming gel, leading to better retention of the bioactive material within the forming sol-gel composition. Further, the enhanced hydrophobic content of the ultimately formed material can better control the rate of release of bioactive materials into the physiological environment once implanted in a patient. Methods according to the present invention can even further enhance the ability to control bioactive material release into the physiological environment following device implantation by treating the surface of a formed sol-gel composition with an organically modified silane. The hydrophobic trimethyl group of an organically modified silane can help to prevent liquids in the physiological environment of the implanted medical device from diffusing into the composition and solubilizing the bioactive materials causing their early release.

The sol-gel compositions of the present invention can also enhance adhesion to a substrate by providing pores in the form of continuously interconnected channels that allow for strong interdigitation between inorganic substrates and organic coatings.

Specifically, one embodiment according to the present invention includes a medical device comprising a structural element and a bioactive material reservoir, wherein the bioactive material 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 using a sol-gel process wherein the environment of the sol-gel process was tailored to the characteristics of a bioactive material to be incorporated into the matrix composition, the tailoring affecting the amount of the bioactive material within the matrix composition once formed and/or the rate of release of the bioactive material into the physiological environment once implanted in a patient. Matrix compositions can comprise, without limitation, a material selected from the group consisting of a sol-gel derived inorganic oxide; a sol-gel derived organically modified silane; a hybrid oxide comprising an organically modified silane; and an oxide having mesopores created using a template.

In certain embodiments, matrix compositions according to the present invention will comprise an inorganic oxide fabricated via the above described sol-gel process. The inorganic oxide can be selected from the group consisting of an oxide of silicon and an oxide of titanium. The matrix composition can also be a mesoporous inorganic oxide. Mesoporous inorganic oxides can be obtained using a sacrificial pore-generating template component and a self-assembly or guided-assembly fabrication process. The template component can be selected from the group consisting of an amphiphilic block copolymer, an ionic surfactant, and a non-ionic surfactant. The template component can also be a polyethylene oxide/polypropylene oxide/polyethylene oxide triblock copolymer.

Mesoporous inorganic oxides according to the present invention can comprise substantially continuous interconnected channels. The inner surfaces of the substantially continuous interconnected channels can be coated or compounded with an agent, such as an organically modified silane, that modifies a characteristic of the mesoporous inorganic oxide selected from the group consisting of hydrophobicity, charge, biocompatibility, mechanical properties, bioactive material affinity, storage capacity, and combinations thereof. Further, one or more bioactive materials can be loaded into the interconnected channels after the coating is applied to the surface of the structural element.

In certain embodiments according to the present invention, the oxide of the matrix composition can be compounded with an agent that modifies a characteristic of the oxide selected from the group consisting of hydrophobicity, charge, biocompatibility, mechanical properties, bioactive material affinity, storage capacity and combinations thereof. In one embodiment, the modifying agent is an organically modified silane. Organically modified silences can be selected from the group consisting of alkylsilanes; methyltrimethoxysilane; methyltriethoxysilane; dimethyldiethoxysilane; trimethylethoxysilane; vinyltrimethoxysilane; vinyltriethoxysilane; ethyltriethoxysilane; isopropyltriethoxysilane; butyltriethoxysilane; octyltriethoxysilane; dodecyltriethoxysilane; octadecyltriethoxysilane; aryl-functional silanes; phenyltriethoxysilane; aminosilanes; aminopropyltriethoxysilane; aminophenyltrimethoxysilane; aminopropyltrimethoxysilane; acrylate functional silanes; methacrylate-functional silanes; acryloxypropyltrimethoxysilane; carboxylate; phosphonate; ester; sulfonate; isocyanate; epoxy functional silanes; chlorosilanes; chlorotrimethylsilane; chlorotriethylsilane; chlorotrihexylsilane; dichlorodimethylsilane; trichloromethylsilane; N,O-Bis (Trimethylsilyl)-acetamide (BSA); N,O-Bis (Trimethylsilyl) Trifluoroacetamide (BSTFA); Hexamethyldisilazane (HMDS); N-Methyltrimethylsilyltrifluoroacetamide (MSTFA); N-Methyl-N-(t-butyldimethylsilyl)trifluoroacetamide (MTBSTFA); Trimethylchlorosilane (TMCS); Trimethylsilyimidazole (TMSI); and combinations thereof.

One embodiment according to the present invention includes a medical device comprising a structural element and a bioactive material-eluting coating, wherein the bioactive material-eluting coating comprises at least one layer applied over the surface of the medical device wherein the at least one layer is formed using a sol-gel process and comprises an organically modified silane. In certain embodiments, this at least one layer is a base coat applied to the surface of the medical device and the medical device further comprises a top coat applied over the base coat. Bioactive material-containing spheres can be found in a location selected from the group consisting of within the base coat, within the top coat, between the base coat and the top coat and combinations thereof. The bioactive material-containing spheres can comprise of a biodegradable polymer.

In one embodiment, the base coat and/or the top coat comprise a sol-gel inorganic oxide composition. In another embodiment, the base coat comprises a mesoporous oxide with substantially continuous interconnected channels.

Yet another embodiment according to the present invention includes a medical device comprising a structural element and a bioactive material-eluting coating, wherein the bioactive material-eluting coating comprises at least two layers wherein at least one of the at least two layers comprises a matrix composition formed using a sol-gel process wherein the environment of the sol-gel process was tailored to the characteristics of a bioactive material to be incorporated into the matrix composition, the tailoring affecting the amount of the bioactive material within the matrix composition once formed and/or the rate of release of the bioactive material into the physiological environment once implanted in a patient. These two layers can comprise, without limitation, a base coat and a top coat. In these embodiments according to the present invention, each layer can individually comprise a form selected from the group consisting of a sol-gel oxide layer without bioactive material; a sol-gel oxide layer with bioactive material incorporated in the oxide; a sol-gel oxide compounded with an organically modified silane without bioactive material; a sol-gel oxide compounded with an organically modified silane with bioactive material; an organically modified silane layer without bioactive material; an organically modified silane layer with bioactive material; a mesoporous oxide without bioactive material; a mesoporous oxide with bioactive material incorporated in the oxide; a mesoporous oxide with bioactive material incorporated in the oxide and additional bioactive material loaded into its interconnected channels after the mesoporous oxide is applied to the surface of the medical device; a mesoporous oxide with no bioactive material incorporated in the oxide but with bioactive material loaded into its interconnected channels after the oxide is applied to the surface of the medical device; and a collection of bioactive material-containing polymer spheres.

A further embodiment according to the present invention includes a medical device comprising a structural element and a bioactive material reservoir, wherein the bioactive material reservoir comprises a coating applied to the surface of the structural element, wherein the coating comprises a matrix composition formed using a sol-gel process wherein the environment of the sol-gel process was tailored to the characteristics of a bioactive material to be incorporated into the matrix composition, the tailoring affecting the amount of the bioactive material within the matrix composition once formed and/or the rate of release of the bioactive material into the physiological environment once implanted in a patient and wherein when the coating is applied to the surface of the structural element, the coating enhances adhesion between an inorganic surface and an organic surface selected from the group consisting of polymers, tissue, bone and combinations thereof.

Bioactive materials used in accordance with the present invention can, in one embodiment, be selected from the group consisting of an anti-restenotic agent, an anti-inflammatory agent, an HMG-COA reductase inhibitor, an antimicrobial agent, an antineoplastic agent, an angiogenic agent, an anti-angiogenic agent, a thrombolytic agent, an antihypertensive agent, an anti-arrhythmic agent, a calcium channel blocker, a cholesterol-lowering agent, a psychoactive agent, an anti-depressive agent, an anti-seizure agent, a contraceptive, an analgesic, a bone growth factor, a bone remodeling factor, a neurotransmitter, a nucleic acid, an opiate antagonist and combinations thereof. Bioactive materials can also be is selected from the group consisting of paclitaxel, rampamycin, everolimus, tacrolimus, sirolimus, des-aspartate angiotensin 1, nitric oxide, apocynin, gamma-tocopheryl, pleiotrophin, estradiol, aspirin, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and combinations thereof.

Medical devices of the present invention can include, without limitation, a vascular conduit, a stent, a plate, a screw, a spinal cage, a dental implant, a dental filling, a brace, an artificial joint, an embolic device, a ventricular assist device, an artificial heart, a heart valve, a venous filter, a staple, a clip, a suture, a prosthetic mesh, a pacemaker, a pacemaker lead, a defibrillator, a neurostimulator, a neurostimulator lead, an implantable sensor, and an external sensor.

DETAILED DESCRIPTION

The present invention encompasses sol-gel compositions and their uses. Specifically the sol-gel compositions of the present invention have properties that make them useful as: (1) bioactive material reservoirs and in certain embodiments, controlled release bioactive material reservoirs, and (2) as coatings used to enhance adhesion between organic and inorganic surfaces. Methods used to produce the sol-gel compositions of the present invention can enhance the incorporation of bioactive materials into a forming gel during sol-gel processing and can also provide the formed sol-gel composition with characteristics that help control the rate of bioactive material release into the physiological environment once the composition has been implanted in a patient. Specifically, depending on the characteristics of a particular bioactive material, the chemical environment of the sol-gel process is adjusted to control how the bioactive material interacts with the environment during the sol-gel process and how it will be released from the formed composition to the physiological environment once implanted. The rate of elution of various bioactive materials entrapped in the forming gel and from the sol-gel composition once it is formed, can be more finely controlled by changing the composition of the solutions used during sol-gel processing. Further, treatment of the formed sol-gel composition with an organically modified silane can help prevent the bioactive materials from being solubilized and released from the sol-gel composition into the physiological environment after implantation.

As stated, the present invention encompasses sol-gel compositions that can be applied to the surface of an implantable medical device to function as a bioactive material reservoir or as a bioactive material coating. The sol-gel composition can be a mesoporous inorganic oxide fabricate via a template-based sol-gel synthetic route, the mesoporous material having substantially continuously interconnected channels that are adapted to act as a bioactive material reservoir capable of retaining a bioactive material and releasing it over a defined period of time. The sol-gel compositions of the present invention can act as a bioactive material reservoir by having bioactive material within the substance of the material itself before application to the surface of an implantable medical device and/or by having bioactive material loaded into the material's interconnected channels after application onto the surface of an implantable medical device. Bioactive material incorporation into the sol-gel compositions of the present invention can be enhanced or more finely controlled in one embodiment by adding an organically modified silane to the solvent during the sol-gel process. Organically modified silanes can alter the chemical environment of the sol-gel process, including the hydrophobicity/hydrophilicity of the process and the forming gel material so that the bioactive material cannot move as freely between the forming gel and aqueous environment. In one embodiment, the bioactive material is retained near the gel as it forms due to electrostatic forces and/or chemical or hydrogen bonding.

The mesoporous sol-gel compositions of the present invention exhibit a highly ordered surface-accessible pore channel network including substantially continuously interconnected channels in three dimensions throughout the film. This ordered interconnected structure provides one mechanism through which the sol-gel compositions of the present invention can act as a bioactive material reservoir. A bioactive material applied to the surface of the film will penetrate the porous film, loading the interconnected channels with bioactive materials that are later released by diffusion, osmotic or electrochemical inducement or other means.

The mesoporous sol-gel compositions of the present invention are made using a triblock copolymer template that, when mixed with a sol-gel precursor (without limitation an alkoxide silica precursor), can self-assemble into a highly-ordered 3-dimensional structure (FIG. 1 (see Original Patent)). Thermal treatment (or room temperature exposure to a UV lamp/ozone source) removes the template and induces cross-linking (aging) of the surrounding inorganic phase into a mechanically robust network. Thus, a final sol-gel composition is the negative of what is shown in FIG. 1, with the block copolymer being removed to leave a network of interconnected channels. The channels so formed have predictable uniformity. In this described example, the pores and channels have diameters in the mesoscopic range, generally from about 2-30 nm and more usually from about 5-30 nm. Diameter of the channels can be precisely controlled via hydrothermal treatment or the addition of hydrophobic swelling agents in the initial solution. Thus, pores and channels of the present invention can be made to have any desired diameter including, without limitation, from about 2-100 nm, about 3-75 nm, about 5-50 nm, about 7-30 nm or about 10-20 nm.

As stated, sustained, controlled and time-release bioactive material delivery can be achieved using the sol-gel composition bioactive material delivery reservoir (and corresponding bioactive material delivery devices) of the present invention. By varying the properties of the sol-gel composition, different bioactive material delivery release rates and profiles can be achieved for various bioactive materials. For example, a bioactive material can be released with about first order or about second order kinetics. Delivery can begin upon implantation of the bioactive material delivery device, or at a particular time after implantation, and can increase rapidly from zero to a maximal rate over a short period of time, for example less than an about an hour, less than about 30 minutes, less than about 15 minutes or less than about 5 minutes. Such maximal delivery can continue for a predetermined period until the delivery rate suddenly drops. For example, delivery can continue at a maximal rate for at least about 8 hours, about 2 days, about 4 days, about 7 days, about 10 days, about 15 days, about 30 days, about 60 days or at least about 90 days. On the other hand, the bioactive material delivery rate can follow an about bell-shaped curve over time, with an initially slow but exponentially increasing delivery rate rising to a maximal rate and wherein the rate then exponentially decreases over time, finally tailing off to zero. In the field of sustained-release bioactive material delivery it is generally considered desirable to avoid a large bioactive material delivery "burst" wherein the majority of the bioactive material is delivered in a short amount of time. The methods of the present invention that allow for enhanced incorporation of bioactive material into the forming sol-gel composition can help to alleviate this problem. Embodiments adopting treating the surface and/or channels of the sol-gel composition with an organically modified silane can also be used to slow the rate of drug elution. In this approach, the hydrophobic group of the organically modified silane inhibits the ability of liquids to diffuse into the sol-gel composition and solubilize the bioactive materials leading to their early release. In accordance with the present invention then, a variety of parameters can be adjusted to produce numerous variations in delivery profiles depending on what is desirable for a particular bioactive material/disease/patient combination.

Bioactive material loading and release properties (e.g., maximum bioactive material loading, the rate of bioactive material elution, and the way the elution profile changes over time) are dependant upon the properties of both the sol-gel composition bioactive material reservoir (including whether the bioactive material is found within the material itself (pre-application to bioactive material delivery device), within the interconnected channels of the material (loaded after application to the bioactive material delivery device) or both) and the bioactive material formulation. Release kinetics can be altered by altering bioactive material formulation, changing pore size of the sol-gel materials, coating the interior of the channels, treating the surface and/or channels of the sol-gel composition with an organically modified silane and by doping the material with various substances.

There are several known methods for engineering the pore size of a sol-gel material. Pore size can be altered by altering the type of template material used and the amount used in the sol, since the size of the hydrophobic part of the amphiphilic molecule dictates, to a significant degree, the pore diameter. For example, the pore size of MCM-41 can be adjusted in a range of from about 1.6 nm up to about 10 nm (U.S. Pat. Nos. 5,057,296 and 5,102,643, and Beck et al., 1992, J. Am. Chem. Soc. 114, 10834). Another method for altering pore size is by incorporating into the sol a hydrophobic organic co-solvent that swells the hydrophobic regions after template self-assembly. The most widely used swelling agent is 1,3,5 trimethylbenzene (TMB) (Schmidt-Winkel et al., Chemistry of Materials, 2000, 12, p. 686-696), although in principle many other organic materials could play this role, such as triisopropylbenzene, perfluorodecalin, alkanes, alkenes, and long-chain amines (including N,N-dimethylhexadecylamine, trioctylamine, tridodecylamine). Other appropriate methods involve post-synthesis hydrothermal treatment of the self-assembled gel (Khushalani et al., Advanced Materials, 1995, 7, p. 842) or modifying temperature. For example, Galarneau et al., 2003 (New J. Chem. 27:73-39) demonstrates that synthesis temperature affects the structure of mesoporous substances formed in a binary way. When synthesized below 80.degree. C., SBA-15 possesses mesopores with a diameter of about 5 nm and "ultramicropores" with a diameter of about <1 nm. When synthesized above 80.degree. C., SBA-15 possesses mesopores with a diameter of about >9 mm and no ultramicropores.

Bioactive material release kinetics can also be altered by modifying the surface properties of the channels within the sol-gel composition. After completion of the sol-gel synthesis and removal of the structure-directing template, the interior surface of the pore channels can be modified to impart the desired surface functionality. The channels can be coated with a hydrophobic or a hydrophilic coating or with a charged surface coating to better interact with a bioactive material or other substance to be carried within the channels. One method for achieving this is by using an organically modified silane. Organically modified silanes can be used as linker agents to impart either a more hydrophobic or more hydrophilic property to a surface, depending on what termination moiety is used. If, for example, a carboxyl group is used as the termination molecule, then a hydrophilic property will be imparted, but if a long-chain fatty acid or a thyol is used, then a more hydrophobic property will be imparted. Various hydrophilic and hydrophobic moieties are well known in the art.

Alternatively, the channel walls can be modified by exposure to a Cl.sub.2 working gas rendered reactive (Cl.sub.2.fwdarw.Cl*) by UV light, so that the channel surface becomes covered by chlorosilyl (Si--Cl) groups, which could then be further transformed to any desired functionality by processing according to the principles of organic chemistry. Similar results could also be obtained via, for example, initial treatment of the pore wall surface with other working gases, including phosgene (SOCl), isocyanate (--N.dbd.C.dbd.O), malamides and others. These are chemicals that would easily react with the silanol (Si--OH) groups of the pore wall surface, thus replacing the silanols with alternative groups (e.g. Si--Cl in the case of phosgene) that can then at a subsequent step be reacted upon to impart any desired chemical functionality to the pore walls.

Another way of engineering channel properties is treatment with strong acidic or basic liquid solutions to impart surface charges. Specifically, exposure to a solution with a pH lower than the isoelectric point of the surface (pI=2 for silica) results in the protonation of surface silanol moieties (Si--OH.fwdarw.Si--OH.sup.2+), whereupon the surface becomes positively charged. Similarly, treatment with a solution of pH higher than the surface pI will result in deprotonation of surface silanols and a negative net surface charge (Si--OH.fwdarw.Si--O.sup.-). It is important to note that this charge will not be sustained upon removal from the acidic or basic solution, unless the solution also contains a charged solute of opposite sign that can attach to the charged surface via electrostatic attraction. In the latter case, the surface will remain charged and the solute attached to it even after removal from the acidic or basic solution. These properties can be used to stimulate elution of polar or electrically charged bioactive molecules from a mesoporous matrix (discussed further below).

One or more of the above methods can be chosen based on the particular bioactive material or bioactive materials that will be loaded into the channels because different bioactive materials have different properties in terms of size, hydrophobicity and charge. This will influence bioactive material loading and release from a sol-gel composition. For example, paclitaxel is a hydrophobic (lipophilic) molecule of about 1-2 nm in size. Other hydrophobic bioactive materials include, for example and without limitation, most antipsychotics, antibiotics such as amphotericin, dexamethasone and flutamide. Paclitaxel is somewhat more hydrophobic than rapamycin, and corticosteroids are generally less hydrophobic than rapamycin or paclitaxel. If using a hydrophobic bioactive material it could be desirable to coat the channels with a hydrophobic coating to maximize bioactive material loading. Bioactive materials that are highly hydrophilic and water soluble, could benefit from a hydrophilic coating to maximize bioactive material loading. Hydrophilic bioactive materials include, without limitation, most hormonal peptides, antibiotics such as vancomycin, and phenobarbital, cimetidine, atenolol, aminoglycosides, hormones (e.g., thyrotropin-releasing hormone), p-nitrophenyl beta-cellopentaoside and leutinizing hormone-releasing hormone, and many others. Well known cationic bioactive materials include, without limitation, vincristine, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin and the aminoglycosides. Anionic bioactive materials include, without limitation, penicillin and many diuretics. Thus, in determining whether a channel treatment would be beneficial, the characteristics of the bioactive material(s) to be loaded and the desired release profile should be considered.

Once within a matrix or channel according to the present invention, bioactive materials can be eluted in several ways. Simple diffusion can be used to release bioactive material, in which case the bioactive material moves down a concentration gradient into the environmental solution (body fluid). Osmotic effects can also be used whereby a dissolved bioactive material can be carried by bulk fluid flow from an area of higher to lower osmotic potential. Osmotic effects can also be used to force bioactive material from the matrix. For example, a hydrophobic bioactive material can be forced from the matrix by filling the matrix with an increasing volume of an aqueous solution. This might be done, for example, by filling half of the sol-gel matrix composition with a hydrophobic bioactive material, and partially filling the other half with a soluble salt. When implanted into a patient, water from body fluids would dissolve the salt, creating a strong osmotic potential that would draw water into the matrix. The incoming water would displace the hydrophobic bioactive material, forcing it out of the matrix into the surrounding physiological environment. Such a system could be designed in a number of ways, and the osmotic pump could be separate from the sol-gel matrix composition.

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

Other methods used to elute a bioactive material from the sol-gel composition include the use of electrophoretic mechanisms for charged bioactive material particles, physical gating, such as controlling the surface area of the bioactive material reservoir exposed to the environment, and the use of various biodegradable and semi-permeable membranes that can be used to control the rate of release of a bioactive material from the reservoir.

One important aspect of the current invention is the delivery of anti-restenosis bioactive materials. One especially effective anti-restenosis bioactive material appears to be the lipophilic bioactive material paclitaxel (N-benzyl-beta-phenylisoserine ester, M.W. 853.9), an anti-tumor agent isolated from the bark of the yew tree.

As stated, the sol-gel compositions according to the present invention are very well suited for enhancing adhesion between organic and inorganic surfaces because of the highly ordered, open, surface-accessible channel network that is continuously interconnected throughout the entire film volume. For example, organic bioactive material-containing polymers deposited on the top surface of an inorganic sol-gel composition of the present invention can access and penetrate the porous film throughout its thickness, creating a tough nanocomposite phase that extends all the way to the underlying inorganic substrate surface. Such molecular interdigitation of the polymer and the sol-gel composition creates a very strong bond, resistant to corrosion and mechanical removal.

FIG. 2 (see Original Patent) illustrates the tri-layer structure 10 of the present invention used to enhance adhesion between organic and inorganic surfaces. In this example a sol-gel composition 110 is deposited on an inorganic substrate 100. An organic polymer 120 is interdigitated through the sol-gel composition 110. In a typical sol-gel composition of the present invention, the average diameter of the pores 130 can be between about 5-30 nm and the surface density of pores (access points to the channel network) from the film top can be on the order of about 10.sup.12/cm.sup.2.

In using the sol-gel compositions of the present invention to enhance adhesion, the polymer to which adhesion is sought can be deposited on top of the sol-gel composition by the spin-coating of a precursor formulation or any other suitable method. The polymer material then enters the pores of the sol-gel composition by, without limitation, capillary action or pressure or thermal treatment, thereby penetrating the sol-gel composition substantially, in one embodiment through its entire thickness. This penetration is followed by cross-linking of the polymer via thermal curing, by photocontrolled reaction or other suitable methods. Optionally, this step can be accompanied or followed by formation of covalent or other chemical bonds between the organic polymer 120 and the modified walls of the pores 130 and the surface of the inorganic substrate 100 so as to further improve adhesion.

Whether for the purpose of providing a bioactive material reservoir or for enhancing adhesion, the sol-gel compositions of the present invention can be produced and deposited onto a substrate by the following non-limiting method: (1) first, a substrate is provided, for example and without limitation surgical steel, a nickel-titanium alloy (NiTi), a cobalt-chrome alloy (Co--Cr), a carbon-fiber material, a plastic or other suitable biocompatible material; (2) the substrate surface is then cleaned of any undesired contamination; (3) the substrate is microblasted; (4) the sol-gel composition is produced by mixing the inorganic precursor with amphiphilic tri-block co-polymer templating agent, one or more bioactive materials and an organically modified silane. Non-limiting examples of typical inorganic precursors include SiO.sub.2 and TiO.sub.2 such as tetraethoxysilane and titanium orthopropoxide. At this stage, if desired, other solvents can also be added e.g., a rheology modifier such as ethanol or the swelling agent such as 1,3,5 trimethylbenzene; and (5) the template-assisted sol-gel composition is then deposited on the surface of the substrate, generally by, without limitation, spin-coating, dip-coating or spray-coating or painting of the object to be coated. Further, in certain embodiments, the sol-gel composition can be treated on its surface or within its channels with an organically modified silane.

Appropriate organically modified silanes for use in accordance with the present invention include, without limitation, alkylsilanes (such as, but not limited to, methyltrimethoxysilane, methyltriethoxysilane, dimethyldiethoxysilane, trimethylethoxysilane, vinyltrimethoxysilane, vinyltriethoxysilane, ethyltriethoxysilane, isopropyltriethoxysilane, butyltriethoxysilane, octyltriethoxysilane, dodecyltriethoxysilane, octadecyltriethoxysilane, etc), aryl-functional silanes (e.g. phenyltriethoxysilane, etc.), aminosilanes (e.g. aminopropyltriethoxysilane, aminophenyltrimethoxysilane, aminopropyltrimethoxysilane, etc.), acrylate- and methacrylate-functional silanes (e.g. acryloxypropyltrimethoxysilane, ect), carboxylate, phosphonate, ester, sulfonate, isocyanate, epoxy functional silanes, chlorosilanes, (e.g. chlorotrimethylsilane, chlorotriethylsilane, chlorotrihexylsilane, dichlorodimethylsilane, trichloromethylsilane, etc), N,O-Bis (trimethylsilyl)-acetamide (BSA); N,O-Bis (trimethylsilyl) trifluoroacetamide (BSTFA); hexamethyldisilazane (HMDS); N-methyltrimethylsilyltrifluoroacetamide (MSTFA); N-methyl-N-(t-butyldimethylsilyl)trifl uoroacetamide (MTBSTFA); trimethylchlorosilane (TMCS); trimethylsilyimidazole (TMSI); and combinations thereof.

Dip-coating or spray-coating can be easily used for coating objects with complex shapes and arbitrary curvature, 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 (typically ethanol) to the solution, so that in the final working solution the concentration of all the ingredients is reduced by the same amount and their relative concentration and molar ratios remain constant. Sol-gel composition thickness can also be adjusted by changing the spin-coating or dip-coating rate, or both, as described in the examples. The template material that defines the channels is then removed by thermal treatment or by room-temperature exposure to a UV lamp/ozone source. This will remove the template and induce cross-linking of the surrounding inorganic phase into a mechanically robust network. UV/ozone treatment is particularly useful if the inorganic precursor is heat sensitive.

In certain embodiments according to the present invention patterning techniques to template the sol-gel compositions at multiple length-scales can be used. For example, coating with a sol-gel mesoporous oxide such as silica requires a hydrophilic surface with available --OH moieties that can partake in condensation reactions with the sol-gel precursor molecules. If traditional lithography, or soft lithography (Whitesides et al., Angew. Chem. Intl. Ed, 1998, 37, p. 550) or any other surface patterning method is used to strip selected surface regions of --OH functionality before deposition, the mesoporous coating would be patterned accordingly. Alternatively, the sol-gel composition coating can be patterned via, for example, micro-molding in capillaries (Trau et al., Nature. 1997, 390, p. 674) where a limited amount of the liquid sol can be compressed between a flexible silicone mold and the substrate surface.

Alternatively, a second sacrificial porogen can be employed to pattern the deposition of a sol-gel composition coating. For example, it is a well established method to create macroporous inorganic materials (100 nm<d<10 .mu.m) by templating the sol-gel solid via commercially available or custom-synthesized latex particles, such as monodisperse polystyrene spheres with radii in the 100-500 nm range (Stein et al., Science, 1998, 281, p. 538-540) or phase-separated emulsions, such as oil in formamide systems (Pine et al., Nature, 1997, 389, p. 948-951). These and other related methods can be combined with the self-assembling template processes that generate the presently described sol-gel compositions. The end result would be hierarchically ordered inorganic solids with multi-scale porosities (Whitesides et al., Science, 1998, 282, p. 2244). Such an approach could be particularly powerful in orthopedic applications, where a macro-scale porous implant surface is desirable to allow cell migration and bone/implant integration, whereas meso-scale porosity can be exploited for local bioactive material delivery.

Another embodiment according to the present invention is the use of mesoporous materials that are relatively easy to obtain (such as silica) as intermediate molds for patterning other inorganic solids for which no appropriate sol-gel precursor exists, including noble metals such as, without limitation, gold and platinum and extending all the way to even carbon-based polymers. For example, a mesoporous silica coating could be first deposited on an implantable device, followed by "casting" via a volatile precursor or liquid-based suspension of, without limitation, Pd or Au nanoparticles, followed by dissolution of the mesoporous silica via, for example, hydrofluoric acid treatment, thus resulting in a mesoporous noble-metal replica of the silica framework (Schuth, in Studies in Surface Science and Catalysis, v.135, p. 1-12).
 

Claim 1 of 16 Claims

1. A medical device comprising a structural element and a bioactive material reservoir, wherein said bioactive material reservoir comprises a coating applied to the surface of said structural element wherein said coating comprises one or more layers and wherein at least one of said layers comprises a matrix composition having an inorganic oxide formed using a sol-gel process wherein the inorganic oxide is compounded with an agent that modifies a characteristic of said inorganic oxide selected from the group consisting of hydrophobicity, charge, biocompatibility, mechanical properties, bioactive material affinity, storage capacity, and combinations thereof wherein the environment of said sol-gel process was is tailored to the characteristics of a bioactive material to be incorporated into said matrix composition said tailoring affecting the amount of said bioactive material within said matrix composition once formed and/or the rate of release of said bioactive material into the physiological environment once implanted in a patient.

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